Haploinsufficiency of Adenomatous Polyposis Coli Coupled with Kirsten Rat Sarcoma Viral Oncogene Homologue Activation and P53 Loss Provokes High-Grade Glioblastoma Formation in Mice.

Glioblastoma multiforme (GBM) is the most common and deadly type of brain tumor originating from glial cells. Despite decades of clinical trials and research, there has been limited success in improving survival rates. However, molecular pathology studies have provided a detailed understanding of the genetic alterations associated with the formation and progression of glioblastoma-such as Kirsten rat sarcoma viral oncogene homolog (KRAS) signaling activation (5%), P53 mutations (25%), and adenomatous polyposis coli (APC) alterations (2%)-laying the groundwork for further investigation into the biological and biochemical basis of this malignancy. These analyses have been crucial in revealing the sequential appearance of specific genetic lesions at distinct histopathological stages during the development of GBM. To further explore the pathogenesis and progression of glioblastoma, here, we developed the glial-fibrillary-acidic-protein (GFAP)-Cre-driven mouse model and demonstrated that activated KRAS and p53 deficiencies play distinct and cooperative roles in initiating glioma tumorigenesis. Additionally, the combination of APC haploinsufficiency with mutant Kras activation and p53 deletion resulted in the rapid progression of GBM, characterized by perivascular inflammation, large necrotic areas, and multinucleated giant cells. Consequently, our GBM models have proven to be invaluable resources for identifying early disease biomarkers in glioblastoma, as they closely mimic the human disease. The insights gained from these models may pave the way for potential advancements in the diagnosis and treatment of this challenging brain tumor.

TGF-ß1 induces PD-1 expression in macrophages through SMAD3/STAT3 cooperative signaling in chronic inflammation.

Programmed cell death protein 1 (PD-1), a coinhibitory T cell checkpoint, is also expressed on macrophages in pathogen- or tumor-driven chronic inflammation. Increasing evidence underscores the importance of PD-1 on macrophages for dampening immune responses. However, the mechanism governing PD-1 expression in macrophages in chronic inflammation remains largely unknown. TGF-ß1 is abundant within chronic inflammatory microenvironments. Here, based on public databases, significantly positive correlations between PDCD1 and TGFB1 gene expression were observed in most human tumors. Of note, among immune infiltrates, macrophages as the predominant infiltrate expressed higher PDCD1 and TGFBR1/TGFBR2 genes. MC38 colon cancer and Schistosoma japonicum infection were used as experimental models for chronic inflammation. PD-1hi macrophages from chronic inflammatory tissues displayed an immunoregulatory pattern and expressed a higher level of TGF-ß receptors. Either TGF-ß1-neutralizing antibody administration or macrophage-specific Tgfbr1 knockdown largely reduced PD-1 expression on macrophages in animal models. We further demonstrated that TGF-ß1 directly induced PD-1 expression on macrophages. Mechanistically, TGF-ß1-induced PD-1 expression on macrophages was dependent on SMAD3 and STAT3, which formed a complex at the Pdcd1 promoter. Collectively, our study shows that macrophages adapt to chronic inflammation through TGF-ß1-triggered cooperative SMAD3/STAT3 signaling that induces PD-1 expression and modulates macrophage function.

