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1.
Int. braz. j. urol ; 50(6): 727-736, Nov.-Dec. 2024. tab, graf
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-1575093

RESUMO

ABSTRACT Introduction: We aim to compare the safety and effectiveness of the KangDuo (KD)-Surgical Robot-01 (KD-SR-01) system and the da Vinci (DV) system for robot-assisted radical nephroureterectomy (RARNU). Materials and Methods: This multicenter prospective randomized controlled trial was conducted between March 2022 and September 2023. Group 1 included 29 patients undergoing KD-RARNU. Group 2 included 29 patients undergoing DV-RARNU. Patient demographic and clinical characteristics, perioperative data, and follow-up outcomes were collected prospectively and compared between the two groups. Results: There were no significant differences in patient baseline demographic and preoperative characteristics between the two groups. The success rates in both groups were 100% without conversion to open or laparoscopic surgery or positive surgical margins. No significant difference was observed in docking time [242 (120-951) s vs 253 (62-498) s, P = 0.780], console time [137 (55-290) min vs 105 (62-220) min, P = 0.114], operative time [207 (121-460) min vs 185 (96-305) min, P = 0.091], EBL [50 (10-600) mL vs 50 (10-700) mL, P = 0.507], National Aeronautics and Space Administration Task Load Index scores, and postoperative serum creatinine levels between the two groups. None of the patients showed evidence of distant metastasis, local recurrence, or equipment-related adverse events during the four-week follow-up. One (3.4%) patient in Group 2 experienced postoperative enterovaginal and enterovesical fistulas (Clavien-Dindo grade III). Conclusions: The KD-SR-01 system is safe and effective for RARNU compared to the DV Si or Xi system. Further randomized controlled studies with larger sample sizes and longer durations are required.

2.
J Org Chem ; 2024 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-39485271

RESUMO

A novel and straightforward method for the iron-catalyzed regioselective cross-dehydrogenative coupling of para-quinone methides (p-QMs) with formamides has been developed, facilitated by the in situ activation of the C(sp2)-H bonds of the formyl and alkenyl substituents via a radical strategy. This method does not require the preactivation of the substrates, and it can accommodate a wide range of p-QMs and formamides under the optimized reaction conditions, resulting in the formation of the expected C-7 acetamides-functionalized para-quinone methides with moderate to good yields. The control experiments revealed that the reaction follows the fundamental equation of second-order kinetics. Additionally, an exploration of the Hammett effect was undertaken to elucidate the impact of the substituents for the reaction. In combination with the DFT calculation, a plausible reaction mechanism was proposed through meticulously controlled experiments.

3.
Nat Prod Res ; : 1-6, 2024 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-39374371

RESUMO

Two new polyketones, exserone B (1) and cytosporone F (2), along with three known metabolites, were isolated from the mangrove endophytic fungus Aspergillus TH4b. The structures of 1 and 2 were determined by detailed NMR, and MS spectroscopic data. The absolute configurations of 1 and 2 were determined by single crystal X-ray diffraction analysis and the combination of experimental ECD and computational ECD, respectively. Compounds 1-2 have strong inhibitory activity against citrus Psyllid (Diaphorina citri) with 95.4% and 93.7% lethal at 1000 mg/kg.

4.
Fitoterapia ; 179: 106253, 2024 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-39396653

RESUMO

Phytochemical investigation of the stems of Mallotus paxii Pamp. led to the isolation and identification of four new compounds, including three neolignans (1-3) and one phenol (13), along with eight known neolignans (4-12) and one known phenol (14). Their structures were determined by spectroscopic methods, including NMR, MS and ECD analyses. Bioassay demonstrated that malloapelin A (4) exhibited a most potent anti-inflammatory activity to NO release with IC50 value of 21.32 µM. Furthermore, malloapelin A (4) markedly decreased the secretion of TNF-α, iNOS, and NF-κB and inhibited the expression of COX-2 and NF-κB/p65 in LPS-induced RAW264.7 cells in a dose-dependent manner.

