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1.
J Cardiothorac Surg ; 19(1): 46, 2024 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-38310273

RESUMO

OBJECTIVE: To investigate the independent risk factors for postoperative prolonged ICU stay in patients with Stanford type A aortic dissection (TAAD) and assess the clinical outcomes of prolonged ICU stay. METHOD: The clinical data of 100 patients with TAAD admitted to the Department of Cardiovascular Surgery, First Affiliated Hospital of Anhui Medical University from December 2018 to September 2022 were retrospectively collected and analyzed. Patients were divided into two groups, based on the postoperative ICU stay (7 days as the threshold), regular ICU stay group (< 7 days) and prolonged ICU stay group (≥ 7 days). First, preoperative and intraoperative materials were collected for univariate analysis. Then, the significant variables after univariate analysis were analyzed using logistic regression, and the final independent risk factors for prolonged ICU stay were determined. Meanwhile, the postoperative clinical outcomes were analyzed with the aim of assessing the clinical outcomes due to prolonged ICU stay. RESULTS: There were 65 and 35 patients in the regular ICU stay group and the prolonged ICU stay group, respectively. In accordance with the result of univariate analysis in the two groups, emergency surgery (χ2 = 13.598; P < 0.001), preoperative urea nitrogen (t = 3.006; P = 0.004), cardiopulmonary bypass (CPB) time (t = 2.671; P = 0.001) and surgery time (t = 2.630; P = 0.010) were significant. All significant variates were analyzed through logistic regression, and it was found that emergency surgery (OR = 0.192; 95% CI: 0.065-0.561), preoperative urea nitrogen (OR = 0.775; 95% CI: 0.634-0.947) and cardiopulmonary time (OR = 0.988; 95% CI: 0.979-0.998) were independent risk factors for prolonged postoperative ICU stay. The Receiver Operating Characteristic (ROC) curves of these three factors were also effective in predicting postoperative prolonged ICU stay (Emergency surgery, AUC = 0.308, 95% CI: 0.201-0.415; Preoperative urea nitrogen, AUC = 0.288, 95% CI: 0.185-0.392; cardiopulmonary time, AUC = 0.340, 95% CI: 0.223-0.457). Moreover, compared with a single factor, the predictive value of combined factors was more significant (AUC = 0.810, 95% CI: 0.722-0.897). For the comparison of postoperative data in the two groups,, compared with the regular ICU stay group, the incidence of adverse events in the prolonged ICU stay group increased significantly, including limb disability of limbs (χ2 = 22.182; P < 0.001), severe organ injury (χ2 = 23.077; P < 0.001), tracheotomy (χ2 = 17.582; P < 0.001), reintubation (χ2 = 28.020; P < 0.001), 72 h tracheal extubation after surgery (χ2 = 29.335; P < 0.001), 12 h consciousness recovery after surgery (χ2 = 18.445; P < 0.001), ICU re-entering (χ2 = 9.496; P = 0.002) and irregular discharging (χ2 = 24.969; P < 0.001). CONCLUSION: Emergency surgery, preoperative urea nitrogen, and CPB time are risk factors for postoperative prolonged ICU stay after TAAD surgery. Furthermore, prolonged ICU stay is associated with worse clinical outcomes. Hence, a reasonable strategy should be adopted proactively focusing on the risk factors to shorten ICU stays and improve clinical outcomes.


Assuntos
Dissecção Aórtica , Azidas , Desoxiglucose/análogos & derivados , Humanos , Estudos Retrospectivos , Dissecção Aórtica/cirurgia , Fatores de Risco , Unidades de Terapia Intensiva , Nitrogênio , Ureia , Tempo de Internação
2.
Radiographics ; 44(2): e230129, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38300813

RESUMO

The breasts undergo marked physiologic changes during lactation that can make conventional imaging evaluation with mammography and US challenging. MRI can be a valuable diagnostic aid to differentiate physiologic and benign processes from malignancy in patients who are lactating. In addition, MRI may allow more accurate delineation of disease involvement than does conventional imaging and assists in locoregional staging, screening of the contralateral breast, assessment of response to neoadjuvant chemotherapy, and surgical planning. Although the American College of Radiology recommends against patients undergoing contrast-enhanced MRI during pregnancy because of fetal safety concerns, contrast-enhanced MRI is safe during lactation. As more women delay childbearing, the incidence of pregnancy-associated breast cancer (PABC) and breast cancer in lactating women beyond the 1st year after pregnancy is increasing. Thus, MRI is increasingly being performed in lactating women for diagnostic evaluation and screening of patients at high risk. PABC is associated with a worse prognosis than that of non-PABCs, with delays in diagnosis contributing to an increased likelihood of advanced-stage disease at diagnosis. Familiarity with the MRI features of the lactating breast and the appearance of various pathologic conditions is essential to avoid diagnostic pitfalls and prevent delays in cancer diagnosis and treatment. The authors review clinical indications for breast MRI during lactation, describe characteristic features of the lactating breast at MRI, and compare MRI features of a spectrum of benign and malignant breast abnormalities. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material. See the invited commentary by Chikarmane in this issue.


