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1.
Hepatol Int ; 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34850325

RESUMO

BACKGROUND & AIMS: Immunotherapy with hepatitis B virus (HBV)-specific TCR redirected T (HBV-TCR-T) cells in HBV-related hepatocellular carcinoma (HBV-HCC) patients after liver transplantation was reported to be safe and had potential therapeutic efficacy. We aim to investigate the safety of HBV-TCR-T-cell immunotherapy in advanced HBV-HCC patients who had not met the criteria for liver transplantation. METHODS: We enrolled eight patients with advanced HBV-HCC and adoptively transferred short-lived autologous T cells expressing HBV-specific TCR to perform an open-label, phase 1 dose-escalation study (NCT03899415). The primary endpoint was to evaluate the safety of HBV-TCR-T-cell therapy according to National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03) during the dose-escalation process. The secondary endpoint was to assess the efficacy of HBV-TCR-T-cell therapy by evaluating the anti-tumor responses using RECIST criteria (version 1.1) and the overall survival. RESULTS: Adverse events were observed in two participants among the 8 patients enrolled. Only one patient experienced a Grade 3 liver-related adverse event after receiving a dose of 1 × 105 HBV-TCR-T cells/kg, then normalized without interventions with immunosuppressive agents. Among the patients, one achieved a partial response lasting for 27.7 months. Importantly, most of the patients exhibited a reduction or stabilization of circulating HBsAg and HBV DNA levels after HBV-TCR-T-cell infusion, indicating the on-target effects. CONCLUSIONS: The adoptive transfer of HBV-TCR-T cells into advanced HBV-HCC patients were generally safe and well-tolerated. Observations of clinical efficacy support the continued development and eventual application of this treatment strategy in patients with advanced HBV-related HCC. CLINICAL TRIALS REGISTRATION: This study was registered at ClinicalTrials.gov (NCT03899415).

2.
J Med Chem ; 64(22): 16801-16819, 2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34781680

RESUMO

Endomorphins (EMs) are potent pharmaceuticals for the treatment of pain. Herein, we investigated several novel EM analogues with multiple modifications and oligoarginine conjugation. Our results showed that analogues 1-6 behaved as potent µ-opioid agonists and enhanced stability and lipophilicity. Analogues 5 and 6 administered centrally and peripherally induced significant and prolonged antinociceptive effects in acute pain. Both analogues also produced long-acting antiallodynic effects against neuropathic and inflammatory pain. Furthermore, they showed a reduced acute antinociceptive tolerance. Analogue 6 decreased the extent of chronic antinociceptive tolerance, and analogue 5 exhibited no tolerance at the supraspinal level. Particularly, they displayed nontolerance-forming antinociception at the peripheral level. In addition, analogues 5 and 6 exhibited reduced or no opioid-like side effects on gastrointestinal transit, conditioned place preference (CPP), and motor impairment. The present investigation established that multiple modifications and oligoarginine-vector conjugation of EMs would be helpful in developing novel analgesics with fewer side effects.

3.
Front Pharmacol ; 12: 675350, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34737693

RESUMO

K. galanga is an aromatic medicinal herb. It is locally to India and distributed in China, Myanmar, Indonesia, Malaysia, and Thailand. K. galanga is a Traditional Chinese Herb Medicine (TCHM), which has been applied to treat cold, dry cough, toothaches, rheumatism, hypertension and so on. In addition, it has been used widely as spices since its highly aromas. The aim of this review is to compile and update the current progresses of ethnomedicinal uses, phytochemistry, pharmacology and toxicology of K. galanga. All the data on K. galanga were based on different classical literary works, multiple electronic databases including SciFinder, Web of Science, PubMed, etc. The results showed that ninety-seven compounds have been identified from rhizome of K. galanga, including terpenoids, phenolics, cyclic dipeptides, flavonoids, diarylheptanoids, fatty acids and esters. Modern pharmacology studies revealed that extracts or secondary metabolites of the herb possessed anti-inflammatory, anti-oxidant, anti-tumorous, anti-bacterial, and anti-angiogenesis effects, which were closely related to its abundant ethnomedicinal uses. In conclusion, although previous research works have provided various information of K. galanga, more in-depth studies are still necessary to systemically evaluate phytochemistry, pharmacological activities, toxicity and quality control of this herb.

