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1.
Ann Hepatol ; : 101572, 2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39278407

RESUMO

INTRODUCTION AND OBJECTIVE: Due to the high heterogeneity of HCC, which leads to poor prognostic outcomes for patients, there is a need to develop a novel predictive model for accurate classification of HCC in order to improve patient survival rates. MATERIALS AND METHODS: The data of the HCV, cirrhosis, and HCC were obtained from TCGA and GEO databases. Multivariable Cox regression analysis and survival analysis was conducted to assess the prognostic relevance of these differentially expressed genes. Single-cell sequencing was used to explore the intercellular interaction patterns and identify relevant signaling pathways. Drug sensitivity analysis was conducted to determine personalized treatment strategies for patients. RESULTS: In this study, we conducted integrated analysis of hepatitis, cirrhosis, and hepatocellular carcinoma datasets and identified 10 liver disease progression genes associated with prognosis. These genes exhibited significant downregulation in expression as the disease advanced, suggesting their crucial involvement in HCC development. By performing multivariable Cox analysis, we established a prognostic model for liver disease progression to predict the prognosis of HCC patients. The model was validated using ROC analysis, demonstrating good accuracy and stability in prognostic evaluation. Single-cell sequencing analysis revealed that these genes primarily exert their effects through the MIF signaling pathway during HCC progression. Furthermore, we observed that patients in the low-risk group exhibited higher sensitivity to TACE treatment, while patients in the high-risk group showed better response to sorafenib treatment. CONCLUSIONS: In summary, we have elucidated the key genes involved in the progression of liver diseases and established a precise prognostic model for assessing the prognosis of HCC patients. Our study provides novel insights and strategies for the treatment of HCC.

2.
J Fungi (Basel) ; 10(7)2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-39057337

RESUMO

Recent studies have predominantly spotlighted bacterial diversity within coral microbiomes, leaving coral-associated fungi in the shadows of scientific inquiry. This study endeavors to fill this knowledge gap by delving into the biodiversity, distribution and functional differences of fungi associated with soft corals Cladiella krempfi and Sarcophyton tortuosum, gorgonian coral Dichotella gemmacea and stony coral Favia speciosa from the South China Sea. Leveraging high-throughput sequencing of fungal internal transcribed spacer-1 (ITS1) region of the rRNA gene, a total of 431 fungal amplicon sequence variants (ASVs) were identified in this study, which indicated that a large number of fungal communities were harbored in the South China Sea corals. Noteworthy among our findings is that 10 fungal genera are reported for the first time in corals, with Candolleomyces, Exophiala, Fomitopsis, Inaequalispora, Kneiffiella, Paraphaeosphaeria, and Yamadazyma belonging to the Ascomycota, and Cystobasidium, Psathyrella, and Solicoccozyma to the Basidiomycota. Moreover, significant differences (p < 0.05) of fungal communities were observed among the various coral species. In particular, the gorgonian coral D. gemmacea emerged as a veritable haven for fungal diversity, boasting 307 unique ASVs. Contrastingly, soft corals S. tortuosum and C. krempfi exhibited modest fungal diversity, with 36 and 21 unique ASVs, respectively, while the stony coral F. speciosa hosted a comparatively sparse fungal community, with merely 10 unique ASVs in total. These findings not only provide basic data on fungal diversity and function in the South China Sea corals, but also underscore the imperative of nuanced conservation and management strategies for coral reef ecosystems worldwide.

