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1.
J Ultrasound Med ; 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-35005793

RESUMO

OBJECTIVES: To assess the changes of blood flow in adenomyosis (AM) after higher-dose oxytocin (OT) in different doses, and to evaluate the safety for patients. METHODS: A total of 124 patients with AM were randomly divided into 4 groups with continuous intravenous infusion of OT as 0.06, 0.12, 0.24 and 0.36 U/min, respectively. The changes of arteries of AM before and after intravenous infusion of OT were observed by color Doppler ultrasound. The changes of blood flow volume of the artery of AM before and after intravenous infusion of OT were compared among the 4 groups, and the vital signs and adverse drug reactions were monitored during intravenous drip. RESULTS: During the trial, no severe adverse reactions occurred and the vital signs of all the patients were stable. Among the 4 groups, it was found that there was a significant difference in the change of blood flow volume of blood artery in AM lesions between 0.06 U/min OT group and the other three groups after intravenous drip of OT (P < .05), but there was no significant difference in blood flow volume among the three groups (P > .05), and the difference of adverse drug reactions was statistically significant with the increase of OT dose (P < .05). CONCLUSION: OT can effectively reduce the blood flow volume of AM lesions, and continuous intravenous infusion of 0.12 U/min OT is an appropriate dose that can not only minimize the blood flow volume but also reduce the incidence of adverse drug reactions.

2.
Gene ; : 146132, 2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-34999180

RESUMO

B-acute lymphoblastic leukemia (B-ALL) is characterized by clonal expansion of immature B-lymphocytes in the bone marrow, blood, or other tissues. Chromosomal translocations have often been reported in B-ALL, which are important for its prognosis. B-ALL patients with ETV6-RUNX1 fusion have favorable outcomes, but the mechanisms remain to be clarified. In the present study, we crossed the selected WGCNA module genes and differential expression genes to obtain core genes, and random forest algorithm, a type of supervised learning analysis, was conducted to evaluate the importance of those core genes in distinguishing B-ALL samples with ETV6-RUNX2 fusion with extracting 5 genes as gene markers for ETV6-RUNX2 fusion. Moreover, we calculated the immune infiltration profiles and screened out the ETV6-RUNX2 association immune cells using the CIBERSORT algorithm. In conclusion, combined with various solid informatics methods, we depicted the underlying molecular and immune mechanism of ETV6-RUNX2 fusion and providing potential biological targets for diagnosing and treating B-ALL in the future.

3.
WIREs Mech Dis ; 14(1): e1538, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35023325

RESUMO

Tetracycline and its derivative tigecycline are clinical options against Gram-negative bacterial infections. The emergence of mobile Tet(X) enzymes that destruct tetracycline-type antibiotics is posing a big challenge to antibacterial therapy and food/environmental securities. Here, we present an update on a growing number of Tet(X) variants. We describe structure and action of Tet(X) enzyme, and discuss the evolutional origin. In addition, potential Tet(X) inhibitors are given. This mini-review might benefit better understanding of Tet(X)-mediated tigecycline resistance. This article is categorized under: Infectious Diseases > Genetics/Genomics/Epigenetics Infectious Diseases > Environmental Factors Infectious Diseases > Molecular and Cellular Physiology.

4.
Biomater Sci ; 2022 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-35024701

RESUMO

Modern medicine has increasingly higher requirements for antibacterial materials. To overcome this challenge, we use alkynyl monomers, amino monomers, formaldehyde, and acetic acid as raw materials to synthesize a series of poly-tetrahydropyrimidine (P-THP) polymers through multicomponent polymerizations (MCPs). P-THP polymers can effectively inhibit the growth of Gram-positive bacteria (Staphylococcus aureus, S. aureus) and Gram-negative bacteria (Escherichia. coli, E. coli), and can prevent bacteria from developing drug resistance within at least 16 generations. Besides, we prepared P-THP antibacterial coatings and explored their antibacterial properties. In vitro antibacterial experiments showed that P-THP coatings can prevent the formation of bacterial biofilms, and the coatings have a lasting killing effect on E. coli and S. aureus. The mouse wound infection experiments proved that P-THP polymers can significantly accelerate skin tissue regeneration and wound healing. Moreover, the P-THP textile obtained by electrospinning also has antibacterial properties and has great application prospects in the field of N95 masks. Generally speaking, P-THP polymers have considerable application potential in the field of treating bacterial infections and promoting wound healing.

