Isolicoflavonol ameliorates acute liver injury via inhibiting NLRP3 inflammasome activation through boosting Nrf2 signaling in vitro and in vivo.

BACKGROUND: NOD like receptor pyrin domain containing 3 (NLRP3) inflammasome is involved in innate immunity, and related to liver injury. However, no inflammasome inhibitors are clinically available until now. Our previous research suggests that isolicoflavonol (ILF), isolated from Macaranga indica, is a potent NLRP3 inflammasome inhibitor, but its mechanism is unclear. METHODS: Fluorescent imaging and Western blot assay were used to ascertain the effects of ILF on pyroptosis and NLRP3 inflammasome activation in macrophages. Next, Nrf2 signal pathway, its downstream gene transcription and expression were further investigated. ML385, a Nrf2 inhibitor, was used to verify whether ILF targets Nrf2 signaling. A carbon tetrachloride induced liver injury model was introduced to evaluate the liver protection activity of ILF in mice. RESULTS: This work revealed that ILF inhibited macrophage LDH release and IL-1ß secretion in a dose-dependent manner. ILF had no significant cytotoxic effect on macrophage, it reduced pyroptosis and Gasdermin D N-terminal fragment formation. Moreover, ILF inhibited IL-1ß maturation and Caspase-1 cleavage, but did not affect NLRP3, pro-Caspase-1, pro-IL-1ß and ASC expression. ILF decreased ASC speck rate and reduced ASC oligomer formation. ILF decreased aggregated JC-1 formation restoring mitochondria membrane potential. In addition, ILF increased Nrf2 expression, extended Nrf2 lifespan and upregulated Nrf2 signaling pathway in macrophages whether the NLRP3 inflammasome was activated or not. Besides, ILF increased Nrf2 nuclear translocation, maintained a high proportion of Nrf2 in the nucleus, and upregulated ARE-related gene transcription and expression. Furthermore, Nrf2 signal inhibition attenuated compound ILF-mediated inhibition of pyroptosis, inflammasome activation and upregulation of Nrf2 signaling. ILF in a liver injury mouse model inhibited NLRP3 inflammasome activation and enhanced Nrf2 signaling. CONCLUSION: Our study verified that ILF ameliorates liver injury via inhibiting NLRP3 inflammasome activation through boosting Nrf2 signaling, and highlighted that ILF is a potent anti-inflammatory drug for inflammasome-related liver diseases.

Characterization of HPV6/11-reactive T-cell subsets in papillomas of patients with juvenile-onset recurrent respiratory papillomatosis and identification of HPV11 E7-specific candidate TCR clonotypes.

Juvenile-onset recurrent respiratory papillomatosis (JORRP) is caused by persistent infection of epithelial cells by low-risk human papillomavirus (HPV) types 6 and 11. While multiple infiltrated immune cells have been reported to mediate disease progress, knowledge of HPV-reactive T-cell subsets in papillomas remains elusive. Through single-cell RNA sequencing and RNA microarray, we found that CD8+ tissue-resident memory T (CD8+ TRM) cells with strong interferon-gamma (IFN-γ) production expanded, and were negatively correlated to the disease severity in the frequency of surgery. These IFN-γ+ CD8+ memory T cells were readily activated and expanded in vitro by autologous dendritic cells loaded with HPV11 E7 peptide pool. Moreover, T cell receptor (TCR) clonal expansion was observed in JORRP papilloma tissues, indicating a biased TCR repertoire toward HPV-specific recognition. Finally, we identified and characterized HPV11 E7-specific candidate TCR clonotypes from IFN-γ+ CD8+ memory T cells, suggesting their potential application in TCR-engineered T cells (TCR-T) therapy for HPV11-related diseases. Our findings provided insights into the specific local immune response to HPV6/11 infection and highlighted the importance of IFN-γ+ CD8+ TRM cells in anti-HPV6/11 T-cell immunity.IMPORTANCEThe persistent recurrence of human papillomavirus (HPV) 6/11 infection in papillomas underscores the failure of local immune responses in patients with juvenile-onset recurrent respiratory papillomatosis (JORRP). Our previous study demonstrated that T cells constitute the predominant immune cell population in JORRP papilloma tissues. Understanding the T-cell-mediated immune responses within JORRP papilloma tissues is crucial for disease control. In the present study, we characterized CD8+ tissue-resident memory T (CD8+ TRM) cells as the primary T-cell subset responsible for local anti-HPV6/11 immunity. Moreover, we identified two HPV11 E7-specific candidate T cell receptor (TCR) clonotypes out of IFN-γ+ CD8+ memory T cells. Overall, our findings provided insights into the local immune responses to HPV6/11 infection and offered information for developing more effective immunotherapeutic strategies against JORRP.