3.
Intern Med J ; 54(9): 1531-1540, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38856155

RESUMO

BACKGROUND: Identification of hypoxaemia and hypercapnia is essential for the diagnosis and treatment of acute respiratory failure. While arterial blood gas (ABG) analysis is standard for PO2 and PCO2 measurement, venous blood gas (VBG) analysis is increasingly used as an alternative. Previous systematic reviews established that VBG reporting of PO2 and PCO2 is less accurate, but the impacts on clinical management and patient outcomes are unknown. AIMS: This study aimed to systematically review available evidence of the clinical impacts of using ABGs or VBGs and examine the arteriovenous difference in blood gas parameters. METHODS: A comprehensive search of the MEDLINE, Embase and Cochrane Library databases since inception was conducted. Included studies were prospective or cross-sectional studies comparing peripheral ABG to peripheral VBG in adult non-critical care inpatients presenting with respiratory symptoms. RESULTS: Of 15 119 articles screened, 15 were included. No studies were found that examined clinical impacts resulting from using VBG compared to ABG. Included studies focused on the agreement between ABG and VBG measurements of pH, PO2, PCO2 and HCO3 -. Due to the heterogeneity of the included studies, qualitative evidence synthesis was performed. While the arteriovenous difference in pH and HCO3 - was generally predictable, the difference in PO2 and PCO2 was more significant and less predictable. CONCLUSIONS: Our study reinforces the notion that VBG is not comparable to ABG for physiological measurements. However, a key revelation from our research is the significant lack of data regarding the clinical implications of using VBG instead of ABG, a common scenario in clinical practice. This highlights a critical knowledge gap.


Assuntos
Gasometria , Adulto , Humanos , Artérias , Gasometria/métodos , Dióxido de Carbono/sangue , Estudos Transversais , Hospitalização , Hipercapnia/sangue , Hipercapnia/diagnóstico , Hipercapnia/fisiopatologia , Hipóxia/sangue , Hipóxia/diagnóstico , Hipóxia/fisiopatologia , Oxigênio/sangue , Estudos Prospectivos , Insuficiência Respiratória/sangue , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/fisiopatologia , Veias
4.
J Pain Symptom Manage ; 67(5): 453-462, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38365070

RESUMO

INTRODUCTION/AIM: Despite clear benefit from palliative care in end-stage chronic diseases, access is often limited, and rural access largely undescribed. This study sought to determine if a palliative approach is provided to people with chronic disease in their terminal hospital admission. METHODS: Multisite, retrospective medical record audit, of decedents with a primary diagnosis of chronic lung, heart, or renal failure, or multimorbidity of these conditions over 2019. RESULTS: Of 241 decedents, across five clinical sites, 143 (59.3%) were men, with mean age 80.47 years (SD 11.509), and diagnoses of chronic lung (n = 56, 23.2%), heart (n = 56, 23.2%), renal (n = 24, 10.0%) or multimorbidity disease (n = 105, 43.6%), and had 2.88 (3.04SD) admissions within 12 months. Outpatient chronic disease care was evident (n = 171, 73.7%), however, contact with a private physician (n = 91, 37.8%), chronic disease program (n = 61, 25.3%), or specialist nurse (n = 17, 7.1%) were less apparent. "Not-for-resuscitation" orders were common (n = 139, 57.7%), however, advance care planning (n = 71, 29.5%), preferred place of death (n = 18, 7.9%), and spiritual support (n = 18, 7.5%) were rarely documented. Referral to and input from palliative services were low (n = 74, 30.7% and n = 49, 20.3%), as was review of nonessential medications or blood tests (n = 86, 35.7%, and n = 78, 32.4%). Opioids were prescribed in 45.2% (n = 109). Hospital site and diagnosis were significantly associated with outpatient care and palliative approach (P<0.001). CONCLUSIONS: End-of-life planning and specialist palliative care involvement occurred infrequently for people with chronic disease who died in rural hospitals. Targeted strategies are necessary to improve care for these prevalent and high needs rural populations.


Assuntos
População Rural , Assistência Terminal , Masculino , Humanos , Idoso de 80 Anos ou mais , Feminino , Estudos Retrospectivos , Cuidados Paliativos , Doença Crônica , Hospitais
5.
Proc Natl Acad Sci U S A ; 120(46): e2307480120, 2023 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-37943835

RESUMO

Ischemic diseases lead to considerable morbidity and mortality, yet conventional clinical treatment strategies for therapeutic angiogenesis fall short of being impactful. Despite the potential of biomaterials to deliver pro-angiogenic molecules at the infarct site to induce angiogenesis, their efficacy has been impeded by aberrant vascular activation and off-target circulation. Here, we present a semisynthetic low-molecular sulfated chitosan oligosaccharide (SCOS) that efficiently induces therapeutic arteriogenesis with a spontaneous generation of collateral circulation and blood reperfusion in rodent models of hind limb ischemia and myocardial infarction. SCOS elicits anti-inflammatory macrophages' (Mφs') differentiation into perivascular Mφs, which in turn directs artery formation via a cell-to-cell communication rather than secretory factor regulation. SCOS-mediated arteriogenesis requires a canonical Notch signaling pathway in Mφs via the glycosylation of protein O-glucosyltransferases 2, which results in promoting arterial differentiation and tissue repair in ischemia. Thus, this highly bioactive oligosaccharide can be harnessed to direct efficiently therapeutic arteriogenesis and perfusion for the treatment of ischemic diseases.


