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BACKGROUND: Evidence associating body mass index (BMI) with the prognosis of Staphylococcus aureus sepsis remains scarce. OBJECTIVE: To explore the association between BMI and clinical outcomes in intensive care units patients with Staphylococcus aureus sepsis. METHODS: A retrospective analysis of patients with Staphylococcus aureus sepsis was conducted using the MIMIC-IV database from the Critical Care Medicine Information. Data were collected within the first 24 hours of intensive care units admission. The primary endpoint was 28-day mortality. The association between BMI and 28-day all-cause mortality was assessed using multivariable logistic regression, subgroup analyses, restricted cubic spline curves and Kaplan-Meier survival analysis. RESULTS: The study included 2,295 patients with an average age of 63.5 (16.1) years, 60.2% of whom were male. Multivariate analysis revealed that each 1 kg/m2 increase in BMI was linked to a 2.8% decrease in the risk of 28-day mortality (adjusted OR = 0.972, 95% CI: 0.955-0.990, P = 0.002). Patients in the medium and high BMI categories had significantly lower risks of 28-day mortality compared to those in the low BMI group (OR [95% CI] 0.650 [0.474-0.891]; OR [95% CI] 0.516 [0.378-0.705]; P trend < 0.0001). The RCS model showed a non-linear association between BMI and 28-day mortality (P = 0.014). Kaplan-Meier analysis showed that patients with elevated BMI had lower 28-day mortality (P < 0.0001). Notably, significant interactions between AKI and SOFA with BMI were observed (P<0.05). CONCLUSION: Increased BMI is associated with a reduced risk of 28-day all-cause mortality in patients with Staphylococcus aureus sepsis.
Subject(s)
Body Mass Index , Intensive Care Units , Sepsis , Staphylococcal Infections , Staphylococcus aureus , Humans , Male , Female , Middle Aged , Retrospective Studies , Staphylococcal Infections/mortality , Staphylococcal Infections/microbiology , Aged , Sepsis/mortality , Sepsis/microbiology , Kaplan-Meier Estimate , Prognosis , Hospital Mortality , Critical CareABSTRACT
Chronic obstructive pulmonary disease (COPD) is a common chronic respiratory disease worldwide. Macrophage polarization plays a substantial role in the pathogenesis of COPD. This study is aimed to explore the regulatory mechanism of regulator of telomere elongation 1 (RTEL1) in COPD. COPD model mouse was conducted by cigarette smoke (CS). The pathological features of lung in mice were observed by histological staining. After extracting exosomes, macrophages were co-cultured with fibroblasts-derived exosomes. Then, the effects of RTEL1 and exosomal secreted frizzled-related protein 2 (SFRP2) on macrophage proliferation, inflammation, apoptosis, and M1, M2 macrophage polarization (iNOS and CD206) were evaluated by cell counting kit-8, EdU assay, enzyme-linked immuno sorbent assay, and western blotting, respectively. CS-induced COPD model mouse was successfully constructed. Through in vitro experiments, knockdown of RTEL1 inhibited macrophage proliferation, inflammation (MMP9, IL-1ß and TNF-α), and promoted apoptosis (Bax, cleaved-caspase3, Bcl-2) in CS extract-induced lung fibroblasts. Meanwhile, RTEL1 knockdown promoted M1 and suppressed M2 macrophage polarization in COPD. Additionally, silencing SFRP2 in fibroblasts-derived exosomes reversed the effects of RTEL1 knockdown on proliferation, inflammation, apoptosis, and M1, M2 macrophage polarization. Collectively, down-regulation of RTEL1 improved M1/M2 macrophage polarization by promoting SFRP2 in fibroblasts-derived exosomes to alleviate CS-induced COPD.