5.
Mar Drugs ; 22(10)2024 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-39452883

RESUMO

Six new highly oxidized seco-terpenoids, including three 3-nor-labdane type diterpenes, talaroterpenoids A-C (1-3), and three meroterpenoids containing an orthoester group, talaroterpenoids D-F (6-8), together with five known compounds (4-5 and 9-11), were isolated from the marine-derived fungus Talaromyces aurantiacus. Their chemical structures were elucidated through 1D, 2D NMR, HRESIMS, J-based configuration analysis (JBCA), computational ECD calculations, and single-crystal X-ray diffraction analysis. Compounds 1 and 2 contain an unusual 6,20-γ-lactone-bridged scaffold. Compounds 10 and 11 presented inhibitory effects on NO release in lipopolysaccharide (LPS)-induced BV-2 cells with IC50 values of 11.47 and 11.32 µM, respectively. Talaroterpenoid C (3) showed moderate antifungal activity against A. alternata and P. theae Steyaert.


Assuntos
Talaromyces , Talaromyces/química , Animais , Terpenos/farmacologia , Terpenos/química , Terpenos/isolamento & purificação , Antifúngicos/farmacologia , Antifúngicos/química , Antifúngicos/isolamento & purificação , Camundongos , Organismos Aquáticos , Estrutura Molecular , Linhagem Celular , Óxido Nítrico/metabolismo , Cristalografia por Raios X
6.
BMC Cancer ; 24(1): 1194, 2024 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-39333992

RESUMO

BACKGROUND: Robot-assisted radical prostatectomy (RARP) gains increasing popularity in the surgical management of prostate cancer (PCa) but is challenged by its prohibitive expense. A domestic robotic system has been developed to address this issue, but data comparing the self-developed robot with the widely used robot is lacking. We performed a randomized clinical trial to compare KD-SR-01® and DaVinci® robots in terms of perioperative, short-term oncological and functional outcomes in RARP. MATERIALS AND METHODS: We prospectively enrolled patients with clinically localized PCa. Patients were randomized to undergo either KD-SR-01®-RARP (K-RARP) or DaVinci®-RARP (D-RARP) by the same surgical team. The baseline, perioperative, short-term oncologic and urinary functional data were collected and compared. RESULTS: We enrolled 39 patients, including 20 patients undergoing K-RARP and 19 undergoing D-RARP. Demographic and tumor characteristics were comparable between groups. All surgeries were performed successfully with no conversion to open. The operative time was similar (P = 0.095) and K-RARP offered less volume of intraoperative bleeding (P < 0.001). Four patients in the K-RARP group and three in the D-RARP group developed postoperative complications (P = 0.732). Patients undergoing K-RARP had less volume of drainage (P = 0.022). Positive surgical margins were observed in three patients undergoing K-RARP and five undergoing D-RARP (P = 0.451). During the follow up, one patient receiving K-RARP group and two receiving D-RARP group had measurable prostate specific antigen (P = 0.605). Urine leakage, urinary control and pad usage were comparable between groups at six weeks post-surgery. CONCLUSIONS: The two surgical robots yielded similar results in feasibility, safety and short-term oncologic and functional efficacy for RARP. TRIAL REGISTRATION: The trial has been registered at www.chictr.org.cn with a registration number of ChiCTR2200057000 on 25th February 2022.


Assuntos
Estudos de Viabilidade , Prostatectomia , Neoplasias da Próstata , Procedimentos Cirúrgicos Robóticos , Humanos , Masculino , Prostatectomia/métodos , Prostatectomia/efeitos adversos , Procedimentos Cirúrgicos Robóticos/métodos , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Neoplasias da Próstata/cirurgia , Pessoa de Meia-Idade , Idoso , Estudos Prospectivos , Resultado do Tratamento , Duração da Cirurgia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia
7.
J Nat Prod ; 87(9): 2327-2334, 2024 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-39258410

RESUMO

Two sulfur-containing heterodimers of a cytochalasan and a macrolide, sucurchalasins A and B (1 and 2), and four known cytochalasan monomers (3-6), as well as four known macrolide derivatives (7-10), were obtained from the endophytic fungus Aspergillus spelaeus GDGJ-286. Sucurchalasins A and B (1 and 2) are the first cytochalasan heterodimers formed via a thioether bridge between cytochalasan and curvularin macrolide units. Their structures were elucidated by detailed analysis of NMR, LC-MS/MS, and X-ray crystallography. In bioassays, 1 and 2 exhibited cytotoxic effects on A2780 cells, with IC50 values of 3.9 and 8.3 µM, respectively. They also showed antibacterial activities against E. faecalis and B. subtilis with MIC values of 3.1 and 6.3 µg/mL, respectively.