KLHDC8A Regulates M1/M2 Macrophage Polarization Through the PD-1/STAT3 Pathway to Promote Papillary Thyroid Cancer Development.

BACKGROUND: Papillary thyroid cancer (PTC) is one of the most frequent endocrine malignancies. Kelch domain containing 8A (KLHDC8A) is reported as an epigenetically driven oncogene, but the role of KLHDC8A in PTC is still unclear. This study aimed to explore the function of KLHDC8A in PTC progression. METHODS: KLHDC8A expression was analyzed by the Gene Expression Profiling Interactive Analysis (GEPIA) website, quantitative real-time PCR (qRT-PCR), and western blot. The viability of PTC cells (TPC-1 and BCPAP) was assessed by cell counting kit-8 (CCK-8) kit. A transwell assay was carried out to evaluate the invasion and migration of PTC cells. Macrophage polarization-associated markers were determined by qRT-PCR and western blot. Mice tumor xenograft models were established to analyze the role of KLHDC8A in vivo. Pathway-related proteins (programmed cell death protein 1 (PD-1) and signal transducer and activator of transcription 3 (STAT3)) were determined by western blot. RESULTS: GEPIA demonstrated that KLHDC8A was highly expressed in PTC (p < 0.05). Knockdown of KLHDC8A hindered cell viability, invasion, and migration of PTC cells (p < 0.0001). Additionally, KLHDC8A knockdown inhibited M2 polarization while promoting M1 polarization (p < 0.0001). Meanwhile, KLHDC8A silencing inhibited tumor growth in mice xenografted models (p < 0.0001). Moreover, the PD-1/STAT3 pathway was suppressed by KLHDC8A silencing (p < 0.01), and the STAT3 activator (colivelin) attenuated the inhibitory effects of KLHDC8A silencing on PTC progression (p < 0.01). CONCLUSIONS: Through in vivo and in vitro experiments, KLHDC8A silencing could restrain PTC cell viability, migration, and invasion, inhibit tumor growth, and promote M1 polarization via the PD-1/STAT3 axis, providing a new therapeutic idea for PTC clinical treatment.

Very severe aplastic anemia in a child with pulmonary mucormycosis: a case report.

Aplastic anemia (AA), is a rare but potentially life-threatening disease characterized by pancytopenia and a hypocellular bone marrow. Pulmonary mucormycosis (PM) is a rare but life-threatening fungal infection observed in immunocompromised patients, particularly those with neutropenia and those using corticosteroids, with a high mortality rate from 40 to 80%. However, PM diagnosis and treatment remain challenging. This study reports a case of very severe aplastic anemia (VSAA) in a male child with PM. The innovation of this article lies in the following aspects: the patient exhibited typical clinical manifestations, the reverse halo sign (RHS) on chest computed tomography (CT), and a positive metagenomic next-generation sequencing (mNGS) analysis; despite aggressive anti-infective treatment and left lower lobectomy, he experienced a poor clinical outcome. Reflecting on cases with poor prognosis can indeed offer valuable insights and opportunities for learning. This study underlines the diagnostic challenges in mucormycosis, which should be considered in persistent fever that is unresponsive to standard antibiotic and antifungal therapies, and conduct a comprehensive examination to achieve early detection, diagnosis and treatment. It was concluded that, in addition to antifungal treatment, early surgery is essential for treating mucormycosis.

An attachment glycoprotein nanoparticle elicits broadly neutralizing antibodies and protects against lethal Nipah virus infection.