Assuntos
Azidas , Neoplasias da Mama , Lactação , Propanolaminas , Gravidez , Feminino , Humanos , Mama/diagnóstico por imagem , Mama/patologia , Neoplasias da Mama/diagnóstico por imagem , Mamografia/métodos , Imageamento por Ressonância Magnética/métodos
3.
Sci Rep ; 14(1): 3318, 2024 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-38337014

RESUMO

This study aimed to explore the effectiveness and safety of azvudine, nirmatrelvir/ritonavir, and molnupiravir in adult patients with mild-to-moderate COVID-19. This retrospective cohort study included patients with mild-to-moderate COVID-19 (asymptomatic, mild, and common types) at the First Hospital of Changsha (Hunan Province, China) between March and November 2022. Eligible patients were classified into the azvudine, nirmatrelvir/ritonavir, or molnupiravir groups according to the antiviral agents they received. The outcomes were the times to nucleic acid negative conversion (NANC). This study included 157 patients treated with azvudine (n = 66), molnupiravir (n = 66), or nirmatrelvir/ritonavir (n = 25). There were no statistically significant differences in the time from diagnosis to NANC among the azvudine, molnupiravir, and nirmatrelvir/ritonavir groups [median, 9 (95% CI 9-11) vs. 11 (95% CI 10-12) vs. 9 (95% CI 8-12) days, P = 0.15], time from administration to NANC [median, 9 (95% CI 8-10) vs. 10 (95% CI 9.48-11) vs. 8.708 (95% CI 7.51-11) days, P = 0.50], or hospital stay [median, 11 (95% CI 11-13) vs. 13 (95% CI 12-14) vs. 12 (95% CI 10-14) days, P = 0.14], even after adjustment for sex, age, COVID-19 type, comorbidities, Ct level, time from diagnosis to antiviral treatment, and number of symptoms. The cumulative NANC rates in the azvudine, molnupiravir, and nirmatrelvir/ritonavir groups were 15.2%/12.3%/16.0% at day 5 (P = 0.858), 34.8%/21.5%/32.0% at day 7 (P = 0.226), 66.7%/52.3%/60.0% at 10 days (P = 0.246), and 86.4%/86.2%/80.0% at day 14 (P = 0.721). No serious adverse events were reported. Azvudine may be comparable to nirmatrelvir/ritonavir and molnupiravir in adult patients with mild-to-moderate COVID-19 regarding time to NANC, hospital stay, and AEs.


Assuntos
Azidas , COVID-19 , Citidina/análogos & derivados , Desoxicitidina/análogos & derivados , Hidroxilaminas , Lactamas , Leucina , Nitrilas , Prolina , Ritonavir , Adulto , Humanos , Estudos Retrospectivos , Ritonavir/uso terapêutico , Tratamento Farmacológico da COVID-19 , Antivirais/uso terapêutico
4.
BMJ Open ; 14(2): e074541, 2024 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-38341200

RESUMO

OBJECTIVES: Anthracycline-induced cardiotoxicity is a debilitating cardiac dysfunction for which there are no effective treatments, making early prevention of anthracycline-induced subclinical cardiotoxicity (AISC) crucial. High-density lipoprotein cholesterol (HDL-C) plays a role in cardioprotection, but its impact on AISC remains unclear. Our study aims to elucidate the protective capacity of HDL-C in AISC in patients with diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone and rituximab). DESIGN: Prospective observational study. SETTING: Conducted in China from September 2020 to September 2022. PARTICIPANTS: 70 chemotherapy-naïve patients newly diagnosed with DLBCL who were scheduled to receive the standard dose of R-CHOP; 60 participants included in a case-control study (DOI: 10.1186/s12885-022-10085-6). PRIMARY OUTCOME MEASURES: Serum biomarkers, 2D speckle tracking echocardiography and conventional echocardiography were measured at baseline, at the end of the third and sixth cycles of R-CHOP and 6 and 12 months after chemotherapy. RESULTS: 24 patients experienced AISC, while 10 did not. 36 patients were lost to follow-up and death. Cox regression analysis showed that higher levels of HDL-C were associated with a significantly lower risk of AISC (unadjusted HR=0.24, 95% CI 0.09 to 0.67, p=0.006; adjusted HR=0.27, 95% CI 0.09 to 0.79, p=0.017). Patients without AISC had a more stable and higher HDL-C level during the follow-up period. HDL-C levels significantly decreased from the end of the third cycle of chemotherapy to the end of the sixth cycle of chemotherapy in all patients (p=0.034), and particularly in the AISC group (p=0.003). The highest level of HDL-C was significantly higher in patients without AISC than in those with AISC (1.52±0.49 vs 1.22±0.29, p=0.034). CONCLUSIONS: Our study suggests that higher HDL-C levels may associate with lower AISC risk in patients with DLBCL treated with R-CHOP. HDL-C could be a cardioprotective target, but further research is needed to confirm its benefits and limitations. STUDY REGISTRATION NUMBER: Study registration number: ChiCTR2100054721.


