Advanced metastatic cancer poses utmost clinical challenges and may present molecular and cellular features distinct from an early-stage cancer. Herein, we present single-cell transcriptome profiling ...of metastatic lung adenocarcinoma, the most prevalent histological lung cancer type diagnosed at stage IV in over 40% of all cases. From 208,506 cells populating the normal tissues or early to metastatic stage cancer in 44 patients, we identify a cancer cell subtype deviating from the normal differentiation trajectory and dominating the metastatic stage. In all stages, the stromal and immune cell dynamics reveal ontological and functional changes that create a pro-tumoral and immunosuppressive microenvironment. Normal resident myeloid cell populations are gradually replaced with monocyte-derived macrophages and dendritic cells, along with T-cell exhaustion. This extensive single-cell analysis enhances our understanding of molecular and cellular dynamics in metastatic lung cancer and reveals potential diagnostic and therapeutic targets in cancer-microenvironment interactions.
Propiconazole (PRO) is a triazole fungicide that is frequently detected in the water. In this study, we investigated the kinetics and degradation mechanism of PRO during the UV photolysis and UV/H2O2 ...processes. PRO was removed by the pseudo-first-order kinetics in both processes. The removal of PRO was enhanced by increasing H2O2 concentration in the UV/H2O2 process. The highest removal under neutral conditions, and lower removal of PRO were observed in acidic and alkaline pHs in the UV/H2O2 process. The presence of natural water ingredients such as Cl−, NO3−, humic acid acted as radical scavengers, but HCO3− ion acted as both radical promoter and scavenger in the UV/H2O2 process. The transformation products (TPs) of PRO during both processes were identified using LC-QTOF/MS. Four TPs (M+H+ = 238, 256, 306, and 324) were identified during UV photolysis, and six TPs (M+H+ = 238, 256, 306, 324, 356, and 358) were identified in the UV/H2O2 process. Among the identified TPs, TP with M+H+ values of 356 and 358 were newly identified in the UV/H2O2 process. In addition, ionic byproducts, such as Cl−, NO3−, formate (HCOO−), and acetate (CH3COO−), were newly identified, indicating that significant mineralization was achieved in the UV/H2O2 process. Based on the identified TPs and ionic byproducts, the degradation mechanisms of PRO during two processes were proposed. The major reactions in both processes were ring cleavage and cyclization, and hydroxylation by OH radicals. The Microtox test with Vibrio fischeri showed that, while the toxicity of the reaction solution increased first, then gradually decreased during UV photolysis, the UV/H2O2 process initially increased toxicity at 10 min due to the production of TPs, but toxicity was completely removed as the reaction progressed. The results obtained in this study imply that the UV/H2O2 process is an effective treatment for eliminating PRO, its TPs, and the resulting toxicity in water.
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•Degradation of propiconazole (PRO) in UV photolysis and UV/H2O2 were examined.•The water components mostly acted as radical scavengers in the UV/H2O2 reaction.•Six transformation products (TPs) of PRO during both processes were identified.•Ionic byproducts as mineralization were identified in the UV/H2O2 process.•The degradation mechanisms of PRO during two processes were proposed.
Background
The safety of immune‐checkpoint inhibitors (ICIs) has not been thoroughly investigated in non–small cell lung cancer (NSCLC) patients with chronic hepatitis B (CHB) or occult hepatitis B ...infection (OBI). The authors analyzed the incidence of hepatitis B virus (HBV) reactivation, immune‐related hepatitis and jaundice in NSCLC patients in a real‐world setting.
Methods
A total of 1277 NSCLC patients treated with ICIs were analyzed. Among them, 52 patients were hepatitis B surface antigen (HBsAg) (+) (group A, CHB), 759 patients were HBsAg (–)/hepatitis B core antibody immunoglobulin G (anti‐HBc IgG) (+) (group B, OBI), and 466 patients were HBsAg (–)/anti‐HBc IgG (–) (group C). Among the 52 patients with CHB, 38 (73.1%) were receiving antiviral therapy. The primary end point was HBV reactivation, immune‐related hepatitis, and jaundice. The secondary end points included other immune‐related adverse events and efficacy.
Results
HBV reactivation was observed in two patients (0.2%) who were both in group A (CHB). Among CHB patients who were not receiving antiviral therapy, HBV reactivation was observed in 14.3% (2 of 14 patients). The incidences of immune‐related hepatitis and jaundice were comparable among the three groups. The incidence of ≥grade 3 other immune‐related adverse events and efficacy were all comparable among the three groups (p > .05 for all comparisons).
Conclusions
In this large, real‐world cohort study, the safety and efficacy of ICIs were comparable in patients with CHB and OBI. HBV reactivation was observed in patients with CHB without antiviral therapy indicating antiviral prophylaxis should be required for them. For patients with OBI, the risk of HBV reactivation was minimal.
Hepatitis B virus (HBV) reactivation was observed in patients with chronic hepatitis B without antiviral therapy indicating antiviral prophylaxis should be required for them. For patients with occult hepatitis B infection, the risk of HBV reactivation was minimal.
