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1.
Sci Total Environ ; : 152766, 2022 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-35007603

RESUMO

Integrons are genetic elements that can facilitate rapid spread of antibiotic resistance by insertion and removal of genes. However, knowledge about the diversity and distribution of gene cassettes embedded in class 1 integron is still limited. In this study, we sequenced integron gene cassettes using nanopore sequencing and quantified antibiotic resistance genes (ARGs) and integrase genes in the manured soils and sewages of a bioreactor. The results showed that class 1 integron integrase genes were the most abundant in soils and sewages compared with class 2 and class 3 integrase genes. Long-term manure application exacerbated the enrichment of total ARGs, integrase genes and antibiotic resistance-associated gene cassettes, while antibiotics and heavy metals showed no impact on the overall resistome profile. Sewage treatment could efficiently remove the absolute abundance of integrase genes (~3 orders of magnitude, copies/L) and antibiotic resistance gene cassettes. The resistance gene cassettes mainly carried the ARGs conferring resistance to aminoglycoside and beta-lactams in soils and sewages, some of which were persistent during the sewage treatment. This study underlined that soil and sewage were potential reservoirs for integron-mediated ARGs transfer, indicating that anthropogenic activity played a vital role in the prevalence and diversity of resistance gene cassettes in integrons.

2.
Fitoterapia ; : 105124, 2022 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-35007685

RESUMO

Four new cytochalasans, arbuschalasins A-D (1-4), along with thirteen known analogues (5-17), were isolated from the solid rice medium of endophytic fungus Xylaria arbuscula. Arbuschalasins A-B feature a rare 5/6/6/6 fused ring system while arbuschalasin D was characterized as the first example of natural cytochalasans that possesses a 5/5/11 fused scaffold. The structures of 1-4 were assigned by spectroscopic data, with their absolute structures being determined by electronic circular dichroism (ECD) calculations. All of the isolates were evaluated against the human colorectal adenocarcinoma cell lines (HCT15). Compounds 6 and 7 showed significant inhibitory effects (IC50 values were 13.5 and 13.4 µM, respectively), being more active than those of the positive control, fluorouracil (103.1 µM).

3.
J Hazard Mater ; 426: 128127, 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-34953254

RESUMO

Globally distributed earthworms affect compositions of soil compounds, microbial community structures, as well as antibiotic resistance genes (ARGs). Compared to their surroundings, earthworm gut is a simpler environment which could filter out microbes when soil passes through it. However, little is known about how earthworms affect the dissemination of ARGs in soil, and the understanding of the relationship between microbe-microbe interactions and ARGs is still lacking. Here, we designed a microcosm experiment with earthworm addition, and determined bacterial and fungal community compositions based on amplicon sequencing. We also examined mobile genetic elements (MGEs) and ARGs in earthworm gut and soils using high-throughput qPCR. The results showed significant differences of bacterial, fungal and ARG patterns between gut and soil. Earthworms indirectly impacted the patterns of ARGs in soils by affecting bacterial communities and soil properties, which play key roles in the distribution of ARGs and MGEs. The absolute abundances of MGEs in earthworm gut were significantly lower than those in soils, and earthworms reduce the absolute abundance of MGEs in soils. Earthworms changed the microbial co-occurrence patterns, and reduced bacterial connectivity, which were significantly and positively correlated with MGE abundance. These results highlight the importance of earthworm on the distribution and dissemination of ARGs in soils.

5.
Yonsei Med J ; 63(1): 95-103, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34913289

RESUMO

PURPOSE: Acute respiratory viral infections pose significant morbidity and mortality, making it essential to diagnose respiratory viral infections rapidly. In this study, the diagnostic efficacy of the Luminex xTAG Respiratory Virus Panel (RVP) FAST v2 test was evaluated on respiratory viral infections. MATERIALS AND METHODS: Information was retrieved from electronic databases, including Embase, Web of Science, PubMed, and Cochrane Library, for systematic review. Studies that fulfilled predefined inclusion criteria were included. After the extraction of information, statistical software was utilized for quality evaluation, data analysis, and assessment of publication bias. RESULTS: Eighty groups in fourfold tables from nine articles were included to perform statistical analyses. Therein, the mean specificity and mean sensitivity of Luminex xTAG RVP FAST v2 test for the detection of respiratory viral infections were 0.99 (0.98-0.99) and 0.88 (0.87-0.90), respectively. Additionally, the negative and positive likelihood ratios were 0.14 (0.11-0.19) and 87.42 (61.88-123.50), respectively. Moreover, the diagnostic odds ratio and area under the curve of summary receiver operating characteristic were 714.80 and 0.9886, respectively. CONCLUSION: The Luminex xTAG RVP FAST v2 test could be a reliable and rapid diagnostic method for multiple respiratory viral infections.