CD1d protects against hepatocyte apoptosis in non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Hepatocyte apoptosis, a well-defined form of cell death in non-alcoholic steatohepatitis (NASH), is considered the primary cause of liver inflammation and fibrosis. However, the mechanisms underlying the regulation of hepatocyte apoptosis in NASH remain largely unclear. We explored the anti-apoptotic effect of hepatocyte CD1d in NASH. METHODS: Hepatocyte CD1d expression was analyzed in patients with NASH and mouse models. Hepatocyte-specific gene overexpression or knockdown and anti-CD1d crosslinking were used to investigate the anti-apoptotic effect of hepatocyte CD1d on lipotoxicity-, Fas-, and concanavalin (ConA)-mediated liver injuries. A high-fat diet, a methionine-choline-deficient diet, a Fas agonist, and ConA were used to induce lipotoxic and/or apoptotic liver injuries. Palmitic acid was used to mimic lipotoxicity-induced apoptosis in vitro. RESULTS: We identified a dramatic decrease in CD1d expression in hepatocytes of patients with NASH and mouse models. Hepatocyte-specific CD1d overexpression and knockdown experiments collectively demonstrated that hepatocyte CD1d protected against hepatocyte apoptosis and alleviated hepatic inflammation and injuries in NASH mice. Furthermore, decreased JAK2-STAT3 signaling was observed in NASH patient livers. Mechanistically, anti-CD1d crosslinking on hepatocytes induced tyrosine phosphorylation of the CD1d cytoplasmic tail, leading to the recruitment and phosphorylation of JAK2. Phosphorylated JAK2 activated STAT3 and subsequently reduced apoptosis in hepatocytes, which was associated with an increase in anti-apoptotic effectors (Bcl-xL and Mcl-1) and a decrease in pro-apoptotic effectors (cleaved-caspase 3/7). Moreover, anti-CD1d crosslinking effectively protected against Fas- or ConA-mediated hepatocyte apoptosis and liver injury in mice. CONCLUSIONS: Our study uncovered a previously unrecognized anti-apoptotic CD1d-JAK2-STAT3 axis in hepatocytes that conferred hepatoprotection and highlighted the potential of hepatocyte CD1d-directed therapy for liver injury and fibrosis in NASH, as well as in other liver diseases associated with hepatocyte apoptosis. IMPACT AND IMPLICATIONS: Excessive and/or sustained hepatocyte apoptosis is critical in driving liver inflammation and injury. The mechanisms underlying the regulation of hepatocyte apoptosis in non-alcoholic steatohepatitis (NASH) remain largely unclear. Here, we found that CD1d expression in hepatocytes substantially decreases and negatively correlates with the severity of liver injury in patients with NASH. We further revealed a previously unrecognized anti-apoptotic CD1d-JAK2-STAT3 signaling axis in hepatocytes, which confers significant protection against liver injury in NASH and acute liver diseases. Thus, hepatocyte CD1d-targeted therapy could be a promising strategy to manipulate liver injury in both NASH and other hepatocyte apoptosis-related liver diseases.

LPGAT1 controls MEGDEL syndrome by coupling phosphatidylglycerol remodeling with mitochondrial transport.

Phosphatidylglycerol (PG) is a mitochondrial phospholipid required for mitochondrial cristae structure and cardiolipin synthesis. PG must be remodeled to its mature form at the endoplasmic reticulum (ER) after mitochondrial biosynthesis to achieve its biological functions. Defective PG remodeling causes MEGDEL (non-alcohol fatty liver disease and 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like) syndrome through poorly defined mechanisms. Here, we identify LPGAT1, an acyltransferase that catalyzes PG remodeling, as a candidate gene for MEGDEL syndrome. We show that PG remodeling by LPGAT1 at the ER is closely coordinated with mitochondrial transport through interaction with the prohibitin/TIMM14 mitochondrial import motor. Accordingly, ablation of LPGAT1 or TIMM14 not only causes aberrant fatty acyl compositions but also ER retention of newly remodeled PG, leading to profound loss in mitochondrial crista structure and respiration. Consequently, genetic deletion of the LPGAT1 in mice leads to cardinal features of MEGDEL syndrome, including 3-methylglutaconic aciduria, deafness, dilated cardiomyopathy, and premature death, which are highly reminiscent of those caused by TIMM14 mutations in humans.

The effect of bone remodeling with photobiomodulation in dentistry: a review study.

Photobiomodulation (PBM) has been emerging as a promising alternative therapy in dentistry. However, various parameters of PBM are used in different studies, and there is limited cumulative data on PBM for improving bone formation in clinical trials. The aim of this review was to evaluate the effectiveness of PBM in the process of bone remodeling in dentistry using randomized controlled trials. Initially, a total of 1,011 articles published from January 2008 to December 2021 were retrieved from five electronic databases (PubMed, Scopus, Cochrane Library, EMBASE, and CINAHL). After a two-step review, nine articles met the inclusion criteria. The parameter of PBM, group, treatment sessions, assessment times and outcomes of the included studies were reviewed. Eighty-nine percent of the studies revealed positive effects on bone formation between the laser group and the control group. Only one article reported that light-emitting diode did not significantly enhance osteogenesis. Additionally, the present study shows that Gallium aluminum arsenide of near infrared (NIR) laser with continuous mode is the most commonly used form of PBM. The biostimulatory effects are dependent on several parameters, with wavelength and dose being more important than others. Based on this review, it is suggested that the NIR range and an appropriate dose of PBM could be used to increase the efficiency of stimulating bone healing and remodeling. However, standardization of treatment protocols is needed to clarify therapeutic strategies in dentistry.