Assuntos
Neovascularização Fisiológica , Sulfatos , Camundongos , Animais , Neovascularização Fisiológica/fisiologia , Sulfatos/metabolismo , Camundongos Knockout , Músculo Esquelético/metabolismo , Isquemia/metabolismo , Macrófagos/metabolismo , Membro Posterior/irrigação sanguínea , Modelos Animais de Doenças
6.
Eur J Med Chem ; 261: 115843, 2023 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-37832229

RESUMO

Based on the facts that significant synergistic effect existed between PARP inhibitors and DNA damage agents and the DNA damage caused by indirubin's derivatives, we herein adopted the strategy to combine the pharmacophores of PARP inhibitors and the unique scaffold of indirubin to design a series of bifunctional molecules inducing DNA damage and targeting PARP. After SAR studies, the most potent compound 12a, encoded as KWWS-12a, exhibited improved inhibitory effect against PARP1 compared with PARP1 inhibitor Olaparib (IC50 = 1.89 nM vs 7.48 nM) and enhanced antiproliferative activities than the combination of Olaparib and indirubin-3'-monoxime towards HCT-116 cells (IC50 = 0.31 µM vs 1.37 µM). In the normal NCM-460 cells, 12a showed low toxicity (IC50 > 60 µM). The mechanism research indicated that 12a could increase the levels of γH2AX concentration dependently, arrest the cell cycle in S phase and induce apoptosis in HCT-116 cells. In vivo experiments showed that 12a displayed more significant antitumor potential than that of the positive controls. Our studies demonstrated that 12a could be a promising candidate for cancer therapy.


Assuntos
Antineoplásicos , Neoplasias , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Linhagem Celular Tumoral , Dano ao DNA , Apoptose , Ftalazinas/farmacologia , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico
7.
Bioorg Med Chem ; 91: 117386, 2023 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-37379621

RESUMO

Aberrant expression of EZH2 is frequently observed in cancers, and the EZH2 inhibitors are only effective in hematological malignancies and almost noneffective against solid tumors. It has been reported that the combination of EZH2 and BRD4 inhibitors may be a promising strategy to treat solid tumors being insensitive to EZH2 inhibitors. Thus, a series of EZH2/BRD4 dual inhibitors were designed and synthesized. The optimized compound 28, encoded as KWCX-28, was the most potential compound by the SAR studies. Further mechanism studies showed that KWCX-28 inhibited HCT-116 cells proliferation (IC50 = 1.86 µM), induced HCT-116 cells apoptosis, arrested cell cycle arrest at G0/G1 phase and resisted the histone 3 lysine 27 acetylation (H3K27ac) upregulation. Therefore, KWCX-28 was a potential dual EZH2/BRD4 inhibitors for treating solid tumors.


Assuntos
Neoplasias , Proteínas Nucleares , Humanos , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Neoplasias/tratamento farmacológico , Proteínas Nucleares/metabolismo , Fatores de Transcrição
8.
Bioorg Chem ; 139: 106683, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37379778

RESUMO

Inhibition of PARP is synthetic lethal with defects in BRCA, which provide effective targeted therapy strategy for BRCA mutation type of TNBC patients. However, approximately 80% of TNBC patients do not have BRCA mutations. Recent studies have shown that CDK4/6 inhibitors can increase the sensitivity of wild-type BRCA cells to PARP inhibitors. We designed a series of dual PARP and CDK6 inhibitors, and the most promising compound, P4i, showed good inhibitory activity against PARP1 and CDK6 and good inhibitory effects on MDA-MB-231 (IC50 = 1.96 µM), MDA-MB-468 (IC50 = 2.81 µM) and BT-549 (IC50 = 2.37 µM) cells with wild-type BRCA. Compared with Olaparib, the inhibition capacity of the three BRCA wild-type (MDA-MB-231, MDA-MB-468 and BT-549) cells was about 10-20 times higher, and even better than the combination of Olaparib and Palbociclib. As a novel PARP multifunctional molecule, it is a potential compound for the treatment of BRCA wild-type TNBC.