Assuntos
Infecções Respiratórias , Viroses , Vírus , Humanos , Sistema Respiratório , Infecções Respiratórias/diagnóstico , Sensibilidade e Especificidade , Viroses/diagnóstico
6.
Artigo em Inglês | MEDLINE | ID: mdl-34850013

RESUMO

OBJECTIVES: To examine the direction, strength and causality of the associations of resting heart rate (RHR) with cardiometabolic traits. METHODS: We assessed the strength of associations between measured RHR and cardiometabolic traits in 506,211 and 372,452 participants from China Kadoorie Biobank (CKB) and UK Biobank (UKB). Mendelian randomization (MR) analyses were used to make causal inferences in 99,228 and 371,508 participants from CKB and UKB, respectively. RESULTS: We identified significant, directionally-concordant observational associations between RHR and higher total cholesterol, triglycerides (TG), low-density lipoprotein, C-reactive protein (CRP), glucose, body mass index, waist-hip ratio (WHR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) after the Bonferroni correction. MR analyses showed that 10 beat/min higher genetically-predicted RHR were trans-ethnically associated with a higher DBP (beta 2.059 [95%CI 1.544, 2.574] mmHg in CKB; 2.037 [1.845, 2.229] mmHg in UKB), higher CRP (0.180 [0.057, 0.303] log mg/L in CKB; 0.154 [0.134, 0.174] log mg/L in UKB), higher TG (0.052 [-0.009, 0.113] log mmol/L in CKB; 0.020 [0.010, 0.030] log mmol/L in UKB) and higher WHR (0.218 [-0.033, 0.469] % in CKB; 0.225 [0.111, 0.339] % in UKB). In the opposite direction, higher genetically-predicted SBP, TG, glucose, WHR and lower high-density lipoprotein were associated with elevated RHR. CONCLUSION: Our large-scale analyses provide causal evidence between RHR and cardiometabolic traits, highlighting the importance of monitoring heat rate as a means of alleviating the adverse effect of metabolic disorders.

7.
Front Cell Dev Biol ; 9: 733908, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34858973

RESUMO

The dynamic balance of cardiomyocytes and neurons is essential to maintain the normal physiological functions of heart and brain. If excessive cells die in tissues, serious Cardio-Cerebrovascular Diseases would occur, namely, hypertension, myocardial infarction, and ischemic stroke. The regulation of cell death plays a role in promoting or alleviating Cardio-Cerebrovascular Diseases. Ferroptosis is an iron-dependent new type of cell death that has been proved to occur in a variety of diseases. In our review, we focus on the critical role of ferroptosis and its regulatory mechanisms involved in Cardio-Cerebrovascular Diseases, and discuss the important function of ferroptosis-related inhibitors in order to propose potential implications for the prevention and treatment of Cardio-Cerebrovascular Diseases.

8.
BMC Pregnancy Childbirth ; 21(1): 804, 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34861845

RESUMO

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a severe and life-threatening disease. Given its heterogeneous clinical presentation, the phenotype of TTP during pregnancy and its management have not been well documented. CASE PRESENTATION: We report here a 25-year-old woman, G1P0 at 36 weeks gestation, who developed severe thrombocytopenia and anemia. She was performed an emergent caesarean section 1 day after admission because of multiple organ failure. As ADAMTS 13 enzyme activity of the patient was 0% and antibodies were identified by enzyme-linked immunosorbent assay, she was diagnosed as acquired thrombotic thrombocytopenic purpura (aTTP). Furthermore, asymptomatic primary Sjögren's syndrome was incidentally diagnosed on screening. After treatment with rituximab in addition to PEX and steroids, the activity of the ADAMTS 13 enzyme increased significantly from 0 to 100%. CONCLUSIONS: To the best of our knowledge, this is the first case report of concomitant TTP and asymptomatic Sjögren's syndrome in a pregnant woman. It highlights the association between pregnancy, autoimmune disease, and TTP. It also emphasizes the importance of an enzyme-linked immunosorbent assay in the diagnosis and rituximab in the treatment of patients with acquired TTP.

