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1.
Free Radic Res ; : 1-15, 2022 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-34979841

RESUMO

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are the production of renal ischemia/reperfusion (I/R). The current study is to elucidate a mechanism of SIRT2 tyrosine nitration to accelerate the cell apoptosis induced by peroxynitrite (ONOO‾), the most reactive and deleterious RNS type in renal ischemia/reperfusion (I/R) injury. Our results demonstrate that there is a significant enhancement of the 3-nitrotyrosine levels in renal tissues of Acute Kidney Injury (AKI) patients and rats that underwent renal I/R, and a positive correlation between the 3-nitrotyrosine level and renal function impairment, indicative of an accumulation of peroxynitrite. Notably, peroxynitrite-evoked nitration of SIRT2 destroyed its enzymatic activity and the capability to deacetylate FOXO3a, and enhanced expression of Bim and caspase3, facilitating renal cell apoptosis in renal ischemia/reperfusion and SIN-1(peroxynitrite donor) treatment in vitro, and these effects were reversed by FeTMPyP, a peroxynitrite decomposition scavenger. Importantly, we identified that the tyrosine 86 is responsible for SIRT2 nitration and inactivation using site-mutation assay and Mass Spectrography analysis. Altogether, these findings point to a novel protective mechanism that an inhibition of SIRT2 tyrosine nitration can be a promising strategy to prevent ischemic renal diseases involving AKI.

2.
J Inflamm Res ; 15: 53-70, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35023943

RESUMO

Background: Alcoholic liver disease (ALD) is liver damage caused by long-term drinking. Inflammation plays a central role in the progression of ALD. CD73 is a ubiquitously expressed glycosylphosphatidylinositol-anchored glycoprotein that is a key enzyme that converts ATP into adenosine. Evidence has shown that CD73 plays an important role in many diseases, but the role and mechanism of CD73 in alcohol-induced liver injury and inflammation is still unclear. Methods: The alcohol-induced liver injury and inflammation mouse model was established. The rAAV9-CD73 was used to overexpress CD73. Isolation of primary macrophages (MΦ) from the liver was conducted. The effects of CD73 on alcohol-induced liver injury and inflammation were evaluated by quantitative real­time PCR, Western blotting, ELISA, and immunohistochemical assay. Flow cytometry was used to detect the cell cycle and apoptosis. Results: Our results showed that overexpression of CD73 can reduce alcohol-induced liver damage, lipid accumulation, and the secretion of inflammatory cytokines. pEX3-CD73 can promote RAW264.7 cells proliferation and inhibit apoptosis via suppressing the activation of TLR4/MyD88/NF-κB signaling pathway. Inhibition of TLR4 further enhanced the anti-inflammatory effect of overexpression of CD73. Conclusion: Overexpression of CD73 can reduce alcohol-induced liver injury and inflammation. CD73 may serve as a potential therapeutic target for ALD.

3.
Langmuir ; 2022 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-35019652

RESUMO

A biological nanopore is one of the predominant single-molecule approaches as a result of its controllable single-biomolecule interface, which could reflect the "intrinsic" information on an individual molecule in a label-free way. Because the current blockage is normally treated as the most important parameter for nanopore identification of every single molecule, the fluctuation of current blockage for certain types of molecules, defined as full width at half maximum (fwhm) of current blockage, actually owns a dominant influence on nanopore resolution. Therefore, controlling the fwhm of current blockage of molecules is critical for the sensing capability of the nanopore. Here, taking an aerolysin nanopore as a model, by precisely controlling the functional group in this single-biomolecule interface, we could narrow the fwhm of nanopore current blockage for DNA identification and prolong the duration inside the nanopore. Moreover, a substantial correlation between fwhm of current blockage and duration is established, showing a non-monotonic variation. Besides, the mechanism is also clarified with studying the detailed current blockage events. This proposed correlation is further demonstrated to be applied uniformly across different mutant aerolysins for a certain DNA. This study proposes a new strategy for regulating molecular sensing from the duration of the analyte, which could guide the resolution of heterogeneity analysis using nanopores.