Assuntos
Antraciclinas , Cardiotoxicidade , HDL-Colesterol , Linfoma Difuso de Grandes Células B , Humanos , Antraciclinas/toxicidade , Antibióticos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azidas , Cardiotoxicidade/etiologia , Cardiotoxicidade/prevenção & controle , Estudos de Casos e Controles , Ciclofosfamida/uso terapêutico , Cimarina/análogos & derivados , Doxorrubicina/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Prednisona/uso terapêutico , Rituximab/uso terapêutico , Vincristina/uso terapêutico
5.
Virol J ; 21(1): 46, 2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38395970

RESUMO

BACKGROUND: Azvudine has been approved for the treatment of coronavirus disease 2019 (COVID-19) patients in China, and this meta-analysis aims to illustrate the safety of azvudine and its effectiveness in reducing mortality. METHODS: PubMed, Embase, Web of science, Cochrane Library and the Epistemonikos COVID-19 Living Overview of Evidence database (L.OVE) were searched to aggregate currently published studies. Cochrane risk of bias tool and ROBINS-I tool were used to assess the risk of bias of randomized controlled study and cohort study respectively. Odds radios (ORs) with 95% confidence interval (CIs) were combined for dichotomous variables. Publication bias was assessed by Egger's test and funnel plots. RESULTS: A total of 184 articles were retrieved from the included databases and 17 studies were included into the final analysis. Pooled analysis showed that azvudine significantly reduced mortality risk in COVID-19 patients compared with controls (OR: 0.41, 95%CI 0.31-0.54, p < 0.001). Besides, either mild to moderate or severe COVID-19 patients could benefit from azvudine administration. There was no significant difference in the incidence of ICU admission (OR: 0.90, 95%CI 0.47-1.72, p = 0.74) and invasive ventilation (OR: 0.94, 95%CI 0.54-1.62, p = 0.82) between azvudine and control group. The incidence of adverse events was similar between azvudine and control (OR: 1.26, 95%CI 0.59-2.70, p = 0.56). CONCLUSIONS: This meta-analysis suggests that azvudine could reduce the mortality risk of COVID-19 patients, and the safety of administration is acceptable. TRIAL REGISTRATION: PROSPERO; No.: CRD42023462988; URL: https://www.crd.york.ac.uk/prospero/ .


Assuntos
Azidas , COVID-19 , Desoxicitidina/análogos & derivados , Humanos , Estudos de Coortes , China , Bases de Dados Factuais
6.
Int J Mol Sci ; 25(4)2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38396686

RESUMO

Staudinger reaction on the solid phase between an electronodeficit organic azide, such as sulfonyl azide, and the phosphite triester formed upon phosphoramidite coupling is a convenient method for the chemical modification of oligonucleotides at the internucleotidic phosphate position. In this work, 4-carboxybenzenesulfonyl azide, either with a free carboxy group or in the form of an activated ester such as pentafluorophenyl, 4-nitrophenyl, or pentafluorobenzyl, was used to introduce a carboxylic acid function to the terminal or internal internucleotidic phosphate of an oligonucleotide via the Staudinger reaction. A subsequent treatment with excess primary alkyl amine followed by the usual work-up, after prior activation with a suitable peptide coupling agent such as a uronium salt/1-hydroxybenzotriazole in the case of a free carboxyl, afforded amide-linked oligonucleotide conjugates in good yields including multiple conjugations of up to the exhaustive modification at each phosphate position for a weakly activated pentafluorobenzyl ester, whereas more strongly activated and, thus, more reactive aryl esters provided only single conjugations at the 5'-end. The conjugates synthesized include those with di- and polyamines that introduce a positively charged side chain to potentially assist the intracellular delivery of the oligonucleotide.