9.
Comput Struct Biotechnol J ; 19: 6201-6211, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34900133

RESUMO

Farmers apply broiler chicken litter to soils to enrich organic matter and provide crops with nutrients, following varying periods of stockpiling. However, litter frequently harbors fecal-derived microbial pathogens and associated antibiotic resistance genes (ARGs), and may be a source of microbial contamination of produce. We coupled a cutting-edge Loop Genomics long-read 16S rRNA amplicon-sequencing platform with high-throughput qPCR that targeted a suite of ARGs, to assess temporal (five time points over a 60-day period) and spatial (top, middle and bottom layers) microbiome and resistome dynamics in a broiler litter stockpile. We focused on potentially pathogenic species from the Enterobacteriaceae, Enterococcaceae and Staphylococcaceae families associated with food-borne disease. Bacterial diversity was significantly lower in the middle of the stockpile, where targeted pathogens were lowest and Bacillaceae were abundant. E. coli was the most abundant Enterobacteriaceae species, and high levels of the opportunistic pathogen Enterococcus faecium were detected. Correlation analyses revealed that the latter was significantly associated with aminoglycoside (aac(6')-Ib(aka aacA4), aadA5), tetracycline (tetG), vancomycin (vanC), phenicol (floR) and MLSB (mphB) resistance genes. Staphylococcaceae were primarily non-pathogenic, but extremely low levels of the opportunistic pathogen S. aureus were detected, as was the opportunistic pathogen S. saprophyticus, which was linked to vancomycin (vanSA, vanC1), MLSB (vatE, ermB) and tetracycline (tetK) resistance genes. Collectively, we found that stockpile microbiomes and resistomes are strongly dictated by temporal fluctuations and spatial heterogeneity. Insights from this study can be exploited to improve stockpile management practice to support sustainable antimicrobial resistance mitigation policies in the future.

10.
Can Respir J ; 2021: 5888783, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34956429

RESUMO

Introduction: Postoperative ineffective cough is easy to occur after thoracic surgery, and it is also a risk factor for postoperative pulmonary complications (PPCs). Objectives: To explore the value of peak expiratory flow rate (PEF) in evaluating cough ability in patients undergoing lung surgery and evaluate the effectiveness of chest wall compression during the expiratory phase by PEF. Methods: From September 2020 to May 2021, the researchers collected the data of patients who underwent lung surgery. Eventually, 153 patients who met the criteria were included, 102 cases were included in the effective cough group and 51 cases were included in the ineffective cough group. The receiver working curve (ROC curve) was used to analyze whether PEF could evaluate cough ability. At the same time, the researchers collected the pulmonary function data of the first 30 patients of the ineffective cough group while compressing the chest wall during the expiratory phase to evaluate the effectiveness of chest wall compression. Results: The area under the curve (AUC) of postoperative PEF to evaluate the postoperative cough ability was 0.955 (95% CI: 0.927-0.983, P < 0.001). The values of PEF (127.17 ± 34.72 L/min vs. 100.70 ± 29.98 L/min, P < 0.001, 95% CI: 18.34-34.59) and FEV1 (0.72 (0.68-0.97) L vs. 0.64 (0.56-0.82) L, P < 0.001) measured while compressing the chest wall were higher than those without compression. Conclusions: PEF can be used as a quantitative indicator of cough ability. Chest wall compression could improve cough ability for patients who have ineffective cough.

11.
Bioresour Technol ; : 126578, 2021 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-34953993

RESUMO

Agriculture bio-waste is one of the largest sectors for nutrient circulation and resource recovery. This review intends to summarize the possible scheme through coupling chemical conversion of crop straws to biochar and biological conversion of livestock waste to value-added products thus reaching key nutrient circulation. Chemical conversion of crop straws to biochar was reviewed through summarizing the preparation methods and functional modification of biochar. Then, high-solid two-phase anaerobic conversion of agriculture bio-waste to value-added products and improved performance of bio-conversion through byproduct gases reuse and biochar supplementation were reviewed. Finally, high quality compost production through amendment of biochar and residual digestate was proposed with analysis of reduced nitrogen emission and carbon balance. The biological mechanism of synergistic regulation of carbon and nitrogen loss during bio-conversion with biochar was also reviewed. This will provide a model for synergistic conversion of agricultural wastes to value added products pursuing key nutrient circulation.