ABSTRACT
Chronic obstructive pulmonary disease (COPD) is a common chronic disease characterized by airflow obstruction, which seriously threatens people's health. The COPD mouse model was established with cigarette smoke induction. Hematoxylin-eosin staining and Masson staining were carried out to observe the pathological changes of lung tissues in COPD mice. RTEL1 was silenced in COPD mice, and immunohistochemistry was used to detect RTEL1, ki67 and Caspase-3 expression. The role of RTEL1 in inflammation were evaluated by ELISA, and the impacts of RTEL1 on M1 and M2 macrophage markers (iNOS and CD206) were evaluated by qPCR and western blotting. In COPD model, there was an increase in the number of inflammatory cells, with slightly disorganized cell arrangement, unclear hierarchy, condensed and solidified nuclei, while knockdown of RTEL1 improved the inflammatory infiltration. Moreover, knockdown of RTEL1 reduced ki67-positive cells and increased Caspase-3 positive cells in COPD group. The increased inflammatory factors (IL-1ß, MMP-9, TNF-α, IL-4, IL-6, and IL-23) in COPD were suppressed by knockdown of RTEL1, while iNOS was raised and CD206 was inhibited. In conclusion, knockdown of RTEL1 promoted M1 and inhibited M2 macrophage polarization and inflammation to alleviate COPD.
Subject(s)
Pulmonary Disease, Chronic Obstructive , Humans , Mice , Animals , Pulmonary Disease, Chronic Obstructive/genetics , Pulmonary Disease, Chronic Obstructive/therapy , Pulmonary Disease, Chronic Obstructive/metabolism , Caspase 3/metabolism , Ki-67 Antigen/metabolism , Macrophages/metabolism , Macrophages/pathology , Inflammation/metabolism , DNA Helicases/metabolismABSTRACT
Early blight of tomato caused by Alternaria solani results in significant crop losses. In this study, Bacillus subtilis J3 and Pseudomonas fluorescens J8 were co-cultured as a synthetic microbial community (BCA) for synergistic biocontrol of A. solani, and the inhibition mechanism was investigated. BCA presented an inhibition ration against A. solani at 94.91%, which lowered the disease incidence by 38.26-42.87%; reduced peroxidase, catalase, superoxide dismutase activity of tomatoes by 73.11-90.22%; and promoted the biomass by 66.91-489.21%. With BCA protection, the relative expression of tomato resistance genes (including gPAL2, SWRKY, PR-10, and CHI) in roots and leaves was 12.83-90.70% lower than without protection. BCA also significantly altered the rhizosphere and phyllosphere microbial community. The abundance of potentially beneficial bacteria, including Bacillus, Pseudomonas, Arthrobacter, Lysobacter, and Rhizobium, elevated by 6.58-192.77%. They were negatively correlated with resistance gene expression, indicating their vital involvement in disease control. These results provided essential information on the synergistic biocontrol mechanism of bacteria against pathogens, which could contribute to developing novel biocontrol strategies. KEY POINTS: ⢠Bacillus and Pseudomonas present a synergistic biocontrol effect against A. solani. ⢠Biocontrol prevents pathogen damage and improves tomato growth and systemic resistance. ⢠Beneficial bacteria thrive in the rhizosphere is the key to microbial regulation.
Subject(s)
Bacillus , Pseudomonas fluorescens , Solanum lycopersicum , Pseudomonas fluorescens/physiology , Bacillus subtilis , Pseudomonas , Plant Diseases/prevention & control , Plant Diseases/microbiologyABSTRACT
Aging is accompanied by deterioration in physical condition, and creates high risks of diseases. Stem cell therapy exhibited promising potential in delaying aging. However, the unelucidated therapeutic mechanism limits future clinical application. Herein, to systematically understand the response to stem cell transfusion at the molecular level, we performed quantitative serum proteomic and peptidomics analyses in the 24-month-old aging mice model with or without mesenchymal stem cell (MSC) treatment. As a result, a total of 560 proteins and 2131 endogenous peptides were identified, among which, 6 proteins and 9 endogenous peptides derived from 6 precursor proteins were finally identified as therapeutic biomarkers after MSC transfusion on aging mice both by untargeted label-free quantification and targeted parallel reaction monitoring (PRM) quantification. Amazingly, the biological function of these differential proteins was mainly related to inflammation, which is not only the important hallmark of aging, but also the main cause of inducing aging. The reduction of these inflammatory protein content after MSC treatment further suggests the anti-inflammatory effect of MSC therapy reported elsewhere. Therefore, our study provides new evidence for the anti-inflammatory effect of MSC therapy for anti-aging and offers abundant data to support deeper investigations of the therapeutic mechanism of MSC in delaying aging.