Assuntos
Oligonucleotídeos , Fosfatos , Oligonucleotídeos/química , Azidas , Amidas/química , Ésteres
7.
Molecules ; 29(3)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38338431

RESUMO

In this article, we present the synthesis and the optical properties of three original molecules as potential fluorescent ribonucleoside analogues incorporating a 1,6-naphthyridin-7(6H)-one scaffold as a fluorescent nucleobase and a 1,2,3-triazole as a linkage. The nucleosides were prepared via a Cu alkyne-azide cycloaddition (CuAAC) reaction between a ribofuranosyl azide and a 4-ethynylpyridine partner. Construction of substituted 1,6-naphthyridin-7(6H)-ones was achieved through two additional steps. Optical property studies were investigated on nucleoside analogues. Powerful fluorescence properties have been evidenced with a remarkable change of emissivity depending on the polarity of the solvent, making these molecules suitable as a new class of artificial fluorescent nucleosides for investigating enzyme binding sites as well as probing nucleic acids. In addition, we are convinced that such analogues could be of great interest in the search for new antiviral or antitumoral drugs based on nucleosides.


Assuntos
Nucleosídeos , Ribonucleosídeos , Nucleosídeos/química , Azidas/química , Ribonucleosídeos/química , Corantes
8.
Science ; 383(6685): 849-854, 2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38386756

RESUMO

Securines and securamines are cytotoxic alkaloids that contain reactive alkene and heterocyclic residues embedded in skeletons comprising four to six oxidized rings. This structural complexity imparts a rich chemistry to the isolates but has impeded synthetic access to the structures in the nearly three decades since their isolation. We present a flexible route to eight isolates that exemplify the three skeletal classes of metabolites. The route proceeds by the modular assembly of the advanced azides 38 and 49 (13 steps, 6 to 10% yield), sequential oxidative photocyclizations, and late-stage functional group manipulations. With this approach, the targets were obtained in 17 to 19 steps, 12 to 13 purifications, and 0.5 to 3.5% overall yield. The structure of an advanced intermediate was elucidated by microcrystal electron diffraction (MicroED) analysis. The route will support structure-function and target identification studies of the securamines.


Assuntos
Alcaloides , Briozoários , Alcaloides/síntese química , Alcenos/química , Azidas/química , Elétrons , Animais , Catálise , Oxirredução
9.
Eur J Med Chem ; 265: 116102, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38176359

RESUMO

Study on corrole photosensitizers (PSs) for photodynamic therapy (PDT) has made remarkable progress. Targeted delivery of PSs is of great significance for enhancing therapeutic efficiency, decreasing the dosage, and reducing systemic toxicity during PDT. The development of PSs that can be specifically delivered to the subcellular organelle is still an attractive and challenging work. Herein, we synthesize a series of azide-modified corrole phosphorus and gallium complex PSs, in which phosphorus corrole 2-P could not only precisely target the endoplasmic reticulum (ER) with a Pearson correlation coefficient (PCC) up to 0.92 but also possesses the highest singlet oxygen quantum yields (ΦΔ = 0.75). This renders it remarkable PDT activity at a very low dosage (IC50 = 23 nM) towards HepG2 tumor cell line while ablating solid tumors in vivo with excellent biosecurity. Furthermore, 2-P exhibits intense red fluorescence (ΦF = 0.25), outstanding photostability, and a large Stokes shift (190 nm), making it a promising fluorescent probe for ER. This study provides a clinically potential photosensitizer for cancer photodynamic therapy and a promising ER fluorescent probe for bioimaging.


Assuntos
Neoplasias , Fotoquimioterapia , Porfirinas , Azidas , Fluorescência , Fósforo , Corantes Fluorescentes/farmacologia , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Retículo Endoplasmático , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico
10.
Sci Rep ; 14(1): 1522, 2024 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-38233509

RESUMO

Acute type A aortic dissection (a-TAAD) is a severe disease characterized by high mortality, which can be fatal in elderly patients. The objective of this study was to investigate the safety and efficacy of two-stage type II hybrid aortic arch repair (HAR) in elderly patients with acute type A aortic dissection (a-TAAD). This was a single-center, retrospective study involving 119 patients with a-TAAD, including 82 males and 37 females, aged 22-81 years old. Eighty-eight patients underwent total aortic arch replacement (TAR) with frozen elephant trunk (FET) implantation (TAR with FET group) and 31 patients underwent two-stage type II HAR (HAR group). Propensity score matching was applied to adjust for preoperative data, and match 25 pairs. The preoperative, perioperative, postoperative and follow-up data were recorded. Fifteen patients died during the perioperative period; 13 cases were in the TAR with FET group and 2 cases were in the HAR group. The age, body mass index, cerebral infarction, renal insufficiency were significantly higher, and the 24-h fluid drainage, the incidence of acute liver injury, acute kidney injury and pulmonary infection were lower in the HAR group (all P < 0.05). Moreover, the mechanical ventilation time, intensive care unit time, hospital stay time were shorter in the HAR group (all P < 0.05). The follow-up period ranged from 12 to 54 months, with 7 deaths (9.3%) in the TAR with FET group and 2 deaths (6.9%) in the HAR group. The true lumen of the aortic arch and the middle descending thoracic aorta were larger and the false lumen thrombosis rates of the middle descending thoracic aorta and renal artery level were higher in the HAR group (all P < 0.05). Two-stage type II HAR is a safe and effective method for the treatment of elderly patients with a-TAAD. It may be a good choice for elderly patients with a-TAAD and comorbidities.