4.
Curr Neurovasc Res ; 2021 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-34809545

RESUMO

OBJECTIVE: Previous studies revealed that 18F-FDOPA uptake was significantly decreased in the subregions of striatum contralateral to the side with predominant symptoms and was helpful for improving the early diagnostic accuracy of PD. However, in these studies, more than half of the PD patients already have bilateral motor symptoms (mH&Y stage≥2). This study was aimed to extend previous findings to a milder disease stage. METHODS: Sixteen PD patients with only mild and unilateral motor symptoms (mH&Y stage=1 and disease duration≤2 years) and 22 healthy controls were involved. Striatal 18F-FDOPA uptake was analyzed using a ratio approach. RESULTS: The SORs in the subregions of the contralateral striatum, including caudate, anterior putamen and posterior putamen were significantly decreased in the mild stage PD patients. The SOR for the contralateral posterior putamen had the largest area under the receiver operating characteristic curve (0.963) and separated mild stage PD patients from healthy controls with a sensitivity of 93.75% and a specificity of 95.45% when the cut-off value of <2.160 was selected. CONCLUSION: These data indicate that contralateral posterior putaminal 18F-FDOPA uptake may represent a potential marker for early diagnosis of PD, especially in patients with only mild and unilateral motor symptoms.

5.
Radiother Oncol ; 164: 163-166, 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34619235

RESUMO

We assessed the impact of different PCI fractionation schedules (30 Gy in 10 versus 15 fractions) on brain metastases-free survival (BMFS) and toxicity in stage III NSCLC. Our results suggest that 30 Gy in 10 fractions is associated with increased toxicity, while no conclusive evidence of improving BMFS was seen with this schedule.

6.
Curr Neurovasc Res ; 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34636310

RESUMO

BACKGROUND: Chronic cerebral hypoperfusion (CCH) is a contributing factor for neurodegenerative diseases. As a recently identified heptapeptide of the brain renin-angiotensin system, angiotensin-(1-7) was revealed to activate its receptor MAS1 and thus ameliorated cognitive impairments in rats with CCH. Since hippocampal synaptic degeneration represents an important pathological basis of cognitive deficits, we hypothesize that activation of MAS1-mediated signaling may alleviate CCH-induced synaptic degeneration in the hippocampus. METHODS: In this study, we tested this hypothesis and uncovered the underlying mechanisms in a rat model of CCH induced by bilateral common carotid artery ligation surgery. At 1 week after the surgery, rats received a daily intraperitoneal injection of vehicle or a non-peptidic MAS1 agonist AVE0991 for 8 weeks. During this procedure, cerebral blood flow (CBF) was recorded. The levels of MAS1, amyloid-ß (Aß), neuroinflammatory cytokines, glial cell markers and synaptophysin in the hippocampus were assessed at the end of the treatment period. RESULTS: We showed that AVE0991 significantly alleviated hippocampal synaptic degeneration in rats with CCH. This protection might be achieved by facilitating CBF recovery, reducing hippocampal Aß levels and suppressing neuroinflammatory responses. CONCLUSIONS: These findings indicate that MAS1-mediated signaling may represent a novel therapeutic target for CCH-related neurodegenerative diseases.

7.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 39(4): 464-468, 2021 Aug 01.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34409804