Background:The predictive role of the vasoactive-inotropic score (VIS) for clinical outcomes after venoarterial extracorporeal membrane oxygenation (VA-ECMO) in patients with cardiogenic shock is not ...well known. This study investigated the predictive value of VIS on in-hospital outcomes and the determination of optimal timing for the initiation of VA-ECMO.Methods and Results:Overall, 160 patients with cardiogenic shock requiring VA-ECMO who were treated between December 2012 and August 2018 were analyzed. The in-hospital outcomes according to VIS were compared. Pre-ECMO VIS had an area under the receiver-operating characteristic curve (AUC) of 0.60 (P=0.03) for the prediction of in-hospital death. When the patients were divided into the high (≥32) and low (<32) VIS groups, the high VIS group had a higher rate of in-hospital death (P=0.002) and a lower rate of ECMO weaning (P=0.004). The difference in in-hospital death according to VIS was significant only in patients with a cardiogenic shock of non-ischemic etiology (P=0.01). Extracorporeal cardiopulmonary resuscitation (hazard ratio HR, 1.99), age (HR, 1.02), pre-ECMO lactate (HR, 1.06), and VIS ≥32 (HR, 2.46) were independently predictive of in-hospital death.Conclusions:Among patients with cardiogenic shock requiring VA-ECMO, the initiation of VA-ECMO before reaching high VIS (≥32) showed better in-hospital outcomes, suggesting that VIS may be a potential marker for determining the initiation of hemodynamic support with VA-ECMO.
Three different UV-LED wavelengths (265, 310, and 365 nm) were used in the UV-LED/chlorine reaction to investigate the degradation mechanism of iopromide (IPM) at different wavelengths, a ...representative iodinated contrast media compound. The degradation rate (k′IPM) increased from pH 6–8 at 265 nm, but, decreased as the pH increased up to 9 at 310 nm and 365 nm. Radical scavenging experiments showed that reactive chlorine species (RCS) are the dominant radical species at all wavelengths, but a higher contribution of OH• was observed at lower pH and longer wavelengths. The contribution of RCS decreased but the contribution of OH• increased as the wavelength increased. Among RCS, the largest contribution was found to be ClO•. Total nine transformation products (TPs) were identified by LC-QTOF-MS during the UV-LED/chlorine reaction at 265 nm. Based on the identified TPs and their time profiles, we proposed a degradation pathway of IPM during UV-LED/chlorine reaction. The Microtox test using V. fischeri showed that no significant increase in toxicity was observed at all wavelengths. The synergistic effect of UV-LED and chlorine was greater at a higher wavelength by the electrical efficiency per order (EEO) calculation.
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•Effects of wavelength and pH were examined in UV-LED/chlorine reaction of iopromide.•Reactive chlorine species (RCS), especially ClO radical, are the dominant radical.•As wavelength increased, the contribution of the RCS and OH radical decreased.•Nine transformation products were identified, and three TPs were newly identified.•No significant increase in toxicity of iopromide treated water was observed after the reaction.
Organisms must be able to respond to low oxygen in a number of homeostatic and pathological contexts. Regulation of hypoxic responses via the hypoxia-inducible factor (HIF) is well established, but ...evidence indicates that other, HIF-independent mechanisms are also involved. Here, we report a hypoxic response that depends on the accumulation of lactate, a metabolite whose production increases in hypoxic conditions. We find that the NDRG3 protein is degraded in a PHD2/VHL-dependent manner in normoxia but is protected from destruction by binding to lactate that accumulates under hypoxia. The stabilized NDRG3 protein binds c-Raf to mediate hypoxia-induced activation of Raf-ERK pathway, promoting angiogenesis and cell growth. Inhibiting cellular lactate production abolishes the NDRG3-mediated hypoxia responses. Our study, therefore, elucidates the molecular basis for lactate-induced hypoxia signaling, which can be exploited for the development of therapies targeting hypoxia-induced diseases.
Tonsil-derived mesenchymal stem cells (TMSCs) showed therapeutic effects on acute and chronic murine colitis models, owing to their immunomodulatory properties; therefore, we evaluated enhanced ...therapeutic effects of TMSCs on a murine colitis model using three-dimensional (3D) culture method. The expression of angiogenic factors, VEGF, and anti-inflammatory cytokines, IL-10, TSG-6, TGF-β, and IDO-1, was significantly higher in the 3D-TMSC-treated group than in the 2D-TMSC-treated group (P < 0.05). At days 18 and 30 after inducing chronic colitis, disease activity index scores were estimated to be significantly lower in the 3D-TMSC-treated group than in the colitis control (P < 0.001 and P < 0.001, respectively) and 2D-TMSC-treated groups (P = 0.022 and P = 0.004, respectively). Body weight loss was significantly lower in the 3D-TMSC-treated group than in the colitis control (P < 0.001) and 2D-TMSC-treated groups (P = 0.005). Colon length shortening was significantly recovered in the 3D-TMSC-treated group compared to that in the 2D-TMSC-treated group (P = 0.001). Histological scoring index was significantly lower in the 3D-TMSC-treated group than in the 2D-TMSC-treated group (P = 0.002). These results indicate that 3D-cultured TMSCs showed considerably higher therapeutic effects in a chronic murine colitis model than those of 2D-cultured TMSCs via increased anti-inflammatory cytokine expression.