Vaccination against the HDL receptor of S. japonicum inhibits egg embryonation and prevents fatal hepatic complication in rabbit model.

BACKGROUND: Schistosomiasis is one of the most important neglected tropical infectious diseases to overcome and the primary cause of its pathogenesis is ectopic maturation of the parasite eggs. Uptake of cholesteryl ester from the host high-density lipoprotein (HDL) is a key in this process in Schistosoma japonicum and CD36-related protein (CD36RP) has been identified as the receptor for this reaction. Antibody against the extracellular domain of CD36RP (Ex160) efficiently blocked the HDL cholesteryl ester uptake and the egg embryonation in vitro. However, whether Ex160 immunization could efficiently raise proper antibody responses to sufficiently block HDL cholesteryl ester uptake and the egg embryonation to protect host in vivo is very interesting but unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study, rabbits were immunized with the recombinant Ex160 peptide (rEx160) to evaluate its anti-pathogenic vaccine potential. Immunization with rEx160 induced consistent anti-Ex160 IgG antibody and significant reduction in development of the liver granulomatosis lesions associated with suppressed intrahepatic maturation of the schistosome eggs. The immunization with rEx160 rescued reduction of serum HDL by the infection without changing its size distribution, being consistent with interference of the HDL lipid uptake by the parasites or their eggs by antibody against Ex160 in in vitro culture. CONCLUSIONS/SIGNIFICANCE: The results demonstrated that vaccination strategy against nutritional supply pathway of the parasite is effective for reducing its pathogenesis.

MiR-155 promotes acute organ injury in LPS-induced endotoxemic mice by enhancing CCL-2 expression in macrophages.

ABSTRACT: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Macrophages play important roles in the inflammatory process of sepsis by secreting chemokines. Chemokine (CC-motif) ligand 2 (CCL-2) is one of the main pro-inflammatory chemokines secreted by macrophages that plays a critical role in the recruitment of more monocytes and macrophages to the sites of injury in sepsis, but the mechanisms that regulate CCL-2 expression in macrophages during sepsis are still unknown. In the present study, by using the lipopolysaccharide (LPS)-induced endotoxemia model, we found that LPS induced the expression of microRNA (miR)-155 and CCL-2 in endotoxemic mice and RAW264.7 cells. MiR-155 mimics or miR-155 inhibitor treatment experiment suggested that miR-155 was sufficient to increase LPS-induced CCL-2 expression in macrophages, but miR-155 was not the only factor promoting CCL-2 expression. We further demonstrated that miR-155-induced increase of CCL-2 promoted chemotaxis of additional macrophages, which subsequently enhanced lung injury in endotoxemic mice. Serum/glucocorticoid regulated kinase family member 3 (SGK3), a potential target of miR-155, was identified by RNA sequencing and predicted by TargetScan and miRDB. We further confirmed miR-155 regulated SGK3 to increase LPS-induced CCL-2 by using miR-155 mimics and SGK3 overexpression. Thus, our study demonstrates that miR-155 targets SGK3 to increase LPS-induced CCL-2 expression in macrophages, which promotes macrophage chemotaxis and enhances organs injury during endotoxemia. Our study contributed to a better understanding of the mechanisms underlying the inflammatory response during sepsis.

Efficacy of intraoperative thoracoscopic intercostal nerve blocks in nonintubated and intubated video-assisted thoracic surgery: A randomized study.

