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1.
J Hematol Oncol ; 14(1): 160, 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34620200

RESUMO

In this era of precision medicine, with the help of biomarkers, immunotherapy has significantly improved prognosis of many patients with malignant tumor. Deficient mismatch repair (dMMR)/microsatellite instability (MSI) status is used as a biomarker in clinical practice to predict favorable response to immunotherapy and prognosis. MSI is an important characteristic which facilitates mutation and improves the likelihood of a favorable response to immunotherapy. However, many patients with dMMR/MSI still respond poorly to immunotherapies, which partly results from intratumor heterogeneity propelled by dMMR/MSI. In this review, we discuss how dMMR/MSI facilitates mutations in tumor cells and generates intratumor heterogeneity, especially through type II interferon (IFN-γ) signaling and tumor-infiltrating lymphocytes (TILs). We discuss the mechanism of immunotherapy from the perspective of dMMR/MSI, molecular pathways and TILs, and we discuss how intratumor heterogeneity hinders the therapeutic effect of immunotherapy. Finally, we summarize present techniques and strategies to look at the tumor as a whole to design personalized regimes and achieve favorable prognosis.

2.
J Magn Reson Imaging ; 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34611963

RESUMO

BACKGROUND: In experimental animal models, implantation location might influence the heterogeneity and overall development of the tumor, leading to an interpretation bias. PURPOSE: To investigate the effects of implantation location in experimental tumor model using magnetic resonance imaging (MRI) and pathological findings. STUDY TYPE: Prospective. SUBJECTS: Forty-five breast cancer-bearing mice underwent orthotopic (N = 15) and heterotopic (intrahepatic [N = 15] and subcutaneous [N = 15]) implantation. FIELD STRENGTH/SEQUENCE: Sequences including: T1-weighted turbo spin echo sequence, T2-weighted blade sequence, diffusion-weighted imaging, pre- and post-contrast T1 mapping, multi-echo T2 mapping at 3.0 T. ASSESSMENT: MRI was performed at 7, 14, and 21 days after implantation. Native T1, post-contrast T1, T2, and apparent diffusion coefficient (ADC) of tumors, the tumor volume and necrosis volume within tumor were obtained. Lymphocyte cells from H&E staining, Ki67-positive, and CD31-positive cells from immunohistochemistry were determined. STATISTICAL TESTS: One-way analysis of variance and Spearman's rank correlation were performed. P value <0.05 was considered statistically significant. RESULTS: The tumor volume (intrahepatic vs. orthotopic vs. subcutaneous: 587.50 ± 77.62 mm3 vs. 814.00 ± 43.85 mm3 vs. 956.13 ± 119.22 mm3 ), necrosis volume within tumor (89.10 ± 26.60 mm3 vs. 292.41 ± 57.92 mm3 vs. 179.91 ± 31.73 mm3 , respectively), ADC at day 21 (543.41 ± 42.28 vs. 542.92 ± 99.67 vs. 369.83 ± 42.90, respectively), and post-contrast T1 at all timepoints (day 7: 442.00 ± 11.52 vs. 435.00 ± 22.90 vs. 394.33 ± 29.95; day 14: 459.00 ± 26.11 vs. 436.83 ± 26.01 vs. 377.00 ± 27.83; day 21: 463.50 ± 23.49 vs. 458.00 ± 34.28 vs. 375.00 ± 30.55) were significantly different between three groups. Necrosis volumes of subcutaneous and intrahepatic tumors were significantly lower than those of orthotopic tumors. The CD31-positive rate in the intrahepatic implantation was significantly higher than in orthotopic and subcutaneous groups. Necrosis volume (r = -0.71), ADC (r = -0.85), and post-contrast T1 (r = -0.75) were strongly correlated with vascular invasion index. DATA CONCLUSION: Orthotopic and heterotopic tumors have their unique growth kinetics, necrosis volume, and vascular invasion. Non-invasive MR quantitative parameters, including ADC and post-contrast T1, may reflect vascular invasion in mice. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 3.

