Purinergic P2X7 receptor involves in anti-retinal photodamage effects of berberine.

Berberine (BBR) is a Chinese herb with antioxidant and anti-inflammatory properties. In a previous study, we found that BBR had a protective effect against light-induced retinal degeneration in BALB/c mice. The purinergic P2X7 receptor (P2X7R) plays a key role in retinal degeneration via inducing oxidative stress, inflammatory changes, and cell death. The aim of this study was to investigate whether BBR can induce protective effects in light damage experiments and whether P2X7R can get involved in these effects. C57BL/6 J mice and P2X7 knockout (KO) mice on the C57BL/6 J background were used. We found that BBR preserved the outer nuclear layer (ONL) thickness and retinal ganglion cells following light stimulation. Furthermore, BBR significantly suppressed photoreceptor apoptosis, pro-apoptotic c-fos expression, pro-inflammatory responses of Mϋller cells, and inflammatory factors (TNF-α, IL-1ß). In addition, protein levels of P2X7R were downregulated in BBR-treated mice. Double immunofluorescence showed that BBR reduced overexpression of P2X7R in retinal ganglion cells and Mϋller cells. Furthermore, BBR combined with the P2X7R agonist BzATP blocked the effects of BBR on retinal morphology and photoreceptor apoptosis. However, in P2X7 KO mice, BBR had an additive effect resulting in thicker ONL and more photoreceptors. The data suggest that the P2X7 receptor is involved in retinal light damage, and BBR inhibits this process by reducing histological impairment, cell death, and inflammatory responses.

Hypoxic Exosomal circPLEKHM1-Mediated Crosstalk between Tumor Cells and Macrophages Drives Lung Cancer Metastasis.

Intercellular communication often relies on exosomes as messengers and is critical for cancer metastasis in hypoxic tumor microenvironment. Some circular RNAs (circRNAs) are enriched in cancer cell-derived exosomes, but little is known about their ability to regulate intercellular communication and cancer metastasis. Here, by systematically analyzing exosomes secreted by non-small cell lung cancer (NSCLC) cells, a hypoxia-induced exosomal circPLEKHM1 is identified that drives NSCLC metastasis through polarizing macrophages toward to M2 type. Mechanistically, exosomal circPLEKHM1 promoted PABPC1-eIF4G interaction to facilitate the translation of the oncostatin M receptor (OSMR), thereby promoting macrophage polarization for cancer metastasis. Importantly, circPLEKHM1-targeted therapy significantly reduces NSCLC metastasis in vivo. circPLEKHM1 serves as a prognostic biomarker for metastasis and poor survival in NSCLC patients. This study unveils a new circRNA-mediated mechanism underlying how cancer cells crosstalk with macrophages within the hypoxic tumor microenvironment to promote metastasis, highlighting the importance of exosomal circPLEKHM1 as a prognostic biomarker and therapeutic target for lung cancer metastasis.

Interacting and joint effects of triglyceride-glucose index (TyG) and body mass index on stroke risk and the mediating role of TyG in middle-aged and older Chinese adults: a nationwide prospective cohort study.