12.
Sci Total Environ ; : 151915, 2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34826462

RESUMO

Antibiotic resistance genes (ARGs) constitute emerging pollutants of significant public health concern. Antibiotics applied in aquaculture may stimulate the proliferation and dissemination of ARGs. This study investigated the prevalence and diversity of ARGs in Pangasianodon hypophthalmus (formerly Pangasius) and Oreochromis niloticus (formerly Tilapia) commercial aquaculture ponds from four economically important divisions (i.e. regions) of Bangladesh using a high-throughput qPCR ARG SmartChip and further aimed to explore effects of aquaculture pond management and water quality on the observed ARG prevalence patterns. A total of 160 ARGs and 10 mobile genetic elements (MGEs) were detected across all samples (n = 33), of which 76 ARGs and MGEs were shared between all regions. Multidrug resistance genes were the most frequently encountered ARGs, followed by ARGs conferring resistance to ß-lactams, aminoglycosides, tetracyclines, and macrolide-lincosamide-streptogramin B (MLSB). Research ponds managed by the Bangladesh Agricultural University had the lowest abundance and diversity of ARGs, suggesting that proper management such as regular water quality monitoring, fortnightly water exchange and use of probiotics instead of antibiotics may mitigate the dissemination of antibiotic resistance from aquaculture ponds. The Adonis test (R2 = 0.35, p < 0.001) and distance decay relationships revealed that the ARGs composition displayed a significant biogeographical pattern (i.e., separation based on geographic origin). However, this effect could possibly be due to feed type as different feed types were used in different regions. In conclusion, our results indicate that there is a vast potential for improving aquaculture pond management practices in Bangladesh to mitigate the environmental dissemination of ARGs and their subsequent transmission to humans.

13.
J Hazard Mater ; : 127774, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34801300

RESUMO

The demand for facial masks remains high. However, little is known about discarded masks as a potential refuge for contaminants and to facilitate enrichment and spread of antibiotic resistance genes (ARG) in the environment. We address this issue by conducting an in-situ time-series experiment to investigate the dynamic changes of ARGs, bacteria and protozoa associated with discarded masks. Masks were incubated in an estuary for 30 days. The relative abundance of ARGs in masks increased after day 7 but levelled off after 14 days. The absolute abundance of ARGs at 30 days was 1.29 × 1012 and 1.07 × 1012 copies for carbon and surgical masks, respectively. According to normalized stochasticity ratio analysis, the assembly of bacterial and protistan communities was determined by stochastic (NST = 62%) and deterministic (NST = 40%) processes respectively. A network analysis highlighted potential interactions between bacteria and protozoa, which was further confirmed by culture-dependent assays, that showed masks shelter and enrich microbial communities. An antibiotic susceptibility test suggested that antibiotic resistant pathogens co-exist within protozoa. This study provides an insight into the spread of ARGs through discarded masks and highlights the importance of managing discarded masks with the potential ecological risk of mask contamination.

14.
Exp Hematol Oncol ; 10(1): 52, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34758872

RESUMO

BACKGROUND: MET amplification plays an important role in the development of non-small-cell lung cancer (NSCLC) either de novo or in resistance to epidermal growth factor receptor tyrosine-kinase inhibitor (EGFR-TKI) settings. Fluorescence in situ hybridization (FISH) is the standard method for MET amplification. With more and more discoveries of oncogenic driver genes, next-generation sequencing (NGS) plays a significant role in precision oncology. Meanwhile, the role of NGS in MET amplification remains uncertain. METHODS: Forty patients diagnosed with advanced NSCLC were included. FISH and NGS were conducted prior to MET inhibitors treatment. MET amplification by FISH was defined as a MET/CEP7 ratio of > 2.0 and/or copy number (CN) > 5. MET amplification by NGS was defined as gene copy number (GCN) ≥ 5. RESULTS: The concordance rate among FISH and NGS was 62.5% (25/40). MET amplification identified by FISH showed the optimal predictive value. The partial response (PR) rate was 68.0% (17/25 with MET amplification) vs. 6.7% (1/15 without MET amplification); the median progression-free survival (PFS) was 5.4 months versus 1.0 months (P < 0.001). MET amplification identified by NGS failed to distinguish significant clinical outcomes. The PR rate was 60.0% (6/10, with MET GCN ≥ 5) vs. 40.0% (12/30, with MET GCN < 5); the median PFS was 4.8 months vs. 2.2 months (P = 0.357). The PR rate was 68.8% (11/16) and the median PFS was 4.8 months in patients with focal amplification by NGS. CONCLUSIONS: MET amplification identified by FISH remains the optimal biomarker to identify suitable candidates for MET-TKI therapy. In comparison, amplification identified by NGS seems not as robust to be effective predictive biomarker. Further exploration is needed regarding the focal amplification by NGS in predicting the efficacy.