4.
Pest Manag Sci ; 2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-34984795

RESUMO

BACKGROUND: Unmanned aerial vehicles (UAVs) have been developed to improve the efficiency of pesticide applications, and they are now widely utilized in Asia. The deposition and retention periods of pesticides on plant surfaces present serious challenges for modern precision agriculture, as these factors directly affect pesticide bioavailability, efficacy, and loss. Tank-mix adjuvants have been utilized to improve pesticide performance, but their effects on physicochemical properties and dosage delivery at low dilutions are not well understood. RESULTS: We found that different tank-mix adjuvants affected droplet impact behavior, the wetting and spreading of spray dilutions and pesticide deposition on rice leaves by changing the physicochemical properties of spray dilutions. The adjuvant methyl oxirane polymer with oxirane, mono (3,5,5-trimethylhexyl) ether (adjuvant c) significantly reduced the dynamic surface tension of the spray dilution and inhibited the rebound of large droplets (D0  = 2 ± 0.2 mm) and spray droplets (0.2 MPa with a LU-01 nozzle) on rice leaves and improved the wetting and spreading performance of the spray dilution on rice leaves. Field tests showed that adjuvant c could significantly increase the deposition of chlorantraniliprole on rice leaves. CONCLUSION: Overall, the use of appropriate tank-mix adjuvants at low dilution ratios for UAVs application in paddy fields can improve the performance of spray dilutions, increase the effective deposition and wetting spread of pesticides on rice leaves, further reduce the dosage of pesticide products and improve pesticide utilization.

5.
Artigo em Inglês | MEDLINE | ID: mdl-34662694

RESUMO

BACKGROUND: Accumulating evidence suggest that behavioral sensitization is involved in the process of drug addiction. Zebrafish are sensitive to a variety of addictive drugs and are thus suitable for the study of behavioral sensitization. However, in contrast to mature rodent models of behavioral sensitization, how this phenomenon manifests in aquatic organisms, especially zebrafish, is largely unknown. In this study, we developed a morphine-induced behavioral sensitization adult zebrafish model and performed a preliminary investigation of the underlying mechanisms. METHODS: Behavioral sensitization was established in zebrafish by observing their behavior after treatment and challenge with morphine. The effect of morphine was evaluated by a behavioral locomotor test. Different doses of morphine and withdrawal times were used to evaluate the establishment of the behavioral sensitization model. RESULTS: Hyperlocomotion was induced after administration of morphine in adult zebrafish. After withdrawing the drug for a period, challenge with low-dose morphine evoked behavioral sensitization in zebrafish acutely pre-treated with morphine. Low-dose morphine failed to induce behavioral sensitization in zebrafish if the withdrawal time was less than 5 days or more than 7 days. Morphine induced behavioral sensitization in zebrafish may involve dopaminergic, glutamatergic and opioid systems. CONCLUSION: A single low-dose of morphine could induce behavioral sensitization in zebrafish acutely pre-treated with morphine, and this phenomenon was highly correlated with drug dose and withdrawal time. These findings suggest that zebrafish is a suitable model for the study of behavioral sensitization.

6.
Gene ; 808: 145973, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34592350

RESUMO

INTRODUCTION: Abnormal expression of ionotropic glutamate receptor NMDA type subunit 1, the key subunit of the NMDA receptor, may be related to many neuropsychiatric disorders. In this study, we explored the functional sequence of the 5' regulatory region of the human GRIN1 gene and discussed the transcription factors that may regulate gene expression. MATERIALS AND METHODS: Twelve recombinant pGL3 vectors with gradually truncated fragment lengths were constructed, transfected into HEK-293, U87, and SK-N-SH cell lines, and analyzed through the luciferase reporter gene assay. JASPAR database is used to predict transcription factors. RESULTS: In SK-N-SH and U87 cell lines, regions from -337 to -159 bp, -704 to -556 bp inhibited gene expression, while -556 to -337 bp upregulated gene expression. In HEK-293 and U87 cell lines, the expression of fragment -1703 to + 188 bp was significantly increased compared to adjacent fragments -1539 to + 188 bp and -1843 to + 188 bp. The protein expressions of fragments -2162 to + 188 bp and -2025 to + 188 bp, -1539 to + 188 bp and -1215 to + 188 bp, -1215 to + 188 bp and -1066 to + 188 bp were significantly different in HEK-293 and SK-N-SH cells. According to the predictions of the JASPAR database, the transcription factors REST, EGR1, and CREB1/HIC2 may bind the DNA sequences of GRIN1 gene from the -337 to -159, -556 to -337, and -704 to -556, respectively. In addition, zinc finger transcription factors may regulate the expression of other differentially expressed fragments. CONCLUSIONS: Abnormal transcription regulation in the proximal promoter region of GRIN1 (-704 to + 188 bp) may be involved in the course of neuropsychiatric diseases.


