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1.
Eur J Pharm Sci ; 180: 106334, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36402309

RESUMO

OBJECTIVE: There is a paucity of published data to evaluate the efficacy and safety of imipenem, cefepime and piperacillin/tazobactam dosing regimens against bloodstream infections caused by Klebsiella aerogenes (BSIs-Kae) and Enterobacter cloacae complex (BSIs-Ecc) in patients with various degrees of renal function. METHODS: Pathogens were isolated from China's blood bacterial resistant investigation network. The dosing regimens of imipenem, cefepime and piperacillin were simulated with intermittent infusion and extended infusion. Monte Carlo simulation was performed to calculate the probability of target attainment and a cumulative fraction of response (CFR) against BSIs-Kae/Ecc. RESULTS: In total, 203 BSIs-Kae, and 785 BSIs-Ecc were isolated from the surveillance network. Imipenem showed the highest in vitro activity against BSIs-Kae/Ecc, followed by cefepime (85%) and piperacillin/tazobactam (70-80%). The MIC90 values of imipenem, cefepime and piperacillin/tazobactam aginst BSIs-Kae and BSIs-Ecc were 1/1 mg/L, 16/16 mg/L, and 64/128 mg/L, respectively. The simulation results showed imipenem achieved the highest CFRs in patients with normal or decreased renal function, with values of 91-99%, followed by FEP (88-96%), without risk of excessive dosing. However, the intermittent and extended dosing regimens of piperacillin/tazobactam were unlikely to provide adequate exposure for empirical management of BSIs-Kae/Ecc (CFRs, 50-80%), regardless of renal function. Besides, the traditional intermittent piperacillin/tazobactam dosing regimens were highly likely to contribute to suboptimal therapeutic exposure when MIC was close to clinical breakpoints. CONCLUSIONS: Cefepime, not piperacillin/tazobactam, can be a reasonable carbapenem-sparing option in empirically treating BSIs-Kae/Ecc.


Assuntos
Enterobacter , Sepse , Humanos , Cefepima , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Testes de Sensibilidade Microbiana , Combinação Piperacilina e Tazobactam , Imipenem/farmacologia , Método de Monte Carlo
2.
Indian J Pathol Microbiol ; 64(2): 362-368, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33851636

RESUMO

There were rare clinical reports on clear cell tumor of the lung (CCTL). The clinical characteristics and underlying genetic mutation status of CCTL are poorly understood. From 2012 to 2017, patients pathologically diagnosed with CCTL in our hospital were investigated and analyzed based on clinical manifestations, pathological characteristics, prognosis and full gene mutation status through next generation sequencing (NGS) technology. During a 6-year period, four eligible patients were diagnosed with CCTL through surgical resection and were included in this study. All patients showed solitary nodules or lumps located in the left lung. The average maximum diameter of lesions was 2.5 ± 1.1 cm. Computed tomography (CT) imaging characteristics of these nodules/lumps demonstrated the features of benign tumors. The hematoxylin-eosin (HE) morphology and immunohistochemistry were consistent with the histopathological features of benign CCTL. Subsequent NGS analysis showed frame shift mutations of F2421/E2419, K1466E mutation, and p. 1450_1456 deletion mutation in mTOR gene in two of four patient samples and amplifications of MCL1 were observed in three of four samples. CCTL is a rare type of primary pulmonary mesenchymal tumor with good prognosis. Preliminary diagnosis on CT is usually sclerosing pneumocytoma. It is still unclear whether the occurrence and development of the disease are related to specific gene mutation. In this study, the genomic findings of frame shift mutation of mTOR genes and amplification of MCL1 gene in CCTL suggest that these mutations might play a role in proliferation of CCTL.


Assuntos
Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Serina-Treonina Quinases TOR/genética , Adenocarcinoma de Células Claras/diagnóstico , Feminino , Mutação da Fase de Leitura/genética , Amplificação de Genes/genética , Glicogênio/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/diagnóstico , Masculino , Pessoa de Meia-Idade , Prognóstico , Tomografia Computadorizada por Raios X
3.
Ann Palliat Med ; 10(1): 778-784, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33545799