Assuntos
Injúria Renal Aguda , Aneurisma da Aorta Torácica , Dissecção Aórtica , Azidas , Implante de Prótese Vascular , Desoxiglucose/análogos & derivados , Masculino , Idoso , Feminino , Humanos , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Aorta Torácica/cirurgia , Estudos Retrospectivos , Implante de Prótese Vascular/métodos , Resultado do Tratamento , Dissecção Aórtica/cirurgia , Injúria Renal Aguda/cirurgia , Aneurisma da Aorta Torácica/cirurgia
11.
Trials ; 25(1): 77, 2024 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-38254211

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 will coexist with humans for a long time, and it is therefore important to develop effective treatments for coronavirus disease 2019 (COVID-19). Recent studies have demonstrated that antiviral therapy is a key factor in preventing patients from progressing to severe disease, even death. Effective and affordable antiviral medications are essential for disease treatment and are urgently needed. Azvudine, a nucleoside analogue, is a potential low-cost candidate with few drug interactions. However, validation of high-quality clinical studies is still limited. METHODS: This is a multicentre, randomized, double-blind, placebo-controlled phase III clinical trial involving 1096 adult patients with mild-to-moderate symptoms of COVID-19 who are at high risk for progression to severe COVID-19. Patients will be randomized to (1) receive azvudine tablets 5 mg daily for a maximum of 7 days or (2) receive placebo five tablets daily. All participants will be permitted to use a standard treatment strategy except antiviral therapy beyond the investigational medications. The primary outcome will be the ratio of COVID-19-related critical illness and all-cause mortality among the two groups within 28 days. DISCUSSION: The purpose of this clinical trial is to determine whether azvudine can prevent patients at risk of severe disease from progressing to critical illness and death, and the results will identify whether azvudine is an effective and affordable antiviral treatment option for COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT05689034. Registered on 18 January 2023.


Assuntos
Azidas , COVID-19 , Desoxicitidina/análogos & derivados , Adulto , Humanos , Estado Terminal , SARS-CoV-2 , Antivirais/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como Assunto , Ensaios Clínicos Fase III como Assunto
12.
J Cardiothorac Surg ; 19(1): 16, 2024 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-38254116

RESUMO

BACKGROUND: Delirium is a common postoperative complication among patients who undergo Stanford Type A aortic dissection (TAAD). It is associated with increased mortality, as well as other serious surgical outcomes. This study aimed to analyze the risk factors for delirium in TAAD patients. METHODS: Pubmed, Web of science, Embase, the Cochrane Library and CINAHL were searched by computer to collect literatures on risk factors for postoperative delirium (POD) after TAAD. The retrieval period was from the establishment of the database to September 2022. After literature screening, two reviewers independently assessed the quality of the included studies using the Newcastle-Ottawa Scale (NOS). Data were extracted according to standard protocols, and then meta-analysis was performed using Revman 5.3 software. RESULTS: A total of 9 articles, comprising 7 case-control studies and 2 cohort studies, were included in this analysis. The sample size consisted of 2035 patients. POD was associated with increased length of ICU stay (MD 3.24, 95% CI 0.18-6.31, p = 0.04) and length of hospital stay (MD 9.34, 95% CI 7.31-11.37, p < 0.0001) in TAAD patients. Various perioperative risk factors were identified, including age (MD 4.40, 95% CI 2.06-6.73, p = 0.0002), preoperative low hemoglobin levels (MD - 4.44, 95% CI - 7.67 to - 1.20, p = 0.007), body mass index (MD 0.92, 95% CI 0.22-1.63, p = 0.01), history of cardiac surgery (OR 3.06, 95% CI 1.20-7.83, p = 0.02), preoperative renal insufficiency (OR 2.50, 95% CI 1.04-6.04, p = 0.04), cardiopulmonary bypass (CPB) duration (MD 19.54, 95% CI 6.34-32.74, p = 0.004), surgery duration (MD 44.88, 95% CI 5.99-83.78, p = 0.02), mechanical ventilation time (SMD 1.14, 95% CI 0.34-1.94, p = 0.005), acute physiology and chronic health evaluation (APACHE II) score (MD 2.67, 95% CI 0.37-4.98, p = 0.02), postoperative renal insufficiency (OR 2.82, 95% CI 1.40-5.68, p = 0.004), electrolyte disturbance (OR 6.22, 95% CI 3.08-12.54, p < 0.0001) and hypoxemia (OR 3.56, 95% CI 1.70-7.44, p = 0.0007). CONCLUSIONS: POD can prolong ICU stay and hospital stay in TAAD patients. This study identified a number of risk factors for POD after TAAD, suggesting the possibility of early identification of high-risk patients using relevant data.