Assuntos
Inibidores de Poli(ADP-Ribose) Polimerases , Neoplasias de Mama Triplo Negativas , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Linhagem Celular Tumoral , Quinase 6 Dependente de Ciclina
9.
J Med Chem ; 65(19): 12838-12859, 2022 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-36153841

RESUMO

Aberrance of epigenetic modification is one of the important factors leading to hematological malignancies. Histone deacetylase (HDAC) inhibitors and enhancers of zeste homologue 2 (EZH2) inhibitors are demonstrated to be significant epigenic modulators. Cocktail therapy of HDAC inhibitors and EZH2 inhibitors was demonstrated to be a promising strategy in hematological malignancies. We designed HDAC and EZH2 dual inhibitors based on the strong synergistic effect of SAHA and GSK126. Compound 20 exhibited excellent inhibitory activity against HDAC1 (IC50 = 0.12 µM) and EZH2 (IC50 = 0.059 µM), it also showed good antiproliferation activity against MV4-11 (IC50 = 0.17 µM), which has more potential than the cocktail therapy of SAHA and GSK126 (IC50 = 0.40 µM). 20 suppressed tumor growth in vivo, which was as good as the combination therapy. These results suggested that 20 may be a promising drug candidate for treating hematological malignancies.


Assuntos
Neoplasias Hematológicas , Neoplasias , Linhagem Celular Tumoral , Proliferação de Células , Proteína Potenciadora do Homólogo 2 de Zeste , Epigênese Genética , Neoplasias Hematológicas/tratamento farmacológico , Histona Desacetilase 1 , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Humanos , Neoplasias/tratamento farmacológico
10.
Eur J Med Chem ; 238: 114462, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35623249

RESUMO

EZH2 is usually overexpressed in TNBC and other tumors, which has a great influence on the occurrence, development and prognosis of tumors. However, current EZH2 inhibitors, including Tazemetostat and GSK126, affect the methyl catalytic capacity of EZH2 and have little effect on the tumorigenic activity of EZH2 itself, resulting in poor efficacy against most solid tumors. Herein, we designed and optimized proteolytic targeting chimeras (PROTACs) precision targeting EZH2. The most active PROTAC molecule U3i has a high affinity for PRC2 complex (KD = 16.19 nM) and show good inhibitory effects on MDA-MB-231 (IC50 = 0.57 µM) and MDA-MB-468 (IC50 = 0.38 µM) cells. Compared with that of the GSK126, the growth inhibitory activities of U3i against these two TNBC cells increased by approximately 20- and 30-fold. Further studies showed that U3i can degrade PRC2 complex in TNBC cells, induce apoptosis, and cause little damage to normal cells. Therefore, U3i is a potential anticancer molecule for TNBC treatment.


Assuntos
Neoplasias de Mama Triplo Negativas , Apoptose , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/farmacologia , Inibidores Enzimáticos/farmacologia , Humanos , Neoplasias de Mama Triplo Negativas/patologia
11.
Intern Med J ; 52(11): 1925-1933, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35384242

RESUMO

BACKGROUND: Chronic breathlessness is a disabling symptom that is often under-recognised and challenging to treat despite optimal disease-directed therapy. Low-dose, oral opioids are recommended to relieve breathlessness, but little is known regarding long-term opioid prescription in this setting. AIM: To investigate the long-term efficacy of, and side-effects from, opioids prescribed for chronic breathlessness to patients with advanced, non-malignant, respiratory diseases. METHODS: A prospective cohort study of all patients managed by the advanced lung disease service, an integrated respiratory and palliative care service, at the Royal Melbourne Hospital from 1 April 2013 to 3 March 2020. RESULTS: One hundred and nine patients were prescribed opioids for chronic breathlessness. The median length of opioid use was 9.8 (interquartile range (IQR) = 2.8-19.8) months. The most commonly prescribed initial regimen was an immediate-release preparation (i.e. Ordine) used as required (37; 33.9%). For long-term treatment, the most frequently prescribed regimen included an extended-release preparation with an as needed immediate-release (37; 33.9%). The median dose prescribed was 12 (IQR = 8-28) mg oral morphine equivalents/day. Seventy-one (65.1%) patients reported a subjective improvement in breathlessness. There was no significant change in the mean modified Medical Research Council dyspnoea score (P = 0.807) or lung function measurements (P = 0.086-0.727). There was no association between mortality and the median duration of opioid use (P = 0.201) or dose consumed (P = 0.130). No major adverse events were reported. CONCLUSION: Within this integrated respiratory and palliative care service, patients with severe, non-malignant respiratory diseases safely used long-term, low-dose opioids for breathlessness with subjective benefits reported and no serious adverse events.