15.
Chem Sci ; 12(42): 14254-14259, 2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34760211

RESUMO

Controlled synthesis of hydrogen-bonded organic frameworks (HOFs) remains challenging, because the self-assembly of ligands is not only directed by weak hydrogen bonds, but also affected by other competing van der Waals forces. Herein, we demonstrate the coordination-bond-directed synthesis of HOFs using a preformed metal-organic framework (MOF) as the template. A MOF (CuI-TTFTB) based on two-coordinated CuI centers and tetrathiafulvalene-tetrabenzoate (TTFTB) ligands was initially synthesized. CuI-TTFTB was subsequently oxidized to the intermediate (CuII-TTFTB) and hydrated to the HOF product (TTFTB-HOF). Single-crystal-to-single-crystal (SC-SC) transformation was realized throughout the MOF-to-HOF transformation so that the evolution of structures was directly observed by single-crystal X-ray diffraction. The oxidation and hydration of the CuI center are critical to breaking the Cu-carboxylate bonds, while the synergic corbelled S⋯S and π⋯π interactions in the framework ensured stability of materials during post-synthetic modification. This work not only provided a strategy to guide the design and discovery of new HOFs, but also linked the research of MOFs and HOFs.

16.
Opt Lett ; 46(21): 5441-5444, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34724496

RESUMO

In this Letter, a metasurface combined with emerging 3D printing technology is proposed. The proposed metasurface regards the simple cube as the unit cell, and the height of the cube is the only variable. A nearly linear transmission phase range covering 360° operating at 20 GHz is obtained when the height is regulated in [2.26 mm, 11.20 mm]. Therefore, the proposed unit cell can be adopted to any metasurface with various functions. Taking the generation of a non-diffractive Bessel beam as an example, two metasurfaces composed of 30×30 units with different focusing directions are designed based on non-diffractive theory and the generalized law of refraction. Two prototypes are 3D printed and measured by a near-field scanning system. The measured results validate our design with satisfactory focusing and beam deflection performance. Additionally, the 3D printed metasurface has lower cost and a shorter processing cycle, and avoids metal loss. Therefore, a 3D printed metasurface is an excellent candidate that can be applied in millimeter wave or even higher frequency bands.

17.
Nat Commun ; 12(1): 6450, 2021 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-34750392

RESUMO

The ADJUVANT study reported the comparative superiority of adjuvant gefitinib over chemotherapy in disease-free survival of resected EGFR-mutant stage II-IIIA non-small cell lung cancer (NSCLC). However, not all patients experienced favorable clinical outcomes with tyrosine kinase inhibitors (TKI), raising the necessity for further biomarker assessment. In this work, by comprehensive genomic profiling of 171 tumor tissues from the ADJUVANT trial, five predictive biomarkers are identified (TP53 exon4/5 mutations, RB1 alterations, and copy number gains of NKX2-1, CDK4, and MYC). Then we integrate them into the Multiple-gene INdex to Evaluate the Relative benefit of Various Adjuvant therapies (MINERVA) score, which categorizes patients into three subgroups with relative disease-free survival and overall survival benefits from either adjuvant gefitinib or chemotherapy (Highly TKI-Preferable, TKI-Preferable, and Chemotherapy-Preferable groups). This study demonstrates that predictive genomic signatures could potentially stratify resected EGFR-mutant NSCLC patients and provide precise guidance towards future personalized adjuvant therapy.