Subject(s)
Mesenchymal Stem Cells , Proteomics , Humans , Mice , Animals , Child, Preschool , Anti-Inflammatory Agents/metabolism , Mesenchymal Stem Cells/metabolism , Biomarkers/metabolism , AgingABSTRACT
This study investigates the radiobiological effects of gold nanoparticles (GNPs) as radiosensitizers for proton beam therapy (PBT). Specifically, we explore the enhanced production of reactive oxygen species (ROS) in GNP-loaded tumor cells irradiated by a 230 MeV proton beam in a spread-out Bragg peak (SOBP) zone obtained by a passive scattering system. Our findings indicate that the radiosensitization enhancement factor is 1.24 at 30% cell survival fraction, 8 days after 6 Gy proton beam irradiation. Since protons deposit the majority of their energy at the SOBP region and interact with GNPs to induce more ejected electrons from the high-Z GNPs, these ejected electrons then react with water molecules to produce excessive ROS that can damage cellular organelles. Laser scanning confocal microscopy reveals the excessive ROS induced inside the GNP-loaded cells immediately after proton irradiation. Furthermore, the damage to cytoskeletons and mitochondrial dysfunction in GNP-loaded cells caused by the induced ROS becomes significantly severe, 48 h after proton irradiation. Our biological evidence suggests that the cytotoxicity of GNP-enhanced ROS production has the potential to increase the tumoricidal efficacy of PBT.
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The quantity and quality of cropland plays an important role in ensuring food security. In order to explore spatiotemporal patterns of the extent to which cropland satisfies people's grain need, we integrate multi-source heterogeneous data to investigate in which era, and in which region, the cultivated land can meet people's food demands. It turns out that in the past 30 years, with the exception of the late 1980s, the amount of cropland could satisfy people's grain needs at the nation scale. However, more than 10 provinces (municipality/autonomous region), mainly located in western China and southeast coastal areas, have been unable to meet the grain needs of local people. We projected the guarantee rate to the late 2020s. Our study concludes that the guarantee rate of cropland is estimated to be higher than 150% in China. Compared to 2019, except Beijing, Tianjin, Liaoning, Jilin, Ningxia, as well as Heilongjiang in the Sustainability scenario, and Shanghai in the Sustainability and the Equality scenarios, the guarantee rate of cultivated land will increase in every province (municipality/autonomous region) in 2030. This study has reference value for the study of China's cultivated land protection system, as well as important significance for China's sustainable development.
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Electrochemical bacteria Shewanella oneidensis MR-4 (MR-4) was used to biologically generate cadmium sulfide (bio-CdS) nanocrystals and construct a self-assembled intimately coupled photocatalysis-biodegradation system (SA-ICPB) to remove cadmium (Cd) and tetracycline hydrochloride (TCH) from wastewater. The characterization using EDS, TEM, XRD, XPS, and UV-vis confirmed the successful CdS bio-synthesis and its visible-light response capacity (520 nm). 98.4% of Cd2+ (2 mM) was removed during bio-CdS generation within 30 min. The electrochemical analysis confirmed the photoelectric response capability of the bio-CdS as well as its photocatalytic efficiency. Under visible light, SA-ICPB entirely eliminated TCH (30 mg/L). In 2 h, 87.2% and 43.0% of TCH were removed separately with and without oxygen. 55.7% more chemical oxygen demand (COD) was removed with oxygen participation, indicating the degradation intermediates elimination by SA-ICPB required oxygen participation. Biodegradation dominated the process under aerobic circumstances. Electron paramagnetic resonance analysis indicated that h+ and ·O2- played a decisive role in photocatalytic degradation. Mass spectrometry analysis proved that TCH was dehydrated, dealkylated, and ring-opened before mineralizing. In conclusion, MR-4 can spontaneously generate SA-ICPB and rapidly-deeply eliminate antibiotics by coupling photocatalytic and microbial degradation. Such an approach was efficient for the deep degradation of persistent organic pollutants with antimicrobial properties.