Assuntos
Dissecção Aórtica , Azidas , Desoxiglucose/análogos & derivados , Delírio do Despertar , Insuficiência Renal , Humanos , Fatores de Risco , Dissecção Aórtica/cirurgia
13.
J Am Chem Soc ; 146(3): 2151-2159, 2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38214237

RESUMO

We report here a Cu-catalyzed azide-alkyne-thiol reaction forming thiotriazoles as the major byproduct under widely used bio-orthogonal protein labeling "click" conditions. The development of Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) had a tremendous impact on many biological discoveries. However, the considered chemoselectivity of CuAAC is hampered by the high reactivity of cysteine free thiols, yielding thiotriazole protein conjugates. The reaction byproducts generate false-positive protein hits in functional proteomic studies. The reported detail investigation of conjugates between chemical probes containing terminal alkynes, azide tags, and cell lysates reveals the formation of thiotriazoles, which can be readily detected by in-gel fluorescence scanning or after peptide and protein enrichment by mass spectrometry-based proteomics. In protein level identification and quantification experiments, the produced fluorescent bands or enriched proteins may not result from the important enzymatically driven reaction and can be falsely assigned as hits. This study provides a complete list of the most common background proteins. The knowledge of this previously overlooked reactivity now leads to the introduction of modified CuAAC conditions, which avoids the undesired product formation, diminishes the background, and hence improves the signal-to-noise ratio.


Assuntos
Azidas , Compostos de Sulfidrila , Alcinos , Proteômica , Proteínas , Catálise , Reação de Cicloadição , Cobre , Química Click
14.
EMBO Mol Med ; 16(1): 132-157, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38177536

RESUMO

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition associated with Marfan syndrome (MFS), a disease caused by fibrillin-1 gene mutations. While various conditions causing TAAD exhibit aortic accumulation of the proteoglycans versican (Vcan) and aggrecan (Acan), it is unclear whether these ECM proteins are involved in aortic disease. Here, we find that Vcan, but not Acan, accumulated in Fbn1C1041G/+ aortas, a mouse model of MFS. Vcan haploinsufficiency protected MFS mice against aortic dilation, and its silencing reverted aortic disease by reducing Nos2 protein expression. Our results suggest that Acan is not an essential contributor to MFS aortopathy. We further demonstrate that Vcan triggers Akt activation and that pharmacological Akt pathway inhibition rapidly regresses aortic dilation and Nos2 expression in MFS mice. Analysis of aortic tissue from MFS human patients revealed accumulation of VCAN and elevated pAKT-S473 staining. Together, these findings reveal that Vcan plays a causative role in MFS aortic disease in vivo by inducing Nos2 via Akt activation and identify Akt signaling pathway components as candidate therapeutic targets.


Assuntos
Aneurisma da Aorta Torácica , Doenças da Aorta , Dissecção Aórtica , Azidas , Desoxiglucose , Síndrome de Marfan , Animais , Humanos , Camundongos , Aneurisma da Aorta Torácica/complicações , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/metabolismo , Doenças da Aorta/complicações , Desoxiglucose/análogos & derivados , Síndrome de Marfan/complicações , Síndrome de Marfan/genética , Síndrome de Marfan/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Versicanas/metabolismo
15.
Chem Commun (Camb) ; 60(12): 1509-1516, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38224214

