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1.
Brain Behav Immun ; 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33737172

RESUMO

Impaired amyloid-ß (Aß) clearance is believed to be a primary cause of Alzheimer's disease (AD), and peripheral abnormalities in Aß clearance have recently been linked to AD pathogenesis and progression. Data from recent genome-wide association studies have linked genetic risk factors associated with altered functions of more immune cells to AD pathology. Here, we first identified correlations of Smad3 signaling activation in peripheral macrophages with AD progression and phagocytosis of Aß. Then, manipulating the Smad3 signaling regulated macrophage phagocytosis of Aß and induced switch of macrophage inflammatory phenotypes in our cell cultures. In our mouse models, flag-tagged or fluorescent-dye conjugated Aß was injected into the lateral ventricles or tail veins, and traced. Interestingly, blocking Smad3 signaling efficiently increased Aß clearance by macrophages, reduced Aß in the periphery and thereby enhanced Aß efflux from the brain. Moreover, in our APP/PS1 transgenic AD model mice, Smad3 inhibition significantly attenuated Aß deposition and neuroinflammation, and ameliorated cognitive deficits, probably by enhancing the peripheral clearance of Aß. In conclusion, enhancing Aß clearance by peripheral macrophages through Smad3 inhibition attenuated AD-related pathology and cognitive deficits, which may provide a new perspective for understanding AD and finding novel therapeutic approaches.

2.
Transl Oncol ; 14(6): 101074, 2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33744726

RESUMO

PURPOSE: Carrimycin is a newly synthesized macrolide antibiotic with good antibacterial effect. Exploratory experiments found its function in regulating cell physiology, proliferation and immunity, suggesting its potential anti-tumor capacity. The aim of this study is to investigate the anti-tumor effect of carrimycin against human oral squamous cell carcinoma cells in vitro and in vivo. METHODS: Human oral squamous cell carcinoma cells (HN30/HN6/Cal27/HB96 cell lines) were treated with gradient concentration of carrimycin. Cell proliferation, colony formation and migration ability were analyzed. Cell cycle and apoptosis were assessed by flow cytometry. The effect of carrimycin on OSCC in vivo was investigated in tumor xenograft models. Immunohistochemistry, western blot assay and TUNEL assays of tissue samples from xenografts were performed. The key proteins in PI3K/AKT/mTOR pathway and MAPK pathway were examined by western blot. RESULTS: As the concentration of carrimycin increased, the proliferation, colony formation and migration ability of OSCC cells were inhibited. After treating with carrimycin, cell cycle was arrested in G0/G1 phase and cell apoptosis was promoted. The tumor growth of xenografts was significantly suppressed. Furthermore, the expression of p-PI3K, p-AKT, p-mTOR, p-S6K, p-4EBP1, p-ERK and p-p38 were down-regulated in vitro and in vivo. CONCLUSIONS: Carrimycin can inhibit the biological activities of OSCC cells in vitro and in vivo, and regulate the PI3K/AKT/mTOR and MAPK pathways.

3.
Oral Dis ; 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33751732

RESUMO

OBJECTIVES: To determine the clinicopathological features of epithelioid sarcoma presenting in head and neck region (HNES) and elucidate diagnostic key points and treatment options for HNES. MATERIALS AND METHODS: A total of 12 HNES cases were collected in our department from 2010 to 2020. Their clinical information and pathological features were documented, and relevant follow-up was performed. Immunohistochemistry was carried to analyze the protein markers of HNES. RESULTS: Of the 12 HNES cases, 10 were primary tumors and 2 were metastasized from foot and shoulder, respectively. The patients with primary tumors were significantly younger than those with metastasized ones (22.7 vs 41.5, p = .0157), and male patients outnumbered female patients (3:1). Of all HNES cases, 9 were classic subtype, and 3 were proximal subtype. HNES patients had a poor prognosis, with 5-year overall survival of 41.5% and 5-year relapse-free survival of 22.5%. A loss of INI1 was identified as the hallmark of HNES with 83.3% (10/12) of HNES cases presenting as EZH2 positive. CONCLUSIONS: HNES is more prevalent at younger ages and in males, has a poor prognosis, and exhibits a greater proportion of classic subtype than proximal subtype. EZH2 inhibitor has therapeutic potential in HNES.