RESUMO

OBJECTIVES: This study aimed to explore the short-term clinical efficacy and factors influencing low-dose superficial X-ray for treating infantile maxillofacial hemangioma. METHODS: Retrospective analysis was conducted on 161 cases of infants with maxillofacial hemangioma treated with superficial X-ray in the Laser Center of Dermatology Department of Sichuan Provincial People's Hospital from January 2015 to December 2017. Clinical efficacy was analyzed by comparing the photos before and after treatment. Patients were further divided into groups according to different genders, age at the start of treatment, preterm birth or low birth weight, hemangioma site, longest diameter of hemangioma, and type of hemangioma to analyze whether differences existed in clinical efficacy and therapeutic dose between different groups. RESULTS: Twelve months after the end of treatment, the overall cure rate was 93.8%, and the significant efficiency was 97.5%. The clinical efficacy was related to the age of children at the beginning of treatment and the type of hemangioma (P<0.05). The clinical efficacy of children aged less than or equal to 12 months and superficial hemangioma group was better than that of children aged more than 12 months and deep subtype or mixed hemangioma group, respectively. Therapeutic doses associa-ted with hemangioma treatment with diameter, category, age (P<0.05), diameter greater than or equal to 4 cm hemangioma group, the mixed type or deep in the group, the children older than 12 months hemangioma group, respectively, the dia-meter is less than 4 cm hemangioma, superficial hemangioma group and age less than or equal to 12 months hemangioma total treatment group exposure dose is greater. CONCLUSIONS: Low-dose superficial X-ray is safe and effective for the treatment of infantile maxillofacial hemangioma. Age and type of hemangioma at the time of treatment are the factors influencing therapeutic dose and clinical efficacy.


Assuntos
Hemangioma , Nascimento Prematuro , Neoplasias Cutâneas , Criança , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Gravidez , Estudos Retrospectivos , Resultado do Tratamento , Raios X
8.
Phytomedicine ; 91: 153700, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34425474

RESUMO

BACKGROUND: Transcatheter arterial chemoembolization (TACE) is a standard therapy to treat hepatocellular carcinoma (HCC), but often limited for its complications. Ginsenosides, including total ginsenosides (GS), Rg3, Rh2 and CK, have been clinically used as adjuvants of TACE in HCC therapy. However, partial clinical observations concerning the efficacy and safety of the combinational treatment were contradictory. PURPOSE: To investigate the efficacy and safety of TACE and ginsenosides combination for HCC therapy. METHODS: Randomized controlled trials (RCTs) regarding TACE and ginsenosides for HCC up to May 2021 were screened from six databases (PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, Chinese VIP Information and Web of Science). The outcomes of tumor response, adverse reactions (ADRs), quality of life (QOL), survival rates (OS) and liver function were extracted and evaluated by meta-analysis, respectively. RESULTS: A total of 18 RCTs with 1308 HCC patients were enrolled, and most of the eligible studies had unclear bias risk. Compared with TACE, combining ginsenosides improved objective response rate [ORR, risk ratio (RR) 1.39, 95% confidence intervals (CI) 1.20∼1.61], disease control rate (DCR, RR 1.21, 95% CI 1.12∼1.30), QOL (RR 1.54, 95% CI 1.25∼1.90), one- (RR 1.37, 95% CI 1.16∼1.62) and two- (RR 1.43, 95% CI 1.06∼1.95) year OS, and A level of Child-pugh, as well as reduced the risks of nausea and vomiting, pyrexia, ache, hyperbilirubinemia, anorexia, fatigue, leukopenia, thrombocytopenia and myelosuppression. Subgroup analyses showed that both short- and long- treatment durations of ginsenosides enhanced the A level of Child-pugh, and reduced nausea and vomiting, ache and hyperbilirubinemia. Besides, combining Rg3 benefited DCR, ORR and QOL, and alleviated nausea and vomiting, hyperbilirubinemia, leukopenia, myelosuppression, thrombocytopenia and α-fetoprotein, while combining GS alleviated nausea and vomiting, ache and hyperbilirubinemia, combining Rh2 alleviated thrombocytopenia, and combining CK alleviated nausea and vomiting, pyrexia, ache and leukopenia, respectively. CONCLUSION: The results suggested that combining ginsenosides could continuously benefit the efficacy and safety of TACE in HCC treatment, and Rg3 is the prior selection during the combination.


Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Ginsenosídeos , Neoplasias Hepáticas , Carcinoma Hepatocelular/terapia , Terapia Combinada , Ginsenosídeos/farmacologia , Humanos , Neoplasias Hepáticas/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
9.
Artigo em Inglês | MEDLINE | ID: mdl-34380082

RESUMO

BACKGROUND: Previous sleep electroencephalography studies have detected abnormalities in sleep architecture and sleep spindle deficits in schizophrenia (SCZ), but the consistency of these results was not robust, which might be due to the small sample size and the influence of clinical factors such as the various medication therapies and symptom heterogeneity. This study aimed to regard auditory verbal hallucinations (AVHs) as a pointcut to downscale the heterogeneity of SCZ and explore whether some sleep architecture and spindle parameters were more severely impaired in SCZ patients with AVHs compared with those without AVHs. METHODS: A total of 90 SCZ patients with AVHs, 92 SCZ patients without AVHs, and 91 healthy control subjects were recruited, and parameters of sleep architecture and spindle activities were compared between groups. The correlation between significant sleep parameters and clinical indicators was analyzed. RESULTS: Deficits of sleep spindle activities at prefrontal electrodes and intrahemispheric spindle coherence were observed in both AVH and non-AVH groups, several of which were more serious in the AVH group. In addition, deficits of spindle activities at central and occipital electrodes and interhemispheric spindle coherence mainly manifested accompanying AVH symptoms, most of which were retained in the medication-naive first-episode patients, and were associated with Auditory Hallucination Rating Scale scores. CONCLUSIONS: Our results suggest that the underlying mechanism of spindle deficits might be different between SCZ patients with and without AVHs. In the future, the sleep feature of SCZ patients with different symptoms and the influence of clinical factors, such as medication therapy, should be further illustrated.

10.
J Mol Graph Model ; 107: 107967, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34157438

RESUMO

We applied Monte Carlo simulation to investigate the thermodynamic properties and hysteresis loops of the hexagonal core-shell nanoparticle described by a ferrimagnetic mixed-spin (3/2, 5/2) Ising model. The results revealed the significance of the single-ion anisotropy, exchange coupling, external magnetic field in dominating various thermodynamic quantities and hysteresis loops. We obtained the variation of the critical temperature with various parameters. Under certain parameter conditions, the system may exhibit rich multiple-loop hysteresis behaviors, depending on the competition among the physical parameters.


Assuntos
Campos Magnéticos , Nanopartículas , Simulação por Computador , Método de Monte Carlo , Temperatura
11.
Front Oncol ; 11: 629394, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33912453

RESUMO

Background: Cisplatin-based chemotherapy was previously considered as the standard adjuvant therapy for improved overall survival (OS) in patients with non-small cell lung cancer (NSCLC) after surgery. However, the benefit was limited due to high risks of recurrence and adverse events. In the present study, the efficacy of adjuvant epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for EGFR-mutant patients after surgery was investigated using the latest updated data. Methods: This meta-analysis included a comprehensive range of relevant studies identified from database searches. Disease-free survival (DFS) and OS with hazard ratios (HRs) were calculated using random-effect or fixed-effect models. Subgroup analysis was also performed. Results: A total of seven randomized clinical trials were included in the meta-analysis and involved 1,283 NSCLC patients harboring EGFR mutations. In resected EGFR-mutant NSCLC patients, adjuvant EGFR-TKIs were significantly better than chemotherapy in terms of DFS (HR: 0.41; 95%CI: 0.24-0.70, P = 0.001), without showing any benefit in OS (HR: 0.72; 95%CI: 0.37-1.41, P = 0.336). No significant difference in DFS was observed between patients with EGFR exon 19 deletion and those with L858R mutation. Resected EGFR-mutant NSCLC patients treated with osimertinib experienced improved DFS and a lower risk of brain recurrence than those treated with gefitinib or erlotinib. Adjuvant EGFR-TKIs reduced the risk of bone and lung relapse, without decreasing the risk of local recurrence and liver relapse. Conclusion: This meta-analysis shows that adjuvant EGFR-TKI therapy could significantly prolong DFS in patients with resected EGFR-mutant NSCLC. Treatment with osimertinib showed improved DFS with a lower risk of brain recurrence than treatment with gefitinib or erlotinib for resected disease.

