Synergistic pathogenicity of vertically transmitted chicken infectious anemia virus and avian leukosis virus subgroup J coinfection in chickens.

Avian leukemia virus subgroup J (ALV-J) and chicken infectious anemia virus (CIAV) can be vertically transmitted; however, the pathogenicity of vertically transmitted coinfection with these 2 pathogens has not been studied. In this study, we created a model of chick morbidity in which chicks carried either ALV-J, CIAV, or both viruses via embryo inoculation. Thereafter, we analyzed the effects of vertically transmitted coinfection with CIAV and ALV-J on the pathogenicity of ALV-J and performed a purification assay based on hatching, mortality viremia positivity, and detection of fecal ALV-p27 antigen rates, and body weight. The hatching rate of the ALV-J+CIAV group was 68.57%, lower than those of the single infection and control groups. The survival curve showed that the mortality rates of the CIAV and ALV-J coinfection groups were higher than those of the single infection and control groups. Body weight statistics showed that coinfection aggravated the 7-d growth inhibition effect. The results of ALV-p27 antigen detection in cell culture supernatants showed that the positivity rates of the ALV-J and ALV-J+CIAV groups were 100% at all ages and 0% in the control group. The results of ALV-p27 antigen detection by anal swabs showed that the positivity rates of the ALV-J group were 92.86, 90.90, 88.89, and 93.33% at all ages, and that the ALV-J p27 positivity detection rate of anal swabs was lower than that of plasma virus isolation. The immune organ index of the ALV-J+CIAV group was significantly or very significantly lower than those of the single infection and control groups. The immune organ viral load showed that coinfection with CIAV and ALV-J promoted the proliferation of ALV-J and CIAV in immune organs. Coinfection with ALV-J and CIAV reduced chicken embryo hatchability and increased chick mortality and growth inhibition relative to their respective single infections. Additionally, coinfection with ALV-J + CIAV was even more detrimental in inducing immune organ atrophy (e.g., the thymus, spleen, and bursa), and promoted individual virus replication during coinfection.

Immunopotentiating effect of lentinan on chicks and its inhibitory effect on Marek's disease virus infection.

Marek's disease virus (MDV) is a significant tumorigenic virus that causes severe immunosuppression in chickens. Lentinan (LNT) is an immunomodulator containing ß-glucans and is widely used in areas such as antiviral, anticancer, and immune regulation. To investigate the immunomodulatory effects of LNT on specific pathogen-free (SPF) chicks and its potential to inhibit MDV infection, we conducted an MDV challenge experiment and observed the immune-enhancing effect of LNT on SPF chicks. The results showed that LNT promoted the growth and development of SPF chicks and induced the upregulation of cytokines such as Mx protein, interferon-γ (INF-γ), tumor necrosis factor-α (TNF-α), and interleukin-2 (IL-2). The specific gravity of CD4+ T-lymphocytes and CD8+ T-lymphocytes and their ratios were also significantly upregulated. Prophylactic use of LNT inhibited MDV replication in lymphocytes, liver, and spleen. It also alleviated MDV-induced weight loss and hepatosplenomegaly in SPF chicks. The present study confirms that LNT can enhance the levels of innate and cellular immunity in SPF chicks and contributes to the inhibition of MDV replication in vivo and mitigation of immune organ damage in chicks due to MDV infection. This provides an adjunctive measure for better control of MDV infection.