5.
Ecotoxicol Environ Saf ; 231: 113173, 2022 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-35007830

RESUMO

A growing body of evidence associated particulate matter (PM) exposure with lipid metabolism disorders, yet, the underlying mechanism remains to be elucidated. Among the major lipid metabolism modulators, peroxisome proliferator-activated receptor (PPAR) alpha plays an important role. In the current study, an individually ventilated cage (IVC) system was used to expose C57/B6 mice to real-ambient PM for six weeks, with or without co-treatment of PPAR alpha agonist WY14,643. The general parameters, liver and adipose tissue pathology, serum lipids, metal deposition and lipid profile of liver were assessed. The results indicated that six weeks of real-ambient PM exposure induced dyslipidemia, including increased serum triglycerides (TG) and decreased high density lipoprotein cholesterol (HDL-C) level, along with steatosis in liver, increased size of adipocytes in white adipose tissue (WAT) and whitening of brown adipose tissue (BAT). ICP-MS results indicated increased Cr and As deposition in liver. Lipidomics analysis revealed that glycerophospholipids and cytochrome P450 pathway were most significantly affected by PM exposure. Several lipid metabolism-related genes, including CYP4A14 in liver and UCP1 in BAT were downregulated following PM exposure. WY14,643 treatment alleviated PM-induced dyslipidemia, liver steatosis and whitening of BAT, while enhancing CD36, SLC27A1, CYP4A14 and UCP1 expression. In conclusion, PPAR alpha pathway participates in PM-induced lipid metabolism disorder, PPAR alpha agonist WY14,643 treatment exerted protective effects on PM-induced dyslipidemia, liver steatosis and whitening of BAT, but not on increased adipocyte size of WAT.

6.
World J Surg Oncol ; 20(1): 17, 2022 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-35027071

RESUMO

BACKGROUND: This study aimed to analyze the clinical and pathological features of extrauterine endometrial stromal sarcoma (EESS) and explore an effective therapeutic regimen to reduce the recurrence rate in low-grade EESS patients. METHODS: Ten LG-EESS patients who were treated at the Chinese Academy of Medical Sciences Cancer Institute and Hospital from June 1999 to June 2019 were collected and analyzed. RESULTS: (1) Patient demographics are summarized in manuscript. Preoperative CA125 examination showed that 8 patients had a median level of 49.5 U/L (15.4-168.0 U/L). (2) All ten patients underwent tumor cytoreductive surgery. Five patients underwent optimal tumor resection and achieved an R0 resection. After the initial surgery, 7 patients who had multiple metastasis were treated with adjuvant chemotherapy, 2 patients with vaginal ESS were treated with chemotherapy and radiation therapy, and 6 patients with ER/PR positive received hormone therapy with or without chemotherapy. (2) Most EESS patients had multiple tumors. The omentum was the most commonly affected site, followed by the ovaries. (3) The median follow-up was 94 (range: 27-228) months, and recurrence was observed in 3 patients (n = 10, 30%) who underwent non-optimal surgery and no hormone therapy. The 5-year and 10-year DFS rates were both 70%, as shown in Fig. 2. OS was both 100% at 5 and 10 years. CONCLUSION: As a conclusion, EESS is a rare disease and LG-EESS has a good prognosis. Surgery remains the available treatment for patients. LG-EESS has a risk of late recurrence which requires a long-term follow-up. With a limited sample size, our study shows optimal tumor reductive surgery and adjuvant hormone therapy may significantly reduce the risk of recurrence.

7.
Nanoscale ; 2022 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-35018953

RESUMO

The external quantum efficiency of a high-Al content (>0.6) AlGaN deep-ultraviolet (DUV) light-emitting diode is typically below 1% in the sub-250 nm wavelength range. One of the main reasons for this low efficiency is the fundamental properties of high-Al content AlGaN comprising the transverse-magnetic (TM)-dominant emission and low light extraction due to the total internal reflection (TIR). This work demonstrates a truncated pyramid nanostructure with fine-tuned multiple facets in an (AlN)8/(GaN)2 digital alloy to achieve highly efficient DUV emission at 234 nm. By applying nanoimprint lithography, dry and wet etching, a hexagonal truncated pyramid nanohole structure is fabricated featuring multiple crystal facets of (0001), (10-13), and (20-21) planes. These fine-tuned multiple facets act as reflecting mirrors that can effectively modulate the light propagation and extraction patterns to overcome the TIR via multiple reflections and enhanced scattering. Consequently, significant light extraction enhancements of 5.6 times and 1.1 times for TM and transverse-electric emissions are achieved in the truncated pyramid nanohole structure, respectively. The total luminous intensity of this unique nanostructure is greatly increased by 191% compared to that of a conventional planar structure. The truncated pyramid AlN/GaN nanostructure with fine-tuned multiple facets used in this work provides a promising approach for realizing highly efficient sub-250 nm DUV light-emitting devices.