Subject(s)
Cadmium , Tetracycline , Tetracycline/metabolism , Cadmium/metabolism , Anti-Bacterial Agents/chemistry , Light , Bacteria/metabolism , Oxygen/metabolism , CatalysisABSTRACT
Nanodiamonds (NDs) are emerging with great potential in biomedical applications like biomarking through fluorescence and magnetic resonance imaging (MRI), targeted drug delivery, and cancer therapy. The magnetic and optical properties of NDs could be tuned by selective doping. Therefore, we report multifunctional manganese-incorporated NDs (Mn-NDs) fabricated by Mn ion implantation. The fluorescent properties of Mn-NDs were tuned by inducing the defects by ion implantation and enhancing the residual nitrogen vacancy density achieved by a two-step annealing process. The cytotoxicity of Mn-NDs was investigated using NCTC clone 929 cells, and the results revealed no cytotoxicity effect. Mn-NDs have demonstrated dual mode contrast enhancement for both T 1- and T 2-weighted in vitro MR imaging. Furthermore, Mn-NDs have illustrated a significant increase in longitudinal relaxivity (fivefold) and transversal relaxivity (17-fold) compared to the as-received NDs. Mn-NDs are employed to investigate their ability for in vivo MR imaging by intraperitoneal (ip) injection of Mn-NDs into mice with liver tumors. After 2.5 h of ip injection, the enhancement of contrast in T 1- and T 2-weighted images has been observed via the accumulation of Mn-NDs in liver tumors of mice. Therefore, Mn-NDs have great potential for in vivo imaging by MR imaging in cancer therapy.
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There is considerable potential for integrating transarterial chemoembolization (TACE), programmed death-(ligand)1 (PD-[L]1) inhibitors, and molecular targeted treatments (MTT) in hepatocellular carcinoma (HCC). It is necessary to investigate the therapeutic efficacy and safety of TACE combined with PD-(L)1 inhibitors and MTT in real-world situations. In this nationwide, retrospective, cohort study, 826 HCC patients receiving either TACE plus PD-(L)1 blockades and MTT (combination group, n = 376) or TACE monotherapy (monotherapy group, n = 450) were included from January 2018 to May 2021. The primary endpoint was progression-free survival (PFS) according to modified RECIST. The secondary outcomes included overall survival (OS), objective response rate (ORR), and safety. We performed propensity score matching approaches to reduce bias between two groups. After matching, 228 pairs were included with a predominantly advanced disease population. Median PFS in combination group was 9.5 months (95% confidence interval [CI], 8.4-11.0) versus 8.0 months (95% CI, 6.6-9.5) (adjusted hazard ratio [HR], 0.70, P = 0.002). OS and ORR were also significantly higher in combination group (median OS, 19.2 [16.1-27.3] vs. 15.7 months [13.0-20.2]; adjusted HR, 0.63, P = 0.001; ORR, 60.1% vs. 32.0%; P < 0.001). Grade 3/4 adverse events were observed at a rate of 15.8% and 7.5% in combination and monotherapy groups, respectively. Our results suggest that TACE plus PD-(L)1 blockades and MTT could significantly improve PFS, OS, and ORR versus TACE monotherapy for Chinese patients with predominantly advanced HCC in real-world practice, with an acceptable safety profile.
Subject(s)
Carcinoma, Hepatocellular , Chemoembolization, Therapeutic , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/pathology , Chemoembolization, Therapeutic/adverse effects , Chemoembolization, Therapeutic/methods , Cohort Studies , Liver Neoplasms/pathology , Molecular Targeted Therapy , Retrospective StudiesABSTRACT
Antibiotic residue in husbandry waste has become a serious concern. In this study, contaminated chicken manure composting was conducted to reveal the bioaugmentation effect on tetracyclines residue and antibiotics resistance genes (ARGs). The bioaugmented composting removed most of the antibiotics in 7 days. Under bioaugmentation, 96.88 % of tetracycline and 92.31 % of oxytetracycline were removed, 6.32 % and 20.93 % higher than the control (P < 0.05). The high-temperature period was the most effective phase for eliminating antibiotics. The treatment showed a long high-temperature period (7 days), while no high-temperature period was in control. After composting, the treatment showed 13.87 % higher TN (26.51 g/kg) and 13.42 % higher NO3--N (2.45 g/kg) than control (23.28 and 2.16 g/kg, respectively) but 12.72 % lower C/N, indicating fast decomposition and less nutrient loss. Exogenous microorganisms from bioaugmentation significantly reshaped the microbial community structure and facilitated the enrichment of genera such as Truepera and Fermentimonas, whose abundance increased by 71.10 % and 75.37 % than the control, respectively. Remarkably, ARGs, including tetC, tetG, and tetW, were enhanced by 198.77 %, 846.77 %, and 62.63 % compared with the control, while the integron gene (intl1) was elevated by 700.26 %, indicating horizontal gene transfer of ARGs. Eventually, bioaugmentation was efficient in regulating microbial metabolism, relieving antibiotic stress, and eliminating antibiotics in composting. However, the ability to remove ARGs should be further investigated. Such an approach should be further considered for treating pollutants-influenced organic waste to eliminate environmental concerns.