Nipah virus (NiV) is a zoonotic emergent paramyxovirus that can cause severe encephalitis and respiratory infections in humans, with a high fatality rate ranging from 40% to 75%. Currently, there are no approved human vaccines or antiviral drugs against NiV. Here, we designed a ferritin-based self-assembling nanoparticle displaying the NiV G head domain on the surface (NiV G-ferritin) and assessed immune responses elicited by the soluble NiV G head domain (NiV sG) or NiV G-ferritin. Immunization with NiV G-ferritin or NiV sG conferred complete protection against lethal NiV challenge without detection of viral RNA in Syrian golden hamsters. Compared to NiV sG, NiV G-ferritin induced significantly faster, broader, and higher serum neutralizing responses against three pathogenic henipaviruses (NiV-Malaysia, NiV-Bangladesh, and Hendra virus). Moreover, NiV G-ferritin induced a durable neutralizing immunity in mice as antisera potently inhibited NiV infection even after six months of the third immunization. Additionally, we isolated a panel of 27 NiV G-binding monoclonal antibodies (mAbs) from NiV G-ferritin immunized mice and found that these mAbs targeted four distinct antigenic sites on NiV G head domain with two sites that have not been defined previously. Notably, 25 isolated mAbs have potent neutralizing activity with 50% inhibitory concentrations less than 10 ng/mL against NiV pseudovirus. Collectively, these findings provide new insights into the immunogenicity of NiV G protein and reveal that NiV G-ferritin is a safe and highly effective vaccine candidate against Nipah virus infection.

Evolutionary trajectory and characteristics of Mpox virus in 2023 based on a large-scale genomic surveillance in Shenzhen, China.

The global epidemic of Mpox virus (MPXV) continues, and a local outbreak has occurred in Shenzhen city since June 2023. Herein, the evolutionary trajectory and characteristics of MPXV in 2023 were analyzed using 92 MPXV sequences from the Shenzhen outbreak and the available genomes from GISAID and GenBank databases. Phylogenetic tracing of the 92 MPXVs suggests that MPXVs in Shenzhen may have multiple sources of importation, and two main transmission chains have been established. The combination of phylogenetic relationships, epidemiological features, and mutation characteristics supports the emergence of a new lineage C.1.1. Together with the B.1 lineage diverging from the A.1 lineage, C.1.1 lineage diverging from the C.1 lineage may serve as another significant evolutionary events of MPXV. Moreover, increasing apolipoprotein B mRNA-editing catalytic polypeptide-like 3 (APOBEC3) related mutations, higher rate of missense mutations, and less mutations in the non-coding regions have been shown during MPXV evolution. Host regulation proteins of MPXV have accumulated considerable amino acid mutations since the B.1 lineage, and a lineage-defining APOBEC3-related mutation that disrupts the N2L gene encoding a viral innate immune modulator has been identified in the C.1.1 lineage. In summary, our study provides compelling evidence for the ongoing evolution of MPXV with specific features.

Simultaneous nitrification and denitrification in a hybrid activated sludge-membrane aerated biofilm reactor (H-MABR) for nitrogen removal from low COD/N interflow: A pilot-scale study.

There are a large number of simple landfills in hilly areas, and the results of previous studies have shown that pollutants in landfills can spread via interflow and cause surface source pollution. The hybrid activated sludge-membrane aerated bioreactor (H-MABR) developed in a previous study can be used for the treatment of interflow with a low chemical oxygen demand (COD)/total nitrogen (TN) ratio, and it has been shown to be effective in laboratory simulations. To investigate the effectiveness of the H-MABR in treating interflow around landfills in real-world applications, an in-situ pilot-scale evaluation of the effectiveness of H-MABR operation was conducted at a landfill. The results indicated that the removal efficiencies of COD, TN, and ammonia nitrogen in interflow by H-MABR were 87.1 ± 6.0%, 80.9 ± 7.9%, and 97.9 ± 1.4%, respectively. The removal rate of TN reached 148.6-205.6 g-N/m3·d. The concentration of each pollutant in the effluent was in accordance with China's "Standard for pollution control on the landfill site of municipal solid waste (GB16889-2008)," wherein the COD, TN, and ammonia nitrogen of effluent should be less than 100 mg/L, 40 mg/L, and 25 mg/L, respectively. The results of community composition analysis and PICRUSt analysis based on 16S rRNA gene sequencing showed that there were different dominant functional bacteria between the inner and outer rings, but functional genes involved in the nitrification-denitrification, assimilated nitrate reduction, and dissimilated nitrate reduction pathway were all detected. Furthermore, except for the nitrite oxidation gene narG, the abundance of which did not significantly differ between the inner and outer rings, the abundance of the other functional genes was higher in the outer ring than in the inner ring. An economic evaluation revealed that the operation cost of interflow treatment by the H-MABR was as low as ¥2.78/m3; thus, the H-MABR is a shock-load-resistant and cost-effective technology for interflow treatment.