Assuntos
Regiões 5' não Traduzidas/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Linhagem Celular Tumoral , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Genes Reporter , Células HEK293 , Humanos , Regiões Promotoras Genéticas/genética , Fatores de Transcrição/genética , Transcrição Genética/genética , Ativação Transcricional/genética
7.
Neural Regen Res ; 17(5): 1080-1087, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-34558536

RESUMO

Baicalin is a natural active ingredient isolated from Scutellariae Radix that can cross the blood-brain barrier and exhibits neuroprotective effects on multiple central nervous system diseases. However, the mechanism behind the neuroprotective effects remains unclear. In this study, rat models of spinal cord injury were established using a modified Allen's impact method and then treated with intraperitoneal injection of Baicalin. The results revealed that Baicalin greatly increased the Basso, Beattie, Bresnahan Locomotor Rating Scale score, reduced blood-spinal cord barrier permeability, decreased the expression of Bax, Caspase-3, and nuclear factor κB, increased the expression of Bcl-2, and reduced neuronal apoptosis and pathological spinal cord injury. SH-SY5Y cell models of excitotoxicity were established by application of 10 mM glutamate for 12 hours and then treated with 40 µM Baicalin for 48 hours to investigate the mechanism of action of Baicalin. The results showed that Baicalin reversed tight junction protein expression tendencies (occludin and ZO-1) and apoptosis-related protein expression (Bax, Bcl-2, Caspase-3, and nuclear factor-κB), and also led to up-regulation of PI3K and Akt phosphorylation. These effects on Bax, Bcl-2, and Caspase-3 were blocked by pretreatment with the PI3K inhibitor LY294002. These findings suggest that Baicalin can inhibit blood-spinal cord barrier permeability after spinal cord injury and reduce neuronal apoptosis, possibly by activating the PI3K/Akt signaling pathway. This study was approved by Animal Ethics Committee of Xi'an Jiaotong University on March 6, 2014.

8.
J Exp Med ; 219(1)2022 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-34825915

RESUMO

Targeted therapies represent attractive combination partners with immune checkpoint blockade (ICB) to increase the population of patients who benefit or to interdict the emergence of resistance. We demonstrate that targeting WEE1 up-regulates immune signaling through the double-stranded RNA (dsRNA) viral defense pathway with subsequent responsiveness to immune checkpoint blockade even in cGAS/STING-deficient tumors, which is a typical phenotype across multiple cancer types. WEE1 inhibition increases endogenous retroviral elements (ERVs) expression by relieving SETDB1/H3K9me3 repression through down-regulating FOXM1. ERVs trigger dsRNA stress and interferon response, increasing recruitment of anti-tumor T cells with concurrent PD-L1 elevation in multiple tumor models. Furthermore, combining WEE1 inhibition and PD-L1 blockade induced striking tumor regression in a CD8+ T cell-dependent manner. A WEE1 inhibition-induced viral defense signature provides a potentially informative biomarker for patient selection for combination therapy with WEE1 and ICB. WEE1 inhibition stimulates anti-tumor immunity and enhances sensitivity to ICB, providing a rationale for the combination of WEE1 inhibitors and ICB in clinical trials.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Retrovirus Endógenos/genética , Neoplasias Experimentais/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , RNA de Cadeia Dupla/genética , Transdução de Sinais/efeitos dos fármacos , Células A549 , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Retrovirus Endógenos/metabolismo , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/farmacologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Experimentais/genética , Neoplasias Experimentais/imunologia , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Pirimidinonas/administração & dosagem , Pirimidinonas/farmacologia , RNA de Cadeia Dupla/metabolismo , Transdução de Sinais/genética , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Carga Tumoral/imunologia
9.
J Pharm Biomed Anal ; 209: 114526, 2022 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-34915323