3.
4.
Hepatology ; 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34482560

RESUMO

BACKGROUND AND AIMS: Nonalcoholic steatohepatitis (NASH) is a complicated disease characterized by hepatocyte steatosis, inflammation infiltration, and liver fibrosis. Accumulating evidence suggests that the innate immunity plays a key role in NASH progression. Here, we aimed to reveal the role of melanoma-differentiation-associated gene 5 (MDA5, also known as Ifih1), a conventional innate immune regulator upon viral infection, in the progression of NASH and investigate its underlying mechanism. APPROACH AND RESULTS: We first examined the expression of MDA5 and found that MDA5 was markedly downregulated in the livers with NASH in human individuals and mice models. MDA5 overexpression significantly inhibited the free fatty acid (FFA) induced lipid accumulation and inflammation in hepatocyte in vitro, while MDA5 knockdown promotes hepatocyte lipotoxicity. Using hepatocyte-specific Mda5 gene knockout and transgenic mice, we found that diet induced hepatic steatosis, inflammation and liver fibrosis were markedly exacerbated by Mda5 deficiency but suppressed by Mda5 overexpression. Mechanistically, we found that the activation of ASK1-MAPK pathway was significantly inhibited by MDA5 but enhanced by MDA5 deletion. We further validated that MDA5 directly interacted with ASK1 and suppressed its N-terminal dimerization. Importantly, blockage of ASK1 with adenovirus expressing dominant negative ASK1 (dnASK1) obviously reversed the lipid accumulation and ASK1 pathway activation when Mda5 knockout. CONCLUSIONS: These data indicate that MDA5 is an essential suppressor in NASH, the findings support MDA5 as a novel regulator of ASK1 and a promising therapeutic target for NASH.

5.
Eur J Hosp Pharm ; 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34497128

RESUMO

PURPOSE: To investigate the efficacy and safety of programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) plus cytotoxic T lymphocyte antigen-4 (CTLA-4) antibodies ± other therapies in patients with advanced lung cancer. METHODS: In accordance with the retrieval strategy, we searched electronic databases for randomised controlled trials testing PD-1/PD-L1 plus CTLA-4 antibodies in patients with lung cancer; RR (for objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and immune-related adverse events (irAEs)) from individual studies were calculated and pooled by using random-effects models or fixed-effects models; heterogeneity and publication bias analyses were also performed, using Review Manager 5.3 and Stata 15.1 for statistical analysis. RESULTS: We included six studies. Four different immune checkpoint inhibitors (nivolumab, pembrolizumab, durvalumab, tremelimumab) were used. Dual checkpoint inhibitors ± other therapies for advanced lung cancer showed significant improvements in ORR (RR 1.49, 95% CI 1.11 to 1.98; p=0.007), OS (HR 0.72, 95% CI 0.63 to 0.83; p<0.00001), and PFS (HR 0.72, 95% CI 0.63 to 0.82; p<0.00001). The subgroup analyses were consistent with the pooled results. The PD-L1 ≥1% (HR 0.67, 95% CI 0.54 to 0.82; p<0.0001) subgroup differences indicated a statistically significant subgroup effect, but the PD-L1 <1% subgroup (HR 0.88, 95% CI 0.75 to 1.05; p=0.15) was not statistically significant. The incidence of adverse events (grade ≥3) was lower than that of the control group (RR 0.90, 95% CI 0.80 to 1.02; p=0.09), but was not significant. CONCLUSIONS: PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors ± other therapies can improve the ORR, OS and PFS of patients with advanced or metastatic lung cancer, but the incidence of adverse reactions is high although generally tolerable. PROSPERO REGISTRATION: CRD42020149216.

7.
J Int Med Res ; 49(9): 3000605211039798, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34521242

RESUMO

OBJECTIVE: The long non-coding RNA (lncRNA) growth arrest­specific transcript 5 (GAS5) plays an important role in various tumors, and an increasing number of studies have explored the association of the GAS5 rs145204276 polymorphism with cancer risk with inconclusive results. METHODS: PubMed, Medline, EMBASE, Cochrane databases, and Web of Science were searched, and nine studies involving 6107 cases and 7909 controls were deemed eligible. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to evaluate the relationship between rs145204276 and cancer risk in six genetic models. RESULTS: The pooled results suggest that the variant allele del was not associated with overall cancer risk. However, the subgroup analysis showed that allele del was significantly associated with a 22% decreased risk of gastrointestinal cancer (OR = 0.78, 95% CI: 0.72-0.85). Both sensitivity analyses and trial sequential analyses (TSA) demonstrated that the subgroup results were reliable and robust. Moreover, False-Positive Report Probability (FPRP) analysis indicated that the results had true significant correlations. CONCLUSION: These findings provide evidence that the GAS5 rs145204276 polymorphism is associated with the susceptibility to gastrointestinal cancer. Further studies with different ethnicities and larger sample sizes are warranted to confirm these results.