Spatiotemporal cerebral blood flow dynamics underlies emergence of the limbic-sensorimotor-association cortical gradient in human infancy.

Infant cerebral blood flow (CBF) delivers nutrients and oxygen to fulfill brain energy consumption requirements for the fastest period of postnatal brain development across the lifespan. However, organizing principle of whole-brain CBF dynamics during infancy remains obscure. Leveraging a unique cohort of 100+ infants with high-resolution arterial spin labeled MRI, we found the emergence of the cortical hierarchy revealed by the highest-resolution infant CBF maps available to date. Infant CBF across cortical regions increased in a biphasic pattern with initial rapid and sequentially slower rate, with break-point ages increasing along the limbic-sensorimotor-association cortical gradient. Increases in CBF in sensorimotor cortices were associated with enhanced language and motor skills, and frontoparietal association cortices for cognitive skills. The study discovered emergence of the hierarchical limbic-sensorimotor-association cortical gradient in infancy, and offers standardized reference of infant brain CBF and insight into the physiological basis of cortical specialization and real-world infant developmental functioning.

Two nickel-added poly(polyoxometalate)s built of Keggin-type {Ni6PW9} and Anderson-type NiW6O24via WO4/Sb2O bridges and Ni-O-W linkages with efficient hydrogen evolution activity.

Two Ni-added poly(polyoxometalate)s built of Keggin-type {Ni6PW9} and Anderson-type NiW6O24 units via WO4/Sb2O bridges and Ni-O-W linkages, Na4H8[Ni(enMe)2][(Sb2O)2(NiW6O24)-{Ni12O2(OH)4(enMe)4(H2O)3(WO4)2(B-α-PW9O34)2}2]·39H2O (1) and H9[Ni(en)2(H2O)][Ni0.5(en)2(H2O)][Ni-(enMe)2(H2O)][(Sb2O)2(NiW6O24){Ni12O2(OH)4(en)2(enMe)2(H2O)3(WO4)2}-{Ni12O2(OH)4(en)4(H2O)3(WO4)2}(B-α-PW9O34)4]·45H2O (2), have been hydrothermally synthesized and characterized, in which the {Ni12(WO4)2(PW9)2} subunit was obtained by the synergistic directing effect of 2 lacunary PW9O34 (PW9) fragments and further linked by a central Anderson-type (Sb2O)2(NiW6O24) bridge. Both compounds represent the first example of Ni-added polyoxometalates (POMs) simultaneously based on Keggin-type and Anderson-type POM components. Photocatalytic studies revealed that 2 can work as an efficient heterogeneous catalyst towards a light-driven H2 evolution reaction, achieving a hydrogen evolution rate of as high as 19 214 µmol g-1 h-1 (TON = 1500), which is superior to most of the reported POM-based heterogeneous catalysts.

Bibliometric analysis of the association between periodontal disease and cardiovascular disease.

Purpose: Conduct a bibliometric analysis to review the knowledge structure and research trends regarding the association between periodontal disease and cardiovascular disease (CVD). Methods: The Web of Science Core collection database was searched for retrieving publications related to periodontitis and CVD between January 1, 2003 and December 31, 2022. The VOSviewer, CiteSpace, and R software package "bibliometrix" were employed for the bibliometric analysis. Results: In total, 3447 articles were collected from 98 countries over the past 20 years, with the United States (1,003), Japan (377), and China (321) contributing the most publications. The literature in this field exhibited exponential growth. The University of Helsinki (n = 125, 1.37 %) holds the distinction of being the research institution with the highest number of publications, with a predominant representation from institutions in the United States. Notably, the Journal of Periodontology emerges as the most popular journal in the field, whereas the Journal of Clinical Periodontology takes the lead in terms of citations. These publications originated from 15,236 authors, with Pussinen (n = 40) having the highest number of published papers and Tonetti (n = 976) garnering the most citations. The visualization analysis of keywords identified "oral microbiome," "inflammation," and "porphyromonas gingivalis" as emerging research hotspots in exploring the relationship between periodontitis and CVDs. Conclusion: Through a comprehensive bibliometric analysis, this study posits that periodontitis may heighten the risk of cardiovascular events, offering valuable academic references for scholars investigating the link between periodontitis and CVDs.

Comparative analysis of adverse events among intravesical drugs in bladder cancer: a real-world study on FAERS database.