RESUMO

Pogostemon cablin Benth (PCB) is a well-known traditional Chinese medicine that has been used for treatment of many ailments for several centuries. In presently, the chemical profiling and quality control study of PCB has mainly concentrated on the volatile fractions. However, the non-volatile chemical profile of PCB was still unclear. In this study, 73 non-volatile constituents (i.e., 33 flavonoids, 21 organic acids, 9 phenylpropanoids, 4 sesquiterpenes, 3 alkaloids, and 3 other types of compounds) were identified and characterized in PCB using high performance liquid chromatography coupled with quadruple time-of-flight tandem mass spectrometry (HPLC-Q-TOF-MS). Meanwhile, to assess PCB samples, an established HPLC-Q-TOF-MS fingerprint was combined with multivariate statistical analysis that included similarity analysis (SA), hierarchical cluster analysis (HCA), principal component analysis (PCA), and orthogonal partial least squares-discriminant analysis (OPLS-DA). The PCB samples could be classified into two groups (herbal decoction pieces and processed medicinal materials), and acteoside, isoacteoside, 4',6-Dihydroxy-5,7-dimethoxyflavone, pachypodol and pogostone were screened as the potential chemical markers that attributed classification. In addition, nine representative components (pachypodol, vicenin-2, apigenin, rhamnocitrin, acteoside, isoacteoside, chlorogenic acid, azelaic acid and pogostone) in PCB were simultaneously determined by using an ultra-high-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry (UPLC-QQQ-MS/MS). This study is the first to describe the chemical profile of PCB using liquid chromatography tandem mass spectrometry, which would improve our understanding of the substance basis of PCB and is helpful to the PCB further quality evaluation.


Assuntos
Medicamentos de Ervas Chinesas , Pogostemon , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/análise , Pogostemon/química , Espectrometria de Massas em Tandem
11.
Front Biosci (Landmark Ed) ; 26(11): 1191-1203, 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34856763

RESUMO

Background: Our previous studies have reported that polycomb chromobox 4 (CBX4) has a potential promoting hepatocellular carcinoma (HCC) angiogenesis and tumor progression. However, it is unclear whether genetic single-nucleotide polymorphisms (SNPs) in this gene are associated with HCC prognosis. Methods: We conducted a hospital-based two-phase study, including 598 patients with pathologically diagnosed HCC for the SNPs screening phase and 328 HCC patients for clinic significance validating phase, to elucidate the association between SNPs of CBX4 and the survival of HCC. The genotypes of CBX4 were tested using the SNaPshot method and the effects of CBX4 SNPs on HCC prognosis were analyzed using Kaplan-Meier survival model and Cox regression model. Results: A total of 33 SNPs were selected and genotyped in this study. We found the rs77447679 SNP was significantly related to survival in individuals with HCC. Specifically, survival was noticeably decreased in HCC patients who have mutant homozygote AA of this SNP (rs77447679-AA) compared with these with wild type (rs77447679-CC). An additive effect of rs77447679 polymorphism and aflatoxin B1 exposure level was also observed in the survival analyses of HCC cases. Furthermore, this SNP was positively correlated not only with tumor size, grade, stage, and microvessel density (correlation coefficient r = 0.17, 0.23, 0.23, and 0.42, respectively), but also with increasing CBX4 expression (r = 0.57). Interestingly, the mutant genotypes of rs77447679 can significantly improve the therapeutic response of HCC cases on post-operative adjuvant transarterial chemoembolization (pa-TACE), but wild type not. Conclusions: These data suggest that genetic polymorphisms in the CBX4 may be a prognostic biomarker for HCC, and the rs77447679 SNP is such a potential candidate.

12.
Front Plant Sci ; 12: 754887, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34858458

RESUMO

The allometric relationship among different functional traits is an ecological strategy for plants to promote resource utilization, which indicates the ability of plants to adapt to environmental changes coordinately. In this study, we conducted a field survey on Haloxylon ammodendron and H. persicum among different terrains (dune crest, eastern slope, western slope and inter-dune) in the Gurbantunggut Desert, obtained their quantitative and morphological characteristics, and analyzed their allometric relationships between plant height and canopy radius, plant height and basal diameter by using standardized major axis estimation. We found that: (1) The dominated terrains of H. ammodendron and H. persicum were different; (2) The individual morphology of the two Haloxylon species changed significantly with the terrains (p < 0.05), with the largest and smallest ones growing on the eastern slope and the inter-dune lowland, respectively; (3) Fixed allometric patterns were observed in the above-ground parts of the two Haloxylon species, as the growth of canopy and basal stem was preferentially to plant height; (4) These allometric relationships were significantly affected by the terrain, and exhibited discrepancy between two species, they both invested less in plant height in windy habitats, such as the dune crest and western slope, but H. ammodendron growing on the western slope and H. persicum growing on the eastern slope invested more in basal diameter for strengthening mechanical support and resources acquisition, respectively. These results indicated that both studied species adopted an ecological strategy that allocating more resources to horizontal expansion rather than vertical growth, the terrain has an important influence on the allometric relationship of their above-ground parts, and the trade-off mechanism of main components investing was different for these two species due to habitat heterogeneity and ecological adaptability.