RESUMO

There is currently no standard treatment for multiple primary lung cancer (MPLC). We report a case of synchronous MPLC presenting as one ground-glass opacity (GGO) with predominant consolidation accompanied by at least parietal pleura involvement, and another with >30 GGOs distributed across bilateral lungs, which was ineligible for complete resection. CT-guided percutaneous biopsy of the nearly pure-solid mass showed invasive lung adenocarcinoma mainly composed of acinar type. Capture-based, ultra-deep targeted sequencing (Burning Rock, Guangzhou, China) was performed on the tumor tissue biopsy. The result revealed no druggable mutations according to the guideline and a high TMB of 34.1 Mb. Immunohistochemical staining (22C3; Dako, Denmark) was positive for PD-L1 expression with a tumor expression level of 30%. Based on the clinical information and patient's decision, he received 3 cycles of pemetrexed plus pembrolizumab and was subsequently forced to withdraw due to acquired immune-related pneumonitis. After discontinuation of corticosteroids, he was subjected to wedge resection for the nearly pure-solid lesion, and then refused further treatment for the other tumors. After a follow-up of 12 months from termination of immunotherapy, almost all GGOs achieved radiographically complete remission, attributed to the tailing effect of the programmed cell death protein 1 (PD-1) antibody of pembrolizumab. Through the case study we found that unresectable synchronous MPLC presenting as GGOs may respond well to immunotherapy.


Assuntos
Neoplasias Pulmonares , Neoplasias Primárias Múltiplas , China , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Receptor de Morte Celular Programada 1 , Tomografia Computadorizada por Raios X
4.
J Int Med Res ; 48(9): 300060520937163, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32962498

RESUMO

OBJECTIVE: To study the effects of saikosaponin D (SSD) on proliferation and apoptosis in human non-small cell lung cancer cell lines, and to explore underlying mechanisms. METHODS: Following treatment with saikosaponin D, A549 and H1299 cells were assessed for anti-proliferation effects using cell cycle kit-8 assays, changes in nuclear morphology using 4',6-diamidino-2-phenylindole (DAPI) staining, and cell apoptosis using annexin V/propidium iodide double staining. Proliferation- and apoptosis-related proteins were detected by immunoblotting. RESULTS: Saikosaponin D had dose-dependent inhibitory effects on A549 cells (IC50, 3.57 µM) and H1299 cells (IC50, 8.46 µM). DAPI staining revealed decreased cell numbers, and most H1299 cells became round after treatment with 20 µM saikosaponin D. As saikosaponin D concentration increased, the proportions of cells in G0/G1 phase, and cells undergoing apoptosis, increased. Levels of phosphorylated p44/42 and signal transducer and activator of transcription (STAT)3 were significantly downregulated in both cell lines, while total STAT3 levels were not significantly affected. The cleaved form of caspase 3 was significantly upregulated. CONCLUSIONS: Saikosaponin D inhibits proliferation, inducing cell cycle arrest and apoptosis, in lung cancer cells in a dose-dependent manner, possibly through inhibition of STAT3 phosphorylation and activation of caspase 3.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Apoptose , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Fator de Transcrição STAT3/metabolismo , Saponinas
5.
Cancer Biomark ; 28(4): 549-559, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32623387

RESUMO

OBJECTIVE: Studies have suggested that miR-21-5p and WWC2 are key players in most cancer types, yet the underlying mechanisms in lung adenocarcinoma (LUAD) remain elusive. This study made in-depth research on the two factors-dependent mechanisms underlying LUAD occurrence and development. METHODS: Bioinformatics methods were employed to identify the miRNA and its target gene of interest. In all, 20 pairs of LUAD tumor tissue samples and matched adjacent normal samples along with 5 LUAD cell lines were collected for evaluating the aberrant expression of miR-21-5p and WWC2. Dual-luciferase reporter assay was performed to validate the targeted relationship between miR-21-5p and WWC2. A series of in vitro experiments including colony formation assay, EdU, wound healing assay and Transwell were conducted for assessment of the LUAD cell biological behaviors. In addition, Western blot was carried out to determine the protein expression of epithelial-mesenchymal transition (EMT)-related proteins. RESULTS: miR-21-5p was found to be considerably increased in LUAD tissue and cells relative to that in the adjacent tissue and the human bronchial epithelial cells, whereas WWC2 was significantly decreased. Dual-luciferase reporter assay revealed that miR-21-5p targeted WWC2 and down-regulated its expression. Besides, silencing miR-21-5p or overexpressing WWC2 played an inhibitory role in PC-9 cancer cell proliferation, migration and invasion, but such effect was suppressed when miR-21-5p was overexpressed. Furthermore, Western blot uncovered that WWC2 overexpression impeded the EMT process in LUAD cells. CONCLUSION: miR-21-5p facilitates LUAD cell proliferation, migration and invasion through targeting WWC2, which provides a novel therapeutic target for LUAD treatment.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/genética , MicroRNAs/metabolismo , Adenocarcinoma de Pulmão/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Biologia Computacional , Regulação para Baixo , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Regulação para Cima
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