BACKGROUND: Individuals who are overweight or obese often develop insulin resistance, mediation of the association between body mass index (BMI) and stroke risk through the triglyceride-glucose index (TyG) seems plausible but has not been investigated. This study aims to examine whether TyG mediates associations of BMI with stroke risk and the extent of interaction or joint relations of TyG and BMI with stroke outcome. METHODS: The China Health and Retirement Longitudinal Study, initiated in 2011, is a nationally representative, ongoing prospective cohort study involving 8 231 middle-aged and older Chinese adults without a stroke history at baseline. Exposures examined include BMI and the TyG, the latter being the logarithmized product of fasting triglyceride and glucose concentrations. The primary study outcome is stroke incidence, as determined through self-reports, with a follow-up period extending from June 1, 2011, to June 30, 2018. RESULTS: Of the 8 231 participants, 3 815 (46.3%) were men; mean (SD) age was 59.23 (9.32) years. During a median follow-up of 7.1 years, 585 (7.1%) participants developed stroke. The TyG was found to mediate the association between BMI and incident stroke, proportions mediated were 16.3% for BMI in the 24.0-27.9 kg/m2 group and 53.8% for BMI ≥ 28.0 kg/m2 group. No significant multiplicative and additive interactions were found between BMI and TyG on incident stroke (Additive: RERI = 1.78, 95% CI - 1.29-4.86; Multiplicative, HR = 1.40, 95% CI 0.86-2.27). HRs for individuals with BMI ≥ 28.0 kg/m2 and quartile 4 of TyG compared with those with BMI < 24.0 kg/m2 and quartile 1 of TyG were 2.05 (95% CI 1.37-3.06) for incident stroke. Combining BMI and TyG enhanced predictive performance for stroke when compared to their individual (AUCBMI+TyG vs AUCBMI vs AUCTyG, 0.602 vs 0.581 vs 0.583). CONCLUSIONS: TyG appeared to be associated with stroke risk and mediates more than 50% of the total association between BMI and stroke in middle-aged and older Chinese adults. Public health efforts aiming at the reduction of body weight might decrease the stroke risk due to insulin resistance and the burden of stroke.

Exosomes derived from microglia overexpressing miR-124-3p alleviate neuronal endoplasmic reticulum stress damage after repetitive mild traumatic brain injury.

JOURNAL/nrgr/04.03/01300535-202409000-00033/figure1/v/2024-01-16T170235Z/r/image-tiff We previously reported that miR-124-3p is markedly upregulated in microglia-derived exosomes following repetitive mild traumatic brain injury. However, its impact on neuronal endoplasmic reticulum stress following repetitive mild traumatic brain injury remains unclear. In this study, we first used an HT22 scratch injury model to mimic traumatic brain injury, then co-cultured the HT22 cells with BV2 microglia expressing high levels of miR-124-3p. We found that exosomes containing high levels of miR-124-3p attenuated apoptosis and endoplasmic reticulum stress. Furthermore, luciferase reporter assay analysis confirmed that miR-124-3p bound specifically to the endoplasmic reticulum stress-related protein IRE1α, while an IRE1α functional salvage experiment confirmed that miR-124-3p targeted IRE1α and reduced its expression, thereby inhibiting endoplasmic reticulum stress in injured neurons. Finally, we delivered microglia-derived exosomes containing miR-124-3p intranasally to a mouse model of repetitive mild traumatic brain injury and found that endoplasmic reticulum stress and apoptosis levels in hippocampal neurons were significantly reduced. These findings suggest that, after repetitive mild traumatic brain injury, miR-124-3 can be transferred from microglia-derived exosomes to injured neurons, where it exerts a neuroprotective effect by inhibiting endoplasmic reticulum stress. Therefore, microglia-derived exosomes containing miR-124-3p may represent a novel therapeutic strategy for repetitive mild traumatic brain injury.

Value of multi-center 18 F-FDG PET/CT radiomics in predicting EGFR mutation status in lung adenocarcinoma.