18.
Environ Sci Technol ; 55(20): 13913-13922, 2021 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-34613706

RESUMO

Agricultural soils are important reservoirs for antibiotic resistance genes (ARGs), which have close linkage to human health via crop production. Metal stress in environments may function as a selection pressure for antibiotic resistomes. However, there is still a lack of field studies focusing on the effect of historical mercury (Hg) contamination on antibiotic resistomes in agricultural soils. Here, we explored the ARG profile in soils with different cropping systems (paddy and upland) and linked them to legacy Hg exposure. We found that ARG profiles were significantly different between paddy and upland soils. However, both paddy and upland soils with long-term field Hg contamination harbored higher diversity and abundance of ARGs than non-polluted soils. The co-occurrence network reveals significant associations among Hg, Hg resistance genes, mobile genetic elements (MGEs), and ARGs. Together with path analysis showing legacy Hg possibly affecting soil resistomes through the shifts of soil microbiota, Hg resistance genes, and MGEs, we suggest that legacy Hg-induced potential co-selection might elevate the ARG level. Redundancy analysis further supports that legacy Hg pollution had a significant association with ARG variations in the paddy and upland soils (P < 0.01). Collectively, our results highlight the underappreciated role of legacy Hg as a potential persistent selecting agent in contributing to soil ARGs in agroecosystems.


Assuntos
Mercúrio , Solo , Antibacterianos/farmacologia , Resistência Microbiana a Medicamentos/genética , Genes Bacterianos , Humanos , Microbiologia do Solo
19.
Environ Sci Technol ; 55(20): 13881-13890, 2021 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-34596377

RESUMO

Antibiotic resistance is a global health concern. Long-term organic fertilization can influence the antibiotic resistome of agricultural soils, posing potential risks to human health. However, little is known about the contribution of viruses to the dissemination of antibiotic resistance genes (ARGs) in this context. Here, we profiled the viral communities and virus-associated ARGs in a long-term (over 10 years) organic fertilized field by viral metagenomic analysis. A total of 61,520 viral populations (viral operational taxonomic units, vOTUs) were retrieved, of which 21,308 were assigned at the family level. The viral community structures were significantly correlated with the bacterial community structures (P < 0.001) and the dosage of applied sewage sludge (r2 = 0.782). A total of 16 unique ARGs were detected in soil viromes, and the number of virus-associated ARG subtypes was higher in sewage sludge treatments (except for 1 SS) than others. The network analysis showed that the application of the organic fertilizer increased the bacteria-virus interactions, suggesting that the chances of ARG exchange between viruses and their hosts may increase. Overall, our results provide a novel understanding about virus-associated ARGs and factors affecting the profile of viral community in fertilized soil.


Assuntos
Fertilizantes , Solo , Antibacterianos/farmacologia , Resistência Microbiana a Medicamentos/genética , Fertilizantes/análise , Genes Bacterianos , Humanos , Esterco , Microbiologia do Solo
20.
Transl Oncol ; 15(1): 101254, 2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34715621

RESUMO

BACKGROUND: Treatment by immune checkpoint blockade (ICB) provides a remarkable survival benefit for multiple cancer types. However, disease aggravation occurs in a proportion of patients after the first couple of treatment cycles. METHODS: RNA sequencing data was retrospectively collected. 6 tumour-immune related features were extracted and combined to build a lung cancer-specific predictive model to distinguish responses as progression disease (PD) or non-PD. This model was trained by 3 public pan-cancer datasets and a lung cancer cohort from our institute, and generated a lung cancer-specific integrated gene expression score, which we call LITES. It was finally tested in another lung cancer dataset. RESULTS: LITES is a promising predictor for checkpoint blockade (area under the curve [AUC]=0.86), superior to traditional biomarkers. It is independent of PD-L1 expression and tumour mutation burden. The sensitivity and specificity of LITES was 85.7% and 70.6%, respectively. Progression free survival (PFS) was longer in high-score group than in low-score group (median PFS: 6.0 vs. 2.4 months, hazard ratio=0.45, P=0.01). The mean AUC of 6 features was 0.70 (range=0.61-0.75), lower than in LITES, indicating that the combination of features had synergistic effects. Among the genes identified in the features, patients with high expression of NRAS and PDPK1 tended to have a PD response (P=0.001 and 0.01, respectively). Our model also functioned well for patients with advanced melanoma and was specific for ICB therapy. CONCLUSIONS: LITES is a promising biomarker for predicting an impaired response in lung cancer patients and for clarifying the biological mechanism underlying ICB therapy.

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