Nanodrug-bacteria conjugates-mediated oncogenic collagen depletion enhances immune checkpoint blockade therapy against pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) cancer cells specifically produce abnormal oncogenic collagen to bind with integrin α3ß1 receptor and activate the downstream focal adhesion kinase (FAK), protein kinase B (AKT), and mitogen-activated protein kinase (MAPK) signaling pathway. Collectively, this promotes immunosuppression and tumor proliferation and restricts the response rate of clinical cancer immunotherapies. METHODS: Here, by leveraging the hypoxia tropism and excellent motility of the probiotic Escherichia coli strain Nissle 1917 (ECN), we developed nanodrug-bacteria conjugates to penetrate the extracellular matrix (ECM) and shuttle the surface-conjugated protein cages composed of collagenases and anti-programmed death-ligand 1 (PD-L1) antibodies to PDAC tumor parenchyma. FINDINGS: We found the oncogenic collagen expression in human pancreatic cancer patients and demonstrated its interaction with integrin α3ß1. We proved that reactive oxygen species (ROS) in the microenvironment of PDAC triggered collagenase release to degrade oncogenic collagen and block integrin α3ß1-FAK signaling pathway, thus overcoming the immunosuppression and synergizing with anti-PD-L1 immunotherapy. CONCLUSIONS: Collectively, our study highlights the significance of oncogenic collagen in PDAC immunotherapy, and consequently, we developed a therapeutic strategy that can deplete oncogenic collagen to synergize with immune checkpoint blockade for enhanced PDAC treatment efficacy. FUNDING: This work was supported by the University of Wisconsin Carbone Cancer Center Research Collaborative and Pancreas Cancer Research Task Force, UWCCC Transdisciplinary Cancer Immunology-Immunotherapy Pilot Project, and the start-up package from the University of Wisconsin-Madison (to Q.H.).

Prediction Model of Ocular Metastases in Gastric Adenocarcinoma: Machine Learning-Based Development and Interpretation Study.

Background: Although gastric adenocarcinoma (GA) related ocular metastasis (OM) is rare, its occurrence indicates a more severe disease. We aimed to utilize machine learning (ML) to analyze the risk factors of GA-related OM and predict its risks. Methods: This is a retrospective cohort study. The clinical data of 3532 GA patients were collected and randomly classified into training and validation sets in a ratio of 7:3. Those with or without OM were classified into OM and non-OM (NOM) groups. Univariate and multivariate logistic regression analyses and least absolute shrinkage and selection operator were conducted. We integrated the variables identified through feature importance ranking and further refined the selection process using forward sequential feature selection based on random forest (RF) algorithm before incorporating them into the ML model. We applied six ML algorithms to construct the predictive GA model. The area under the receiver operating characteristic (ROC) curve indicated the model's predictive ability. Also, we established a network risk calculator based on the best performance model. We used Shapley additive interpretation (SHAP) to identify risk factors and to confirm the interpretability of the black box model. We have de-identified all patient details. Results: The ML model, consisting of 13 variables, achieved an optimal predictive performance using the gradient boosting machine (GBM) model, with an impressive area under the curve (AUC) of 0.997 in the test set. Utilizing the SHAP method, we identified crucial factors for OM in GA patients, including LDL, CA724, CEA, AFP, CA125, Hb, CA153, and Ca2+. Additionally, we validated the model's reliability through an analysis of two patient cases and developed a functional online web prediction calculator based on the GBM model. Conclusion: We used the ML method to establish a risk prediction model for GA-related OM and showed that GBM performed best among the six ML models. The model may identify patients with GA-related OM to provide early and timely treatment.

Comparison of intrathecal low-dose bupivacaine and morphine with intravenous patient control analgesia for postoperative analgesia for video-assisted thoracoscopic surgery.

BACKGROUND: Thoracoscopic surgical techniques continue to advance, yet the intensity of postoperative pain remains significant, impeding swift patient recovery. This study aimed to evaluate the differences in postoperative pain and recuperation between patients receiving intrathecal morphine paired with low-dose bupivacaine and those administered general anesthesia exclusively. METHODS: This randomized controlled trial enrolled 100 patients, who were allocated into three groups: Group M (5 µg/kg morphine intrathecal injection), Group B (5 µg/kg morphine combined with bupivacaine 3 mg intrathecal injection) and Group C (intrathecal sham injection). The primary outcome was the assessment of pain relief using the Numeric Rating Scale (NRS). Additionally, intraoperative remifentanil consumption was quantified at the end of the surgery, and postoperative opioid use was determined by the number of patient-controlled analgesia (PCIA) compressions at 48 h post-surgery. Both the efficacy of the treatments and any complications were meticulously recorded. RESULTS: Postoperative NRS scores for both rest and exercise at 6, 12, 24, and 48 h were significantly lower in groups M and B than in group C (P<0.05). The intraoperative remifentanil dosage was significantly greater in groups M and C than in group B (P<0.05), while there was no significant difference between groups M and C (P>0.05). There was no significant difference in intraoperative propofol dosage across all three groups (P>0.05). Postoperative dosages of both sufentanil and Nonsteroidal anti-inflammatory drugs (NSAIDs) were significantly less in groups M and B compared to group C (P<0.05). The time of first analgesic request was later in both groups M and B than in group C (P<0.05). Specific and total scores were elevated at 2 days postoperative when compared to scores at 1 day for all groups (P<0.05). Furthermore, at 1 day and 2 days postoperatively, both specific scores and total scores were higher in groups M and B compared to group C (P<0.05). CONCLUSION: Intrathecal administration of morphine combined with bupivacaine has been shown to effectively ameliorate acute pain in patients undergoing thoracoscopic surgery. TRIAL REGISTRATION: The trial was registered on ClinicalTrials.gov: ChiCTR2200058544, registered 10/04/2022.