Assuntos
Neoplasias , RNA Longo não Codificante , Predisposição Genética para Doença , Humanos , Neoplasias/genética , Polimorfismo Genético , RNA Longo não Codificante/genética , Risco
8.
Mol Ther ; 29(9): 2794-2805, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34365034

RESUMO

The numbers of cases and deaths from coronavirus disease 2019 (COVID-19) are continuously increasing. Many people are concerned about the efficacy and safety of the COVID-19 vaccines. We performed a comprehensive analysis of the published trials of COVID-19 vaccines and the real-world data from the Vaccine Adverse Event Reporting System. Globally, our research found that the efficacy of all vaccines exceeded 70%, and RNA-based vaccines had the highest efficacy of 94.29%; moreover, Black or African American people, young people, and males may experience greater vaccine efficacy. The spectrum of vaccine-related adverse drug reactions (ADRs) is extremely broad, and the most frequent ADRs are pain, fatigue, and headache. Most ADRs are tolerable and are mainly grade 1 or 2 in severity. Some severe ADRs have been identified (thromboembolic events, 21-75 cases per million doses; myocarditis/pericarditis, 2-3 cases per million doses). In summary, vaccines are a powerful tool that can be used to control the COVID-19 pandemic, with high efficacy and tolerable ADRs. In addition, the spectrum of ADRs associated with the vaccines is broad, and most of the reactions appear within a week, although some may be delayed. Therefore, ADRs after vaccination need to be identified and addressed in a timely manner.


Assuntos
Vacinas contra COVID-19/efeitos adversos , COVID-19/epidemiologia , COVID-19/prevenção & controle , Pandemias/prevenção & controle , SARS-CoV-2/imunologia , Vacinação/métodos , Vacinas Sintéticas/efeitos adversos , Adolescente , Adulto , Grupo com Ancestrais do Continente Africano , Idoso , Idoso de 80 Anos ou mais , COVID-19/etnologia , COVID-19/virologia , Ensaios Clínicos Fase III como Assunto , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Imunogenicidade da Vacina , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
9.
Sensors (Basel) ; 21(13)2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206783

RESUMO

Hyperspectral technology is used to obtain spectral and spatial information of samples simultaneously and demonstrates significant potential for use in seed purity identification. However, it has certain limitations, such as high acquisition cost and massive redundant information. This study integrates the advantages of the sparse feature of the least absolute shrinkage and selection operator (LASSO) algorithm and the classification feature of the logistic regression model (LRM). We propose a hyperspectral rice seed purity identification method based on the LASSO logistic regression model (LLRM). The feasibility of using LLRM for the selection of feature wavelength bands and seed purity identification are discussed using four types of rice seeds as research objects. The results of 13 different adulteration cases revealed that the value of the regularisation parameter was different in each case. The recognition accuracy of LLRM and average recognition accuracy were 91.67-100% and 98.47%, respectively. Furthermore, the recognition accuracy of full-band LRM was 71.60-100%. However, the average recognition accuracy was merely 89.63%. These results indicate that LLRM can select the feature wavelength bands stably and improve the recognition accuracy of rice seeds, demonstrating the feasibility of developing a hyperspectral technology with LLRM for seed purity identification.