BACKGROUND: Accurate, noninvasive, and reliable assessment of epidermal growth factor receptor (EGFR) mutation status and EGFR molecular subtypes is essential for treatment plan selection and individualized therapy in lung adenocarcinoma (LUAD). Radiomics models based on 18 F-FDG PET/CT have great potential in identifying EGFR mutation status and EGFR subtypes in patients with LUAD. The validation of multi-center data, model visualization, and interpretation are significantly important for the management, application and trust of machine learning predictive models. However, few EGFR-related research involved model visualization and interpretation, and multi-center trial. PURPOSE: To develop explainable optimal predictive models based on handcrafted radiomics features (HRFs) extracted from multi-center 18 F-FDG PET/CT to predict EGFR mutation status and molecular subtypes in LUAD. METHODS: Baseline 18 F-FDG PET/CT images of 383 LUAD patients from three hospitals and one public data set were collected. Further, 1808 HRFs were extracted from the primary tumor regions using Pyradiomics. Predictive models were built based on cross-combination of seven feature selection methods and seven machine learning algorithms. Yellowbrick and explainable artificial intelligence technology were used for model visualization and interpretation. Receiver operating characteristic curve, classification report and confusion matrix were used for model performance evaluation. Clinical applicability of the optimal models was assessed by decision curve analysis. RESULTS: STACK feature selection method combined with light gradient boosting machine (LGBM) reached optimal performance in identifying EGFR mutation status ([area under the curve] AUC = 0.81 in the internal test cohort; AUC = 0.62 in the external test cohort). Random forest feature selection method combined with LGBM reached optimal performance in predicting EGFR mutation molecular subtypes (AUC = 0.89 in the internal test cohort; AUC = 0.61 in the external test cohort). CONCLUSIONS: Explainable machine learning models combined with radiomics features extracted from multi-center/scanner 18 F-FDG PET/CT have certain potential to identify EGFR mutation status and subtypes in LUAD, which might be helpful to the treatment of LUAD.

Prevalence and Risk Factors of Urinary Retention in Patients With Cervical Cancer: A Meta-analysis and Systematic Review.

BACKGROUND: The literature is inconsistent on the prevalence and risk factors of urinary retention in patients with cervical cancer. OBJECTIVE: The aim of this study was to review the literature on the prevalence of urinary retention in patients with cervical cancer and consolidate the risk factors. METHODS: For this meta-analysis, eligible articles published in English or Chinese by December 10, 2021, were systematically searched for and retrieved from PubMed, Cochrane Library, Ovid-Embase Medline, Web of Science, PsycINFO, CINAHL, and Scopus. Prevalence, odds ratios (ORs), and 95% confidence intervals (CIs) were used for meta-analysis. RESULTS: Twenty-five studies were included in the analysis. The pooled overall prevalence was 0.26 (95% CI, 0.21-0.30, I2 = 95.0%). The identified risk factors were age (OR, 1.13; 95% CI, 1.08-1.19), urinary tract infection (UTI) (OR, 3.33; 95% CI, 1.48-7.49), surgical extent (OR, 2.95; 95% CI, 1.27-6.85), and catheter indwelling time (OR, 3.44; 95% CI, 2.43-3.87). CONCLUSIONS: The prevalence of urinary retention in patients with cervical cancer is 0.26. Older age, UTI, longer catheter indwelling time, and a larger surgical extent may increase the risk of urinary retention. Clinicians should identify patients at risk and adopt interventions such as individualized catheter care. IMPLICATIONS FOR PRACTICE: Nursing staff should assess the risk of urinary retention in a patient with cervical cancer according to her age, presence of UTI, surgical extent, and catheterization time. A carefully chosen surgical procedure and interventions such as individualized education, timely catheter removal, treatment of UTI, and rehabilitation should be offered.

Sinularin stabilizes FOXO3 protein to trigger prostate cancer cell intrinsic apoptosis.

Sinularin, a natural product that purified from soft coral, exhibits anti-tumor effects against various human cancers. However, the mechanisms are not well understood. In this study, we demonstrated that Sinularin inhibited the viability of human prostate cancer cells in a dose-dependent manner and displayed significant cytotoxicity only at high concentration against normal prostate epithelial cell RWPE-1. Flow cytometry assay demonstrated that Sinularin induced tumor cell apoptosis. Further investigations revealed that Sinularin exerted anti-tumor activity through intrinsic apoptotic pathway along with up-regulation of pro-apoptotic protein Bax and PUMA, inhibition of anti-apoptotic protein Bcl-2, mitochondrial membrane potential collapses, and release of mitochondrial proteins. Furthermore, we illustrated that Sinularin induced cell apoptosis via up-regulating PUMA through inhibition of FOXO3 degradation by the ubiquitin-proteasome pathway. To explore how Sinularin suppress FOXO3 ubiquitin-proteasome degradation, we tested two important protein kinases AKT and ERK that regulate FOXO3 stabilization. The results revealed that Sinularin stabilized and up-regulated FOXO3 via inhibition of AKT- and ERK1/2-mediated FOXO3 phosphorylation and subsequent ubiquitin-proteasome degradation. Our findings illustrated the potential mechanisms by which Sinularin induced cell apoptosis and Sinularin may be applied as a therapeutic agent for human prostate cancer.