12.
Radiother Oncol ; 158: 40-47, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33587968

RESUMO

BACKGROUND: Prophylactic cranial irradiation (PCI) was compared to observation in several randomized trials (RCTs), and a reduction greater than 50% was shown regarding the incidence of brain metastases (BM). However, none of these studies showed an improvement of overall survival (OS), possibly related to relatively small sample sizes and short follow-up. The aim of this meta-analysis was therefore to assess the impact of PCI on long term OS for stage III non-small cell lung cancer (NSCLC) compared to observation based on the pooled updated individual patient RCT data. METHODS: Seven RCTs were eligible, and data from the four most recent trials (924 patients) could be retrieved. The log-rank observed minus expected number of events and its variance were used to calculate individual and overall pooled hazard ratios (HRs) and 95% confidence intervals (95% CIs) with a fixed effects model. Inter-trial heterogeneity was studied using the I2 test. In addition, the 5-year absolute survival difference between arms was calculated for all endpoints. The pre-specified toxicities were reported descriptively. RESULTS: The median follow-up was 97 months (74-108). Compared to observation, no statistically significant impact of PCI on OS was observed (HR 0.90 [0.76-1.07] p = 0.23, 5-year absolute difference 1.8% [-5.2-8.8]). PCI significantly prolonged progression-free survival (HR 0.77 [0.66-0.91] p = 0.002) and BM-free survival (HR 0.82 [0.69-0.97] p = 0.02). The number of patients with high-grade (≥3) toxicity was 6.4% (21/330) for PCI. CONCLUSION: No OS benefit by PCI was observed, but PCI prolonged the progression-free survival and BM-free survival at an increased risk of late memory impairment and fatigue.


Assuntos
Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Neoplasias Encefálicas/prevenção & controle , Neoplasias Encefálicas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Irradiação Craniana/efeitos adversos , Humanos , Neoplasias Pulmonares/radioterapia , Intervalo Livre de Progressão
13.
Food Funct ; 12(5): 2225-2241, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33595586

RESUMO

Chemotherapy is applied to treat non-small cell lung cancer (NSCLC), but often limited due to its unstable therapeutic effects and adverse reactions (ADRs). Ginseng and its main ingredients (ginsenosides and polysaccharides) have been clinically used as adjuvants to chemotherapy. However, their efficacies were based on individual trials with relatively small sample sizes, and it is difficult to draw a valid conclusion. In this study, eligible randomized controlled trials (RCTs) were searched in six international and Chinese databases (PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, Chinese VIP Information and Wanfang). The outcomes of the objective response rate (ORR), disease control rate (DCR), ADRs, quality of life (QOL), survival rates and immunity were extracted using standard data extraction forms. The efficacies of ginseng and its ingredients as adjuvants to chemotherapy in NSCLC were investigated and compared by meta-analysis and subgroup meta-analysis, respectively. A total of 28 RCTs including 2503 subjects were enrolled, and most of the eligible studies were of low-to-moderate quality. For the evaluation of ginseng and its ingredients as adjuvants to chemotherapy, the risk ratio (RR) or standardized mean difference (SMD) and 95% confidence intervals (CI) of the ORR, DCR, leucopenia, thrombocytopenia, myelosuppression, hepatotoxicity, nausea and vomiting, diarrhea, CD4+/CD8+ and one- and two-year survival rates, and QOL were 1.35 (1.21,1.50), 1.20 (1.14,1.28), 0.59 (0.50, 0.70), 0.53 (0.37, 0.76), 0.30 (0.17, 0.53), 0.67 (0.52, 0.87), 0.67 (0.53, 0.86), 0.42 (0.19, 0.96), 1.39 (0.63, 2.16), 1.35 (1.13, 1.60), 3.21 (1.51, 6.81) and 1.31 (1.22, 1.41) with significant differences. Subgroup analysis showed that ginseng enhanced nausea and vomiting and QOL, ginsenosides increased ORR, DCR, QOL, leucopenia, thrombocytopenia, myelosuppression, hepatotoxicity, diarrhea, CD4+/CD8+, and one- and two-year survival rates, while polysaccharides improved ORR, DCR, leucopenia, thrombocytopenia, myelosuppression, hepatotoxicity and nausea and vomiting during chemotherapy. In conclusion, ginseng and its ingredients facilitated the therapeutic effects of chemotherapy on NSCLC patients. Ginseng had beneficial effects on alleviating ADRs and enhancing QOL, ginsenosides demonstrated beneficial effects on enhancing therapeutic effects, reducing ADRs, improving immunity, prolonging survival rates and promoting QOL, while polysaccharides showed beneficial effects on promoting therapeutic effects and reducing ADRs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Panax , Extratos Vegetais/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Quimioterapia Adjuvante , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/fisiopatologia , Pessoa de Meia-Idade , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto
14.
Lab Med ; 52(1): 64-73, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-32700735