Assuntos
Oryza , Algoritmos , Modelos Logísticos , Sementes , Tecnologia
10.
BMC Nephrol ; 22(1): 257, 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34238243

RESUMO

BACKGROUND: Few studies have evaluated the clinical presentation, management, and outcomes of patients with end-stage renal disease (ESRD) presenting with acute aortic dissection (AAD) in real-world clinical practice. Thus, this study investigated the clinical characteristics, management, and outcomes of AAD patients with ESRD. METHODS: A total of 217 patients were included. We evaluated the differences in the clinical features, management, and in-hospital outcomes of patients with and without a history of ESRD presenting with AAD. RESULTS: A history of ESRD was present in 71 of 217 patients. Patients with ESRD had atypical clinical manifestations (p < 0.001) and were more likely to be managed medically compared with patients without ESRD (p = 0.002). Hypertension and type B aortic dissection were significantly more common among patients with ESRD. Moreover, patients with ESRD had lower leucocyte and platelet counts than patients without ESRD in laboratory findings (p < 0.001). However, hospitalization days and in-hospital mortality were similar between the two groups (p > 0.05). Multivariate analysis identified Type A aortic dissection as an independent predictor of in-hospital mortality among patients without ESRD (OR, 13.68; 95% CI, 1.92 to 98.90; P = 0.006). CONCLUSIONS: This study highlights differences in the clinical characteristics, management, and outcomes of AAD patients with ESRD. These patients usually have atypical symptoms and more comorbid conditions and are managed more conservatively. However, these patients have no in-hospital survival disadvantage over those without ESRD. Further studies are needed to better understand and optimize care for patients with ESRD presenting with AAD.

11.
Artigo em Chinês | MEDLINE | ID: mdl-34304526

RESUMO

Objective:To explore the value of CT location of the upper airway obstruction site after inducing sleep on the condition of obstructive sleep apnea(OSA) and its surgical efficacy. Methods:Forty patients with moderate-to-severe OSA diagnosed by polysomnography, first performed awake CT scan, then, the patient was slowly injected intravenously with dexmedetomidine to induce sleep, when the patient was apnea during sleep, CT scan of the corresponding part of the upper airway was performed. Compare and measure the cross-sectional area of the upper airway stenosis level in the two states, and evaluate the correlation between the cross-sectional area of the stenosis level after induction of sleep and the patient's AHI, blood oxygen saturation<90% of the time(CT90). According to the change value of the cross-sectional area of each plane, it was divided into 2 groups, 22 cases in first group underwent hypothermia plasma uvulapalatopharyngoplasty, and 18 cases in second group underwent multi-plane combined surgery. After 12 months of follow-up, compare the post-long-term efficacy, changes in cross-sectional area values of various narrow planes before and after surgery, and changes in indicators related to sleep quality between the two groups. Results:Compared with the cross-sectional area of the nasopharyngeal area, posterior soft palate area, the posterior tongue area, and the epiglottis area measured by upper airway CT under awake breathing state, the cross-sectional area of each obstruction plane during sleep state decreased(P<0.01). The minimum cross-sectional area of the upper airway plane sleep phase was negatively correlated with AHI and CT90, and the posterior soft palate and the posterior lingual base were highly correlated with AHI and CT90.12 months after treatment, the minimum cross-sectional area of each phase of the sleep phase in the experimental group 1 was significantly improved(P<0.01) compared with that before treatment, followed by the posterior tongue area(P<0.05). There was no statistical difference between the nasopharyngeal area and the epiglottis area. The differences in nasopharyngeal area, posterior soft palate area, posterior tongue area, and epiglottis area in experimental group 2 after treatment were statistically significant(P<0.01 or P<0.05), compared with that before treatment. The sleep-related indexes ESS, CT90, AHI, and LSaO2 of the two groups were better than those before treatment after 12 months of treatment(P<0.01). Comparison of experiment group 1 and 2, the effective rates were 72.72% and 95.23%(χ²=10.62, P<0.01), the significant efficiency was 58.33% and 80.45%(χ²=8.62, P<0.01), and the cure rates were 12.37% and 17.48%(x²=7.62, P<0.01). Conclusion:CT examination of OSA patients after drug-induced sleep is safe and feasible, and it has important value for the accurate location of the upper airway obstruction site. 64-slice spiral CT upper airway scanning under induced sleep has guiding significance for the evaluation of OSA patients' condition and long-term surgical efficacy.