BACKGROUND: The efficacy of thoracoscopic intercostal nerve blocks (TINBs) for noxious stimulation from video-assisted thoracic surgery (VATS) remains unclear. The efficacy of TINBs may also be different between nonintubated VATS (NIVATS) and intubated VATS (IVATS). We aim to compare the efficacy of TINBs on analgesia and sedation for NIVATS and IVATs intraoperatively. METHODS: Sixty patients randomized to the NIVATS or IVATS group (30 each) received target-controlled propofol and remifentanil infusions, with bispectral index (BIS) maintained at 40-60, and multilevel (T3-T8) TINBs before surgical manipulations. Intraoperative monitoring data, including pulse oximetry, mean arterial pressure (MAP), heart rate, BIS, density spectral arrays (DSAs), and propofol and remifentanil effect-site concentration (Ce) at different time points. A two way ANOVA with post hoc analysis was applied to analyze the differences and interactions of groups and time points. RESULTS: In both groups, DSA monitoring revealed burst suppression and α dropout immediately after the TINBs. The Ce of the propofol infusion had to be reduced within 5 min post-TINBs in both NIVATS (p < 0.001) and IVATS (p = 0.252) groups. The Ce of remifentanil infusion was significantly reduced after TINBs in both groups (p < 0.001), and was significantly lower in NIVATS (p < 0.001) without group interactions. CONCLUSION: The surgeon-performed intraoperative multilevel TINBs allow reduced anesthetic and analgesic requirement for VATS. With lower requirement of remifentanil infusion, NIVATS presents a significantly higher risk of hypotension after TINBs. DSA is beneficial for providing real-time data that facilitate the preemptive management, especially for NIVATS.

Improved Survival Analyses Based on Characterized Time-Dependent Covariates to Predict Individual Chronic Kidney Disease Progression.

Kidney diseases can cause severe morbidity, mortality, and health burden. Determining the risk factors associated with kidney damage and deterioration has become a priority for the prevention and treatment of kidney disease. This study followed 497 patients with stage 3-5 chronic kidney disease (CKD) who were treated at the ward of Taipei Veterans General Hospital from January 2006 to 2019 in Taiwan. The patients underwent 3-year-long follow-up sessions for clinical measurements, which occurred every 3 months. Three time-dependent survival models, namely the Cox proportional hazard model (Cox PHM), random survival forest (RSF), and an artificial neural network (ANN), were used to process patient demographics and laboratory data for predicting progression to renal failure, and important features for optimal prediction were evaluated. The individual prediction of CKD progression was validated using the Kaplan-Meier estimation method, based on patients' true outcomes during and beyond the study period. The results showed that the average concordance indexes for the cross-validation of the Cox PHM, ANN, and RSF models were 0.71, 0.72, and 0.89, respectively. RSF had the best predictive performances for CKD patients within the 3 years of follow-up sessions, with a sensitivity of 0.79 and specificity of 0.88. Creatinine, age, estimated glomerular filtration rate, and urine protein to creatinine ratio were useful factors for predicting the progression of CKD patients in the RSF model. These results may be helpful for instantaneous risk prediction at each follow-up session for CKD patients.

Schistosome egg antigen stimulates the secretion of miR-33-carrying extracellular vesicles from macrophages to promote hepatic stellate cell activation and liver fibrosis in schistosomiasis.

Schistosomiasis is a serious and neglected disease with a high prevalence in tropical and subtropical countries. The primary pathology of hepatic schistosomiasis caused by Schistosoma japonicum (S. japonicum) or Schistosoma mansoni (S. mansoni) infection is egg-induced granuloma and subsequent fibrosis in the liver. Activation of hepatic stellate cells (HSCs) is the central driver of liver fibrosis. Macrophages (Mφ), making up 30% of cells in hepatic granulomas, directly or indirectly regulate HSC activation by paracrine mechanisms, via secreting cytokines or chemokines. Currently, Mφ-derived extracellular vesicles (EVs) are broadly involved in cell communication with adjacent cell populations. However, whether Mφ-derived EVs could target neighboring HSCs to regulate their activation during schistosome infection remains largely unknown. Schistosome egg antigen (SEA) is considered to be the main pathogenic complex mixture involved in liver pathology. Here, we demonstrated that SEA induced Mφ to produce abundant extracellular vesicles, which directly activated HSCs by activating their autocrine TGF-ß1 signaling. Mechanistically, EVs derived from SEA-stimulated Mφ contained increased miR-33, which were transferred into HSCs and subsequently upregulated autocrine TGF-ß1 in HSCs through targeting and downregulating SOCS3 expression, thereby promoting HSC activation. Finally, we validated that EVs derived from SEA-stimulated Mφ utilized enclosed miR-33 to promote HSC activation and liver fibrosis in S. japonicum-infected mice. Overall, our study indicates that Mφ-derived EVs play important roles in the paracrine regulation of HSCs during the progression of hepatic schistosomiasis, representing a potential target for the prevention of liver fibrosis in hepatic schistosomiasis.