8.
Food Chem ; 366: 130554, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34284188

RESUMO

Standard fermentation (SF) mainly affected the metabolism of glycerophospholipid and sphingolipid, and increased the total lipid content of goat milk. Content of total lipid was decreased by magnetic fermentation compared with SF, mainly due to triacylglycerol and diacylglycerol. Comprehensive characteristic of lipids dynamic changes during standard and magnetic fermentation was performed using high-throughput quantitative lipidomics. Totally, 488 lipid molecular species covering 12 subclasses were detected, and triacylglycerol was the highest levels, followed by diacylglycerol and phosphoethanolamine in the whole fermentation stage. Specifically, except for ceramide and simple Glc series, the content of all polar lipids in SF was dropped and neutral lipids subjoined. Compared with SF, the decrease of triacylglycerol (1752.47 to 784.78 µg/mL), diacylglycerol (60.36 to 24.89 µg/mL) and simple Glc series (4.36 to 2.40 µg/mL) were observed, while ceramide (6.54 to 25.87 µg/mL) increased, suggesting magnetic fermentation as effective approach to potentially improve the nutritional of goat milk.


Assuntos
Lipídeos , Leite , Animais , Fermentação , Cabras , Lipídeos/análise , Fenômenos Magnéticos , Leite/química , Valor Nutritivo
9.
Chemosphere ; 289: 133238, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34896427

RESUMO

Fipronil (FP) is an emerging insecticide which could induce reproductive toxicity in male rats at very low dosage, but the occurrence of FP and its transformation products (FPs) in human seminal plasma and their impacts on human semen quality have not been documented. In this study, FPs including FP, fipronil desulfinyl (FP-DES), fipronil sulfone (FP-SFO), fipronil amide (FP-AM), and fipronil sulfide (FP-SFI), were measured in seminal plasma samples (n = 200), which were collected from Shijiazhuang, north China. The cumulative concentration of FPs (ΣFPs), in the seminal plasma samples ranged from 0.003 to 0.180 ng/mL (median: 0.043 ng/mL). FP-SFO was the major target analyte (median: 0.040 ng/mL), accounting for approximately 42.3-100.0% of the ΣFPs. Significantly higher exposure levels of FPs were found in the overweight or obese group (≥25 kg/m2) vs. the normal BMI group (18.5-25 kg/m2) (ΣFPs: 0.047 vs. 0.033 ng/mL), never smoking group vs. current smoking group (ΣFPs: 0.057 vs. 0.037 ng/mL), and low sexual frequency group (<1 time/week) vs. high sexual frequency group (≥3 times/week) (ΣFPs: 0.048 vs. 0.030 ng/mL). No significant association between FPs and impaired semen quality parameter was found in this study. This is the first time to report FPs' occurrence in human seminal plasma and variations in their concentrations among people with different demographic and behavioral characteristics. Further studies on adverse effects of exposure to FPs on reproductive function are needed.


Assuntos
Inseticidas , Sêmen , Animais , China , Humanos , Inseticidas/análise , Inseticidas/toxicidade , Masculino , Pirazóis , Ratos , Sêmen/química , Análise do Sêmen
10.
Food Chem ; 370: 131353, 2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-34788964

RESUMO

A highly effective molecularly imprinted electrochemiluminescence sensor was constructed for prometryn determination in environmental and biological samples by using perovskite quantum dots coated with a molecularly imprinted silica layer (MIP/CsPbBr3-QDs) as the recognition and response element. MIP/CsPbBr3-QDs were immobilized on a glassy carbon electrode (GCE) through electropolymerization, and the electrochemiluminescence (ECL) response of MIP/CsPbBr3-QDs could be motivated under the condition of H2O2 as co-reactant. ECL signal was selectively quenched with prometryn by hindering electron transfer and directly proportional to the logarithm of prometryn concentration (0.10-500.0 µg/L) with a correlation coefficient of 0.9960. Limits of detection in fish and seawater samples were 0.010 µg/kg and 0.050 µg/L, respectively. Excellent recoveries of 88.0%-106.0% were acquired for fish and seawater samples with a relative standard deviation below 4.2%. The constructed MIECL sensor based on MIP/CsPbBr3-QDs showed good stability, accuracy, and precision for sensitive detection of prometryn in aquaculture products and environmental samples.