RESUMO

OBJECTIVE: Long noncoding RNAs (lncRNAs) are widely involved in the carcinogenesis and development of cancers. We conducted a meta-analysis to evaluate the diagnostic performance of lncRNAs in hepatocellular carcinoma (HCC). METHODS: After the inclusion and exclusion process, relevant information was extracted. Heterogeneity between studies was evaluated, and data synthesis was conducted by employing a bivariate random-effects model. RESULTS: In total, 20 eligible studies were enrolled. The pooled sensitivity and specificity were 0.86 (95% confidence interval [CI], 0.80-0.90) and 0.88 (95% CI, 0.82-0.92), respectively. The pooled positive likelihood ratio, pooled negative likelihood ratio, and pooled diagnostic odds ratio were 7.1 (95% CI, 4.9-10.2), 0.16 (95% CI, 0.11-0.23), and 44 (95% CI, 25-79), respectively. The results of the linear regression method and visual inspection of the Deeks funnel plot did not indicate significant publication bias. CONCLUSION: Our meta-analysis suggested that lncRNAs have high diagnostic performance for HCC and have the potential for clinical application.


Assuntos
Carcinoma Hepatocelular/sangue , Neoplasias Hepáticas/sangue , RNA Longo não Codificante/sangue , Carcinoma Hepatocelular/diagnóstico , Humanos , Neoplasias Hepáticas/diagnóstico
15.
Front Immunol ; 11: 1933, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33072067

RESUMO

Background: Limited treatment strategies are available for squamous-cell lung cancer (SQLC) patients. Few studies have addressed whether immune-related genes (IRGs) or the tumor immune microenvironment can predict the prognosis for SQLC patients. Our study aimed to construct a signature predict prognosis for SQLC patients based on IRGs. Methods: We constructed and validated a signature from SQLC patients in The Cancer Genome Atlas (TCGA) using bioinformatics analysis. The underlying mechanisms of the signature were also explored with immune cells and mutation profiles. Results: A total of 464 eligible SQLC patients from TCGA dataset were enrolled and were randomly divided into the training cohort (n = 232) and the testing cohort (n = 232). Eight differentially expressed IRGs were identified and applied to construct the immune signature in the training cohort. The signature showed a significant difference in overall survival (OS) between low-risk and high-risk cohorts (P < 0.001), with an area under the curve of 0.76. The predictive capability was verified with the testing and total cohorts. Multivariate analysis revealed that the 8-IRG signature served as an independent prognostic factor for OS in SQLC patients. Naive B cells, resting memory CD4 T cells, follicular helper T cells, and M2 macrophages were found to significantly associate with OS. There was no statistical difference in terms of tumor mutational burden between the high-risk and low-risk cohorts. Conclusion: Our study constructed and validated an 8-IRG signature prognostic model that predicts clinical outcomes for SQLC patients. However, this signature model needs further validation with a larger number of patients.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Perfilação da Expressão Gênica , Neoplasias Pulmonares/genética , Transcriptoma , Idoso , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/terapia , Bases de Dados Genéticas , Feminino , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Mutação , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Microambiente Tumoral
16.
J Cancer ; 11(20): 6114-6121, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922551