Assuntos
Analgésicos Opioides , Dispneia , Humanos , Analgésicos Opioides/efeitos adversos , Estudos Prospectivos , Dispneia/tratamento farmacológico , Morfina/efeitos adversos , Prescrições
12.
Bioorg Chem ; 120: 105604, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35051708

RESUMO

Overexpression of histone deacetylases (HDACs) are observed in different types of cancers, but histone deacetylase inhibitors (HDACIs) have not shown significant efficacy as monotherapy against solid tumors. Recently, studies demonstrated that it is promising to combine HDACIs with DNA damage agents to improve DNA damage level to gain better effect on treating solid tumor. Harmine has been demonstrated to cause DNA damage by intercalating DNA. Therefore, we designed a series of harmine-based inhibitors targeting HDAC and DNA with multi-target strategy, the most potential compound 27 could bind to DNA and cause DNA damage. Furthermore 27 caused cells apoptosis through p53 signaling pathway, and exhibited significant anti-proliferation effects against HCT-116 cells (IC50 = 1.41 µM). As a DNA damage agent, 27 displayed low toxicity in normal cells. Compound 27 was demonstrated as a dual inhibitor targeting HDAC (HDAC1 IC50 = 0.022 µM and HDAC6 IC50 = 0.45 µM) and DNA, and had the potential in the treatment of solid tumor.


Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , DNA , Harmina/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Neoplasias/tratamento farmacológico
13.
J Med Chem ; 64(23): 17304-17325, 2021 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-34847663

RESUMO

As a vital kinase in the glycolysis system, PKM2 is extensively expressed in colorectal cancer (CRC) to support the energy and biosynthetic needs. In this study, we designed a series of parthenolide (PTL) derivatives through a stepwise structure optimization, and an excellent derivate 29e showed good activity on PKM2 (AC50 = 86.29 nM) and displayed significant antiproliferative activity against HT29 (IC50 = 0.66 µM) and SW480 (IC50 = 0.22 µM) cells. 29e decreased the expression of total PKM2, prevented nucleus translocation of PKM2 dimer, and inhibited PKM2/STAT3 signaling pathway. 29e remarkably increased OCR and decreased the extracellular acidification rate (ECAR). The antiproliferative effect of 29e depended on PKM2, and the Cys424 of PKM2 was the key binding site. Furthermore, 29e significantly suppressed tumor growth in the HT29 xenograft model without obvious toxicity. These outcomes demonstrate that 29e is a promising drug candidate for the treatment of CRC.


Assuntos
Neoplasias Colorretais/patologia , Ativadores de Enzimas/farmacologia , Proteína Quinase C/efeitos dos fármacos , Sesquiterpenos/farmacologia , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/enzimologia , Dimerização , Ativadores de Enzimas/química , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fator de Transcrição STAT3/metabolismo , Sesquiterpenos/química , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
14.
J Med Chem ; 64(17): 12630-12650, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34455779