Assuntos
Aspergillus , Citocalasinas , Macrolídeos , Aspergillus/química , Citocalasinas/farmacologia , Citocalasinas/química , Citocalasinas/isolamento & purificação , Macrolídeos/farmacologia , Macrolídeos/química , Estrutura Molecular , Humanos , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/química , Enxofre/química , Cristalografia por Raios X , Bacillus subtilis/efeitos dos fármacos
8.
Int J Mol Sci ; 25(17)2024 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-39273103

RESUMO

Understanding the mechanisms that regulate plant root growth under soil drying is an important challenge in root biology. We observed that moderate soil drying promotes wheat root growth. To understand whether metabolic and hormonic changes are involved in this regulation, we performed transcriptome sequencing on wheat roots under well-watered and moderate soil drying conditions. The genes upregulated in wheat roots under soil drying were mainly involved in starch and sucrose metabolism and benzoxazinoid biosynthesis. Various plant hormone-related genes were differentially expressed during soil drying. Quantification of the plant hormones under these conditions showed that the concentrations of abscisic acid (ABA), cis-zeatin (CZ), and indole-3-acetic acid (IAA) significantly increased during soil drying, whereas the concentrations of salicylic (SA), jasmonic (JA), and glycosylated salicylic (SAG) acids significantly decreased. Correlation analysis of total root length and phytohormones indicated that CZ, ABA, and IAA are positively associated with wheat root length. These results suggest that changes in metabolic pathways and plant hormones caused by moderate soil drying help wheat roots grow into deeper soil layers.


Assuntos
Regulação da Expressão Gênica de Plantas , Reguladores de Crescimento de Plantas , Raízes de Plantas , Solo , Transcriptoma , Triticum , Triticum/metabolismo , Triticum/crescimento & desenvolvimento , Triticum/genética , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/metabolismo , Raízes de Plantas/genética , Reguladores de Crescimento de Plantas/metabolismo , Solo/química , Ácidos Indolacéticos/metabolismo , Ácido Abscísico/metabolismo , Perfilação da Expressão Gênica/métodos , Dessecação
9.
Artigo em Inglês | MEDLINE | ID: mdl-39257147

RESUMO

Cancer is a high-morbidity disease prevalent worldwide. Chemotherapy is the primarily used regimen for cancer treatment; however, it also brings severe side effects. Chemotherapy-induced Peripheral Neuropathy (CIPN) and Chemotherapy-induced Cognitive Impairment (CICI) are two main complications occurring in chemotherapy. They are both associated with nervous system injury and are therefore collectively referred to as Chemotherapy-induced Neuropathy (CIN). CIPN induces neuralgia and numbness in limbs, while CICI causes amnesia and cognitive dysfunction. Currently, there are no effective therapeutics to prevent or cure CIN, so research into new drugs to alleviate CIN becomes urgent. Oxidative stress and neuroinflammation are the common pathogenic mechanisms of CIPN and CICI. Excessive Reactive Oxygen Species (ROS) and pro-inflammatory cytokines cause peripheral nervous system damage and hence CIPN. Peripheral ROS and cytokines also change the permeability of the blood-brain barrier, thereby increasing oxidative stress and neuroinflammation in the central nervous system, ultimately leading to CICI. Several antidepressants have been used to treat CIN and exhibited good clinical effects. Their potential pharmacological mechanism has been reported to ameliorate oxidative stress and neuroinflammation, guiding a new feasible way for effective therapeutic development against CIN. This mini-review has summarized the latest advances in the research on CIN with respect to clinical status, pathogenesis, and treatment. It has also discussed the potential of repurposing antidepressants for CIN treatment and prospected the strategy of developing therapeutics by targeting oxidative stress and neuroinflammation against CIN.