Influence of different mucosal phenotype on early and long-term marginal bone loss around implants: a systematic review and meta-analysis.

OBJECTIVES: To investigate the influence of different mucosal phenotypes on peri-implant marginal bone loss. MATERIALS AND METHODS: The search was conducted in five databases including PubMed, Embase, Cochrane, Scopus, and Web of Science (until 1st Sept. 2022) to identify relevant clinical studies. Potentially relevant journals were also manually searched. Two reviewers independently screened studies, extracted data, and evaluated the quality of the studies. Prospective clinical trials and observational studies investigating peri-implant marginal bone loss in thick-mucosa and thin-mucosa groups were included. RESULTS: A total of 14 studies were included in this systematic review. Results of the meta-analysis revealed a weighted mean difference of 0.38 mm for marginal bone loss between thick- and thin-mucosa groups (95% confidence interval = 0.02-0.74, P = 0.002). Statistical significance existed in short-term (follow-up ≤ 1 year) data (WMD = 0.41 mm, 95%CI = 0.11-0.70, P = 0.007), but not in long term (follow-up ≥ 3 y) data (WMD = 0.17 mm, 95%CI = - 0.02-0.36, P = 0.07). Survival rate revealed no difference between thick and thin mucosa groups. In subgroup analyses, a positive association between thick mucosa and less marginal bone loss was found in the non-submerged group, cement-retained group, and bone-level group. CONCLUSIONS: A significantly less marginal bone loss occurred in implants with thick mucosa than with thin mucosa in the short term, whereas no significant difference was observed in the long term. Due to the substantial heterogeneity and limited long-term data, further high-quality evidence is warranted to confirm the results. CLINICAL RELEVANCE: Clinicians are advised to use caution in treating patients with thin mucosa and adhere closely to indications and protocols to minimize marginal bone loss.

Fusobacterium nucleatum and its associated systemic diseases: epidemiologic studies and possible mechanisms.

Background: Fusobacterium nucleatum (F. nucleatum) is an anaerobic oral commensal and the major coaggregation bridge organism linking early and late colonisers. In recent years, a large number of studies suggest that F. nucleatum is closely related to the development of various systemic diseases, such as cardiovascular diseases, adverse pregnancy outcomes, inflammatory bowel diseases, cancer, Alzheimer's disease, respiratory infection, rheumatoid arthritis, etc. Objective: To review the effect of F. nucleatum on systemic diseases and its possible pathogenesis and to open new avenues for prevention and treatment of F. nucleatum-associated systemic diseases. Design: The research included every article published up to July 2022 featuring the keywords 'Systemic diseases' OR 'Atherosclerotic cardiovascular diseases' OR 'Atherosclerosis' OR 'Adverse pregnancy outcomes' OR 'Inflammatory bowel disease' OR 'Ulcerative colitis' OR 'Crohn's disease' OR 'Cancers' OR 'Oral squamous cell carcinomas' OR 'Gastrointestinal cancers' OR 'Colorectal cancer' OR 'Breast cancer' OR 'Genitourinary cancers' OR 'Alzheimer's disease ' OR 'Rheumatoid arthritis' OR 'Respiratory diseases' AND 'Fusobacterium nucleatum' OR 'Periodontal pathogen' OR 'Oral microbiota' OR 'Porphyromonas gingivalis' and was conducted in the major medical databases. Results: F. nucleatum can induce immune response and inflammation in the body through direct or indirect pathways, and thus affect the occurrence and development of systemic diseases. Only by continuing to investigate the pathogenic lifestyles of F. nucleatum will we discover the divergent pathways that may be leveraged for diagnostic, preventive and therapeutic purposes.

Online citizen sciences reveal natural enemies and new occurrence data of Meteorusstellatus Fujie, Shimizu & Maeto, 2021 (Hymenoptera, Braconidae, Euphorinae).