BACKGROUND: Intravesical therapy is a commonly utilized treatment for non-muscle invasive bladder cancer (NMIBC). This study focuses on summarizing the signals of all intravesical drugs and aims to highlight the comprehensive differences in adverse events (AEs) between these drugs. RESEARCH DESIGN AND METHODS: We conducted pharmacovigilance data analysis based on the real-world big data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. RESULTS: We elucidated all signals compared with the overall FAERS database or other administration routes for Bacillus Calmette-Guerin (BCG), mitomycin, gemcitabine, valrubicin, and epirubicin. Notably, the distribution of reported AEs associated with intravesical therapy exhibited a noticeable inclination toward male patients. Furthermore, all five drugs demonstrated a disproportionate distribution in local AEs, particularly in renal and urinary disorders. Additionally, specific signals and findings were summarized for each individual drug. Finally, we highlighted the AEs that resulted in serious outcomes for each drug. CONCLUSION: We have compiled an overview of the AEs tied to intravesical drugs whilst considering their individual distinctions. These insightful findings serve to enrich our comprehension of the safety profiles and potential risks linked to intravesical therapy.

Exhaled Anesthetic Xenon Regeneration by Gas Separation Using a Metal-Organic Framework with Sorbent-Sorbate Induced-Fit.

Noble gas xenon (Xe) is an excellent anesthetic gas, but its rarity, high cost and constrained production prohibits wide use in medicine. Here, we have developed a closed-circuit anesthetic Xe recovery and reusage process with highly effective CO2-specific adsorbent CUPMOF-5 that is promising to solve the anesthetic Xe supply problem. CUPMOF-5 possesses spacious cage cavities interconnected in four directions by confinement throat apertures of ~3.4 Å, which makes it an ideal molecular sieving of CO2 from Xe, O2, N2 with the benchmark selectivity and high uptake capacity of CO2. In situ single-crystal X-ray diffraction (SCXRD) and computational simulation solidly revealed the vital sieving role of the confined throat and the sorbent-sorbate induced-fit strengthening binding interaction to CO2. CUPMOF-5 can remove 5 % CO2 even from actual moist exhaled anesthetic gases, and achieves the highest Xe recovery rate (99.8 %) so far, as verified by breakthrough experiments. This endows CUPMOF-5 great potential for the on-line CO2 removal and Xe recovery from anesthetic closed-circuits.

Research Trends and Evolution in Radiogenomics (2005-2023): Bibliometric Analysis.

BACKGROUND: Radiogenomics is an emerging technology that integrates genomics and medical image-based radiomics, which is considered a promising approach toward achieving precision medicine. OBJECTIVE: The aim of this study was to quantitatively analyze the research status, dynamic trends, and evolutionary trajectory in the radiogenomics field using bibliometric methods. METHODS: The relevant literature published up to 2023 was retrieved from the Web of Science Core Collection. Excel was used to analyze the annual publication trend. VOSviewer was used for constructing the keywords co-occurrence network and the collaboration networks among countries and institutions. CiteSpace was used for citation keywords burst analysis and visualizing the references timeline. RESULTS: A total of 3237 papers were included and exported in plain-text format. The annual number of publications showed an increasing annual trend. China and the United States have published the most papers in this field, with the highest number of citations in the United States and the highest average number per item in the Netherlands. Keywords burst analysis revealed that several keywords, including "big data," "magnetic resonance spectroscopy," "renal cell carcinoma," "stage," and "temozolomide," experienced a citation burst in recent years. The timeline views demonstrated that the references can be categorized into 8 clusters: lower-grade glioma, lung cancer histology, lung adenocarcinoma, breast cancer, radiation-induced lung injury, epidermal growth factor receptor mutation, late radiotherapy toxicity, and artificial intelligence. CONCLUSIONS: The field of radiogenomics is attracting increasing attention from researchers worldwide, with the United States and the Netherlands being the most influential countries. Exploration of artificial intelligence methods based on big data to predict the response of tumors to various treatment methods represents a hot spot research topic in this field at present.

Clinical utility of plasma Epstein-Barr virus DNA monitoring in pediatric Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis: a Chinese retrospective observational study.