Subject(s)
Composting , Animals , Manure , Chickens , Tetracyclines , Genes, Bacterial , Anti-Bacterial AgentsABSTRACT
The wetting property of a solid surface has been a hotspot for centuries, and many studies suggest that the hydrophobicity is highly related to the polar components. However, the underlying mechanism of polar moieties on the hydrophobicity remains unclear. Here, we tailor the surface polar moieties of epoxy resin (EP) by ozone modification and assess their wetting properties. Our results show that, for the modified EP with more (60.54%) polar moieties, the polar effect on hydrophobicity cannot be empirically observed. To reveal the underlying mechanism, the absorption parameters, including equilibrium distance, adsorption radius, and effective adsorption sites for water on EP before and after ozone treatment, are calculated on the basis of molecular simulations. After ozone modification, the equilibrium distance (from 1.95 to 1.70 Å), adsorption radius (from 3.80 to 4.50 Å), and effective adsorption sites (from 1 to 2) change slightly and the EP surface remains hydrophobic, although the polar groups significantly increase. Therefore, it is concluded that the wetting properties of solid surfaces are dominated by the equilibrium distance, adsorption radius, and effective adsorption sites for water on solids, and the nonlinear relationship between polar groups and hydrophilicity is clarified.
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High-entropy alloys (HEAs) have recently been applied in the field of heterogeneous catalysis benefiting from vast chemical space. However, huge chemical space also brings extreme challenges for the comprehensive study of HEAs by traditional trial-and-error experiments. Therefore, the machine learning (ML) method is presented to investigate the oxygen reduction reaction (ORR) catalytic activity of millions of reactive sites on HEA surfaces. The well-performed ML model is constructed based on the gradient boosting regression (GBR) algorithm with high accuracy, generalizability, and simplicity. In-depth analysis of the results demonstrates that adsorption energy is a mixture of the individual contributions of coordinated metal atoms near the reactive site. An efficient strategy is proposed to further boost the ORR catalytic activity of promising HEA catalysts by optimizing the HEA surface structure, which recommends a highly efficient HEA catalyst of Ir48Pt74Ru30Rh30Ag74. Our work offers a guide to the rational design and nanostructure synthesis of HEA catalysts.
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BACKGROUND: Coffin-Siris syndrome (CSS) is a rare autosomal dominant disorder characterized by intellectual disability, developmental delay, and characteristic facial features. Few patients with cutaneous phenotype in this rare syndrome have been reported. CASE PRESENTATION: Herein, we describe a 12-year-old Chinese girl diagnosed with CSS, who was referred to our hospital because of intellectual disability and short stature. Prominent characteristics of the cutaneous system were observed: (1) A congenital giant nevus from the left frontal and temporal regions to the entire left scalp; and (2) multiple melanocytic nevi on the face and trunk. Whole exome sequencing revealed a novel heterozygous variant in the ARID1B gene. Recombinant human growth hormone (rhGH) was given for short stature, and resulted in significantly improved height. No enlargement or malignant transformation of nevi occurred within 4 years of follow-up. CONCLUSION: The symptoms in cutaneous system is noteworthy,which may be a neglected phenotype in CSS.The therapeutic response of growth hormone is effective in this patient and no tumor related signs were found.