10.
Genes (Basel) ; 15(8)2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-39202409

RESUMO

Phosphorus is critical for plant growth but often becomes less accessible due to its precipitation with cations in soil. Fabaceae, a diverse plant family, exhibits robust adaptability and includes species like Lupinus albus, known for its efficient phosphorus utilization via cluster roots. Here, we systematically identified phosphorus-utilization-efficiency (PUE) gene families across 35 Fabaceae species, highlighting significant gene amplification in PUE pathways in Fabaceae. Different PUE pathways exhibited variable amplification, evolution, and retention patterns among various Fabaceae crops. Additionally, the number of homologous genes of the root hair development gene RSL2 in L. albus was far more than that in other Fabaceae species. Multiple copies of the RSL2 gene were amplified and retained in L. albus after whole genome triplication. The gene structure and motifs specifically retained in L. albus were different from homologous genes in other plants. Combining transcriptome analysis under low-phosphorus treatment, it was found that most of the homologous genes of RSL2 in L. albus showed high expression in the cluster roots, suggesting that the RSL2 gene family plays an important role in the adaptation process of L. albus to low-phosphorus environments and the formation of cluster roots.


Assuntos
Regulação da Expressão Gênica de Plantas , Lupinus , Fósforo , Proteínas de Plantas , Raízes de Plantas , Fósforo/metabolismo , Lupinus/genética , Lupinus/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Raízes de Plantas/genética , Raízes de Plantas/metabolismo , Raízes de Plantas/crescimento & desenvolvimento , Adaptação Fisiológica/genética , Fabaceae/genética , Fabaceae/metabolismo , Família Multigênica , Filogenia , Genes de Plantas
11.
Eur J Med Chem ; 278: 116799, 2024 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-39213937

RESUMO

Glioma, a common primary brain tumor, is highly infiltrative and invasive, often leading to drug resistance and recurrence. Therefore, the development of novel therapeutic agents is urgently needed. Pseudellone C is a novel marine triindole alkaloid. Screening of its antiproliferative activity against 55 cell lines revealed its anti-CNS cancer potential. A total of 42 derivatives of Pseudellone C were designed and synthesized, and their inhibitory activities against two human glioma cell lines (U-87MG and LN-229) were evaluated using the CCK-8 assay. Ten derivatives exhibited potent antiproliferative activity with IC50 values below 10 µmol, which are 18- to 39- fold more potent than Pseudellone C. Among these, derivative 4o demonstrated favorable blood-brain barrier permeability. Mechanistic studies revealed that 4o induces apoptosis primarily by activating the downstream caspase 3 cascade via the TNF/TNFR pathway. Structure-activity relationship correlations were systematically analyzed, and a pharmacophore model for further rational design was constructed.


Assuntos
Antineoplásicos , Apoptose , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Glioma , Transdução de Sinais , Humanos , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Glioma/tratamento farmacológico , Glioma/patologia , Glioma/metabolismo , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Estrutura Molecular , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Relação Dose-Resposta a Droga , Linhagem Celular Tumoral , Alcaloides Indólicos/farmacologia , Alcaloides Indólicos/química , Alcaloides Indólicos/síntese química , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo
12.
Bioorg Chem ; 151: 107683, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39121595

RESUMO

Eighteen new oleanane-type triterpenoids were isolated from the stems of Sabia limoniacea, including sabialimon A (1), a triterpenoid with an unprecedented 6/6/6/7/7 pentacyclic skeleton and seventeen undescribed triterpenoids, sabialimons B-R (2 - 18), along with six previously described analogs (19 - 24). Their structures were fully elucidated via extensive spectroscopic analysis including 1D and 2D NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS), experimental electronic circular dichroism measurements and X-ray crystallographic studies. Compound 1 is the first triterpenoid that possesses a rare ring system (6/6/6/7/7) with an oxygen-bearing bridge between C-17 and C-18 and a hemiketal form at C-17, which is generated a larger ring by the degradation of C-28 and D/E-ring expansion. Biological evaluation revealed that sabialimon I (9), sabialimon K (11), sabialimon P (16) and 11,13(18)-oleanadien-28-hydroxymethyl 3-one (20) exhibited significantly inhibitory activities against nitric oxide (NO) release with IC50 values of 29.65, 23.41, 18.12 and 26.64 µM, respectively, as compared with the positive control (dexamethasone, IC50 value: 40.35 µM). Furthermore, sabialimon P markedly decreased the secretion of TNF-α, iNOS, IL-6 and NF-κB and inhibited the expression of COX-2 and NF-κB/p65 in LPS-induced RAW264.7 cells in a dose-dependent manner.