Assuntos
Impressão Molecular , Pontos Quânticos , Animais , Compostos de Cálcio , Peróxido de Hidrogênio , Limite de Detecção , Polímeros Molecularmente Impressos , Óxidos , Prometrina , Titânio
11.
Artigo em Inglês | MEDLINE | ID: mdl-34848502

RESUMO

BACKGROUND AND OBJECTIVES: Patients with Alzheimer dementia display evidence of amyloid-related neurodegeneration. Our focus was to determine whether such patients also display evidence of a disease-targeting adaptive immune response mediated by CD4+ T cells. To test this hypothesis, we evaluated the CSF immune profiles of patients with Alzheimer clinical syndrome (ACS), who display clinically defined dementia. METHODS: Innate and adaptive immune profiles of patients with ACS were measured using multicolor flow cytometry. CSF-derived CD4+ and CD8+ T-cell receptor repertoire genetics were measured using next-generation sequencing. Brain-specific autoantibody signatures of CSF-derived antibody pools were measured using array technology or ELISA. CSF from similar-age healthy controls (HCs) was used as a comparator cohort. RESULTS: Innate cells were expanded in the CSF of patients with ACS in comparison to HCs, and innate cell expansion increased with age in the patients with ACS, but not HCs. Despite innate cell expansion in the CSF, the frequency of total CD4+ T cells reduced with age in the patients with ACS. T-cell receptor repertoire genetics indicated that T-cell clonal expansion is enhanced, and diversity is reduced in the patients with ACS compared with similar-age HCs. DISCUSSION: Examination of CSF indicates that CD4+ T cell-mediated adaptive immune responses are altered in patients with ACS. Understanding the underlying mechanisms affecting adaptive immunity will help move us toward the goal of slowing cognitive decline.

12.
Meat Sci ; 183: 108655, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34403850

RESUMO

During the thermal processing, proteins of Hengshan goat meat undergo structural modifications such as degradation, oxidation and denaturation, ultimately affect the palatability and acceptability. The results of several objective metrics demonstrated that thermal processing exhibited significant impacts on the tenderness of goat meat. The 551, 84, 72, and 121 proteins were identified in the control and thermal processed groups (boiled, steamed, and roasted), respectively. Compared with the control group, the 101, 98, and 109 differentially-expressed proteins were explored in the treatment groups. Furthermore, the functions of metabolic and skeletal muscle proteome were investigated and discussed. Sensory evaluation and proteomics analysis showed that steaming and boiling treatment had no significant effect on the tenderness of goat meat, while roasting significantly reduced the tenderness, indicating that the available thermal processing methods to ensure the tenderness of goat meat were steaming and boiling treatments. Thus, the established proteomics database of goat meat provided the valuable reference for rational selection of thermal processing methods.


Assuntos
Culinária/métodos , Proteínas Musculares/análise , Proteoma/análise , Carne Vermelha/análise , Adulto , Animais , Feminino , Cabras , Humanos , Masculino , Músculo Esquelético/química , Resistência ao Cisalhamento , Paladar
13.
Food Chem ; 369: 130948, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34474291

RESUMO

As preservative are extensively applied to prevent the quality degradation of Hengshan goat meat sausages, safety assessment based on lipid and elucidation of dynamic change mechanism is urgently needed. The effect of preservatives on lipidome profiles of sausages was investigated using UHPLC-Q-Orbitrap. Totally, 9 subclasses of 70 characteristic lipids (Cer, DG, LPC, PC, PE, PI, PS, SM, TG) were quantified accurately (LOD with 0.68-2.96 µg kg-1, LOQ with 2.25-9.79 µg kg-1, RSD < 3%). The decrease of TG concentration was the most significant, from 1072.43 mg kg-1 in preservative-free samples to 838.53, 786.41 and 681.35 mg kg-1 in natamycin, potassium sorbate and sodium diacetate treated samples, respectively. With regard to preservation and nutrition, natamycin was a potential preservative than two other preservatives. Significant lipid variables were primarily associated with glycerophospholipid and sphingolipid metabolism. Integration of both techniques provided a guide for meat industries to control spoilage with innovative strategies.