RESUMO

PARP inhibitors have highly significant effects on BRCA mutant cells, allowing targeted therapy of triple-negative breast cancer (TNBC). However, some TBNC patients lack BRCA mutations. Recent studies have shown that EZH2 inhibitors can increase the sensitivity of wild-type BRCA cells to PARP inhibitors. We designed a series of dual PARP and EZH2 inhibitors, and the most promising compound, 5a, showed good inhibitory activity against PARP-1 and EZH2 and good inhibitory effects on MDA-MB-231 (IC50 = 2.63 µM) and MDA-MB-468 (IC50 = 0.41 µM) cells with wild-type BRCA. Compared with that of olaparib, the growth inhibitory activities against these two cell types increased by approximately 15- and 80-fold, respectively, which was even more effective than the combination of olaparib and tazemetostat/GSK126. 5a can induce autophagy death of tumor cells and cause less damage to normal cells. Therefore, 5a, as a first-in-class dual PARP and EZH2 inhibitor, is a potential anticancer drug candidate for the treatment of TNBC.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Genes BRCA1/fisiologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Domínio Catalítico , Linhagem Celular Tumoral , Proteína Potenciadora do Homólogo 2 de Zeste/química , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Humanos , Estrutura Molecular , Inibidores de Poli(ADP-Ribose) Polimerases/química , Ligação Proteica
15.
Int J Biol Macromol ; 183: 2376-2386, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34111485

RESUMO

Bovine pestivirus A and B, previously known as bovine viral diarrhea virus (BVDV)-1 and 2, respectively, are important pathogens of cattle worldwide, which causes significant economic losses. B-cell epitopes in BVDV glycoprotein E2 and nonstructural protein NS2/3 have been extensively identified. In this study, we screened a 12-mer phage display peptide library using commercial goat anti-BVDV serum, and identified a mimotope "LTPHKHHKHLHA" referred to as P3. With sequence alignment, a putative B-cell epitope "77ESRKKLEKALLA88" termed as P3-BVDV1/2 residing in BVDV core protein was identified. The synthesized peptides of both P3 and P3-BVDV1/2 show strong reactivity with BVDV serum in immune blot assay. Immunization of mice with these individual peptides leads to the production of antibody that cannot neutralize virus infectivity. Thus for the first time we identified a B-cell epitope, "77ESRKKLEKALLA88", in BVDV core protein. Interestingly, the epitope was highly conserved in Pestivirus A, B, C, D, as well as emerging Pestivirus E and I, but highly variable in Pestiviruses H, G, F, and J, as well as unclassified Pestivirus originated from non-ruminant animals. Whether this putative B-cell epitope is implicated in pestivirus pathogenesis or evolution needs further investigations once large numbers of isolates are available in the future.


Assuntos
Técnicas de Visualização da Superfície Celular , Vírus da Diarreia Viral Bovina Tipo 1/imunologia , Vírus da Diarreia Viral Bovina Tipo 2/imunologia , Mapeamento de Epitopos , Epitopos de Linfócito B/imunologia , Biblioteca de Peptídeos , Proteínas do Core Viral/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Antivirais/sangue , Bovinos , Vírus da Diarreia Viral Bovina Tipo 1/genética , Vírus da Diarreia Viral Bovina Tipo 1/patogenicidade , Vírus da Diarreia Viral Bovina Tipo 2/genética , Vírus da Diarreia Viral Bovina Tipo 2/patogenicidade , Cães , Epitopos de Linfócito B/administração & dosagem , Epitopos de Linfócito B/genética , Feminino , Imunização , Imunogenicidade da Vacina , Células Madin Darby de Rim Canino , Camundongos Endogâmicos BALB C , Mutação , Proteínas do Core Viral/administração & dosagem , Proteínas do Core Viral/genética , Vacinas Virais/administração & dosagem , Vacinas Virais/genética
16.
Exp Cell Res ; 395(2): 112191, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32738346

RESUMO

Triple-negative breast cancer (TNBC) has the characteristics of fast growth, easy invasion, metastasis, poor prognosis, low tumor-free survival rate and overall survival rate. In this study, the RNA-binding protein MEX3A was selected by using the methods of TCGA database analysis, mRNA microarrays, and tissue chip immunohistochemistry experiments. The high expression of MEX3A is associated with malignancy and poor prognosis of TNBC. In addition, MEX3A knockdown can inhibit the growth and migration of TNBC cells while MEX3A overexpression shows the opposite effect. In vivo experiments, we also demonstrated that downregulating MEX3A can inhibit the tumorigenicity of TNBC cells. The mRNA microarrays and Ingenuity pathway analysis (IPA) were used to explore the downstream of MEX3A, and verified the relationship between PI3K/AKT signaling pathway and MEX3A. Additionally, we have simultaneously up-regulated MEX3A and treated with pathway inhibitors in vitro experiments and found that it can slow down the growth of TNBC cells. In short, we identified MEX3A as a tumor promoter, potential prognostic indicator and therapeutic target for TNBC, may function through the regulation of the PI3K/AKT signaling pathway.