Assuntos
Ácido Oleanólico , Camundongos , Animais , Células RAW 264.7 , Ácido Oleanólico/farmacologia , Ácido Oleanólico/química , Ácido Oleanólico/isolamento & purificação , Ácido Oleanólico/análogos & derivados , Estrutura Molecular , Relação Estrutura-Atividade , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Óxido Nítrico/metabolismo , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Relação Dose-Resposta a Droga , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/metabolismo , Ciclo-Oxigenase 2/metabolismo
14.
Int Braz J Urol ; 50(6): 727-736, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39133792

RESUMO

INTRODUCTION: We aim to compare the safety and effectiveness of the KangDuo (KD)-Surgical Robot-01 (KD-SR-01) system and the da Vinci (DV) system for robot-assisted radical nephroureterectomy (RARNU). MATERIALS AND METHODS: This multicenter prospective randomized controlled trial was conducted between March 2022 and September 2023. Group 1 included 29 patients undergoing KD-RARNU. Group 2 included 29 patients undergoing DV-RARNU. Patient demographic and clinical characteristics, perioperative data, and follow-up outcomes were collected prospectively and compared between the two groups. RESULTS: There were no significant differences in patient baseline demographic and preoperative characteristics between the two groups. The success rates in both groups were 100% without conversion to open or laparoscopic surgery or positive surgical margins. No significant difference was observed in docking time [242 (120-951) s vs 253 (62-498) s, P = 0.780], console time [137 (55-290) min vs 105 (62-220) min, P = 0.114], operative time [207 (121-460) min vs 185 (96-305) min, P = 0.091], EBL [50 (10-600) mL vs 50 (10-700) mL, P = 0.507], National Aeronautics and Space Administration Task Load Index scores, and postoperative serum creatinine levels between the two groups. None of the patients showed evidence of distant metastasis, local recurrence, or equipment-related adverse events during the four-week follow-up. One (3.4%) patient in Group 2 experienced postoperative enterovaginal and enterovesical fistulas (Clavien-Dindo grade III). CONCLUSIONS: The KD-SR-01 system is safe and effective for RARNU compared to the DV Si or Xi system. Further randomized controlled studies with larger sample sizes and longer durations are required.


Assuntos
Nefroureterectomia , Duração da Cirurgia , Procedimentos Cirúrgicos Robóticos , Humanos , Procedimentos Cirúrgicos Robóticos/métodos , Procedimentos Cirúrgicos Robóticos/instrumentação , Feminino , Masculino , Estudos Prospectivos , Pessoa de Meia-Idade , Nefroureterectomia/métodos , Idoso , Resultado do Tratamento , Neoplasias Renais/cirurgia , Tempo de Internação , Laparoscopia/métodos , Laparoscopia/instrumentação , Reprodutibilidade dos Testes , Complicações Pós-Operatórias
15.
Minim Invasive Surg ; 2024: 2466828, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39156951

RESUMO

Background: Robot-assisted nephroureterectomy (RANU) has been more and more applied since 21st century. However, the high cost limits the widespread use of robot system. A relatively low-cost new robotic surgical system (KD-SR-01™) has recently been developed in China. Objective: To assess the safety and efficacy of the KD-SR-01™ Surgical System in RANU. Methods: Patients with upper-tract urothelial tumor and undergoing RANU with the KD-SR-01™ Robotic System were prospectively included. Surgeries were all performed by a single surgeon. Patients' demographic and clinical characteristics, perioperative data, pathology findings, and follow-up data were collected. Key Findings. 9 patients were enrolled in this study, and the surgeries went smoothly with no conversion to open. The 1st docking time, the 2nd docking time, and the operation time were 222 s, 169 s, and 202 min respectively. No equipment-related adverse events occurred. All patients were followed up for at least 3 months, and one patient experienced bladder recurrences. Conclusions and Clinical Implications. This study is the first to verify that the KD-SR-01™ robot system is effective and safe in RANU and has advantages in terms of its rotation boom during redocking and its price. This trial is registered with ChiCTR2200056672.