Subject(s)
Dwarfism , Hand Deformities, Congenital , Micrognathism , Nevus, Pigmented , Abnormalities, Multiple , Child , DNA-Binding Proteins/genetics , Dwarfism/genetics , Face/abnormalities , Female , Hand Deformities, Congenital/diagnosis , Hand Deformities, Congenital/genetics , Humans , Intellectual Disability , Micrognathism/genetics , Neck/abnormalities , Nevus, Pigmented/genetics , Transcription Factors/geneticsABSTRACT
Designing efficient catalysts for hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) is a desirable strategy for overall water splitting and the generation of clean and renewable energies. Herein, the electrocatalytic HER and OER activity of the conductive metal-benzenhexathiolate (M-BHT) frameworks has been evaluated utilizing first-principles calculations. The in-plane π-d conjugation of M-BHT guarantees fast electron transfer during electrocatalytic reactions. Notably, Rh-BHT holds the promise of bifunctional HER/OER activity with the overpotentials of 0.07/0.36 V. Furthermore, the application of strain engineering tailors the adsorption of intermediates and promotes the overall water splitting performance. Rh-BHT with the +1% tensile strain shows the HER/OER overpotential of 0.02/0.37 V. This work not only demonstrates the prospects of conductive metal-organic frameworks in electrocatalysis but also offers new insights into designing efficient catalysts by strain engineering.
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OBJECTIVES: To study the clinical features and fibroblast growth factor receptor 3 (FGFR3) gene mutations of children with achondroplasia (ACH) through an analysis of 17 cases. METHODS: A retrospective analysis was performed on the clinical data and FGFR3 gene detection results of 17 children with ACH who were diagnosed from January 2009 to October 2021. RESULTS: Of the 17 children with ACH, common clinical manifestations included disproportionate short stature (100%, 17/17), macrocephaly (100%, 17/17), trident hand (82%, 14/17), and genu varum (88%, 15/17). The common imaging findings were rhizomelic shortening of the long bones (100%, 17/17) and narrowing of the lumbar intervertebral space (88%, 15/17). Major complications included skeletal dysplasia (100%, 17/17), middle ear dysfunction (82%, 14/17), motor/language developmental delay (88%, 15/17), chronic pain (59%, 10/17), sleep apnea (53%, 9/17), obesity (41%, 7/17), foramen magnum stenosis (35%, 6/17), and hydrocephalus (24%, 4/17). All 17 children (100%) had FGFR3 mutations, among whom 13 had c.1138G>A hotspot mutations of the FGFR3 gene, 2 had c.1138G>C mutations of the FGFR3 gene, and 2 had unreported mutations, with c.1252C>T mutations of the FGFR3 gene in one child and c.445+2_445+5delTAGG mutations of the FGFR3 gene in the other child. CONCLUSIONS: This study identifies the unreported mutation sites of the FGFR3 gene, which extends the gene mutation spectrum of ACH. ACH is a progressive disease requiring lifelong management through multidisciplinary collaboration.
Subject(s)
Achondroplasia , Receptor, Fibroblast Growth Factor, Type 3 , Achondroplasia/diagnosis , Achondroplasia/genetics , Child , Humans , Mutation , Osteochondrodysplasias/genetics , Receptor, Fibroblast Growth Factor, Type 3/genetics , Retrospective StudiesABSTRACT
Anterior gradient 2 (AGR2), a protein disulfide isomerase (PDI), is a multifunctional protein under physiological and pathological conditions. In this study we investigated the roles of AGR2 in regulating cholesterol biogenesis, lipid-lowering efficiency of lovastatin as well as in protection against hypercholesterolemia/statin-induced liver injury. We showed that AGR2 knockout significantly decreased hepatic and serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in mice with whole-body or hepatocyte-specific Agr2-null mutant, compared with the levels in their wild-type littermates fed a normal chow diet (NCD) or high-fat diet (HFD). In contrast, mice with AGR2 overexpression (Agr2/Tg) exhibited an increased cholesterol level. Mechanistic studies revealed that AGR2 affected cholesterol biogenesis via activation of AKT/sterol regulatory element-binding protein-2 (SREBP2), to some extent, in a PDI motif-dependent manner. Moreover, elevated AGR2 led to a significant decrease in the lipid-lowering efficacy of lovastatin (10 mg· kg-1· d-1, ip, for 2 weeks) in mice with hypercholesterolemia (hyperCho), which was validated by results obtained from clinical samples in statin-treated patients. We showed that lovastatin had limited effect on AGR2 expression, but AGR2 was inducible in Agr2/Tg mice fed a HFD. Further investigations demonstrated that drug-induced liver toxicity and inflammatory reactions were alleviated in hypercholesterolemic Agr2/Tg mice, suggesting the dual functions of AGR2 in lipid management and hyperCho/statin-induced liver injury. Importantly, the AGR2-reduced lipid-lowering efficacy of lovastatin was attenuated, at least partially, by co-administration of a sulfhydryl-reactive compound allicin (20 mg· kg-1· d-1, ip, for 2 weeks). These results demonstrate a novel role of AGR2 in cholesterol metabolism, drug resistance and liver protection, suggesting AGR2 as a potential predictor for selection of lipid-lowering drugs in clinic.