Background: Citizen science is a research approach that involves collaboration between professional scientists and non-professional volunteers. The utilisation of recent online citizen-science platforms (e.g. social networking services) has greatly revolutionised the accessibility of biodiversity data by providing opportunities for connecting professional and citizen scientists worldwide. Meteorusstellatus Fujie, Shimizu & Maeto, 2021 (Hymenoptera, Braconidae, Euphorinae) has been recorded from the Oriental Islands of Japan and known to be a gregarious endoparasitoid of two macro-sized sphingid moths of Macroglossum, Ma.passalus (Drury) and Ma.pyrrhosticta Butler. It constructs characteristic star-shaped communal cocoons, suspended by a long cable. Although M.stellatus has been reported only from the Oriental Islands of Japan, the authors recognise its occurrence and ecological data from Taiwan and the Palaearctic Island of Japan through posts on online citizen-science groups about Taiwanese Insects on Facebook and an article on a Japanese citizen-scientist's website. New information: Through collaboration between professional and citizen scientists via social media (Facebook groups) and websites, the following new biodiversity and ecological data associated with M.stellatus are provided: Meteorusstellatus is recorded for the first time from Taiwan and the Palaearctic Region (Yakushima Is., Japan).Cechetraminor (Butler, 1875), Hippotioncelerio (Linnaeus, 1758) and Macroglossumsitiene (Walker, 1856) (Lepidoptera, Sphingidae) are recorded for the first time as hosts of M.stellatus and two of which (C.minor and H.celerio) represent the first genus-level host records for M.stellatus.Mesochorus sp. (Hymenoptera, Ichneumonidae), indeterminate species of Pteromalidae and Trichogrammatidae (Hymenoptera), are recognised as hyperparasitoid wasps of M.stellatus.Parapolybiavaria (Fabricius, 1787) (Hymenoptera, Vespidae) is reported as a predator of pendulous communal cocoons of M.stellatus. The nature of suspended large-sized communal cocoons of M.stellatus and the importance and limitations of digital occurrence data and online citizen science are briefly discussed.

IL-33 induces thymic involution-associated naive T cell aging and impairs host control of severe infection.

Severe infection commonly results in immunosuppression, which leads to impaired pathogen clearance or increased secondary infection in both humans and animals. However, the exact mechanisms remain poorly understood. Here, we demonstrate that IL-33 results in immunosuppression by inducing thymic involution-associated naive T cell dysfunction with aberrant expression of aging-associated genes and impairs host control of infection in mouse disease models of schistosomiasis or sepsis. Furthermore, we illustrate that IL-33 triggers the excessive generation of medullary thymic epithelial cell (mTEC) IV (thymic tuft cells) in a Pou2f3-dependent manner, as a consequence, disturbs mTEC/cortical TEC (cTEC) compartment and causes thymic involution during severe infection. More importantly, IL-33 deficiency, the anti-IL-33 neutralizing antibody treatment, or IL-33 receptor ST2 deficient thymus transplantation rescues T cell immunity to better control infection in mice. Our findings not only uncover a link between severe infection-induced IL-33 and thymic involution-mediated naive T cell aging, but also suggest that targeting IL-33 or ST2 is a promising strategy to rejuvenate T cell immunity to better control severe infection.

Machine Learning Models for the Prediction of Renal Failure in Chronic Kidney Disease: A Retrospective Cohort Study.

This study assessed the feasibility of five separate machine learning (ML) classifiers for predicting disease progression in patients with pre-dialysis chronic kidney disease (CKD). The study enrolled 858 patients with CKD treated at a veteran's hospital in Taiwan. After classification into early and advanced stages, patient demographics and laboratory data were processed and used to predict progression to renal failure and important features for optimal prediction were identified. The random forest (RF) classifier with synthetic minority over-sampling technique (SMOTE) had the best predictive performances among patients with early-stage CKD who progressed within 3 and 5 years and among patients with advanced-stage CKD who progressed within 1 and 3 years. Important features identified for predicting progression from early- and advanced-stage CKD were urine creatinine and serum creatinine levels, respectively. The RF classifier demonstrated the optimal performance, with an area under the receiver operating characteristic curve values of 0.96 for predicting progression within 5 years in patients with early-stage CKD and 0.97 for predicting progression within 1 year in patients with advanced-stage CKD. The proposed method resulted in the optimal prediction of CKD progression, especially within 1 year of advanced-stage CKD. These results will be useful for predicting prognosis among patients with CKD.