RESUMO

Chemical reagents with special groups as enrichable handles have empowered the ability to label and enrich modified peptides. Here is an overview of different chemical reagents with affinity tags to isolate labeled peptides and the latest developments of enrichment strategies. Biotin is the most used affinity tag due to its high interaction with avidin. To decrease the unfavorable influence of biotin for its poor efficiency in ionization and fragmentation in downstream MS analysis, cleavable moieties were installed between the reactive groups and biotin to release labeled peptides from the biotin. To minimize the steric hindrance of biotin, a two-step method was developed, for which alkyne- or azide-tagged linkers were firstly used to label peptides and then biotin was installed through click chemistry. Recently, new linkers using a small phosphonic acid as the affinity tag for IMAC or TiO2 enrichment have been developed and successfully used to isolate chemically labeled peptides in XL-MS. A stable P-C instead of P-O bond was introduced to linkers to differentiate labeled and endogenous phosphopeptides. Furthermore, a membrane-permeable phosphonate-containing reagent was reported, which facilitated the study of living systems. Taking a cue from classic chemical reactions, stable metal-complex intermediates, including cobalt and palladium complexes, have been developed as peptide purification systems. Advanced enrichment strategies have also been proposed, such as the two-stage IMAC enrichment method and biotin-based two-step reaction strategy, allowing the reduction of unwanted peptides and improvements for the analysis of specific labeled peptides. Finally, future trends in the area are briefly discussed.


Assuntos
Biotina , Peptídeos , Biotina/química , Peptídeos/química , Azidas/química
16.
Am J Physiol Cell Physiol ; 326(2): C647-C658, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38189133

RESUMO

Thoracic aortic aneurysm/dissection (TAAD) is a lethal vascular disease, and several pathological factors participate in aortic medial degeneration. We previously discovered that the complement C3a-C3aR axis in smooth muscle cells promotes the development of thoracic aortic dissection (TAD) through regulation of matrix metalloproteinase 2. However, discerning the specific complement pathway that is activated and elucidating how inflammation of the aortic wall is initiated remain unknown. We ascertained that the plasma levels of C3a and C5a were significantly elevated in patients with TAD and that the levels of C3a, C4a, and C5a were higher in acute TAD than in chronic TAD. We also confirmed the activation of the complement in a TAD mouse model. Subsequently, knocking out Cfb (Cfb) or C4 in mice with TAD revealed that the alternative pathway and Cfb played a significant role in the TAD process. Activation of the alternative pathway led to generation of the anaphylatoxins C3a and C5a, and knocking out their receptors reduced the recruitment of inflammatory cells to the aortic wall. Moreover, we used serum from wild-type mice or recombinant mice Cfb as an exogenous source of Cfb to treat Cfb KO mice and observed that it exacerbated the onset and rupture of TAD. Finally, we knocked out Cfb in the FBN1C1041G/+ Marfan-syndrome mice and showed that the occurrence of TAA was reduced. In summary, the alternative complement pathway promoted the development of TAAD by recruiting infiltrating inflammatory cells. Targeting the alternative pathway may thus constitute a strategy for preventing the development of TAAD.NEW & NOTEWORTHY The alternative complement pathway promoted the development of TAAD by recruiting infiltrating inflammatory cells. Targeting the alternative pathway may thus constitute a strategy for preventing the development of TAAD.


Assuntos
Aneurisma da Aorta Torácica , Dissecção Aórtica , Azidas , Desoxiglucose/análogos & derivados , Humanos , Camundongos , Animais , Via Alternativa do Complemento , Metaloproteinase 2 da Matriz , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/metabolismo , Aneurisma da Aorta Torácica/patologia , Dissecção Aórtica/genética , Inflamação
17.
Eur J Cardiothorac Surg ; 65(2)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38212996

RESUMO

OBJECTIVES: In the last decades, 4 different scores for the prediction of mortality following surgery for type A acute aortic dissection (TAAD) were proposed. We aimed to validate these scores in a large external multicentre cohort. METHODS: We retrospectively analysed patients who underwent surgery for TAAD between 2000 and 2020. Patients were enrolled from 10 centres from 2 European countries. Outcomes were the early (30-day and/or in-hospital) and 1-year mortality. Discrimination, calibration and observed/expected (O/E) ratio were evaluated. RESULTS: A total of 1895 patients (31.7% females, mean age 63.72 ± 12.8 years) were included in the study. Thirty-day mortality and in-hospital mortality were 21.7% (n = 412) and 22.5% (n = 427) respectively. The German Registry of Acute Aortic Dissection Type A (GERAADA) score shows to have the best discrimination [area under the curve (AUC) 0.671 and 0.672] in predicting as well the early and the 1-year mortality, followed by the International Registry of Acute Aortic Dissection (IRAD) model 1 (AUC 0.658 and 0.672), the Centofanti (AUC 0.645 and 0.66) and the UK aortic score (AUC 0.549 and 0.563). According to Hosmer-Lemeshow and Brier tests, the IRAD model I and GERAADA, respectively, were well calibrated for the early mortality, while the GERAADA and Centofanti for the 1-year mortality. The O/E analysis showed a marked underestimation for patients labelled as low-risk for UK aortic score and IRAD model I for both outcomes. CONCLUSIONS: The GERAADA score showed the best performance in comparison with other scores. However, none of them achieved together a fair discrimination and a good calibration for predicting either the early or the 1-year mortality.