Crohn's disease (CD) is an intractable inflammatory bowel disease (IBD) of unknown cause. Recent meta-analysis of the genome-wide association studies (GWAS) and Immunochip data identified 163 ...susceptibility loci to IBD in Caucasians, however there are limited studies in other populations.
We performed a GWAS and two validation studies in the Korean population comprising a total of 2311 patients with CD and 2442 controls.
We confirmed four previously reported loci: TNFSF15, IL23R, the major histocompatibility complex region, and the RNASET2-FGFR1OP-CCR6 region. We identified three new susceptibility loci at genome-wide significance: rs6856616 at 4p14 (OR=1.43, combined p=3.60×10(-14)), rs11195128 at 10q25 (OR=1.42, combined p=1.55×10(-10)) and rs11235667 at 11q13 (OR=1.46, combined p=7.15×10(-9)), implicating ATG16L2 and/or FCHSD2 as novel susceptibility genes for CD. Further analysis of the 11q13 locus revealed a non-synonymous single nucleotide polymorphism (SNP) (R220W/rs11235604) in the evolutionarily conserved region of ATG16L2 with stronger association (OR=1.61, combined p=2.44×10(-12)) than rs11235667, suggesting ATG16L2 as a novel susceptibility gene for CD and rs11235604 to be a potential causal variant of the association. Two of the three SNPs (rs6856616 (p=0.00024) and rs11195128 (p=5.32×10(-5))) showed consistent patterns of association in the International IBD Genetics Consortium dataset. Together, the novel and replicated loci accounted for 5.31% of the total genetic variance for CD risk in Koreans.
Our study provides new biological insight to CD and supports the complementary value of genetic studies in different populations.
Background & Aims
Tamoxifen is associated with an increased risk of developing fatty liver. The aim of this systematic review and meta‐analysis was to evaluate the prevalence and incidence of fatty ...liver developed after tamoxifen treatment in breast cancer patients.
Methods
A systematic search of PubMed (Medline), EMBASE, OVID Medline, the Cochrane Library and other databases was performed for this review. The s obtained from the search were reviewed by two investigators who chose manuscripts for full‐text review. The event rates were calculated with a random‐effects model and quality‐effects model.
Results
The search yielded 165 references. Of these, 24 were included in the quantitative summary. We analysed the data of a total of 6,962 patients treated with tamoxifen and 975 patients not treated with tamoxifen. The prevalence of fatty liver among patients with breast cancer taking tamoxifen was 40.25 per 100 patients and the incidence rate was 12.37 per 100 person‐years. The incidence of fatty liver was much higher in the tamoxifen group than in the control group incidence rate ratio: 3.12, 95% CI (confidence interval): 2.05‐4.75, I2 = 61%, regardless of region. The main risk factors were body mass index (BMI) hazard ratio (HR): 1.15, 95% CI: 1.09‐1.22 and hypercholesterolaemia (HR: 1.01, 95% CI: 1.00‐1.02).
Conclusion
The use of tamoxifen was associated with increased risks in the incidence and prevalence of fatty liver, especially in patients with high BMI and hypercholesterolaemia.
Background and Aims Perforation is the adverse event of greatest concern during colorectal endoscopic submucosal dissection (ESD). Accurate risk prediction of perforation may enable prevention ...strategies and selection of the most efficient therapeutic option. This study aimed to develop and validate a risk prediction model for ESD-induced perforation. Methods A multicenter cross-sectional study was performed on 2046 patients who underwent colorectal ESD at 9 Korean ESD Study Group–affiliated hospitals. The enrolled patients were randomly divided into either a derivation set or a validation set. In the derivation set, a prediction score was constructed to assess the risk of perforation using preoperative and procedural-related predictors selected via logistic regression. Discrimination and calibration of the prediction model was assessed using the validation set. Results An ESD-induced perforation occurred in 135 patients (6.6%). In the derivation set, multivariate logistic regression identified endoscopist experience (≥50 ESDs: odds ratio OR = 0.59; 95% confidence interval CI, 0.35-1.00), tumor size (+1-cm increments: OR = 1.39; 95% CI, 1.19-1.62), colonic location (OR = 2.20; 95% CI, 1.24-3.89), and submucosal fibrosis (OR = 2.00; 95% CI, 1.04-3.87) as predictive factors (C-statistic = 0.678; 95% CI, 0.617-0.739). In the validation set, the model showed good discrimination (C-statistic = 0.675; 95% CI, 0.615-0.735) and calibration ( P = .635). When a simplified weighted scoring system based on the OR was used, risk of perforation ranged from 4.1% (95% CI, 2.8%-5.9%) in the low-risk group (score ≤4) to 11.6% (95% CI, 8.5%-15.6%) in the high-risk group (score >4). Conclusions This study developed and internally validated a score consisting of simple clinical factors to estimate the risk of colorectal ESD-induced perforation. This score can be used to identify patients at high risk before colorectal ESD.
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