Explore the use of complementary and alternative medicine among Chinese gynaecological patients with cancer undergoing chemotherapy: a qualitative phenomenological study.

OBJECTIVES: To explore the use of complementary and alternative medicine (CAM) by Chinese gynaecological oncology patients undergoing chemotherapy and discuss measures to address the existing gaps. DESIGN: Qualitative phenomenology. Semistructured in-depth interview. Colaizzi's method data analysis. SETTING: A tertiary general hospital. PARTICIPANTS: 16 gynaecological oncology patients (mean age 51.7) having undergone ≥1 chemotherapy cycle were recruited by purposive sampling. RESULTS: Six themes were generated. The participants were under-informed about CAM concept and options. They were open to explore various modalities after chemotherapy as long as it could alleviate symptoms. The gynaecological patients with cancer sought information about CAM from diverse sources, with professional expertise being the most desirable way to seek information. They used CAM as a strategy to support continued chemotherapy and for symptom alleviation. Financial burden was not stressed but they had concerns about sustainability of some therapies. Their attitudes toward different CAM types varied. Some were sceptical about the efficacy. CONCLUSIONS: The Chinese gynaecological oncology patients may be under-informed about CAM. They are open to use various CAM therapies for symptom relief and as a support strategy. However, their attitudes toward specific therapies may vary. Some may host scepticism about certain CAM modalities. The patients actively seek information on CAM and treatment resources but prefer professional expertise to other sources. Financial burden due to continued CAM use is inconclusive due to possible sampling bias. Sustainability of CAM therapies is a common concern because of limited resources and access. Education on CAM should be incorporated into the curriculum of healthcare professionals. Oncologists and nurses should educate gynaecological patients with cancer on the concept and options of CAM, preferably with information tailored to patient's individual needs. Health authorities should advocate provisions of diverse CAM services and develop the necessary technologies such as network of local care resources.

A novel TOX3-WDR5-ABCG2 signaling axis regulates the progression of colorectal cancer by accelerating stem-like traits and chemoresistance.

The eradication of cancer stem cells (CSCs) with drug resistance confers the probability of local tumor control after chemotherapy or targeted therapy. As the main drug resistance marker, ABCG2 is also critical for colorectal cancer (CRC) evolution, in particular cancer stem-like traits expansion. Hitherto, the knowledge about the expression regulation of ABCG2, in particular its upstream transcriptional regulatory mechanisms, remains limited in cancer, including CRC. Here, ABCG2 was found to be markedly up-regulated in CRC CSCs (cCSCs) expansion and chemo-resistant CRC tissues and closely associated with CRC recurrence. Mechanistically, TOX3 was identified as a specific transcriptional factor to drive ABCG2 expression and subsequent cCSCs expansion and chemoresistance by binding to -261 to -141 segments of the ABCG2 promoter region. Moreover, we found that TOX3 recruited WDR5 to promote tri-methylation of H3K4 at the ABCG2 promoter in cCSCs, which further confers stem-like traits and chemoresistance to CRC by co-regulating the transcription of ABCG2. In line with this observation, TOX3, WDR5, and ABCG2 showed abnormal activation in chemo-resistant tumor tissues of in situ CRC mouse model and clinical investigation further demonstrated the comprehensive assessment of TOX3, WDR5, and ABCG2 could be a more efficient strategy for survival prediction of CRC patients with recurrence or metastasis. Thus, our study found that TOX3-WDR5/ABCG2 signaling axis plays a critical role in regulating CRC stem-like traits and chemoresistance, and a combination of chemotherapy with WDR5 inhibitors may induce synthetic lethality in ABCG2-deregulated tumors.

A novel 3D printed type II silk fibroin/polycaprolactone mesh for the treatment of pelvic organ prolapse.