Assuntos
Obstrução das Vias Respiratórias , Apneia Obstrutiva do Sono , Obstrução das Vias Respiratórias/diagnóstico por imagem , Obstrução das Vias Respiratórias/etiologia , Humanos , Polissonografia , Sono , Apneia Obstrutiva do Sono/diagnóstico por imagem , Tomografia Computadorizada por Raios X
12.
Mol Imaging Biol ; 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34231107

RESUMO

PURPOSE: The aims of this study were threefold: [1] to describe the biodistribution of 18F-AlF-NOTA-octreotide (18F-OC) in normal organs; [2] to evaluate the range of uptake of NEN and benign lesions using the maximum standardized uptake value (SUVmax); and [3] to compare the difference in 18F-OC uptake among tumors of different grades. METHODS: This study included 162 patients (67 females and 95 males) who received 18F-OC positron emission tomography (PET)/computed tomography (CT), 128 of whom were diagnosed with neuroendocrine neoplasms (NENs). The SUVmax and SUVmean of 18F-OC were measured in 21 normal anatomical structures. We compared the differences among G1, G2, and G3 NENs, as well as between NENs and benign lesions. RESULTS: High physiological uptake of 18F-OC (SUVmax > 6.77) was detected in the spleen, adrenal gland, renal parenchyma, pituitary gland, and liver. Moderate uptake (SUVmax 3.00-6.77) was found in the uncinate process of the pancreas (PU), prostate, thyroid, and uterus. Mild uptake (SUVmax 1.34-3.00) was observed in the small intestine, pancreas (pancreas uptake except for the head of the pancreas), gallbladder, and transverse colon. The SUVmax of NENs was higher than that of benign lesions, including fractures, inflamed tissue, reactive hyperplasia, and degenerative disease. However, overlap was noted between the two groups. The SUVmax of 18F-OC uptake by tumors was significantly correlated with tumor grade in primary lesions and those of the lymph node, bone, and other sites (all P < 0.01). CONCLUSIONS: The results obtained from the majority of the samples in this study show the biodistribution of 18F-OC in normal organs and have significance as a reference. Although some benign lesions show variable uptake, the uptake by these lesions is still different from that of NENs. NENs of different grades have differences in 18F-OC uptake levels.

13.
Clin Cancer Res ; 27(16): 4634-4641, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34112711

RESUMO

PURPOSE: Patients with HER2-positive (HER2+) metastatic breast cancer (MBC) have poor prognoses. Pyrotinib has shown promising antitumor activity in MBC to improve progression-free survival (PFS). However, findings based on real-world data to analyze whether pyrotinib affects overall survival (OS) remain scarce. EXPERIMENTAL DESIGN: This real-world study is an exploratory analysis of brain metastasis (BM) and the final update of our preceding study of 168 patients with HER2+ MBC. PFS, OS, tumor mutation burden (TMB), clinical benefit rate (CBR), and overall response rate (ORR) were analyzed. RESULTS: Pyrotinib treatment led to a median PFS time of 8.00 months and a median OS of 19.07 months in the 168 participants. High TMB was associated with poor OS (P = 0.0072) and PFS (P = 0.0028). In the 39 patients with BM, the median PFS and OS were 8.67 and 13.93 months, respectively. The surgery/radiation (S/R) group of patients with BM had prolonged survival (PFS: 9.97 vs. 7.73 months P = 0.19; OS: 20.67 vs. 12.43 months P = 0.021) compared with the no surgery/no radiation group (NS/NR). The CBR was 58.6% (S/R) vs. 41.4% (NS/NR), while the ORR was 24.1% (S/R) vs. 31.0% (NS/NR). CONCLUSIONS: Pyrotinib shows promise as a novel pan-HER2 tyrosine kinase inhibitor (TKI) for the treatment of BM and should be evaluated further. Surgical or radiotherapy in combination with pyrotinib was found to statistically improve OS in our cohort. TMB could be an exploratory biomarker for predicting PFS and OS, but its clinical application still needs further verification.