13.
Small ; : e2105362, 2021 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-34862741

RESUMO

Fluorophores with emission in the second near-infrared (NIR-II) window have displayed salient advantages for biomedical applications. However, exploration of new luminogens with high NIR-II fluorescent brightness is still challenging. Herein, based on the "ring-fusion" strategy, a series of heteroatom-inserted rigid-planar cores is proposed to achieve the bathochromic NIR-II fluorophores with aggregation-induced emission (AIE) performance. Interestingly, one of the representative fluorophores, 4,4'-(5,5'-([1,2,5]thiadiazolo[3,4-i]dithieno[2,3-a:3',2'-c]phenazine-8,12-diyl)bis(4-octylthiophene-5,2-diyl))bis(N,N-diphenylaniline) (TTQiT), enjoys a maximum emission beyond 1100 nm because of the efficiently narrowed energy bandgap by electron-rich sulfur-atom-inserted core, which is verified by theoretical calculation. Taking advantage of the bright NIR-II emission of TTQiT nanoparticles, the desirable in vivo NIR-II imaging with high signal-to-background ratios is successfully performed and a long-term stem cell tracking in the detection of acute lung injury is further realized. Therefore, it is anticipated that this work will provide a promising molecular engineering strategy to enrich the scope of NIR-II fluorophores for catering to diverse demands in biomedical applications.

14.
Aging (Albany NY) ; 13(undefined)2021 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-34862879

RESUMO

Ongoing pandemic and potential resurgence of Coronavirus disease 2019 (COVID-19) has prompted urgent efforts to investigate the immunological memory of convalescent patients, especially in patients with active cancers. Here we performed single-cell RNA sequencing in peripheral blood samples of 3 healthy donors (HDs), 4 COVID-19 patients (Covs) and 4 COVID-19 patients with active gynecological tumor (TCs) pre- and post- anti-tumor treatment. All Covs patients had recovered from their acute infection. Interestingly, the molecular features of PBMCs in TCs are similar to that in Covs, suggesting that convalescent COVID-19 with gynecologic tumors do not have major immunological changes and may be protected against reinfection similar to COVID-19 patients without tumors. Moreover, the chemotherapy given to these patients mainly caused neutropenia, while having little effect on the proportion and functional phenotype of T and B cells, and T cell clonal expansion. Notably, anti-PD-L1 treatment massively increased cytotoxic scores of NK cells, and T cells, and facilitated clonal expansion of T cells in these patients. It is likely that T cells could protect patients from SARS-CoV-2 virus reinfection and anti-PD-L1 treatment can enhance the anti-viral activity of the T cells.

15.
Zhonghua Nan Ke Xue ; 27(8): 738-741, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34914248

RESUMO

The male reproductive system has a structural basis for being invaded by the SARS-CoV-2 virus. Existing evidence shows that SARS-CoV-2 can cause substantial damage to testicular tissues, pituitary-testicular axis hormone homeostasis, and production and quality of sperm in male patients. Local inflammation of the testis, cytokine storm and fever are considered to be the potential pathogenic factors for testis injury. COVID-19, as a rapidly spreading disease, requires close attention for its impact on the male reproductive system.


Assuntos
COVID-19 , SARS-CoV-2 , Fertilidade , Humanos , Masculino , Espermatozoides , Testículo
16.
Front Chem ; 9: 780688, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34912783

RESUMO

Engineering the heterogeneous interface fusing MOFs and inorganic active component is an effective strategy to improve the electrochemical performance. Herein, we report a new Ni3-based MOF (denoted as CTGU-24) with an infrequent two-fold interpenetrating 3D (3,8)-connected network constructed from Ni(II) trimer and mixed tripodal tectonics for the electrocatalytic methanol oxidation reaction (MOR). In order to improve its stability and activities, the heterogeneous hybrid CTGU-24@NiOOH has been fabricated successfully via the first preparation of the NiOOH nanosphere and then in situ formation of CTGU-24 decorated on the NiOOH surface. Moreover, the integration of CTGU-24@NiOOH and different additives [acetylene black (AB) and ketjen black (KB)], resulting in the optimized hybrid sample AB&CTGU-24@NiOOH (4:4). It attains better MOR performance with an area-specific peak current density of 34.53 mA·cm-2 than pure CTGU-24 (14.99 mA·cm-2) and improved durability in an alkali medium. The new findings indicate that the CTGU-24@NiOOH heterostructure formed in situ and the integration of moderate additives are critical to optimizing and improving electrocatalytic activity of pure MOF crystalline material.