Pelvic organ prolapse (POP) is one of the common diseases in middle-aged and elderly women, caused by weakened pelvic floor muscle ligament tissue support. Pelvic floor reconstruction with mesh implantation has been proven to be an effective treatment for POP. However, traditional non-degradable and inflexible pelvic floor implantation meshes have been associated with pain, vaginal infections, and the need for additional surgeries. In this study, novel meshes with pre-designed structures were fabricated with solution-based electrohydrodynamic printing (EHDP) technology, using a series of polycaprolactone/silk fibroin composites as bioinks. The PCL/SF mesh mechanical performances were particularly enhanced with the addition of silk II, leading it to obtain higher adaptability with soft tissue repair. The mesh containing SF showed more robust degradation performance in the in vitro degradation assay. Furthermore, biocompatibility tests conducted on mouse embryonic fibroblasts (NIH/3T3) revealed enhanced cell affinity. Finally, the biocompatibility and tissue repair properties of PCL/SF mesh were verified through the implantation of meshes in the muscle defect site of mice. The results demonstrated that the 3D printed PCL/SF mesh prepared by EHDP exhibits superior mechanical properties, biocompatibility, biodegradability, as well as ligament and muscle fiber repair ability. The novel implantable meshes are promising for curing POP.

Inhibition of neutrophil extracellular trap formation attenuates NLRP1-dependent neuronal pyroptosis via STING/IRE1α pathway after traumatic brain injury in mice.

Introduction: Increased neutrophil extracellular trap (NET) formation has been reported to be associated with cerebrovascular dysfunction and neurological deficits in traumatic brain injury (TBI). However, the biological function and underlying mechanisms of NETs in TBI-induced neuronal cell death are not yet fully understood. Methods: First, brain tissue and peripheral blood samples of TBI patients were collected, and NETs infiltration in TBI patients was detected by immunofluorescence staining and Western blot. Then, a controlled cortical impact device was used to model brain trauma in mice, and Anti-Ly6G, DNase, and CL-amidine were given to reduce the formation of neutrophilic or NETs in TBI mice to evaluate neuronal death and neurological function. Finally, the pathway changes of neuronal pyroptosis induced by NETs after TBI were investigated by administration of peptidylarginine deiminase 4 (a key enzyme of NET formation) adenovirus and inositol-requiring enzyme-1 alpha (IRE1α) inhibitors in TBI mice. Results: We detected that both peripheral circulating biomarkers of NETs and local NETs infiltration in the brain tissue were significantly increased and had positive correlations with worse intracranial pressure (ICP) and neurological dysfunction in TBI patients. Furthermore, the depletion of neutrophils effectively reduced the formation of NET in mice subjected to TBI. we found that degradation of NETs or inhibition of NET formation significantly inhibited nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 1 (NLRP1) inflammasome-mediated neuronal pyroptosis after TBI, whereas these inhibitory effects were abolished by cyclic GMP-AMP (cGAMP), an activator of stimulating Interferon genes (STING). Moreover, overexpression of PAD4 in the cortex by adenoviruses could aggravate NLRP1-mediated neuronal pyroptosis and neurological deficits after TBI, whereas these pro-pyroptotic effects were rescued in mice also receiving STING antagonists. Finally, IRE1α activation was significantly upregulated after TBI, and NET formation or STING activation was found to promote this process. Notably, IRE1α inhibitor administration significantly abrogated NETs-induced NLRP1 inflammasome-mediated neuronal pyroptosis in TBI mice. Discussion: Our findings indicated that NETs could contribute to TBI-induced neurological deficits and neuronal death by promoting NLRP1-mediated neuronal pyroptosis. Suppression of the STING/ IRE1α signaling pathway can ameliorate NETs-induced neuronal pyroptotic death after TBI.

Infection pattern and immunological characteristics of Epstein-Barr virus latent infection in cervical squamous cell carcinoma.