YAP-mediated trophoblast dysfunction: the common pathway underlying pregnancy complications.

Yes-associated protein (YAP) is a pivotal regulator in cellular proliferation, survival, differentiation, and migration, with significant roles in embryonic development, tissue repair, and tumorigenesis. At the maternal-fetal interface, emerging evidence underscores the importance of precisely regulated YAP activity in ensuring successful pregnancy initiation and progression. However, despite the established association between YAP dysregulation and adverse pregnancy outcomes, insights into the impact of aberrant YAP levels in fetal-derived, particularly trophoblast cells, and the ensuing dysfunction at the maternal-fetal interface remain limited. This review comprehensively examines YAP expression and its regulatory mechanisms in trophoblast cells throughout pregnancy. We emphasize its integral role in placental development and maternal-fetal interactions and delve into the correlations between YAP dysregulation and pregnancy complications. A nuanced understanding of YAP's functions during pregnancy could illuminate intricate molecular mechanisms and pave the way for innovative prevention and treatment strategies for pregnancy complications. Video Abstract.

Cutaneous mantle cell lymphoma presenting as a diffuse morbilliform rash: A case report.

This case describes a patient with known mantle cell lymphoma without cutaneous involvement presenting with a diffuse morbilliform rash during an inpatient admission for bacterial pneumonia. The patient was thought to have a hypersensitivity to antibiotics but failed to improve after the offending agents were stopped. A skin biopsy revealed metastatic cutaneous mantle cell lymphoma. Treatment with high-dose corticosteroids and chemotherapy was initiated resulting in the resolution of the rash.

Up-regulated lncRNA CYLD as a ceRNA of miR-2383 facilitates bovine viral diarrhea virus replication by promoting CYLD expression to counteract RIG-I-mediated type-I IFN production.

Bovine viral diarrhea virus (BVDV) is one of the most important pathogens of cattle, causing numerous economic losses to the cattle industry. To date, many potential mechanisms of BVDV evading or subverting innate immunity are still unknown. In this study, an lnc-CYLD/miR-2383/CYLD axis involved in BVDV-host interactions was screened from RNA-seq-based co-expression networks analysis of long noncoding RNAs, microRNAs and mRNAs in BVDV-infected bovine cells, and underlying mechanisms of lnc-CYLD/miR-2383/CYLD axis regulating BVDV replication were explored. Results showed that BVDV-induced up-regulation of the lnc-CYLD competed for binding to the miR-2383, and then promoted CYLD expression, thereby inhibiting RIG-I-mediated type-I interferon (IFN) production, which was subsequently confirmed by treatment with lnc-CYLD overexpression and miR-2383 inhibitor. However, miR-2383 transfection and small interfering RNA-mediated lnc-CYLD knockdown inhibited CYLD expression and enhanced RIG-I-mediated type-I IFN production, inhibiting BVDV replication. In addition, interaction relationship between lnc-CYLD and miR-2383, and colocalization relationship of lnc-CYLD, miR-2383 and CYLD were confirmed by dual-luciferase assay and in situ hybridization assay. Conclusively, up-regulation of the lnc-CYLD as a competing endogenous RNA binds to the miR-2383 to reduce inhibitory effect of the miR-2383 on the CYLD expression, playing an important role in counteracting type-I IFN-dependent antiviral immunity to facilitate BVDV replication.