14.
EJNMMI Res ; 11(1): 55, 2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34106351

RESUMO

OBJECTIVE: To evaluate the diagnostic efficacy of 18F-AlF-NOTA-octreotide (18F-OC) PET/CT compared with that of 68Ga-DOTATATE PET/CT. MATERIALS AND METHODS: Twenty patients (mean age: 52.65 years, range: 24-70 years) with biopsy-proven neuroendocrine neoplasms (NENs) were enrolled in this prospective study. We compared the biodistribution profiles in normal organs based on the maximum standard uptake value (SUVmax) and mean standard uptake value (SUVmean), and uptake in NEN lesions by measuring the SUVmax on 18F-OC and 68Ga-DOTATATE PET/CT images. The tumor-to-liver ratio (TLR) and tumor-to-spleen ratio were calculated by dividing the SUVmax of different tumor lesions by the SUVmean of the liver and spleen, respectively. The Wilcoxon signed-rank test was used to compare nonparametric data. Data were expressed as the median (interquartile range). RESULTS: In most organs, there were no significant differences in the biodistribution of 68Ga-DOTATATE and 18F-OC. 18F-OC had significantly lower uptake in the salivary glands and liver than 68Ga-DOTATATE. 18F-OC detected more lesions than 68Ga-DOTATATE. The uptake of 18F-OC in the tumors was higher in most patients, but the difference was not statistically significant relative to that of 68Ga-DOTATATE. However, the TLRs of 18F-OC were higher in most patients, including for lesions in the liver (p = 0.02) and lymph nodes (p = 0.02). CONCLUSION: Relative to 68Ga-DOTATATE, 18F-OC possesses favorable characteristics with similar image quality and satisfactory NEN lesion detection rates, especially in the liver due to its low background uptake. 18F-OC therefore offers a promising clinical alternative for 68Ga-DOTATATE.

15.
Cell Death Dis ; 12(4): 378, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33828087

RESUMO

Vascular smooth muscle cell (VSMC) phenotypic switching plays a critical role in the formation of abdominal aortic aneurysms (AAAs). FoxO3a is a key suppressor of VSMC homeostasis. We found that in human and animal AAA tissues, FoxO3a was upregulated, SM22α and α-smooth muscle actin (α-SMA) proteins were downregulated and synthetic phenotypic markers were upregulated, indicating that VSMC phenotypic switching occurred in these diseased tissues. In addition, in cultured VSMCs, significant enhancement of FoxO3a expression was found during angiotensin II (Ang II)-induced VSMC phenotypic switching. In vivo, FoxO3a overexpression in C57BL/6J mice treated with Ang II increased the formation of AAAs, whereas FoxO3a knockdown exerted an inhibitory effect on AAA formation in ApoE-/- mice infused with Ang II. Mechanistically, FoxO3a overexpression significantly inhibited the expression of differentiated smooth muscle cell (SMC) markers, activated autophagy, the essential repressor of VSMC homeostasis, and promoted AAA formation. Our study revealed that FoxO3a promotes VSMC phenotypic switching to accelerate AAA formation through the P62/LC3BII autophagy signaling pathway and that therapeutic approaches that decrease FoxO3a expression may prevent AAA formation.


Assuntos
Aneurisma Aórtico/fisiopatologia , Proteína Forkhead Box O3/metabolismo , Músculo Liso Vascular/metabolismo , Animais , Homeostase , Humanos , Masculino , Camundongos , Transfecção
16.
J Cell Mol Med ; 25(7): 3391-3399, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33655701

RESUMO

CLEC10A, (C-type lectin domain family 10, member A), as the member of C-type lectin receptors (CLRs), plays a vital role in modulating innate immunity and adaptive immunity and has shown great potential as an immunotherapy target for cancers. However, there is no functional research of CLEC10A in prognostic risk, immunotherapy or any other treatment of lung adenocarcinoma (LUAD). We performed bioinformatics analysis on LUAD data downloaded from TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus), and jointly analysed with online databases such as HPA, LinkedOmics, TIMER, ESTIMATE and TISIDB. We found that lower expression of CLEC10A was accompanied with worse outcomes of LUAD patients. Moreover, CLEC10A expression was significantly correlated with a variety of the tumour-infiltrating immune cells (TIICs). As a promising prognosis predictor and potential immunotherapy target, the potential influence and mechanisms of CLEC10A in LUAD deserve further exploring.