Assuntos
Cabras , Lipidômica , Animais , Cromatografia Líquida de Alta Pressão , Lipídeos , Carne/análise
15.
China CDC Wkly ; 3(47): 1005-1013, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34888116

RESUMO

Introduction: Antimicrobial resistance has become a major public health threat globally. The prevalence of multidrug-resistant (MDR) bacterial infections increased substantially among inpatients under 18 years of age in recent years. In Zhejiang Province, China, the trends of drug-resistance in non-adult patients from 2014 to 2019 were monitored, aiming to determine the variation patterns and epidemiological features of MDR strains. Methods: Patient data were collected from the Annual Review of Hospital Infection Resistance Survey in Zhejiang Province, 2014-2019. Statistical analysis was performed to analyze the pattern of distribution of five key bacterial pathogens in different age groups, ward settings, and bloodstream infections. Results: From 2014 to 2019, a total of 30,163 multidrug-resistant strains were identified among 212,252 clinical isolates. The prevalence of extended spectrum ß-lactamase-producing Enterobacteriaceae (ESBL-E), carbapenem-resistant Enterobacteriaceae (CRE), carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Pseudomonas aeruginosa (CRPA), and methicillin-resistant Staphylococcus aureus (MRSA) were 40.6%, 2.3%, 14.7%, 9.0%, and 27.4%, respectively. The prevalence of these key pathogens was lower than that reported in the national surveillance system (China Antimicrobial Resistance Surveillance System and Infectious Diseases Surveillance of Pediatrics). The prevalence of ESBL-E and CRE decreased since 2015 but that of CRPA and MRSA increased from 2014 to 2018. Conclusions: Despite an overall decrease in the prevalence of drug-resistant bacteria in 2019, the rising prevalence of MRSA and CRPA still warrant much attention. Multidrug-resistant bacteria prevention and control strategies should be adjusted in a timely manner based on the surveillance results.

16.
Neuroscience ; 2021 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-34848260

RESUMO

Procrastination is generally recognized as a problematic behavior and the consequences of which spread to various aspects of an individual's life such as academic performance, social accomplishment, well-being, and health. Previous studies have indicated that neuroticism is positively correlated with procrastination; however, little is known about the neural substrates underlying the link between neuroticism and procrastination. To address this issue, we employed voxel-based morphometry (VBM) and resting-state functional connectivity (RSFC) methods to investigate the neural underpinning for their relationship in the present study (N = 153). Consistent with our hypothesis, the behavior results verified a positive correlation between neuroticism and procrastination (r = 0.47). The VBM analysis revealed that the gray matter (GM) volumes in the right middle temporal gyrus (RMTG) were positively correlated with neuroticism. Moreover, results from RSFC analysis suggested that the functional connectivity between RMTG and the right superior frontal gyrus (RSFG) was positively associated with neuroticism. More importantly, a mediation analysis demonstrated that neuroticism played a full mediating role in the impact of RMTG-RSFG functional connectivity on procrastination. Overall, the present study offered new insights into the relation between neuroticism and procrastination from a neural basis perspective, which also suggested the importance of emotional regulation with regard to the link between such an association.

17.
Food Res Int ; 150(Pt A): 110721, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34865750

RESUMO

The current study applied an untargeted metabolomics approach by ultra high performance liquid chromatography quadrupole-orbitaltrap high resolution mass spectrometry (UHPLC-Q-Oritrap-MS) to identify the chemical composition of irradiated goat meat and investigate the effect of irradiation on its metabolic profile and meat quality. A total of 103 metabolites were identified as differential metabolites responsible for metabolic changes in irradiated goat meat, which were involved in phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism and purine metabolism. Differential metabolites comprising amino acids, nucleotides and their derivatives were determined as the discriminating factors responsible for the meat quality during irradiation. Specifically, the levels of L-phenylalanine, L-isoleucine, L-histidine, guanosine, guanine, creatinine, glutathione and nicotinic acid were increased while inosine 5'-monophosphate (IMP) and guanosine 5'-monophosphate (GMP) were decreased. Overall, except for L-phenylalanine and guanine, other related metabolites significantly decreased with storage. This study contributes to a comprehensive understanding of the effect of irradiation doses and storage time on goat meat metabolism at the molecular level, so as to assess the quality of irradiated goat meat. Satisfactory results with linearity (R2 > 0.995), precision (RSD less than 8.9%) and recovery (83%-106%) were obtained, demonstrating that the untargeted mebabolomics approach was appropriate for monitoring the changes of small molecular metabolites in irradiated goat meat and irradiation is a feasible method for goat meat preservation.