Assuntos
Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Fosfoproteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/fisiologia
17.
Am J Rhinol Allergy ; 27(6): 502-5, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24274226

RESUMO

BACKGROUND: The prevalence of bronchial asthma (BA) and the underlying risk factors in patients with allergic rhinitis (AR) in China are largely unknown. Thus, this study is designed to assess the BA comorbidity in AR patients in two cities (Guangzhou and Zhuhai) of southern China and to determine the risk factors of BA in these AR patients. METHODS: We performed a cross-sectional, hospital-based survey in two modernized cities in southern China. The BA prevalence was evaluated in 1931 AR patients. Participants were asked to complete a questionnaire containing specific items for AR and BA. A logistic regression analysis was used to assess the risk factors of BA comorbidity in AR patients. RESULTS: The prevalence of concomitant BA in AR patients is 5.33% (103/1931). Most of the participants (98.4%) were sensitized to more than one allergen, and the most common sensitization was to house-dust mites. The strongest risk factor of BA determined by a multiple logistic regression analysis was a duration of AR of >5 years (adjusted odds ratio [OR], 8.67; 95% confidence interval [CI], 3.74-20.06), followed by smoking (adjusted OR, 7.21; 95% CI, 1.86-8.23) and self-medication with antibiotics (adjusted OR, 6.35; 95% CI, 3.43-11.78). CONCLUSION: Our findings suggested the risk factors of concomitant BA in AR patients may be helpful to establish preventive strategies.


Assuntos
Asma/epidemiologia , Rinite Alérgica Perene/epidemiologia , Adolescente , Adulto , Asma/etiologia , Criança , Pré-Escolar , China/epidemiologia , Estudos Transversais , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prevalência , Rinite Alérgica , Fatores de Risco
18.
Zhongguo Zhong Xi Yi Jie He Za Zhi ; 33(2): 180-5, 2013 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-23646471

RESUMO

OBJECTIVE: To observe the clinical efficacy of Baidanhuang lavage fluid nasal irrigation (BLFNI) on postoperative patients with chronic sinusitis with nasal polyps (CRwNP). METHODS: Ninety postoperative patients with CRwNP were randomly assigned to two groups, the treatment group (60 cases) and the control group (30 cases). After nasal endoscopic surgery, all patients received routine therapies, while the nasal cavity perfusion device was used to irrigate. Patients in the treatment group were treated with BLFNI, while those in the control group were irrigated with physiologic saline with dexamethasone and gentamycin. The physic liquor was maintained in the nasal cavity for 15 min, 14 days as one therapeutic course: once per 3 days in first treatment course; once per 5 days in the second treatment course; once per 7 days in the third treatment course. The irrigation times gradually reduced as time went by. The VAS scoring was performed in four clinical symptoms, such as nasal obstruction, rhinorrhea, olfaction disorders, discomforts or pain in the face or head. The Lund-Kenenedy quantification scoring method was used for nasal endoscopy to assess the polyps size, mucous membrane, scar, surface scab, and quality of life (QOL). The SNOT-20 rating scales were filled to investigate the QOL. All the assessments were carried out before surgery, 1.5, 3, and 6 months, respectively. The comprehensive efficacy assessment was conducted 1 year later. RESULTS: The 1-year cure rate was 79.25% in the treatment group and 76.92% in the control group, and the total effective rate was 90.57% in the treatment group and 84.62% in the control group. There was no statistical difference between the two groups (P > 0.05). The nasal cavity cleaning time and the epithelization time was (2.15 +/- 0.13) weeks and (9.17 +/- 1.67) weeks respectively in the treatment group, earlier than those in the control group [(2.65 +/- 0.15) weeks and (10.71 +/- 3.12) weeks, P < 0.05]. At week eight 22 patients in the treatment group ended the lavage due to recovery, while 5 patients in the control group ended the lavage, showing statistical difference (P < 0.05). Compared with the control group, better results were obtained in the treatment group in relieving the total VAS score at postoperative 6 weeks and 3 months, in the single score of symptoms at 3 months after operation, the rhinorrhea at postoperative 6 months and 1 year (P < 0.05). The total endoscopic score, and the single score for nasal mucous membrane edema, and nasal secretion at postoperative 1.5 month were lower in the treatment group than in the control group (P < 0.05). The total score of SNOT-20 questionnaire, and the integrals for five major indicators at postoperative 1.5 and 3 months were lower in the treatment group than in the control group (P < 0.05). CONCLUSIONS: The perioperative application of BLFNI could alleviate postoperative mucosal inflammation, shorten the cavity cleaning time, speed up the process of epithelization, improve the QOL, and elevate the operative efficacy. Its therapeutic roles were more prominent within perioperative 1.5-3 months.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Pólipos Nasais/terapia , Rinite/terapia , Sinusite/terapia , Adolescente , Adulto , Idoso , Doença Crônica , Medicamentos de Ervas Chinesas/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Lavagem Nasal , Pólipos Nasais/complicações , Período Pós-Operatório , Rinite/complicações , Sinusite/complicações , Resultado do Tratamento , Adulto Jovem
19.
Artigo em Chinês | MEDLINE | ID: mdl-22384564