Subject(s)
Chemical and Drug Induced Liver Injury, Chronic , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Hypercholesterolemia , Mice , Animals , Lovastatin/pharmacology , Lovastatin/therapeutic use , Lovastatin/metabolism , Hypercholesterolemia/drug therapy , Hydroxymethylglutaryl-CoA Reductase Inhibitors/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Cholesterol, LDL , Liver/metabolismABSTRACT
Resistance to 5-fluorouracil (5-FU) in chemotherapy and recurrence of colorectal tumors is a serious concern that impedes improvements to clinical outcomes. In the present study, we found that conditioned medium (CM) derived from 5-FU-resistant HCT-8/FU cells reduced 5-FU chemosensitivity in HCT-8 colon cancer cells, with corresponding changes to number and morphology of Cajal bodies (CBs) as observable nuclear structures. We found that U2AF homology motif kinase 1 (UHMK1) altered CB disassembly and reassembly and regulated the phosphorylation of coilin, a major component of CBs. This subsequently resulted in a large number of variations in RNA alternative splicing that affected cell survival following 5-FU treatment, induced changes in intracellular phenotype, and transmitted preadaptive signals to adjacent cells in the tumor microenvironment (TME). Our findings suggest that CBs may be useful for indicating drug sensitivity or resistance in tumor cells in response to stress signals. The results also suggest that UHMK1 may be an important factor for maintaining CB structure and morphology by regulating splicing events, especially following cellular exposure to cytotoxic drugs. Video Abstract.
Subject(s)
Coiled Bodies , Colonic Neoplasms , Fluorouracil , Intracellular Signaling Peptides and Proteins , Protein Serine-Threonine Kinases , Antimetabolites, Antineoplastic/pharmacology , Coiled Bodies/drug effects , Coiled Bodies/genetics , Coiled Bodies/metabolism , Fluorouracil/pharmacology , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Nuclear Proteins/metabolism , Phosphorylation/drug effects , Protein Serine-Threonine Kinases/metabolism , Tumor MicroenvironmentABSTRACT
Our previous clinical study achieved complete remission (CR) rates of >90% following chimeric antigen receptor T cells targeting CD19 (CART19) treatment of refractory/relapsed B cell acute lymphoblastic leukemia (r/r B-ALL); however, the influence of the leukemia burden in peripheral blood (PB) blasts remains unclear. Here, we retrospectively analyzed 143 patients treated with CART19 (including 36 patients with PB blasts) to evaluate the effect of peripheral leukemia burden at the time of apheresis. One hundred seventeen patients with high disease burdens achieved 91.5% CR or incomplete count recovery CR and 86.3% minimal residual disease-negative CR, and 26 patients with low disease burdens obtained 96.2% MRD- CR. Collectively, 9 of 36 (25%) patients with PB blasts and 2 of 107 (1.87%) patients without PB blasts did not respond to CART19 therapy. The leukemia burden in PB negatively influenced ex vivo cell characteristics, including the transduction efficiency of CD3+ T cells and their fold expansion, and in vivo cell dynamics, including peak CART19 proportion and absolute count, fold expansion, and persistence duration. Further studies showed that these patients had higher programmed death-1 expression in CART19 products. Our data imply that PB blasts negatively affected CART19 production and the clinical efficacy of CART19 therapy in patients with r/r B-ALL.