18.
Front Cell Infect Microbiol ; 11: 790036, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34869083

RESUMO

Interferon gamma-inducible protein 16 (IFI16) is a DNA sensor protein, which triggers interferon-beta (IFN-ß) production. However, the role of IFI16 in the innate immunity against hepatitis B virus (HBV) remains controversial. Peripheral blood mononuclear cells (PBMCs) and serum specimens were collected from 20 patients with chronic hepatitis B (CHB) receiving Peg-IFN-α2b therapy. IFI16 mRNA/protein of PBMCs and serum IFI16 at baseline and changes during Peg-IFN-α2b treatment were detected. The interaction between IFI16 and HBV DNA in the PBMCs was analyzed using chromatin immunoprecipitation assay. Leukemic T cell line CEM-C7 and HBV-replicating HepG2.2.15 cells were used to test the effects of interferon treatment and HBV replication on IFI16 expression. Compared with healthy controls, lower levels of IFI16 mRNA but more significant expression of IFI16 protein with heterogeneous degradation were detected in PBMCs of CHB patients. Early changes in IFI16 mRNA, but not IFNB mRNA of PBMCs or serum IFI16, were correlated to HBeAg seroconversion of Peg-IFN-α2b therapy. An interaction between IFI16 and HBV DNA was detected in the PBMCs. In the cultured HepG2.2.15 and CEM-C7 cells, interferons resulted in the translocalization of IFI16 from the cytoplasm to the nucleus and inhibited IFI16 degradation. IFI16 of PBMCs may play a role in sensing HBV infection, and early change in IFI16 mRNA of PBMCs is valuable to predict HBeAg seroconversion in Peg-IFN-α2b treatment. The influences on IFI16 degradation and subcellular location may present a molecular mechanism of antiviral activity of interferon.

20.
Am J Cancer Res ; 11(11): 5428-5439, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34873470

RESUMO

Colorectal cancer (CRC) is one of the most common malignant tumors worldwide, and tumor metastasis is the leading cause of death. Targeting immune inhibitory checkpoint inhibitory pathways has attracted great attention, since the therapeutic efficacy induced by the specific blocking antibodies has been demonstrated even in metastatic CRC patients. However, the clinical outcome is low in many cases, and thus more effective treatments are needed in the clinical settings. A SPARC family member follistatin-like 1 (FSTL1) is known as a key driver of tumor metastasis in various types of cancer. However, the immunological roles of the FSTL1 in the CRC pathogenesis remain to be elucidated. In this study, we investigated the molecular mechanisms underlying the refractory FSTL1+ CRC using murine and human FSTL1-transduced CRC cells. Also, based on the results, we evaluated anti-tumor efficacy induced by agents targeting the identified molecules using murine CRC metastasis models, and validated the clinical relevancy of the basic findings using tumor tissues and peripheral blood obtained from CRC patients. FSTL1 transduction conferred EMT-like properties, such as low proliferative (dormant) and high invasive abilities, on tumor cells. When the transfectants were subcutaneously implanted in mice, CD11b+DIP2A+LAG3+ cells were abundantly expanded locally and systemically in the mice. Simultaneously, apoptotic T cells increased and were lastly excluded from the tumor tissues, allowing tumor aggravation leading to resistance to anti-PD1/PDL1 treatment. Blocking FSTL1 and LAG3, however, significantly suppressed the apoptosis induction, and successfully induced anti-tumor immune responses in the CRC metastasis models. Both treatments synergized in providing better prognosis of the mice. FSTL1 was significantly upregulated in tumor tissues and peripheral blood of CRC patients, and the CD11b+DIP2A+LAG3+ cells were significantly expanded in the PBMCs as compared to those of healthy donors. The expansion level was significantly correlated with decrease of potent Ki67+GZMB+ CTLs. These results suggest that the FSTL1-induced CD11b+DIP2A+LAG3+ cells are a key driver of immune dysfunction in CRC. Targeting the FSTL1-LAG3 axis may be a promising strategy for treating metastatic CRC, and anti-FSTL1/LAG3 combination regimen may be practically useful in the clinical settings.

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