4.
J Neuroinflammation ; 18(1): 68, 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33750404

RESUMO

OBJECTIVE: Neuroinflammation plays a critical role in central nervous system diseases. Exosomal miRNAs released from various cells are implicated in cell-to-cell communication. Prior studies have placed substantial emphasis on the role of cytokines in mast cell-microglia interactions during neuroinflammation. However, it has never been clearly determined whether exosomal miRNAs participate in the interaction between mast cells and microglia and thus mediate neuroinflammation. METHODS: The characteristics of exosomes isolated from cell culture supernatants were confirmed by transmission electron microscopy (TEM), nanoparticle-tracking analysis (NTA) and Western blot. The transfer of PKH67-labelled exosomes and Cy3-labelled miR-409-3p was observed by fluorescence microscopy. Migration and activation of murine BV-2 microglial cells were evaluated through Transwell assays and immunofluorescence staining for Iba1 and CD68. CD86, IL-1ß, IL-6 and TNF-α were assessed via qRT-PCR and ELISA. MiR-409-3p was detected by qRT-PCR. Nr4a2 and NF-κB levels were measured by western blot. Regulatory effects were identified by luciferase reporter assays. RESULTS: Lipopolysaccharide (LPS)-stimulated murine P815 mast cells secreted exosomes that were efficiently taken up by murine BV-2 cells, which promoted murine BV-2 cell migration and activation. LPS-P815 exosomes increased the CD86, IL-1ß, IL-6 and TNF-α levels in murine BV-2 microglia. Furthermore, activated mast cells delivered exosomal miR-409-3p to murine BV-2 microglia. Upregulated miR-409-3p promoted murine BV-2 microglial migration, activation and neuroinflammation by targeting Nr4a2 to activate the NF-κB pathway. CONCLUSION: Exosomal miR-409-3p secreted from activated mast cells promotes microglial migration, activation and neuroinflammation by targeting Nr4a2 to activate the NF-κB pathway, which provides evidence that not only cytokines but also exosomal miRNAs participate in neuroinflammation. In the future, targeting exosomal miRNAs may provide new insights into neuroinflammation.

5.
Cancer Cell Int ; 21(1): 167, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33712015

RESUMO

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a common tumor worldwide with poor prognosis. The pathogenesis of human papillomavirus (HPV)-positive and HPV-negative HNSCCs differs. However, few studies have considered the HPV status when identifying biomarkers for HNSCC. Thus, the identification of biomarkers for HPV-positive and HPV-negative HNSCCs is urgently needed. METHODS: Three microarray datasets from Gene Expression Omnibus (GEO) were analyzed, and the differentially expressed genes (DEGs) were obtained. Then, functional enrichment pathway analysis was performed and protein-protein interaction (PPI) networks were constructed. The expression of hub genes at both the mRNA and protein level was determined in Oncomine, The Cancer Genome Atlas (TCGA) and the Human Protein Atlas (HPA). In addition, survival analysis of the patient stratified by HPV status and the expression levels of key genes were performed based on TCGA data. The role of AREG, STAG3, CAV1 and C19orf57 in cancer were analyzed through Gene set enrichment analysis (GSEA). The top ten small molecule drugs were identified and the therapeutic value of zonisamide, NVP-AUY922, PP-2 and fostamatinib was further evaluated in six HPV-negative HNSCC cell lines. Finally, the therapeutic value of NVP-AUY922 was tested in vivo based on three HPV-negative HNSCC models, and statistical analysis was performed. RESULTS: In total, 47 DEGs were obtained, 11 of which were identified as hub genes. Biological process analysis indicated that the hub genes were associated with the G1/S transition of the mitotic cell cycle. Survival analysis uncovered that the prognostic value of AREG, STAG3, C19orf57 and CAV1 differed between HPV-positive and HPV-negative patients. Gene set enrichment analysis (GSEA) showed the role of AREG, STAG3 and CAV1 in dysregulated pathways of tumor. Ten small molecules were identified as potential drugs specifically for HPV-positive or HPV-negative patients; three-NVP-AUY922, fostamatinib and PP-2-greatly inhibited the proliferation of six HPV-negative HNSCC cell lines in vitro, and NVP-AUY922 inhibited three HPV-negative HNSCC xenografts in vivo. CONCLUSIONS: In conclusion, AREG, STAG3, C19orf57 and CAV1 are key prognostic factors and potential therapeutic targets in HPV-negative HNSCC. NVP-AUY922, fostamatinib and PP-2 may be effective drugs for HPV-negative HNSCC.