16.
Environ Pollut ; 359: 124539, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39019309

RESUMO

Decabromodiphenyl ethane (DBDPE), as one of the important new brominated flame retardants, is widely utilized in a variety of plastic products. However, the pyrolysis mechanism of DBDPE remains uncertain. In this article, the evolution behavior of the main products during the thermal decomposition of DBDPE is investigated using density functional theory at the theoretical level of M06-2X/6-311++G(2df,p)//M06-2X/6-311+G(d). The results show that the initial reaction starts with the cleavage of the ethane bridge bond, with an absorbed heat value of 298 kJ/mol, and the cleavage of the Caromatic-Br bond generates bromine radical, which is the main competitive reaction, with a heat absorption of 317 kJ/mol. The initial degradation of DBDPE generates a large number of pentabromobenzyl radicals and bromine radicals, which facilitate the secondary pyrolysis of DBDPE to a certain extent, resulting in the formation of possible products such as pentabromobenzyl bromide, pentabromobenzene, pentabromotoluene, hexabromobenzene, pentabromostyrene, and hydrogen bromide. In the pyrolysis system of DBDPE with hydrogen radicals, the reactions are classified into two types: extraction reaction and addition reaction. It can be known that the addition reaction plays a dominant role in the degradation process, with a branching ratio of 89.8% at 1600 K. The degradation of DBDPE with hydrogen radicals is mainly characterized by debromination, and the main products are hydrogen bromide, low-brominated diphenyl ethanes, brominated phenanthrenes, and brominated monoaromatic compounds. In addition, the lowest reaction energy barrier (18 kJ/mol) is required for the addition of hydrogen radical to the ipso-C site of DBDPE. DBDPE is dangerous for the environment and humans since its fate includes bioaccumulation, biomagnification, and toxicity via hormones and endocrine disruptors.


Assuntos
Bromobenzenos , Retardadores de Chama , Cinética , Bromobenzenos/química , Pirólise , Modelos Químicos
17.
Lancet Infect Dis ; 24(10): 1141-1150, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38964361

RESUMO

BACKGROUND: The same pneumococcal conjugate vaccines (PCVs) have been used in adults and children in many settings. Differences in the epidemiology of pneumococcal disease between populations necessitates an adult-specific PCV. We aimed to assess the safety, tolerability, and immunogenicity of V116, an investigational 21-valent PCV designed for adults. METHODS: This randomised, double-blind, active comparator controlled, international phase 3 trial enrolled adults with or without stable chronic medical conditions at 112 clinical sites in 11 countries or territories. Random assignment was performed using a central electronic interactive response technology system. Cohort 1 (≥50 years) was stratified by age (50-64, 65-74, 75-84, and ≥85 years) and randomised 1:1 to receive one intramuscular dose of V116, or the active comparator, PCV20. Cohort 2 (18-49 years) was randomised 2:1 to receive one intramuscular dose of V116 or PCV20. Pneumococcal serotype-specific opsonophagocytic activity (OPA) and IgG responses were measured before (day 1) and after vaccination (day 30). Four primary immunogenicity outcomes were assessed per-protocol. First, in cohort 1, non-inferiority of V116 to PCV20 was tested using serotype-specific OPA geometric mean titres (GMT) ratios for serotypes common to both vaccines; the lower bound of the 95% CI had to be greater than 0·5 for non-inferiority. Second, superiority of V116 to PCV20 was tested for OPA GMT ratios for the serotypes unique to V116; the lower bound of the 95% CI had to be greater than 2·0 for superiority. Third, superiority of V116 to PCV20 was evaluated by the proportions of participants with a four-fold or greater rise from day 1 to day 30 for serotypes unique to V116; the lower bound of the 95% CI of the differences in proportions (V116 - PCV20) had to be greater than 10% for superiority. Finally, in cohort 2, immunobridging was assessed for all 21 serotypes in V116 for adults aged 18-49 years to 50-64 years; the lower bound of the 95% CI for the OPA GMTs had to be greater than 0·5 for non-inferiority. The safety analysis included all randomly assigned participants who received study vaccine. The primary safety outcome was the proportion of participants with solicited injection site and solicited systemic adverse events until day 5 and vaccine-related serious adverse events up to 6 months after vaccination. This trial is registered at ClinicalTrials.gov (NCT05425732). FINDINGS: Between July 13, and Nov 22, 2022, 2754 individuals were screened and 2663 participants were randomly assigned. 2656 individuals were vaccinated (1179 in V116 cohort 1; 1177 in PCV20 cohort 1; 200 in V116 cohort 2; and 100 in PCV20 cohort 2). V116 met non-inferiority criteria compared with PCV20 for the ten serotypes common to both vaccines at day 30 in cohort 1 (p<0·0001 for each common serotype). V116 met superiority criteria compared with PCV20 in cohort 1 for ten of the 11 serotypes unique to V116 at day 30 (OPA GMT ratio: p<0·0001 for all unique serotypes except 15C, which was p=0·41; four-fold or greater rise in OPA from day 1-30: p<0·0001 for all serotypes except 15C, which was p=0·67). Immune responses in V116 participants aged 18-49 years were non-inferior compared with V116 participants aged 50-64 years for all V116 serotypes (p<0·0001 for all V116 serotypes). In cohort 1, 685 (58·2%) of participants in V116, and 778 (66·2%) of participants in PCV20 reported one or more adverse event. In cohort 2, 164 (82·0%) participants in V116 and 79 participants (79·0%) in PCV20 reported one or more adverse event. Six deaths were reported, all in cohort 1, none of which were considered vaccine-related (in V116: one due to sepsis, one due to cerebrovascular accident, one due to myocardial infarction, and one due to hepatic cirrhosis and hepatic encephalopathy; in PCV20: one due to cardiac arrest and one due to abdominal abscess). There were no vaccine-related serious adverse events. INTERPRETATION: V116 was non-inferior to PCV20 for the ten serotypes common to both vaccines and superior to PCV20 for all serotypes unique to V116, except for 15C. Immune responses successfully immunobridged between younger and older adults for all serotypes in V116. V116 was generally well tolerated with safety profile similar to PCV20. FUNDING: Merck Sharp & Dohme, subsidiary of Merck & Co, Rahway, NJ, USA (MSD).