RESUMO

Background: This study aimed to develop a predictive model based on the risk of locoregional recurrence (LRR) in epidermal growth factor receptor (EGFR)-mutant stage III-pN2 lung adenocarcinoma after complete resection. Methods: A total of 11,020 patients with lung surgery were screened to determine completely resected EGFR-mutant stage III-pN2 lung adenocarcinoma. Patients were excluded if they received preoperative therapy or postoperative radiation therapy (PORT). The time from surgery to LRR was recorded. Clinicopathological variables with statistical significance predicting LRR in the multivariate Cox regression were incorporated into the competing risk nomogram. Patients were then sub-grouped based on different recurrence risk as a result of the nomogram. Results: Two hundred and eighty-eight patients were enrolled, including 191 (66.3%) with unforeseen N2 (IIIA1-2), 75 (26.0%) with minimal/single station N2 (IIIA3), and 22 (7.6%) with bulky and/or multilevel N2 (IIIA4). The 2-year overall cumulative incidence of LRR was 27.2% (confidence interval [CI], 16.3%-38.0%). IIIA4 disease (hazard ratio, 2.65; CI, 1.15-6.07; P=0.022) and extranodal extension (hazard ratio, 3.33; CI, 1.76-6.30; P<0.001) were independent risk factors for LRR and were incorporated into the nomogram. Based on the nomogram, patients who did not have any risk factor (low-risk) had a significantly lower predicted 2-year incidence of LRR than those with any of the risk factors (high-risk; 4.6% vs 21.9%, P<0.001). Conclusions: Pre-treatment bulky/multilevel N2 and pathological extranodal extension are risk factors for locoregional recurrence in EGFR-mutant stage III-pN2 lung adenocarcinoma. Intensive adjuvant therapies and active follow-up should be considered in patients with any of the risk factors.

17.
Nat Immunol ; 21(9): 1107-1118, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32788748

RESUMO

In coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the relationship between disease severity and the host immune response is not fully understood. Here we performed single-cell RNA sequencing in peripheral blood samples of 5 healthy donors and 13 patients with COVID-19, including moderate, severe and convalescent cases. Through determining the transcriptional profiles of immune cells, coupled with assembled T cell receptor and B cell receptor sequences, we analyzed the functional properties of immune cells. Most cell types in patients with COVID-19 showed a strong interferon-α response and an overall acute inflammatory response. Moreover, intensive expansion of highly cytotoxic effector T cell subsets, such as CD4+ effector-GNLY (granulysin), CD8+ effector-GNLY and NKT CD160, was associated with convalescence in moderate patients. In severe patients, the immune landscape featured a deranged interferon response, profound immune exhaustion with skewed T cell receptor repertoire and broad T cell expansion. These findings illustrate the dynamic nature of immune responses during disease progression.


Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Interferon Tipo I/metabolismo , Pneumonia Viral/imunologia , Receptores Imunológicos/metabolismo , Adolescente , Adulto , Idoso , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , COVID-19 , Estudos de Coortes , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Proteínas Ligadas por GPI/metabolismo , Humanos , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , RNA-Seq , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , SARS-CoV-2 , Índice de Gravidade de Doença , Análise de Célula Única
18.
Nat Commun ; 11(1): 3410, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641700

RESUMO

COVID-19 is associated with 5.1% mortality. Although the virological, epidemiological, clinical, and management outcome features of COVID-19 patients have been defined rapidly, the inflammatory and immune profiles require definition as they influence pathogenesis and clinical expression of COVID-19. Here we show lymphopenia, selective loss of CD4+ T cells, CD8+ T cells and NK cells, excessive T-cell activation and high expression of T-cell inhibitory molecules are more prominent in severe cases than in those with mild disease. CD8+ T cells in patients with severe disease express high levels of cytotoxic molecules. Histochemical studies of lung tissue from one fatality show sub-anatomical distributions of SARS-CoV-2 RNA and massive infiltration of T cells and macrophages. Thus, aberrant activation and dysregulation of CD8+ T cells occur in patients with severe COVID-19 disease, an effect that might be for pathogenesis of SARS-CoV-2 infection and indicate that immune-based targets for therapeutic interventions constitute a promising treatment for severe COVID-19 patients.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/imunologia , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , COVID-19 , Quimiotaxia de Leucócito , China/epidemiologia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/virologia , Citocinas/sangue , Feminino , Humanos , Inflamação , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Contagem de Leucócitos , Pulmão/imunologia , Pulmão/virologia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/virologia , SARS-CoV-2
19.
Aging (Albany NY) ; 12(14): 14819-14829, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32701063