7.
Sci Adv ; 7(9)2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33627421

RESUMO

Current therapeutic strategies such as angiogenic therapy and anti-inflammatory therapy for treating myocardial infarction have limited success. An effective approach may benefit from resolution of excessive inflammation combined with enhancement of angiogenesis. Here, we developed a microRNA-21-5p delivery system using functionalized mesoporous silica nanoparticles (MSNs) with additional intrinsic therapeutic effects. These nanocarriers were encapsulated into an injectable hydrogel matrix (Gel@MSN/miR-21-5p) to enable controlled on-demand microRNA-21 delivery triggered by the local acidic microenvironment. In a porcine model of myocardial infarction, we demonstrated that the released MSN complexes notably inhibited the inflammatory response by inhibiting the polarization of M1 macrophage within the infarcted myocardium, while further microRNA-21-5p delivery by MSNs to endothelial cells markedly promoted local neovascularization and rescued at-risk cardiomyocytes. The synergy of anti-inflammatory and proangiogenic effects effectively reduced infarct size in a porcine model of myocardial infarction.

8.
Nat Commun ; 12(1): 1275, 2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33627666

RESUMO

Synthetic lethality is emerging as an important cancer therapeutic paradigm, while the comprehensive selective treatment opportunities for various tumors have not yet been explored. We develop the Synthetic Lethality Knowledge Graph (SLKG), presenting the tumor therapy landscape of synthetic lethality (SL) and synthetic dosage lethality (SDL). SLKG integrates the large-scale entity of different tumors, drugs and drug targets by exploring a comprehensive set of SL and SDL pairs. The overall therapy landscape is prioritized to identify the best repurposable drug candidates and drug combinations with literature supports, in vitro pharmacologic evidence or clinical trial records. Finally, cladribine, an FDA-approved multiple sclerosis treatment drug, is selected and identified as a repurposable drug for treating melanoma with CDKN2A mutation by in vitro validation, serving as a demonstrating SLKG utility example for novel tumor therapy discovery. Collectively, SLKG forms the computational basis to uncover cancer-specific susceptibilities and therapy strategies based on the principle of synthetic lethality.


Assuntos
Mutações Sintéticas Letais/genética , Linhagem Celular Tumoral , Cladribina/uso terapêutico , Inibidor p16 de Quinase Dependente de Ciclina/genética , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Modelos Teóricos , Mutação/genética
9.
Waste Manag ; 124: 283-292, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33640668

RESUMO

Recycling of spent Li-ion batteries is crucial for achieving sustainable development of battery industry. Current recycling processes mainly focus on valuable metals but less attention has been paid to spent graphite, which generally ends up as secondary waste. In this study, a process for preparing graphene and recovering Li in anode as a by-product from spent graphite was developed. The key point was to re-charge the spent LIBs to generate lithium graphite intercalation compounds. The lithium graphite intercalation compounds were then subjected to a hydrolysis procedure and graphene could be produced through ultrasonic treatment via the expansion/micro-explosion mechanism. Experimental results demonstrated that 1-4 layered graphene could be efficiently produced when spent Li-ion batteries with beyond 50% capacity were re-charged. The prepared graphene showed high quantity containing few defects (ID/IG = 0.33, C/O = 13.2 by energy dispersive spectroscopy and C/O = 8.8 by X-ray photoelectron spectroscopy). In addition, Li was simultaneously recovered in the form of battery-grade lithium carbonate in the above process. Economic analysis indicated that the graphene production cost was extremely low ($540/ton) compared to that of commercial graphene.