Assuntos
Anticorpos Antibacterianos , Infecções Pneumocócicas , Vacinas Pneumocócicas , Vacinas Conjugadas , Humanos , Vacinas Pneumocócicas/imunologia , Vacinas Pneumocócicas/administração & dosagem , Vacinas Pneumocócicas/efeitos adversos , Pessoa de Meia-Idade , Idoso , Método Duplo-Cego , Masculino , Feminino , Adulto , Vacinas Conjugadas/imunologia , Vacinas Conjugadas/administração & dosagem , Vacinas Conjugadas/efeitos adversos , Adolescente , Adulto Jovem , Anticorpos Antibacterianos/sangue , Idoso de 80 Anos ou mais , Infecções Pneumocócicas/prevenção & controle , Infecções Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Imunogenicidade da Vacina , Imunoglobulina G/sangue
18.
Mar Drugs ; 22(6)2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38921563

RESUMO

Breast cancer is one of the leading causes of cancer mortality worldwide, and triple-negative breast cancer (TNBC) is the most problematic subtype. There is an urgent need to develop novel drug candidates for TNBC. Marine toxins are a valuable source for drug discovery. We previously identified αO-conotoxin GeXIVA[1,2] from Conus generalis, which is a selective antagonist of α9 nicotinic acetylcholine receptors (nAChRs). Recent studies indicated that α9 nAChR expression is positively correlated with breast cancer development; thus, α9 nAChR could serve as a therapeutic target for breast cancer. In this study, we aimed to investigate the in vivo antitumor effects of GeXIVA[1,2] on TNBC and to elucidate its underlying anticancer mechanism. Our data showed that GeXIVA[1,2] effectively suppressed 4T1 tumor growth in vivo at a very low dose of 0.1 nmol per mouse. Our results uncovered that the antitumor mechanism of GeXIVA[1,2] simultaneously induced apoptosis and blocked proliferation. Further investigations revealed that GeXIVA[1,2]-induced Caspase-3-dependent apoptosis was achieved through regulating Bax/Bcl-2 balance, and GeXIVA[1,2]-inhibited proliferation was mediated by the downregulation of the AKT-mTOR, STAT3 and NF-κB signaling pathways. Our study provides valuable arguments to demonstrate the potential of GeXIVA[1,2] as a novel marine-derived anticancer drug candidate for the treatment of TNBC.