Lnc-PKNOX1-1 inhibits tumor progression in cutaneous malignant melanoma by regulating NF-κB/IL-8 axis.

Cutaneous malignant melanoma is one of the most lethal cutaneous malignancies. Accumulating evidence has demonstrated the potential influence of long non-coding RNAs (lncRNAs) in biological behaviors of melanoma. Herein, we reported a novel lncRNA, lnc-PKNOX1-1 and systematically studied its functions and possible molecular mechanisms in melanoma. Reverse transcription-quantitative PCR assay showed that lnc-PKNOX1-1 was significantly decreased in melanoma cells and tissues. Low lnc-PKNOX1-1 expression was significantly correlated with invasive pathological type and Breslow thickness of melanoma. In vitro and in vivo experiments showed lnc-PKNOX1-1 dramatically inhibited melanoma cell proliferation, migration and invasion. Mechanically, protein microarray analysis suggested that interleukin-8 (IL-8) was negatively regulated by lnc-PKNOX1-1 in melanoma, which was confirmed by western blot and ELISA. Western blot analysis also showed that lnc-PKNOX1-1 could promote p65 phosphorylation at Ser536 in melanoma. Subsequent rescue assays proved IL-8 overexpression could partly reverse the tumor-suppressing function of lnc-PKNOX1-1 overexpression in melanoma cells, indicating that lnc-PKNOX1-1 suppressed the development of melanoma by regulating IL-8. Taken together, our study demonstrated the tumor-suppressing ability of lnc-PKNOX1-1 in melanoma, suggesting its potential as a novel diagnostic biomarker and therapeutic target for melanoma.

Prediction model of ocular metastasis from primary liver cancer: Machine learning-based development and interpretation study.

BACKGROUND: Ocular metastasis (OM) is a rare metastatic site of primary liver cancer (PLC). The purpose of this study was to establish a clinical predictive model of OM in PLC patients based on machine learning (ML). METHODS: We retrospectively collected the clinical data of 1540 PLC patients and divided it into a training set and an internal test set in a 7:3 proportion. PLC patients were divided into OM and non-ocular metastasis (NOM) groups, and univariate logistic regression analysis was performed between the two groups. The variables with univariate logistic analysis p < 0.05 were selected for the ML model. We constructed six ML models, which were internally verified by 10-fold cross-validation. The prediction performance of each ML model was evaluated by receiver operating characteristic curves (ROCs). We also constructed a web calculator based on the optimal performance ML model to personalize the risk probability for OM. RESULTS: Six variables were selected for the ML model. The extreme gradient boost (XGB) ML model achieved the optimal differential diagnosis ability, with an area under the curve (AUC) = 0.993, accuracy = 0.992, sensitivity = 0.998, and specificity = 0.984. Based on these results, an online web calculator was constructed by using the XGB ML model to help clinicians diagnose and treat the risk probability of OM in PLC patients. Finally, the Shapley additive explanations (SHAP) library was used to obtain the six most important risk factors for OM in PLC patients: CA125, ALP, AFP, TG, CA199, and CEA. CONCLUSION: We used the XGB model to establish a risk prediction model of OM in PLC patients. The predictive model can help identify PLC patients with a high risk of OM, provide early and personalized diagnosis and treatment, reduce the poor prognosis of OM patients, and improve the quality of life of PLC patients.

Disrupted phase behavior of FUS underlies poly-PR-induced DNA damage in amyotrophic lateral sclerosis.

GGGGCC (G4C2) hexanucleotide repeat expansion (HRE) in the first intron of the chromosome 9 open reading frame 72 (C9ORF72) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Among the five dipeptide repeat proteins translated from G4C2 HRE, arginine-rich poly-PR (proline:arginine) is extremely toxic. However, the molecular mechanism responsible for poly-PR-induced cell toxicity remains incompletely understood. Here, we found that poly-PR overexpression triggers severe DNA damage in cultured cells, primary cortical neurons, and the motor cortex of a poly-PR transgenic mouse model. Interestingly, we identified a linkage between poly-PR and RNA-binding protein fused in sarcoma (FUS), another ALS-related gene product associated with DNA repair. Poly-PR interacts with FUS both in vitro and in vivo, phase separates with FUS in a poly-PR concentration-dependent manner, and impairs the fluidity of FUS droplets in vitro and in cells. Moreover, poly-PR impedes the recruitment of FUS and its downstream protein XRCC1 to DNA damage foci after microirradiation. Importantly, overexpression of FUS significantly decreased the level of DNA damage and dramatically reduced poly-PR-induced cell death. Our data suggest the severe DNA damage caused by poly-PR and highlight the interconnection between poly-PR and FUS, enlightening the potential therapeutic role of FUS in alleviating poly-PR-induced cell toxicity.