Previous studies reported the association between Epstein-Barr virus (EBV) and cervical squamous cell carcinoma (CSCC), but its infection pattern and clinical significance unclear. This study aimed to comprehensively investigate the infection pattern, clinicopathology, outcomes, and immunology of this entity in central China. We evaluated a total of 104 untreated CSCC tumor tissue specimens using in situ hybridization for EBV-encoded small RNAs (EBERs), and by employing flowcytometry fluorescence hybridization for human papillomavirus (HPV) genotyping. The expression of EBV latency proteins and immune biomarkers was evaluated and quantified by immunohistochemistry. EBERs transcripts were detected in 21 (20.2%) cases overall (in malignant epithelial cells of 13 cases and in lymphocytes of 8 cases). EBV belonged to latency type I infection in CSCC. The high-risk (HR)-HPV was detected in all of EBV-positive CSCC, and the difference of detection rate of HR-HPV was significant when compared with EBV-negative CSCC (p = 0.001). The specific clinicopathology with increased frequency of advanced clinical stages, tumor-positive lymph nodes, neural invasion, and increased infiltration depth (all p value < 0.05) were observed in cases with EBV. However, EBV infection was found to have no impact on prognosis of patients with CSCC. Increased densities of forkhead box P3 (FoxP3)+-tumor infiltrating lymphocytes (TILs) (p = 0.005) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)+-TILs (p = 0.017) and higher expression of programmed cell death-1 (PD-1) (p = 0.002) and programmed cell death-1 ligand 1 (PD-L1) (p = 0.040) were associated with EBV latent infection in CSCC, and these immunological changes were more likely to be associated with the infection in lymphocytes rather than tumor cells. Moreover, in patients with HPV-positive CSCC, similar significant differences were still found. In conclusions, EBV-positive CSCC may have specific infection pattern and clinicopathology and can exhibit an immunosuppressive microenvironment dominated by Treg cells aggregation and immune checkpoint activation.

Optimal 18F-FDG PET/CT radiomics model development for predicting EGFR mutation status and prognosis in lung adenocarcinoma: a multicentric study.

Purpose: To develop and interpret optimal predictive models to identify epidermal growth factor receptor (EGFR) mutation status and subtypes in patients with lung adenocarcinoma based on multicentric 18F-FDG PET/CT data, and further construct a prognostic model to predict their clinical outcome. Methods: The 18F-FDG PET/CT imaging and clinical characters of 767 patients with lung adenocarcinoma from 4 cohorts were collected. Seventy-six radiomics candidates using cross-combination method to identity EGFR mutation status and subtypes were built. Further, Shapley additive explanations and local interpretable model-agnostic explanations were used for optimal models' interpretation. Moreover, in order to predict the overall survival, a multivariate Cox proportional hazard model based on handcrafted radiomics features and clinical characteristics was constructed. The predictive performance and clinical net benefit of the models were evaluated via area under receiver operating characteristic (AUC), C-index and decision curve analysis. Results: Among the 76 radiomics candidates, light gradient boosting machine classifier (LGBM) combined with recursive feature elimination wrapped LGBM feature selection method achieved best performance in predicting EGFR mutation status (AUC reached 0.80, 0.61, 0.71 in the internal test cohort and two external test cohorts, respectively). And extreme gradient boosting classifier combined with support vector machine feature selection method achieved best performance in predicting EGFR subtypes (AUC reached 0.76, 0.63, 0.61 in the internal test cohort and two external test cohorts, respectively). The C-index of the Cox proportional hazard model achieved 0.863. Conclusions: The integration of cross-combination method and the external validation from multi-center data achieved a good prediction and generalization performance in predicting EGFR mutation status and its subtypes. The combination of handcrafted radiomics features and clinical factors achieved good performance in predicting prognosis. With the urgent needs of multicentric 18F-FDG PET/CT trails, robust and explainable radiomics models have great potential in decision making and prognosis prediction of lung adenocarcinoma.

Association of the ADORA2A receptor and CD73 polymorphisms with epilepsy.