Assuntos
Apoptose , Proliferação de Células , Conotoxinas , NF-kappa B , Proteínas Proto-Oncogênicas c-akt , Fator de Transcrição STAT3 , Transdução de Sinais , Serina-Treonina Quinases TOR , Neoplasias de Mama Triplo Negativas , Animais , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Apoptose/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Serina-Treonina Quinases TOR/metabolismo , NF-kappa B/metabolismo , Feminino , Transdução de Sinais/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Camundongos , Proliferação de Células/efeitos dos fármacos , Conotoxinas/farmacologia , Linhagem Celular Tumoral , Camundongos Endogâmicos BALB C , Humanos , Antineoplásicos/farmacologia
19.
Eur Urol Focus ; 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38862329

RESUMO

BACKGROUND: The KangDuo Surgical Robot (KD-SR) is a newly developed surgical robot. OBJECTIVE: To compare the safety and efficacy of robot-assisted radical prostatectomy (RARP) using the KD-SR with those of the da Vinci Si Surgical System (DV-SS-Si). DESIGN, SETTING, AND PARTICIPANTS: A prospective double-center noninferiority randomized controlled trial was conducted among 18-75-yr-old patients with suspected T1-2N0M0 prostate cancer (PCa) scheduled for RARP. INTERVENTION: RARP with the KD-SR (KD-RARP) versus RARP with the DV-SS-Si (DV-RARP). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was surgical success, defined as follows: surgery can be performed according to the established protocol, without switching to other surgical modalities, and without secondary surgery due to surgical complications after surgery. The secondary outcome was short-term functional and oncological outcomes. The noninferiority threshold was set at 10%. RESULTS AND LIMITATIONS: Eighty patients were enrolled, while the full analysis set finally included 79 patients (40 with KD-RARP and 39 with DV-RARP). The success rate was 100% in both groups. We could not find differences in urinary continence rate at 1, 2, 3, and 4 wk after catheter removal between the groups (p > 0.05). The rate of Clavien-Dindo grade II adverse events was 20% in the KD-RARP group and 17.9% in the DV-RARP group (p = 0.82), and no grade ≥III adverse events occurred. The median operation time was significantly longer in the KD-RARP group than in the DV-RARP group (177.5 vs 145 min, p = 0.012). The main limitations were the short follow-up period and that survival was not considered as the primary outcome. CONCLUSIONS: The KD-SR is a viable option for RARP, with acceptable short-term outcomes compared with the DV-SS-Si for T1-2 PCa. PATIENT SUMMARY: This is the first prospective randomized controlled trial to compare the KangDuo Surgical Robot (KD-SR) versus the da Vinci Si Surgical System (DV-SS-Si) for robot-assisted radical prostatectomy, which determines that the KD-SR is noninferior to the DV-SS-Si regarding safety and efficacy for T1-T2 prostate cancer.

20.
Adv Mater ; 36(30): e2402708, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38837440

RESUMO

Emerging intrinsically flexible fully π-conjugated polymers (FπCPs) are a promising functional material for flexible optoelectronics, attributed to their potential interchain interpenetration and entanglement. However, the challenge remains in obtaining elastic-plastic FπCPs with intrinsic robust optoelectronic property and excellent long-term and cycling deformation stability simultaneously for applications in deep-blue flexible polymer light-emitting diodes (PLEDs). This study, demonstrates a series of elastic-plastic FπCPs (P1-P4) with an excellent energy dissipation capacity via side-chain internal plasticization for the ultra-deep-blue flexible PLEDs. First, the freestanding P1 film exhibited a maximum fracture strain of 34.6%. More interestingly, the elastic behavior is observed with a low strain (≤10%), and the stretched film with a high deformation (>10%) attributed to plastic processing revealed the robust capacity to realize energy absorption and release. The elastic-plastic P1 film exhibits outstanding ultra-deep-blue emission, with an efficiency of 56.38%. Subsequently, efficient PLEDs are fabricated with an ultra-deep-blue emission of CIE (0.16, 0.04) and a maximum external quantum efficiency of 1.73%. Finally, stable and efficient ultra-deep-blue electroluminescence are obtained from PLEDs based on stretchable films with different strains and cycling deformations, suggesting excellent elastic-plastic behavior and deformation stability for flexible electronics.

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