BACKGROUND: Epstein-Barr virus DNA (EBV-DNA) is closely related to the pathogenesis and prognosis of EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH). The quantitative measurement of blood EBV-DNA is widely used in EBV-HLH, but there remains a lack of evidence to guide clinicians. METHODS: A retrospective analysis was conducted on clinical manifestations, laboratory tests, 310 blood EBV-DNA loads, and prognosis of 51 pediatric patients diagnosed with EBV-HLH. Receiver operating characteristic (ROC) curves were utilized to determine the optimal cutoff values of EBV-DNA for predicting mortality and evaluating the active status of EBV-HLH. RESULTS: EBV-positive- lymphoma-HLH had higher initial plasma EBV-DNA load(1.10 × 106copies/ml) compared to the EBV-HLH group (1.98 × 104 copies/ml) (P = 0.006), and experienced recurrently elevated plasma EBV-DNA levels during treatment. The optimal cut-off value of initial plasma EBV-DNA load in predicting mortality was 2.68 × 105 copies/ml, with a sensitivity of 88.57% and a specificity of 56.25%. For determining the active status of HLH, the optimal cutoff value of PBMC EBV-DNA load during treatment was 2.95 × 105 copies/ml, with a sensitivity of 69.14% and a specificity of 64.71%. The cut-off value of plasma EBV-DNA for determining active status was 1.32 × 103 copies/ml, with a sensitivity of 84.34%, and a specificity of 87.67%. Patients with higher PBMC and plasma EBV-DNA at initial and those with repeated elevated plasma EBV-DNA during treatment had worse prognoses (P < 0.05). CONCLUSION: Dynamic monitoring of EBV-DNA is a valuable tool for assessing disease status and predicting the prognosis of EBV-HLH, with plasma EBV-DNA being more effective than PBMC EBV-DNA. Patients with high levels of PBMC and plasma EBV-DNA at initial and those with repeated elevated plasma EBV-DNA during treatment had worse prognoses.

Application of metal artifact reduction algorithm in reducing metal artifacts in post-surgery pediatric low radiation dose spine computed tomography (CT) images.

Background: The commonly used methods for removing metal-induced beam hardening artifacts often rely on the use of high energy photons with either high tube voltage or high energy virtual monoenergetic images in dual-energy computed tomography (CT), the radiation dose was usually relatively high in order to generate adequate signals. This retrospective study is designed to evaluate the application of a metal artifact reduction (MAR) algorithm in reducing pedicle screw metal-caused beam hardening artifacts in post-surgery pediatric low radiation dose spine CT images. Methods: Seventy-seven children (3-15 years) who had undergone a low dose CT with 140 or 100 kV were enrolled. The radiation dose was 1.40 mGy for the 3-8 years old and 2.61 mGy for 9-15 years old children. There were 116 pedicle screws evaluated. The raw data were reconstructed with adaptive statistical iterative reconstruction-V (ASIR-V) at 50% strength, ASIR-V with MAR (AV-MAR), deep learning image reconstruction (DLIR) at high strength and DLIR with MAR (DL-MAR). The image quality concerning pedicle screws was evaluated objectively in terms of the length of beam-hardening artifact (LHA) and artifact index (AI), and subjectively using a 4-point scale (4 points: best, 3 points: acceptable). Results: Both AV-MAR and DL-MAR significantly reduced metal-induced beam hardening artifacts with smaller LHA (15.76±10.12 mm, a reduction of 57.24% and 15.66±10.49 mm, a reduction of 57.40%, respectively), and AI value (62.50±33.51, a reduction of 64.65% and 61.03±32.61, a reduction of 65.01%, respectively) compared to ASIR-V and DLIR (all P<0.01), The subjective image quality scores concerning the screws were 3.37±0.49 and 3.47±0.50 with AV-MAR and DL-MAR, respectively, higher than the respective value of 1.73±0.44 and 1.76±0.43 without MAR (all P<0.01). Conclusions: MAR significantly reduces the low-density artifacts caused by metal screws in post-surgery pediatric low-dose spine CT images, across different tube voltages, radiation dose levels and reconstruction algorithms. Combining DL-MAR further improves the overall image quality under low radiation dose conditions.

Pulmonary Vascular Permeability and Extravascular Lung Water Index in Patients with Liver Cirrhosis and Septic Shock.