17.
Clin Breast Cancer ; 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34963613

RESUMO

OBJECTIVE: To explore the neutrophil-to-lymphocyte ratio (NLR), red cell distribution width (RDW) and serum tumor markers as differential diagnostic markers of breast cancer (BC) and breast fibroadenoma (FA) and their associations with histopathological indicators and molecular typing in BC patients. METHODS: We collected pathological and routine clinical test data [NLR, RDW, serum tumor markers (CEA, CA15-3, CA125, CA19-9)] of 653 patients with BC and 100 patients with FA. After identifying indicators with significant inter-group differences, we used ROC curves to determine clinically significant cutoff values. Binary logistic regression analyses and ROC curves were used to analyze combined models for the differential diagnosis of BC and FA. Ordinal multinomial logistic regression analysis was used to explore correlations between routine clinical test indicators and pathological BC features. RESULTS: The BC and FA groups had significantly different CEA, NLR, and CA19-9 levels (P < .05), with respective areas under the curve (AUC) of 0.799, 0.747, and 0.711 for differentiating BC from FA and respective optimal cutoff values of 1.35 ng/mL, 1.58, and 8.55 U/mL. Binary logistic regression and ROC curve analysis showed that CEA was superior to the other 2 factors for the differential diagnosis of BC and FA. whereas the combined use of all three indicators was diagnostically most effective (AUC = 0.886; 95% confidence interval: 0.838-0.933, P = .000; sensitivity and/or specificity: 76.5%/88.9%). Ordered multinomial logistic regression analysis showed that NLR, CEA, and CA15-3 correlated positively with BC TNM staging; RDW was negatively correlated with BC histological grade; RDW, CA15-3 and CA125 were obviously associated with BC molecular typing. CONCLUSION: The combination of CEA, NLR, and CA19-9 may be used to screen and diagnose BC. NLR, CEA and CA15-3 are related to the TNM staging of BC. RDW is related to BC histological grading. RDW, CA15-3 and CA125 are related to BC molecular typing.

18.
Chin J Nat Med ; 19(12): 900-911, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34961588

RESUMO

Buxue Yimu Pill (BYP) is a classic gynecological medicine in China, which is composed of Angelica sinensis (Oliv.) Diels, Leonurus japonicus Houtt, Astragalus membranaceus (Fisch.) Bunge, Colla corii asini and Citrus reticulata Blanco. It has been widely used in clinical therapy with the function of enriching Blood, nourishing Qi, and removing blood stasis. The current study was designed to determine the bioactive molecules and therapeutic mechanism of BYP against hemorrhagic anemia. Herein, GC-MS and UPLC/Q-TOF-MS/MS were employed to identify the chemical compounds from BYP. The genecards database (https: //www.genecards.org/) was used to obtain the potential target proteins related to hemorrhagic anemia. Autodock/Vina was adopted to evaluate the binding ability of protein receptors and chemical ligands. Gene ontology and KEGG pathway enrichment analysis were conducted using the ClusterProfiler. As a result, a total of 62 candidate molecules were identified and 152 targets related to hemorrhagic anemia were obtained. Furthermore, 34 active molecules and 140 targets were obtained through the virtual screening experiment. The data of molecular-target (M-T), target-pathway (T-P), and molecular-target-pathway (M-T-P) network suggested that 32 active molecules enhanced hematopoiesis and activated the immune system by regulating 57 important targets. Pharmacological experiments showed that BYP significantly increased the counts of RBC, HGB, and HCT, and significantly down-regulated the expression of EPO, IL-6, CSF3, NOS2, VEGFA, PDGFRB, and TGFB1. The results also showed that leonurine, leonuriside B, leosibiricin, ononin, rutin, astragaloside I, riligustilide and levistolide A, were the active molecules closely related to enriching Blood. In conclusion, based on molecular docking, network pharmacology and validation experiment results, the enriching blood effect of BYP on hemorrhagic anemia may be associated with hematopoiesis, anti-inflammation, and immunity enhancement.