Assuntos
Dissecção Aórtica , Azidas , Desoxiglucose/análogos & derivados , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Masculino , Estudos Retrospectivos , Dissecção Aórtica/cirurgia , Mortalidade Hospitalar , Europa (Continente) , Sistema de Registros , Fatores de Risco , Resultado do Tratamento
18.
Nano Lett ; 24(4): 1341-1350, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38252869

RESUMO

In situ drug synthesis using the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction has attracted considerable attention in tumor therapy because of its satisfactory effectiveness and reduced side-effects. However, the exogenous addition of copper catalysts can cause cytotoxicity and has hampered biomedical applications in vivo. Here, we design and synthesize a metal-organic framework (MOF) to mimic copper chaperone, which can selectively modulate copper trafficking for bioorthogonal synthesis with no need of exogenous addition of copper catalysts. Like copper chaperones, the prepared ZIF-8 copper chaperone mimics specifically bind copper ions through the formation of coordination bonds. Moreover, the copper is unloaded under the acidic environment due to the dissipation of the coordination interactions between metal ions and ligands. In this way, the cancer cell-targeted copper chaperone mimics can selectively transport copper ions into cells. Regulation of intracellular copper trafficking may inspire constructing bioorthogonal catalysis system with reduced metal cytotoxicity in live cells.


Assuntos
Alcinos , Cobre , Cobre/farmacologia , Cobre/química , Alcinos/química , Azidas/química , Reação de Cicloadição , Catálise , Íons
19.
J Inorg Biochem ; 252: 112459, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38181613

RESUMO

C-H bond amination is an effective way to obtain nitrogen-containing products. In this work, we demonstrate that myoglobin reconstituted with iron porphycene (rMb(FePc)) catalyzes intramolecular C(sp3)-H bond amination of arylsulfonyl azides to yield corresponding sultam analogs. The total turnover number of rMb(FePc) is up to 5.7 × 104 for the C-H bond amination of 2,4,6-triisopropylbenzenesulfonyl azide. Moreover, rMb(FePc) exhibits higher selectivity for the desired C-H bond amination than the competing azide reduction compared to native myoglobin. Kinetic studies reveal that the kcat value of rMb(FePc) is 4-fold higher than that of native myoglobin. Furthermore, H64A, H64V and H64I mutants of rMb(FePc) enhance the turnover number (TON) and enantioselectivity for the C-H bond amination of 2,4,6-triethylbenzenesulfonyl azide. The present findings indicate that iron porphycene is an attractive artificial cofactor for myoglobin toward the C-H bond amination reaction.


Assuntos
Ferro , Mioglobina , Porfirinas , Ferro/química , Mioglobina/química , Aminação , Azidas/química , Cinética , Catálise
20.
Viruses ; 16(1)2024 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-38257810

RESUMO

The current study investigated the effects of heat treatment (85 °C or 100 °C for 5-20 min) on human norovirus (HuNoV) GII.4's capsid stability in fresh oysters. In addition, propidium monoazide (PMA) was used in viral samples to distinguish infectious viruses and evaluated using real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). Further, we explored the effect of the heat treatment on oyster quality (Hunter color and hardness). The titer of HuNoV for oysters significantly (p < 0.05) decreased to 0.39-1.32 and 0.93-2.27 log10 copy number/µL in the non-PMA and PMA-treated groups, respectively, after heat treatment. HuNoV in oysters not treated with PMA showed a decrease of <1.5 - log10, whereas in PMA-treated oysters, a decrease of >1 - log10 was observed after treatment at 85 °C for 10 min. Treatments for both 15 min and 20 min at 100 °C showed a >99% log10 reduction using PMA/RT-qPCR. In the Hunter color, an increase in heat temperature and duration was associated with a significant decrease in 'L' (brightness+, darkness-) and an increase in 'a' (redness+, greenness-) and 'b' (yellowness+, blueness-) (p < 0.05). Our findings confirmed that the hardness of oyster meat significantly increased with increasing temperature and time (p < 0.05). This study demonstrated that PMA/RT-qPCR was effective in distinguishing HuNoV viability in heat-treated oysters. The optimal heat treatment for oysters was 10 min at 85 °C and 5 min at 100 °C.


Assuntos
Azidas , Crassostrea , Norovirus , Humanos , Animais , Propídio , Capsídeo
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