Association of Gestational Diabetes With Subsequent Long-Term Risk of Mortality.

Importance: Gestational diabetes has been associated with numerous chronic diseases. However, few studies have examined the association of gestational diabetes with long-term mortality risk. Objective: To investigate the associations between gestational diabetes and long-term risks of total and cause-specific mortality. Design, Setting, and Participants: This cohort study analyzed participants of the Nurses' Health Study II who were followed for 30 years (1989-2019). Participants included US female nurses aged 25 to 42 years who reported at least 1 pregnancy (≥6 months) at 18 years or older across their reproductive life span. Data were analyzed from May 1, 2022, to May 25, 2023. Exposure: Gestational diabetes across the reproductive life span. Main Outcomes and Measures: Hazard ratios (HRs with 95% CIs) for total and cause-specific mortality were estimated by Cox proportional hazards regression models. Results: A total of 91 426 parous participants were included, with a mean (SD) age of 34.9 (4.7) years and a body mass index of 24.1 (4.7) at baseline. During a follow-up period of 2 609 753 person-years, 3937 deaths were documented, including 255 deaths from cardiovascular disease and 1397 from cancer. Participants with a history of gestational diabetes had a higher crude mortality rate than those without a history of gestational diabetes (1.74 vs 1.49 per 1000 person-years; absolute difference = 0.25 per 1000 person-years). The corresponding HR for total mortality was 1.28 (95% CI, 1.13-1.44), which did not materially change after additional adjustment for potential confounders and lifestyle factors during the reproductive life span (HR, 1.25; 95% CI, 1.11-1.41). The association persisted regardless of the subsequent development of type 2 diabetes and was more robust among participants who adopted less healthy lifestyles; experienced gestational diabetes in 2 or more pregnancies (HR, 1.48; 95% CI, 0.99-2.19); had gestational diabetes both in the initial and subsequent pregnancies (HR, 1.71; 95% CI, 1.11-2.63); and concurrently reported hypertensive disorders in pregnancy (HR, 1.80; 95% CI, 1.21-2.67), preterm birth (HR, 2.46; 95% CI, 1.66-3.64), or low birth weight (HR, 2.11; 95% CI, 1.21-3.68). Cause-specific mortality analyses revealed that gestational diabetes was directly associated with the risk of mortality due to cardiovascular disease (HR, 1.59; 95% CI, 1.03-2.47). Additionally, gestational diabetes was inversely associated with cancer mortality (HR, 0.76; 95% CI, 0.59-0.98); however, it was only evident among participants who later developed type 2 diabetes. Conclusions and Relevance: Results of this cohort study suggest that participants who reported a history of gestational diabetes exhibited a small but elevated risk of subsequent mortality over 30 years. The findings emphasize the importance of considering gestational diabetes as a critical factor in later-life mortality risk.

Racial/ethnic disparities in the cause of death among patients with prostate cancer in the United States from 1995 to 2019: a population-based retrospective cohort study.