Assuntos
Anemia , Medicamentos de Ervas Chinesas , Anemia/tratamento farmacológico , Humanos , Simulação de Acoplamento Molecular , Espectrometria de Massas em Tandem
19.
Artigo em Inglês | MEDLINE | ID: mdl-34942313

RESUMO

PURPOSE: While definitive chemoradiotherapy (dCRT) remains the most effective treatment modality in limited stage small-cell lung cancer (SCLC), some progress quickly or develop serious radiation-induced thoracic toxicity (RITT). Molecular correlates of response to dCRT remain to be explored. METHODS AND MATERIALS: Genomic profiling was performed retrospectively on 231 limited-stage SCLC patients treated with dCRT between 2015 and 2019 using a customized panel covering cancer- and radiotherapy response-related genes. Exploratory associations of progression-free survival (PFS), overall survival (OS) and RITT with clinical features, tumor genetic, genomic and molecular pathway alterations and single nucleotide polymorphisms (SNPs) were conducted. RESULTS: In addition to the common SCLC genes, such as TP53, RB1, and NOTCH1/2, potentially actionable mutations in EGFR, KRAS and BRCA1/2 were among the top alterations in the cohort. At the single-gene level, CDK4 and GATA6 alterations were independent predictors of poor survival by multivariate analysis. At the genomic level, high tumor mutational burden (TMB) was strongly associated with favorable survival outcome. Pathway-level analysis showed that activating mutations in the MAPK/ERK pathway genes, particularly those in EGFR/ERBB2, correlated with poor survival. Combined analysis enabled optimized risk stratification of post-dCRT survival. On the other hand, our study also confirmed that SNPs in MTHFR, CYP2B6, NQO1, and LIG4 were risk alleles of high-grade RITT. Remarkably, somatic loss-of-function mutations in the DNA damage repair pathway genes were associated increased risk of high-grade RITT, particularly pneumonitis, which likely reflect a complex interplay between the tumor and its immune microenvironment. CONCLUSIONS: Taken together, by examining the mutational landscape of a large cohort of limited-stage SCLC, we identified novel molecular predictors of survival and RITT. Our findings also implicate several key molecular pathways, including the MAPK/ERK and DDR pathways, in the regulation of dCRT response.

20.
Hepatology ; 2021 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-34954829

RESUMO

BACKGROUND & AIMS: Early detection of primary liver cancer (PLC), including hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), combined HCC-ICC (cHCC-ICC), is essential for patients' survival. This study aims to develop an accurate and affordable method for PLC early detection and differentiating ICC from HCC using plasma cell-free DNA (cfDNA) fragmentomic profiles. APPROACH & RESULTS: Whole-genome sequencings (WGS) were performed using plasma cfDNA samples from 192 PLC patients (159 HCC, 26 ICC, 7 cHCC-ICC) and 170 non-cancer controls (including 53 liver cirrhosis[LC] or hepatitis B virus[HBV]-positive) enrolled in the training cohort. An ensembled stacked model for PLC detection was constructed using the training cohort. The model performance was assessed in an independent test cohort (189 PLC patients [157 HCC, 26 ICC, 6 cHCC-ICC], 164 non-cancer controls [including 51 LC/HBV]). Our model showed excellent performance for cancer detection in the test cohort (Area Under the Curve [AUC]:0.995, 96.8% sensitivity at 98.8% specificity). It showed excellent sensitivities in detecting early-stages PLC (I: 95.9%, II: 97.9%), small tumors (<=3cm: 98.2%), and HCC (96.2%) or ICC (100%). The AUC for distinguishing PLC from LC/HBV reached 0.985 (96.8% specificity at 96.1% specificity). Promisingly, our model maintained consistent performances during the downsampling process, even using 1X coverage data (AUC: 0.994, 93.7% sensitivity at 98.8% specificity). A separate model showed potential for distinguishing ICC from HCC (AUC: 0.776). CONCLUSIONS: Our model, out-performing previous reports at a lower cost by using solely low coverage WGS data, exhibits excellent clinical potential for ultra-sensitive and affordable detecting PLC and its subtypes.

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