Assuntos
Adenocarcinoma de Pulmão/genética , Biomarcadores Tumorais/genética , Lectinas Tipo C/genética , Neoplasias Pulmonares/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/metabolismo , Biologia Computacional , Humanos , Lectinas Tipo C/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Microambiente Tumoral/imunologia
17.
Aging (Albany NY) ; 13(5): 7570-7588, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658393

RESUMO

NLRP1 (NLR family, pyrin domain containing 1), the first NLR protein, described to form an inflammasome, plays critical roles in innate immunity and inflammation. However, NLRP1 has not been reported to be linked to LUAD (lung adenocarcinoma) risk, prognosis, immunotherapy or any other treatments. This research aimed to explore the prognostic value and mechanism of NLRP1 in LUAD. We performed bioinformatics analysis on LUAD data downloaded from TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus), and jointly analyzed with online databases such as TCGAportal, LinkedOmics, TIMER, ESTIMATE and TISIDB. NLRP1 expression of LUAD tissue was considerably lower than that in normal lung tissue. Decreased NLRP1 expression of LUAD was associated with relatively high pathological, T and N stages. Kaplan-Meier survival analysis indicated that patients with low NLRP1 expression had a worse prognosis than those with high expression. Multivariate Cox analysis further showed that NLRP1 expression level was an independent prognostic factor of LUAD. Moreover, the level of NLRP1 expression was positively linked to the degree of infiltration of various TIICs (tumor-infiltrating immune cells). Our findings confirmed that reduced expression of NLRP1 was significantly related to poor prognosis and low degree of immune cell infiltration in LUAD patients.


Assuntos
Adenocarcinoma de Pulmão/mortalidade , Neoplasias Pulmonares/mortalidade , Linfócitos do Interstício Tumoral/patologia , Proteínas NLR/metabolismo , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/metabolismo , Feminino , Humanos , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico
18.
Antonie Van Leeuwenhoek ; 114(5): 527-538, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33710455

RESUMO

A Gram-positive, smooth, sub-transparent, faint yellow,0.5-0.7 µm diameter, rod shaped aerobic or facultative aerobic strain P40-2Twas isolated from livestock farms in Northeast China. Strain P40-2T grew at 25-40 °C (optimum 30-38 °C), and in 0-4% (w/v) NaCl (optimum 0%) in LB medium. Based on 16S rRNA gene sequence analysis, strain P40-2T belongs to the class Cellulomonas and is most closely related to C. denverensis strain W6929, C. pakistanensis strain NCCP-11and C. hominis strain CE40.DNA-DNA hybridization rate of strain P40-2T was 29%, and the ANI with C.denverensisstrainW6929 was 85.33%. The genome is 3437431 bp long with a G + C content of 71.99%. Of the 3177 predicted genes, 3119 were protein-coding genes and 58 were RNA encoding genes. The chemotaxonomic data: menaquinone was MK-9(H4), anteiso-C15: 0, C16:0 and anteiso-C17: 0 were the major cellular fatty acids, and the main cell-wall amino acids were ornithine,alanine, glycine and glutamate. The cell wall peptidogly can sugars included glucose, rhamnose, galactose and mannose. The polar lipid present were DPG, PG, PE, and PIM. On the basis of DNA-DNA relatedness, phylogenetic position, complete genome sequence and physiological characteristics, strain P40-2T can be differentiated from other species of the genus Cellulomonas with validly published names and thus represents a novel species, for which the name Cellulomonas taurus is proposed. The type strain is Cellulomonas taurus P40-2T (= CGMCC No.1.17732T).The acute toxicity test in mice showed that LD50 of strain P40-2T was rather high with 1.5 × 1011 CFU/mouse, which indicated low pathogenicity. Drug susceptibility showed that strainP40-2T was resistant to most antibiotics and only sensitive to six antibiotics. Strain P40-2T contained a variety of hydrolytic enzymes including the ability to hydrolyze cellulose, ß-glucan, chitin, xylan, and casein. Microbial flocculant MBF-P40 for sewage was prepared with strain P40-2T, after strain P40-2T was confirmed that had good flocculation effect. MBF-P40 was used to prepare flocculation rate of 99.40%. MBF-P40 treatmented sewage from eight different sources. Flocculation rate for pig farm wastewater was 96.07%, COD removal rate is 71.05%, ammonia nitrogen removal rate is 18.22%. The result shows that MBF-P40 has a good flocculation effect, and good prospect of development and application for wastewater treatment.