Single-nucleotide polymorphisms are connected with the risk of epilepsy on occurrence, progress, and the individual response to drugs. Progress in genomic technology is exposing the complex genetic architecture of epilepsy. Compelling evidence has demonstrated that purines and adenosine are key mediators in the epileptic process. Our previous study found the interconnection of P2Y12 receptor single-nucleotide polymorphisms and epilepsy. However, little is known about the interaction between the purine nucleoside A2A receptor and rate-limiting enzyme ecto-5'-nucleotidase/CD73 and epilepsy from the genetic polymorphism aspect. The aim of the study is to evaluate the impact of A2AR and CD73 polymorphisms on epilepsy cases. The study group encompassed 181 patients with epilepsy and 55 healthy volunteers. A significant correlation was confirmed between CD73 rs4431401 and epilepsy (p < 0.001), with TT genotype frequency being higher and C allele being lower among epilepsy patients in comparison with healthy individuals, indicating that the presence of the TT genotype is related to an increased risk of epilepsy (OR = 2.742, p = 0.006) while carriers of the C allele demonstrated a decreased risk of epilepsy (OR = 0.304, p < 0.001). According to analysis based on gender, the allele and genotype of rs4431401 in CD73 were associated with both male and female cases (p < 0.0001, p = 0.026, respectively). Of note, we found that A2AR genetic variants rs2267076 T>C (p = 0.031), rs2298383 C>T (p = 0.045), rs4822492 T>G (p = 0.034), and rs4822489 T>G (p = 0.029) were only associated with epilepsy in female subjects instead of male. It is evident that the TT genotype and T allele of rs4431401 in CD73 were genetic risk factors for epilepsy, whereas rs2267076, rs2298383, rs4822492, and rs4822489 polymorphisms of the A2AR were mainly associated with female subjects.

Management of Crown-root Fracture with 180-degree Rotation Replantation: a Report of 2 Cases.

Intentional replantation involves a combination of periodontics, endodontics, prosthodontics and oral surgery. Crown-root fracture management is still complicated nowadays. A fracture line extending longitudinally to the subgingival area and intruding bioogical width could affect infection control, gingival health and crown restoration. In the present study, we present two cases. Case 1 involved a 23-year-old man who presented at our hospital with crown-root fracture of the maxillary left central incisor. A radiographic image of the tooth revealed a fracture line under the alveolar crest. The fractured tooth was treated with intentional replantation with 180-degree rotation, root canal treatment and veneer restoration. The patient was followed up for 60 months. The replanted tooth functioned well, and no symptoms of resorption or ankylosis were observed by radiographic examination. Case 2 involved a 20-year-old woman who was referred to our hospital for crown-root fracture of her maxillary teeth. A radiographic examination revealed complicated crown-root fracture of the maxillary right lateral incisor and both maxillary central incisors. The central incisors were treated with intentional replantation with 180-degree rotation. At the 48-month follow-up, the fractured teeth were found to have regained normal function based on clinical and radiographic examination. Limited case reports are available on a long-term follow-up of intentional replantation with 180-degree rotation. These two cases, particularly case 2, presented optimal healing after 4 years with unideal crown-root ratios. This case report suggests that this old method of preserving teeth with crown-root fractures can be used as a last resort to save teeth owing to its timesaving and microinvasive procedure.

CD73: Friend or Foe in Lung Injury.

Ecto-5'-nucleotidase (CD73) plays a strategic role in calibrating the magnitude and chemical nature of purinergic signals that are delivered to immune cells. Its primary function is to convert extracellular ATP to adenosine in concert with ectonucleoside triphosphate diphosphohydrolase-1 (CD39) in normal tissues to limit an excessive immune response in many pathophysiological events, such as lung injury induced by a variety of contributing factors. Multiple lines of evidence suggest that the location of CD73, in proximity to adenosine receptor subtypes, indirectly determines its positive or negative effect in a variety of organs and tissues and that its action is affected by the transfer of nucleoside to subtype-specific adenosine receptors. Nonetheless, the bidirectional nature of CD73 as an emerging immune checkpoint in the pathogenesis of lung injury is still unknown. In this review, we explore the relationship between CD73 and the onset and progression of lung injury, highlighting the potential value of this molecule as a drug target for the treatment of pulmonary disease.