APOBEC-mediated mutagenesis is a favorable predictor of prognosis and immunotherapy for bladder cancer patients: evidence from pan-cancer analysis and multiple databases.

Background: The APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) family-mediated mutagenesis is widespread in human cancers. However, our knowledge of the biological feature and clinical relevance of APOBECs and APOBEC mutagenesis in cancers remains limited. Methods: In this study, with a series of bioinformatic and statistical approaches, we performed a comprehensive analysis of multiple levels of data, including whole-exome sequencing (WES) and targeted next-generation sequencing (NGS), transcriptome (bulk RNA-seq and single-cell RNA-seq), immune signatures and immune checkpoint blockade (ICB) potential, patient survival and drug sensitivity, to reveal the distribution characteristics and clinical significance of APOBECs and APOBEC mutagenesis in pan-cancer especially bladder cancer (BLCA). Results: APOBEC mutagenesis dominates in the mutational patterns of BLCA. A higher enrichment score of APOBEC mutagenesis correlates with favorable prognosis, immune activation and potential ICB response in BLCA patients. APOBEC3A and 3B play a significant role in the malignant progression and cell differentiation within the tumor microenvironment. Furthermore, using machine learning approaches, a prognostic APOBEC mutagenesis-related model was established and validated in different BLCA cohorts. Conclusions: Our study illustrates the characterization of APOBECs and APOBEC mutagenesis in multiple cancer types and highlights its potential value as a promising biomarker for prognosis and immunotherapy in BLCA.

Management of Combined Therapy (Ceritinib, A. cinnamomea, G. lucidum, and Photobiomodulation) in Advanced Non-Small-Cell Lung Cancer: A Case Report.

The 5-year survival rate of non-small-cell lung cancer (NSCLC) is still low (<21%) despite recent improvements. Since conventional therapies have a lot of side effects, combined therapy is strongly recommended. Here, we report a patient with advanced NSCLC who received combined therapy, including ceritinib, photobiomodulation (PBM), ACGL (Antrodia cinnamomea (A. cinnamomea), and Ganoderma lucidum (G. lucidum)). Based on combined therapy, suitable doses of A. cinnamomea, G. lucidum, and PBM are important for tumor inhibition. This case report presents clinical evidence on the efficacy of combined therapy in advanced NSCLC patients, including computed tomography (CT) scan, magnetic resonance imaging (MRI), carcinoembryonic antigen (CEA), and blood tests. The effective inhibition of human lung adenocarcinoma cells is demonstrated. Our case highlights important considerations for PBM and ACGL applications in NSCLC patients, the side effects of ceritinib, and long-term health maintenance.

Strengthening the GABAergic System Through Neurofeedback Training Suppresses Implicit Motor Learning.

Gamma-aminobutyric acid (GABA) activity within the primary motor cortex (M1) is essential for motor learning in cortical plasticity, and a recent study has suggested that real-time neurofeedback training (NFT) can self-regulate GABA activity. Therefore, this study aimed to investigate the effect of GABA activity strengthening via NFT on subsequent motor learning. Thirty-six healthy participants were randomly assigned to either an NFT group or control group, which received sham feedback. GABA activity was assessed for short intracortical inhibition (SICI) within the right M1 using paired-pulse transcranial magnetic stimulation. During the NFT intervention period, the participants tried to modulate the size of a circle, which was altered according to the degree of SICI in the NFT group. However, the size was altered independently of the degree of SICI in the control group. We measured the reaction time before, after (online learning), and 24 h after (offline learning) the finger-tapping task. Results showed the strengthening of GABA activity induced by the NFT intervention, and the suppression of the online but not the offline learning. These findings suggest that prior GABA activity modulation may affect online motor learning.

The changes on anesthetic practice for non-intubated bronchoscopic interventions during Covid-19 pandemic.

Bronchoscopic interventions (BIs) and airway management for bronchoscopy are exceptionally high-risk procedures not only for anesthesiologists, pulmonologists, but also for nursing staff because they expose nurses to COVID-19-containing droplets. However, perioperative changes can be made to the anesthetic management for nonintubated BIs to minimize the spread of COVID-19.