RESUMO

Previously, we revealed that brain Ang-(1-7) deficiency was involved in the pathogenesis of sporadic Alzheimer's disease (AD). We speculated that restoration of brain Ang-(1-7) levels might have a therapeutic effect against AD. However, the relatively short duration of biological effect limited the application of Ang-(1-7) in animal experiments. Since Ang-(1-7) is generated by its metabolic enzyme ACE2, we then tested the efficacy of an ACE2 activator diminazene aceturate (DIZE) on AD-like neuropathology and cognitive impairment in senescence-accelerated mouse prone substrain 8 (SAMP8) mice, an animal model of sporadic AD. Eight-month-old SAMP8 mice were injected intraperitoneally with vehicle or DIZE once a day for 30 consecutive days. DIZE markedly elevated brain Ang-(1-7) and MAS1 levels. Meanwhile, DIZE significantly reduced the levels of Aß1-42, hyperphosphorylated tau and pro-inflammatory cytokines in the brain. The synaptic and neuronal losses in the brain were ameliorated by DIZE. Importantly, DIZE improved spatial cognitive functions in the Morris water maze test. In conclusion, this study demonstrates that DIZE ameliorates AD-like neuropathology and rescues cognitive impairment in SAMP8 mice. These beneficial effects of DIZE may be achieved by activating brain ACE2/Ang-(1-7)/MAS1 axis. These findings highlight brain ACE2/Ang-(1-7)/MAS1 axis as a potential target for the treatment of sporadic AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Enzima de Conversão de Angiotensina 2/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Diminazena/análogos & derivados , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/biossíntese , Peptídeos beta-Amiloides/genética , Angiotensina I/metabolismo , Animais , Química Encefálica/efeitos dos fármacos , Química Encefálica/genética , Disfunção Cognitiva/etiologia , Citocinas/biossíntese , Diminazena/uso terapêutico , Infusões Parenterais , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Mutantes Neurológicos , Fragmentos de Peptídeos/biossíntese , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Proteínas Proto-Oncogênicas/genética , Receptores Acoplados a Proteínas G/genética , Proteínas tau/biossíntese
20.
Cell Metab ; 32(2): 188-202.e5, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32610096

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic presents an unprecedented threat to global public health. Herein, we utilized a combination of targeted and untargeted tandem mass spectrometry to analyze the plasma lipidome and metabolome in mild, moderate, and severe COVID-19 patients and healthy controls. A panel of 10 plasma metabolites effectively distinguished COVID-19 patients from healthy controls (AUC = 0.975). Plasma lipidome of COVID-19 resembled that of monosialodihexosyl ganglioside (GM3)-enriched exosomes, with enhanced levels of sphingomyelins (SMs) and GM3s, and reduced diacylglycerols (DAGs). Systems evaluation of metabolic dysregulation in COVID-19 was performed using multiscale embedded differential correlation network analyses. Using exosomes isolated from the same cohort, we demonstrated that exosomes of COVID-19 patients with elevating disease severity were increasingly enriched in GM3s. Our work suggests that GM3-enriched exosomes may partake in pathological processes related to COVID-19 pathogenesis and presents the largest repository on the plasma lipidome and metabolome distinct to COVID-19.


Assuntos
Infecções por Coronavirus/sangue , Infecções por Coronavirus/patologia , Exossomos/metabolismo , Gangliosídeo G(M3)/sangue , Gangliosídeos/sangue , Pneumonia Viral/sangue , Pneumonia Viral/patologia , Adulto , Idoso , Betacoronavirus , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , COVID-19 , Diglicerídeos/sangue , Feminino , Humanos , Masculino , Metaboloma/fisiologia , Metabolômica/métodos , Pessoa de Meia-Idade , Pandemias , SARS-CoV-2 , Esfingomielinas/sangue , Espectrometria de Massas em Tandem , Adulto Jovem
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