Assuntos
Grafite , Lítio , Fontes de Energia Elétrica , Eletrodos , Reciclagem
11.
J Nanobiotechnology ; 19(1): 29, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33482822

RESUMO

BACKGROUND: Glioblastoma (GBM) is the most invasive primary intracranial tumor, and its effective treatment is one of the most daunting challenges in oncology. The blood-brain barrier (BBB) is the main obstacle that prevents the delivery of potentially active therapeutic compounds. In this study, a new type of pH-sensitive polymersomes has been designed for glioblastoma therapy to achieve a combination of radiotherapy and chemotherapy for U87-MG human glioblastoma xenografts in nude mice and significantly increased survival time. RESULTS: The Au-DOX@PO-ANG has a good ability to cross the blood-brain barrier and target tumors. This delivery system has pH-sensitivity and the ability to respond to the tumor microenvironment. Gold nanoparticles and doxorubicin are designed as a complex drug. This type of complex drug improve the radiotherapy (RT) effect of glioblastoma. The mice treated with Au-DOX@PO-ANG NPs have a significant reduction in tumor volume. CONCLUSION: In summary, a new pH-sensitive drug delivery system was fabricated for the treatment of glioblastoma. The new BBB-traversing drug delivery system potentially represents a novel approach to improve the effects of the treatment of intracranial tumors and provides hope for glioblastoma treatment.

12.
Eur Radiol ; 2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33492472

RESUMO

OBJECTIVE: To investigate the effect of different types of transverse sinus stenosis on blood flow patterns in the ipsilateral superior curve of the sigmoid sinus. METHODS: According to the morphology of transverse and sigmoid sinus sections in pulsatile tinnitus patients, ten idealized models with different degrees and positions of transverse sinus stenosis were constructed. Computational fluid dynamics simulations were performed to compare the hemodynamic characteristics among these models. Follow-up images of previous cases were included, which preliminarily confirmed the hypothesis that bone plate erosion of the sigmoid sinus sulcus is related to blood flow impingement. RESULTS: Blood flow impingement on the superior curve of the sigmoid sinus wall intensified with increasing degree of stenosis and decreased with increasing distance between the stenosis and the sigmoid sinus. The impact zone was generally confined to the anterior and lateral walls of the superior curve of the sigmoid sinus. When the stenosis was located far from the middle of the transverse sinus, the blood flow impingement on the sigmoid sinus wall was very weak. CONCLUSIONS: When stenosis is located far from the sigmoid sinus, the causes of tinnitus should be comprehensively considered instead of assuming that stenosis is the main cause. Bone plate erosion of the sigmoid sinus sulcus was promoted by blood flow impingement. KEY POINTS: • Ten idealized models with different degrees and positions of stenosis were constructed. • The causes of pulsatile tinnitus should be comprehensively considered. • Sigmoid sinus plate dehiscence was promoted by blood flow impingement.

13.
Chem Commun (Camb) ; 57(10): 1214-1217, 2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33416814

RESUMO

A twin-axial pseudorotaxane is constructed using a phenylpyridine salt with diethanolamine (DA-PY) and cucurbit[8]uril (CB[8]), and it not only displays phosphorescence in aqueous solution but it can also be used for targeted cell-imaging.

15.
ISA Trans ; 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33509596

RESUMO

Hysteresis severely reduces positioning accuracy of a piezoelectric nanopositioning system. Inverse hysteresis model-based control is difficult to maintain satisfied performance in presence of uncertainties and disturbances. Linear active disturbance rejection control (LADRC) is a practical approach. However, phase lag of the total disturbance estimation degrades its estimation ability and tracking performance. In this work, a phase-leading extended state observer (PLESO) is constructed by adding a phase-leading network to a linear extended state observer. Advantage of the PLESO on estimating the time-varying total disturbance is analyzed, and influence of the multiplication factor introduced by a PLESO is also discussed. By a leading phase provided by the PLESO, the phase-leading active disturbance rejection control (PLADRC) can compensate the total disturbance timelier, and more satisfied positioning can be guaranteed. Experimental results show that the PLADRC is superior to the LADRC in terms of dynamic responses and disturbance rejection. Without introducing nonlinearities or increasing the order, the PLESO provides an effective way to enhance the active disturbance rejection control (ADRC).