Background: Racial/ethnic disparities in prostate cancer are reported in the United States (US). However, long-term trends and contributors of racial/ethnic disparities in all-cause and cause-specific death among patients with prostate cancer remain unclear. We analysed the trends and contributors of racial/ethnic disparities in prostate cancer survivors according to the cause of death in the US over 25 years. Methods: In this retrospective, population-based longitudinal cohort study, we identified patients diagnosed with first primary prostate cancer between 1995 and 2019, with follow-up until Dec 31, 2019, using population-based cancer registries' data from the Surveillance, Epidemiology, and End Results (SEER) Program. We calculated the cumulative incidence of death for each racial/ethnic group (Black, white, Hispanic, Asian or Pacific Islander [API], and American Indian or Alaska Native [AI/AN] people), by diagnostic period and cause of death. We quantified absolute disparities using rate changes for the 5-year cumulative incidence of death between racial/ethnic groups and diagnostic periods. We estimated relative (Hazard ratios [HR]) racial/ethnic disparities and the percentage of potential factors contributed to racial/ethnic disparities using Cox regression models. Findings: Despite a decreasing trend in the cumulative risk of death across five racial/ethnic groups, AI/AN and Black patients consistently had the highest rate of death between 1995 and 2019 with an adjusted HR of 1.48 (1.40-1.58) and 1.40 (1.38-1.42) respectively. The disparities in all-cause mortality between AI/AN and white patients increased over time, with adjusted HR 1.32 (1.17-1.49) in 1995-1999 and 1.95 (1.53-2.49) in 2015-2019. Adjustment of stage at diagnosis, initial treatment, tumor grade, and household income explained 33% and 24% of the AI/AN-white and Black-white disparities in all-cause death among patients with prostate cancer. Interpretation: The enduring racial/ethnic disparities in patients with prostate cancer, call for new interventions to eliminate health disparities. Our study provides important evidence and ways to address racial/ethnic inequality. Funding: National Key R&D Program of China, National Natural Science Foundation of China, Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support, the Open Research Fund from Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Key Projects of Philosophy and Social Sciences Research, Ministry of Education of China.

Targeting Macrophages for Tumor Therapy.

Macrophages, as one of the most abundant tumor-infiltrating cells, play an important role in tumor development and metastasis. The frequency and polarization of tumor-associated macrophages (TAMs) correlate with disease progression, tumor metastasis, and resistance to various treatments. Pro-inflammatory M1 macrophages hold the potential to engulf tumor cells. In contrast, anti-inflammatory M2 macrophages, which are predominantly present in tumors, potentiate tumor progression and immune escape. Targeting macrophages to modulate the tumor immune microenvironment can ameliorate the tumor-associated immunosuppression and elicit an anti-tumor immune response. Strategies to repolarize TAMs, deplete TAMs, and block inhibitory signaling hold great potential in tumor therapy. Besides, biomimetic carriers based on macrophages have been extensively explored to prolong circulation, enhance tumor-targeted delivery, and reduce the immunogenicity of therapeutics to augment therapeutic efficacy. Moreover, the genetic engineering of macrophages with chimeric antigen receptor (CAR) allows them to recognize tumor antigens and perform tumor cell-specific phagocytosis. These strategies will expand the toolkit for treating tumors, especially for solid tumors, drug-resistant tumors, and metastatic tumors. Herein, we introduce the role of macrophages in tumor progression, summarize the recent advances in macrophage-centered anticancer therapy, and discuss their challenges as well as future applications. Graphical abstract.

Expression of spleen macrophages in a mouse model of alveolar bone resorption periodontitis.

It has been shown that macrophages can be endotoxin-tolerant under the stimulation of continuous endotoxin of Porphyromonas gingivalis. Macrophage transforms into M2-type which inhibits inflammation, and its pro-inflammatory cytokine secretion is reduced to avoid the tissue damaged by inflammation. This experiment established the corresponding animal model to explore the relative number, phenotypic proportion, and function of spleen macrophages in mice with chronic periodontitis. Twenty 16-week-old mice were randomly divided into a true ligation group (LFP group) and a pseudo-ligation group (LFC group). The periodontitis in the LFP group was induced by experimental ligation, and the LFC group was treated as a control. After 10 days of ligation, the maxilla was taken, IHC and HE staining were performed to observe the pathological changes of periodontal tissues, and IHC staining was performed to observe the RANKL/OPG ratio. Spleen mononuclear cells were isolated and counted. The ratio of M1 and M2 phenotypes was determined by fluorescence-activated cell sorting (FACS) in the spleen. The relative expression levels of macrophage-associated inflammatory cytokine TNF-a, IL-1ß and anti-inflammatory cytokine IL-10 mRNA were detected by real-time PCR. Compared with the control group (LFC:M2/M110.04%), the M2 ratio among spleen mature macrophages in the periodontitis group (LFP: M2/M135.86%) was significantly increased (P<0.01) in the spleen. The proportion of M1 macrophages was not significantly different, and the ratio of M1/M2 was significantly decreased (P<0.05) in the spleen. But the expression level of M1-type macrophage inflammatory factor TNF-a mRNA was inclined. Chronic periodontitis can up-regulate the proportion of M2 macrophages, decrease the ratio of macrophage phenotype M1/M2, and incline the expression of pro-inflammatory factor TNF-a mRNA.