Backgrounds and Aims: Patients with cirrhosis are susceptible to sepsis and septic shock. Cirrhotic patients also have increased capillary permeability and are prone to developing volume overload. Patients with septic shock may have an enhanced pulmonary vascular permeability index (PVPI) and extravascular lung water index (EVLWI), both of which are associated with an unfavorable prognosis. It is plausible that pre-existing hyperpermeability may deteriorate when cirrhotic patients develop septic shock. However, it remains unknown whether PVPI and EVLWI can predict the prognosis of cirrhotic patients with septic shock. Pulse Indicator Continuous Cardiac Output (PiCCO) is an established tool to measure PVPI and EVLWI. Therefore, we conducted this retrospective study to investigate the prognostic significance of PVPI and EVLWI in cirrhotic patients with septic shock using PiCCO monitoring. Methods: We included 83 patients with liver cirrhosis and septic shock. EVLW indexed to actual body weight (aEVLWI), EVLW indexed to predicted body weight (pEVLWI), PVPI, disease severity scores, and other biomarkers were analyzed. We collected the PiCCO data on the first 2 days. Results: The overall 28-day mortality was 43.4%. The values of PVPI, aEVLWI, and pEVLWI on day 2 (PVPID2, aEVLWID2, EVLWID2) were significantly higher in non-survivors. The discriminating power of PVPID2 and EVLWID2 to predict 28-day mortality was tested using the area under a ROC curve. The areas under ROC curves (mean ± SEM) were 0.713 ± 0.061 and 0.650 ± 0.063 for PVPID2 and pEVLWID2. In the multivariate analysis, PVPID2, bilirubin, and lactate were independent factors which predicted 28-day mortality. Conclusions: Higher levels of PVPID2 and pEVLWID2 are associated with higher 28-day mortality rates in cirrhotic patients with septic shock. PVPI and pEVLWI may be useful to guide fluid management in this clinical setting.

Antibiotic use attenuates response to immune checkpoint blockade in urothelial carcinoma via inhibiting CD74-MIF/COPA: revealing cross-talk between anti-bacterial immunity and anti-tumor immunity through a tumor marker prognostic study.

BACKGROUND: Immune checkpoint blockade (ICB) has emerged as a promising therapy for both resectable urothelial carcinoma (UC) patients preparing for radical surgery and unresectable UC patients, whereas the objective response rate of ICB remains unsatisfactory due to various factors. Antibiotic (ATB) use can influence intra-tumoral bacteria, which may further reduce ICB efficacy. The study aims to evaluate the effects of ATB use on prognosis and response in UC patients undergoing ICB, and explore potential molecular mechanisms of ATBs and intra-tumoral bacteria impacting UC immune microenvironment. MATERIALS AND METHODS: Pooled analyses, synthesizing evidence from 12 studies and 3496 UC patients with ICB treatment, was conducted via a meta-analysis. In addition, single-cell RNA and single-cell microbiome data were analyzed based on eight UC samples and 63185 single cells. Bulk RNA sequencing and clinical data from a single-arm, multi-center, atezolizumab-treated, phase 2 trial, IMvigor210, were used for validation. The study is registered at PROSPERO (XXX) and at Research Registry (XXX). RESULTS: ATB use exhibited worse overall survival (HR=1.46, 95%CI=[1.20, 1.77], P<0.001, heterogeneity I²=51%) and lower objective response (OR=0.43, 95%CI=[0.27, 0.68], P<0.001, heterogeneity I²=0%) in UC patients receiving ICB. Single-cell transcriptome and single-cell microbiome analyses identified the presence of intra-tumoral bacteria was obviously related to elevated anti-bacterial immune functions; and anti-bacterial immunity was positively correlated to anti-tumor immunity in UC immune microenvironment. Intra-tumoral bacteria could up-regulate CD74-MIF/COPA signaling of immune cells and activation of CD74-MIF/COPA mediated the promotion of T cell anti-tumor function induced by anti-bacterial immune cells. UC patients with higher CD74-MIF/COPA signaling carried better overall survival (HR=1.60, 95%CI=[1.19, 2.15], P=0.002) in IMvigor210 immunotherapy cohort. CONCLUSION: ATB use reduces overall survival and objective response to ICB in UC patients. Anti-bacterial immune cell functions induced by intra-cellular bacteria in UC microenvironment might up-regulate the function of anti-tumor T immune cells via activating CD74-MIF/COPA, whereas ATB could inhibit the above process through killing intra-cellular bacteria and result in poorer clinical benefit of ICB. The use of ATB should be considered carefully during neoadjuvant immunotherapy period for resectable UC patients preparing for radical surgery and during immunotherapy period for unresectable UC patients.