16.
Ecotoxicol Environ Saf ; 208: 111675, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33396007

RESUMO

Metal bioavailability controls its behaviors in soil-plant system, especially involved in biochar amendment. This study compared a rhizospheric pore-water extraction against a BCR sequential extraction method to understand cadmium (Cd) bioavailability in two typical Chinese soils. Soils were spiked with five levels of Cd (CdCl2) and remediated with 3% corn-straw derived biochar. After 60 days of lettuce growth, Cd accumulation and enzyme activities in tissues were analyzed. Results showed that biochar increased soil properties (pH, CEC and SOM) compared to un-amended soils, but decreased contents of bioavailable Cd in soil pore-water (Cdpore-water) and BCR extracted Cd (CdFi+Fii). Contents of Cdpore-water were lower in yellow-brown soils than that in red soils. Pearson analysis showed that bioavailable Cd is negatively correlated with soil pH and CEC (p < 0.05). Cd accumulation in lettuce roots and leaves both were decreased by biochar addition, and the established linear equations proved that soil Cdpore-water is the best predictor for Cd accumulation in lettuce roots (r2 = 0.964) and in leaves (r2 = 0.953), followed by CdFi+Fii. Transfer factor (TF) values of Cd from roots to leaves were lower than 1, and slightly better correlated with soil Cdpore-water (r = -0.674, p < 0.01) than CdFi+Fii (r = -0.615, p < 0.01). Aggregated boosted tree (ABT) analyses indicated that soil properties together with Cdpore-water contribute more than 50% to root enzyme activities. Collectively, soil Cdpore-water is a promising predictor of Cd bioavailability, accumulation and toxicity in soil-plant system with biochar addition.


Assuntos
Bioacumulação/efeitos dos fármacos , Cádmio/toxicidade , Carvão Vegetal/química , Alface/efeitos dos fármacos , Poluentes do Solo/toxicidade , Disponibilidade Biológica , Transporte Biológico , Cádmio/metabolismo , Alface/metabolismo , Modelos Teóricos , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/metabolismo , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/metabolismo , Caules de Planta/química , Rizosfera , Solo/química , Poluentes do Solo/metabolismo , Água/química , Zea mays/química
17.
J Med Chem ; 64(1): 543-565, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33369415

RESUMO

Analogues of the natural product cyclosporine A (CsA) were developed and assessed as antivirals against infection of hepatitis B virus (HBV) and its satellite hepatitis D virus (HDV). An analogue termed 27A exhibits potent inhibition of HBV/HDV infection by specifically blocking viral engagement to its cellular receptor NTCP, while it lacks immunosuppressive activity found in natural CsA. Intraperitoneal injection or oral intake of 27A protects HDV-susceptible mouse model from HDV infection. 27A serves as a promising lead for the development of novel anti-HDV/HBV agents.


Assuntos
Antivirais/uso terapêutico , Ciclosporina/uso terapêutico , Hepatite B/tratamento farmacológico , Hepatite D/tratamento farmacológico , Transportadores de Ânions Orgânicos Dependentes de Sódio/fisiologia , Simportadores/fisiologia , Administração Oral , Animais , Antivirais/administração & dosagem , Antivirais/farmacologia , Ciclosporina/administração & dosagem , Ciclosporina/farmacologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Células Hep G2 , Hepatite B/fisiopatologia , Hepatite D/fisiopatologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL
18.
Int Immunopharmacol ; 91: 107243, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33321467