Assuntos
Cellulomonas , Purificação da Água , Animais , Técnicas de Tipagem Bacteriana , Composição de Bases , Cellulomonas/genética , DNA Bacteriano/genética , Ácidos Graxos/análise , Hidrolases , Gado , Camundongos , Fosfolipídeos/análise , Filogenia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Suínos , Vitamina K 2
19.
Neuro Oncol ; 23(10): 1656-1667, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33659980

RESUMO

BACKGROUND: The antitumor efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapies, such as humanized monoclonal antibody trastuzumab (Herceptin®, Roche), in patients with breast-to-brain cancer metastasis is hindered by the low permeability of the blood-brain barrier (BBB). NEO100 is a high-purity version of the natural monoterpene perillyl alcohol, produced under current good manufacturing practice (cGMP) regulations, that was shown previously to reversibly open the BBB in rodent models. Here we investigated whether NEO100 could enable brain entry of trastuzumab to achieve greater therapeutic activity. METHODS: An in vitro BBB, consisting of human astrocytes and brain endothelial cells, was used to determine trastuzumab penetration in the presence or absence of NEO100. For in vivo studies, we administered intravenous (IV) trastuzumab or the trastuzumab-drug conjugate ado-trastuzumab emtansine (T-DM1; Kadcyla®, Roche), to mouse models harboring intracranial HER2+ breast cancer, with or without BBB opening via IA NEO100. Brain and tumor tissues were examined for the presence of trastuzumab and infiltration of immune cells. Therapeutic impact was evaluated based on overall survival. RESULTS: NEO100 greatly increased trastuzumab penetration across an in vitro BBB. In vivo, IA NEO100-mediated BBB opening resulted in brain tumor-selective accumulation of trastuzumab, without detectable presence in normal brain tissue, along with increased presence of immune cell populations. IV delivery of trastuzumab or T-DM1 achieved significantly greater overall survival of tumor-bearing mice when combined with IA NEO100. CONCLUSION: IA NEO100 facilitates brain tumor entry of trastuzumab and T-DM1 and significantly enhances their therapeutic efficacy, along with increased antibody-dependent immune cell recruitment.


Assuntos
Neoplasias Encefálicas , Neoplasias da Mama , Trastuzumab/administração & dosagem , Animais , Barreira Hematoencefálica , Encéfalo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Células Endoteliais , Feminino , Humanos , Camundongos , Monoterpenos , Receptor ErbB-2
20.
Cell Biol Toxicol ; 37(5): 751-771, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33723744

RESUMO

BACKGROUND: Noise-induced hearing loss represents a commonly diagnosed type of hearing disability, severely impacting the quality of life of individuals. The current work is aimed at assessing the effects of DNA methylation on noise-induced hearing loss. METHODS: Blocking DNA methyltransferase 1 (DNMT1) activity with a selective inhibitor RG108 or silencing DNMT1 with siRNA was used in this study. Auditory brainstem responses were measured at baseline and 2 days after trauma in mice to assess auditory functions. Whole-mount immunofluorescent staining and confocal microcopy of mouse inner ear specimens were performed to analyze noise-induced damage in cochleae and the auditory nerve at 2 days after noise exposure. RESULTS: The results showed that noise exposure caused threshold elevation of auditory brainstem responses and cochlear hair cell loss. Whole-mount cochlea staining revealed a reduction in the density of auditory ribbon synapses between inner hair cells and spiral ganglion neurons. Inhibition of DNA methyltransferase activity via a non-nucleoside specific pharmacological inhibitor, RG108, or silencing of DNA methyltransferase-1 with siRNA significantly attenuated ABR threshold elevation, hair cell damage, and the loss of auditory synapses. CONCLUSIONS: This study suggests that inhibition of DNMT1 ameliorates noise-induced hearing loss and indicates that DNMT1 may be a promising therapeutic target. Graphical Headlights • RG108 protected against noise-induced hearing loss • RG108 administration protected against noise-induced hair cell loss and auditory neural damage. • RG108 administration attenuated oxidative stress-induced DNA damage and subsequent apoptosis-mediated cell loss in the cochlea after noise exposure.

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