Ambiguity-selective consistency regularization for mean-teacher semi-supervised medical image segmentation.

Semi-supervised learning has greatly advanced medical image segmentation since it effectively alleviates the need of acquiring abundant annotations from experts, wherein the mean-teacher model, known as a milestone of perturbed consistency learning, commonly serves as a standard and simple baseline. Inherently, learning from consistency can be regarded as learning from stability under perturbations. Recent improvement leans toward more complex consistency learning frameworks, yet, little attention is paid to the consistency target selection. Considering that the ambiguous regions from unlabeled data contain more informative complementary clues, in this paper, we improve the mean-teacher model to a novel ambiguity-consensus mean-teacher (AC-MT) model. Particularly, we comprehensively introduce and benchmark a family of plug-and-play strategies for ambiguous target selection from the perspectives of entropy, model uncertainty and label noise self-identification, respectively. Then, the estimated ambiguity map is incorporated into the consistency loss to encourage consensus between the two models' predictions in these informative regions. In essence, our AC-MT aims to find out the most worthwhile voxel-wise targets from the unlabeled data, and the model especially learns from the perturbed stability of these informative regions. The proposed methods are extensively evaluated on left atrium segmentation and brain tumor segmentation. Encouragingly, our strategies bring substantial improvement over recent state-of-the-art methods. The ablation study further demonstrates our hypothesis and shows impressive results under various extreme annotation conditions.

Reversing the PAI-1-induced fibrotic immune exclusion of solid tumor by multivalent CXCR4 antagonistic nano-permeator.

Fibrosis is one of the key factors that lead to the immune exclusion of solid tumors. Although degradation of fiber is a promising strategy, its application was still bottlenecked by the side effects of causing metastasis, resulting in the failure of immunotherapy. Here, we developed an antimetastatic polymer (HPA) for the delivery of chemo-drug and antifibrotic siPAI-1 to form the nano-permeator. Nano-permeator shrank after protonation and deeply penetrated into the tumor core to down-regulate the expression of PAI-1 for antifibrosis, and further promoted the sustained infiltration and activation of T cells for killing tumor cells. Moreover, metastasis after fiber elimination was prevented by multivalent CXCR4 antagonistic HPA to reduce the attraction of CXCL12 secreted by distant organs. The administration of stroma-alleviated immunotherapy increased the infiltration of CD8+ T cells to 52.5% in tumor tissues, inhibiting nearly 90% metastasis by HPA in distant organs. The nano-permeator reveals the mechanism and correlation between antifibrosis and antimetastasis and was believed to be the optimizing immunotherapy for solid fibrotic tumors.

Hypoxia caused by unilateral nasal obstruction decreases mandibular density in rats through inhibition of Cyp1a1 expression.

BACKGROUND: Oral breathing has an important impact on morphology and bone mineral density (BMD) in a mandible. This study aimed to investigate the hub genes and mechanism regulating the mandibular BMD decrease induced by nasal obstruction. METHODS: A unilateral nasal obstruction model was established in 1-week-old Wistar rats by electrocautery obstruction. BMD of the mandible was determined by micro-computed tomography. Transcriptome analysis was performed to identify differentially expressed genes (DEGs). Hub genes were identified by building protein-protein interaction network and verified by western blot. A hypoxic cell model was established in bone marrow mesenchymal stem cells (BMSCs) by using CoCl2. The expression of hypoxia-inducible factor-1α (HIF-1α), NF-kB ligand-receptor activator (RANKL), osteoprotegerin (OPG), and Cyp1a1 was detected by western blot. RESULTS: The mandibular BMD of rats in the unilateral nasal obstruction group was significantly decreased. A total of 38 DEGs were identified in nasal obstruction rats compared with normal rats. A ratio of RANKL/OPG in the mandible was elevated by nasal obstruction, while the Cyp1a1 was decreased. In vitro, the HIF-1α expression and RANKL/OPG ratio were upregulated by hypoxia while the Cyp1a1 expression was decreased. Pretreatment with Cyp1a1 activator, FICZ, could increase the expression of Cyp1a1 while attenuating the activation of HIF-1α and RANKL. CONCLUSION: Respiratory changes caused by nasal obstruction contribute to the decrease in Cyp1a1 expression in the mandible of juvenile rats, which is associated with disturbances in bone homeostasis controlled by the RANKL/OPG ratio.