Pulmonary infection in patients with severe fever with thrombocytopenia syndrome: A multicentre observational study.

Co-infection in patients with severe fever with thrombocytopenia syndrome (SFTS) has been reported, posing a serious threat to survival and treatment. We aimed to systematically investigate the SFTS associated pulmonary infection, particularly invasive pulmonary fungal infection (IPFI). During April 2019 to October 2021, we conducted a multicentre observational study on adult hospitalized patients confirmed with SFTS from three tertiary hospital in central China. Demographic, clinical and laboratory data of patients were collected and re-assessed. A total of 443 patients (51.7% were male sex) were included for analysis with median age of 65-year-old. Among them, 190 (42.9%) patients met the criteria for pulmonary infection. Pulmonary infection was associated with shorter survival time (p < 0.0001 by log-rank test), and adjusted hazard ratio was 1.729 [95% confidence interval, 1.076-2.780] (p = 0.024). Age (odds ratio (OR) 1.040 [1.019-1.062], p < 0.001), time from onset to admission (OR 1.163 [1.070-1.264], p < 0.001), having severe status (OR 3.166 [2.020-4.962], p < 0.001) and symptoms of skin change (OR 2.361 [1.049-5.316], p < 0.001) at admission and receiving intravenous immunoglobin (OR 2.185 [1.337-3.569], p = 0.002) were independent risk factors for the occurrence of pulmonary infection. A total of 70 (15.8%) patients were defined as IPFI. Multivariate analysis showed that time from onset to admission (OR 1.117 [1.016-1.229], p = 0.022), severe status (OR 5.737 [3.054-10.779], p < 0.001), having smoking history (OR 3.178 [1.251-8.070], p = 0.015) and autoimmunity disease (OR 7.855 [1.632-37.796], p = 0.010), receiving intravenous immunoglobin (OR 3.270 [1.424-7.508], p = 0.005) were independent risk factors for the occurrence of IPFI. In SFTS patients with pulmonary infection, white blood count <2.09 × 109 per L (OR 11.064 [3.708-33.012], p < 0.001) and CD3+ CD4+ T cell count <104.0 per µL (OR 10.429 [3.395-32.038], p < 0.001) could independently predict IPFI. This study showed the high prevalence and poor outcomes of pulmonary infection and IPFI in patients with SFTS. These findings highlighted the need for active surveillance of fungal pathogens and early antifungal treatment in patients with SFTS.

The Wnt pathway protein Dvl1 targets somatostatin receptor 2 for lysosome-dependent degradation.

The Somatostatin receptor 2 (Sstr2) is a heterotrimeric G protein-coupled receptor that is highly expressed in neuroendocrine tumors and is a common pharmacological target for intervention. Unfortunately, not all neuroendocrine tumors express Sstr2, and Sstr2 expression can be downregulated with prolonged agonist use. Sstr2 is rapidly internalized following agonist stimulation and, in the short term, is quantitatively recycled back to the plasma membrane. However, mechanisms controlling steady state expression of Sstr2 in the absence of agonist are less well described. Here, we show that Sstr2 interacts with the Wnt pathway protein Dvl1 in a ligand-independent manner to target Sstr2 for lysosomal degradation. Interaction of Sstr2 with Dvl1 does not affect receptor internalization, recycling, or signaling to adenylyl cyclase but does suppress agonist-stimulated ERK1/2 activation. Importantly, Dvl1-dependent degradation of Sstr2 can be stimulated by overexpression of Wnts and treatment of cells with Wnt pathway inhibitors can boost Sstr2 expression in neuroendocrine tumor cells. Taken together, this study identifies for the first time a mechanism that targets Sstr2 for lysosomal degradation that is independent of Sstr2 agonist and can be potentiated by Wnt ligand. Intervention in this signaling mechanism has the potential to elevate Sstr2 expression in neuroendocrine tumors and enhance Sstr2-directed therapies.