RESUMO

OBJECTIVE: To study the pathogenesis of the patients with allergic rhinitis diagnosed by Skin Prick Test (SPT), especially about the epidemiologic data of the involved allergens. METHOD: The data was collected from 958 patients referred to the listed three allergy center and subsequently diagnosed as allergic rhinitis by SPT. RESULT: The intermittent mild type was more prevalent in male patients (40.5%); comparably the intermittent moderate type in female patients (70.0%); in the infant patients the moderate-severe type dominated (73.7%). The positive results of SPT comprised mainly of Dermatophagoides pteronyssinus (Der. p, 98.3%), Dermatophagoides farinae(Der. f, 96.8%), and Blomia tropicalis (Blot, 73.8%). Only 1.7% of the patients was allergic to single allergen, in contrary ,the majority of patients were allergic to multiple allergens. The positive rate to Der. p and Der. f was reversely increasing with age of the patients; and contrarily the number of positive allergens was increasing along with the age of the patients. The allergy to outdoor allergen was less common, and the positive rate in skin prick test was lower than the previously reported rate in North China ,such as timothy (3.9%), birch (2.7%), ragweed (2.0%), and mugwort (1.2%). CONCLUSION: Dust Mite is the predominant allergen for patients with allergic rhinitis in Guangdong province; and the positive rate to outdoor allergen is lower than that in North China.


Assuntos
Alérgenos/análise , Antígenos de Dermatophagoides/análise , Ácaros/imunologia , Rinite Alérgica Perene/epidemiologia , Rinite Alérgica Sazonal/epidemiologia , Adolescente , Adulto , Alérgenos/imunologia , Animais , Antígenos de Dermatophagoides/imunologia , Criança , Pré-Escolar , China/epidemiologia , Estudos de Coortes , Dermatophagoides pteronyssinus/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rinite Alérgica Perene/diagnóstico , Rinite Alérgica Sazonal/diagnóstico , Testes Cutâneos , Adulto Jovem
20.
Artigo em Chinês | MEDLINE | ID: mdl-18476607

RESUMO

OBJECTIVES: To investigate the effet of nasal septum operation combined with nasal sinuses on postoperative nasal septum. METHOD: Sixty-five patients with deflection of nasal septum complicating chronic sinusitis were underwent nasal septum and nasal sinus operations under nasal endoscope. Postoperative nasal septum recover were observed and compared with patients underwent only simple nasal septum operation. RESULT: Patients underwent nasal septum operations combined with nasal sinus, postoperative symptoms were more serious at early than simple nasal septum operations. At 3 months after operation, satisfactory degree of the former group were higher than the latter, and the former group didn't have complications such as nasal septum infection. CONCLUSION: Nasal septum operations combined with nasal sinus have no harmful effect on the prognosis of nasal septum, so it was safe and reliable.


Assuntos
Septo Nasal/cirurgia , Seios Paranasais/cirurgia , Sinusite/cirurgia , Adolescente , Adulto , Doença Crônica , Endoscopia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Resultado do Tratamento , Adulto Jovem
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