Oxidised IL-33 drives COPD epithelial pathogenesis via ST2-independent RAGE/EGFR signalling complex.

BACKGROUND: Epithelial damage, repair and remodelling are critical features of chronic airway diseases including chronic obstructive pulmonary disease (COPD). Interleukin (IL)-33 released from damaged airway epithelia causes inflammation via its receptor, serum stimulation-2 (ST2). Oxidation of IL-33 to a non-ST2-binding form (IL-33ox) is thought to limit its activity. We investigated whether IL-33ox has functional activities that are independent of ST2 in the airway epithelium. METHODS: In vitro epithelial damage assays and three-dimensional, air-liquid interface (ALI) cell culture models of healthy and COPD epithelia were used to elucidate the functional role of IL-33ox. Transcriptomic changes occurring in healthy ALI cultures treated with IL-33ox and COPD ALI cultures treated with an IL-33-neutralising antibody were assessed with bulk and single-cell RNA sequencing analysis. RESULTS: We demonstrate that IL-33ox forms a complex with receptor for advanced glycation end products (RAGE) and epidermal growth factor receptor (EGFR) expressed on airway epithelium. Activation of this alternative, ST2-independent pathway impaired epithelial wound closure and induced airway epithelial remodelling in vitro. IL-33ox increased the proportion of mucus-producing cells and reduced epithelial defence functions, mimicking pathogenic traits of COPD. Neutralisation of the IL-33ox pathway reversed these deleterious traits in COPD epithelia. Gene signatures defining the pathogenic effects of IL-33ox were enriched in airway epithelia from patients with severe COPD. CONCLUSIONS: Our study reveals for the first time that IL-33, RAGE and EGFR act together in an ST2-independent pathway in the airway epithelium and govern abnormal epithelial remodelling and muco-obstructive features in COPD.

New perspective on the immunomodulatory activity of ginsenosides: Focus on effective therapies for post-COVID-19.

More than 700 million confirmed cases of Coronavirus Disease-2019 (COVID-19) have been reported globally, and 10-60% of patients are expected to exhibit "post-COVID-19 symptoms," which will continue to affect human life and health. In the absence of safer, more specific drugs, current multiple immunotherapies have failed to achieve satisfactory efficacy. Ginseng, a traditional Chinese medicine, is often used as an immunomodulator and has been used in COVID-19 treatment as a tonic to increase blood oxygen saturation. Ginsenosides are the main active components of ginseng. In this review, we summarize the multiple ways in which ginsenosides affect post-COVID-19 symptoms, including inhibition of lipopolysaccharide, tumor necrosis factor signaling, modulation of chemokine receptors and inflammasome activation, induction of macrophage polarization, effects on Toll-like receptors, nuclear factor kappa-B, the mitogen-activated protein kinase pathway, lymphocytes, intestinal flora, and epigenetic regulation. Ginsenosides affect virus-mediated tissue damage, local or systemic inflammation, immune modulation, and other links, thus alleviating respiratory and pulmonary symptoms, reducing the cardiac burden, protecting the nervous system, and providing new ideas for the rehabilitation of patients with post-COVID-19 symptoms. Furthermore, we analyzed its role in strengthening body resistance to eliminate pathogenic factors from the perspective of ginseng-epidemic disease and highlighted the challenges in clinical applications. However, the benefit of ginsenosides in modulating organismal imbalance post-COVID-19 needs to be further evaluated to better validate the pharmacological mechanisms associated with their traditional efficacy and to determine their role in individualized therapy.