RESUMO

The recurrence in colon cancer contributed to great difficulties in diagnostic and therapeutic treatment. Tumor microenvironment (TME) gains increasing attention recently. After univariate Cox analysis on relapse-free survival (RFS) and ESTIMATE analysis, WGCNA was further conducted to determine the TME and relapse-related genes in I-III colon cancer. Functional enrichment analyses were conducted. Furthermore, seven genes were screened to build a prognostic signature via LASSO and multivariate Cox analysis. Univariate followed multivariate Cox analysis all showed that the risk group calculated by the signature as a significant predictors. The ROC curves showed great prognostic in the internal training group, internal verification group, and independent external verification group. In the training group, the AUC at 1, 3, and 5 years was 0.737, 0.79, and 0.756. In addition, correlation analysis presented that the signature and genes involved in were significantly associated with the TME. Moreover, 3 of 7 genes (FAM78A, SGIP1, and MMP9) were validated to be associated with PDL1 through qRT-PCR.

19.
Mol Cell ; 81(2): 355-369.e10, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33321093

RESUMO

Ferroptosis is a form of necrotic cell death caused by iron-dependent peroxidation of polyunsaturated phospholipids on cell membranes and is actively suppressed by the cellular antioxidant systems. We report here that oxidoreductases, including NADPH-cytochrome P450 reductase (POR) and NADH-cytochrome b5 reductase (CYB5R1), transfer electrons from NAD(P)H to oxygen to generate hydrogen peroxide, which subsequently reacts with iron to generate reactive hydroxyl radicals for the peroxidation of the polyunsaturated fatty acid (PUFA) chains of membrane phospholipids, thereby disrupting membrane integrity during ferroptosis. Genetic knockout of POR and CYB5R1 decreases cellular hydrogen peroxide generation, preventing lipid peroxidation and ferroptosis. Moreover, POR knockdown in mouse liver prevents ConA-induced liver damage. Ferroptosis, therefore, is a result of incidental electron transfer carried out by POR/CYB5R1 oxidoreductase and thus needs to be constitutively countered by the antioxidant systems.


Assuntos
Membrana Celular/química , Sistema Enzimático do Citocromo P-450/genética , Citocromo-B(5) Redutase/genética , Ácidos Graxos Insaturados/metabolismo , Ferroptose/genética , NADP/metabolismo , Animais , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Concanavalina A/farmacologia , Sistema Enzimático do Citocromo P-450/deficiência , Citocromo-B(5) Redutase/deficiência , Transporte de Elétrons/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Células HEK293 , Células HeLa , Humanos , Peróxido de Hidrogênio/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Oxigênio/metabolismo , Compostos de Fenilureia/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Sorafenibe/farmacologia
20.
Clin Cancer Res ; 2020 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-33298472

RESUMO

PURPOSE: The gut microbiome (GM) is involved into anti-tumor immunotherapy and chemotherapy responses; however, evidence-based research on the role of GM in predicting response to neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC) remains scarce. This prospective, longitudinal study aims to evaluate the feasibility of the GM in predicting nCRT responses. EXPERIMENTAL DESIGN: We collected 167 fecal samples from 84 LARC patients before and after nCRT and 31 specimens from healthy individuals for 16S rRNA sequencing. Patients were divided into responders and non-responders according to pathological response to nCRT. After identifying microbial biomarkers related to nCRT responses, we constructed a random forest classifier for nCRT response prediction of a training cohort of baseline samples from 37 patients and validated the classifier in another cohort of 47 patients. RESULTS: We observed significant microbiome alterations represented by a decrease in LARC-related pathogens and an increase in Lactobacillus and Streptococcus during nCRT. Furthermore, a prominent microbiota difference between responders and non-responders was noticed in the baseline samples. Microbes related with butyrate production including Roseburia, Dorea and Anaerostipes, were overrepresented in responders, whereas Coriobacteriaceae and Fusobacterium were overrepresented in non-responders. Ten biomarkers were selected for the response-prediction classifier, including Dorea, Anaerostipes and Streptococcus, which yielded an area under the curve value of 93.57% (95% CI: 85.76%-100.00%) in the training cohort and 73.53% (95% CI: 58.96%-88.11%) in the validation cohort. CONCLUSIONS: The GM offers novel potential biomarkers for predicting nCRT responses, which has important manifestations in the clinical management of these patients.

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