RESUMO
Our previous study revealed that 1-nitropyrene (1-NP) exposure evoked pulmonary fibrosis in mice. However, the exact mechanism remained elusive. We found that 1-NP induced telomere damage and cellular senescence in mice lungs, and two alveolar epithelial cells lines. 1-NP downregulated telomere repeat binding factor 2 (TRF2), and upregulated FBXW7. Mechanistically, 1-NP-caused TRF2 ubiquitination and proteasomal degradation depended on E3 ubiquitin ligase activity of FBXW7. Moreover, 1-NP upregulated FBXW7 m6A modification via an ALKBH5-YTHDF1-dependent manner. Further analysis suggested 1-NP promoted ALKBH5 SUMOylation and subsequent proteasomal degradation. Additionally, 1-NP evoked mitochondrial reactive oxygen species (mtROS) overproduction. Mito-TEMPO, a mitochondrial-targeted antioxidant, mitigated 1-NP-caused mtROS overproduction, ALKBH5 SUMOylation, FBXW7 m6A modification, TRF2 degradation, cellular senescence, and pulmonary fibrosis. Taken together, mtROS-initiated ALKBH5 SUMOylation and subsequent FBXW7 m6A modification is indispensable for TRF2 degradation and cellular senescence in alveolar epithelial cells during 1-NP-induced pulmonary fibrosis. Our study provides target intervention measures towards 1-NP-evoked pulmonary fibrosis.
Assuntos
Adenina/análogos & derivados , Fibrose Pulmonar , Pirenos , Sumoilação , Animais , Camundongos , Proteína 7 com Repetições F-Box-WD/genética , Proteína 7 com Repetições F-Box-WD/metabolismo , Células Epiteliais Alveolares/metabolismo , Fibrose Pulmonar/induzido quimicamenteRESUMO
This study aimed to evaluate the safety and efficacy of camrelizumab combined with chemotherapy during preoperative neoadjuvant therapy in patients with locally advanced resectable esophageal squamous cell carcinoma (ESCC) of clinical Stages II and III. The patients received camrelizumab plus chemotherapy regimen on Day 1 for up to three to four cycles (3 weeks per cycle). The probabilities of overall survival (OS) were 55.6% at 12 months and 35.6% at 18 months (45 patients). The disease-free survival (DFS) rates were 70.0% at 12 months and 63.3% at 18 months (30 patients). The median OS and DFS were not reached. The proportion of patients at postneoadjuvant pathological tumor stages ypT0, ypT2, and ypT3 were 10 (33.3%), 14 (46.7%), and 6 (20.0%), respectively, and those at stages ypN0 and ypN1 were 19 (63.3%) and 11 (36.7%), respectively. Additionally, the pathological complete response rate was 33.3% (95% confidence interval [CI]: 0.154-0.512), and the major pathologic response rate was 46.7% (95% CI: 0.277-0.656). Grade ≥3 adverse events (AEs) were reported in five patients (11.1%), with vomiting being the most common AE (three patients; 3.3%). Other common AEs of any grade included decreased lymphocyte count (48.9%), reactive capillary endothelial proliferation (46.7%), decreased white blood cell count (40.0%), anemia (31.1%), and vomiting (31.1%). The combination of camrelizumab and neoadjuvant chemotherapy in patients with locally advanced resectable ESCC demonstrated promising efficacy and acceptable safety.
Assuntos
Anticorpos Monoclonais Humanizados , Carcinoma , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/cirurgia , Terapia Neoadjuvante , Estudos Retrospectivos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/cirurgia , Vômito , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Minimally invasive esophagectomy is now accepted as a regular treatment modality for esophageal cancer. Upper gastrointestinal (GI) bleeding is a common postoperative adverse event of esophagectomy. However, there are very few reports in the literature on endoscopic management of early upper GI bleeding after an esophagectomy. Here, we report the successful management of such an early case of GI bleeding after thoracolaparoscopic esophagectomy by the use of endoscopic intrathoracic anastomosis.
Assuntos
Neoplasias Esofágicas/cirurgia , Esofagectomia/efeitos adversos , Hemorragia Gastrointestinal/cirurgia , Hemostasia Cirúrgica/métodos , Hemorragia Pós-Operatória/diagnóstico , Anastomose Cirúrgica/efeitos adversos , Endoscopia/métodos , Neoplasias Esofágicas/patologia , Esofagectomia/métodos , Junção Esofagogástrica/cirurgia , Esofagoscopia/métodos , Seguimentos , Hemorragia Gastrointestinal/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Minimamente Invasivos/efeitos adversos , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Hemorragia Pós-Operatória/cirurgia , Reoperação/métodos , Medição de Risco , Resultado do TratamentoRESUMO
We describe a pursestring stapled anastomotic technique for minimally invasive Ivor Lewis esophagectomy, in which a pursestring is hand sewn through the muscular layer of the intact esophagus by using one piece of 3-0 Prolene suture. The anvil of a circular stapler is inserted through an esophageal incision, 2 to 3 cm distal to the pursestring, and secured by the pursestring. The esophagus is transected, and the mucosa of the proximal stump is retained 5 mm longer than the adjacent muscular layer. The gastroesophageal anastomosis is completed and embedded by using the previously reserved 2 cm of mediastinal pleura.
Assuntos
Neoplasias Esofágicas/cirurgia , Esofagectomia/métodos , Esôfago/cirurgia , Laparoscopia/métodos , Técnicas de Sutura/instrumentação , Suturas , Anastomose Cirúrgica/métodos , Humanos , ToracoscopiaRESUMO
BACKGROUND: The renin-angiotensin-aldosterone system is known to play an important role in the pathophysiology and development of heart failure. Several studies have reported the benefits of testosterone in heart failure. However, the mechanisms of testosterone-induced effects on heart failure require further study. AIMS: To determine the effects of castration and testosterone administration on cardiac function and angiotensin II receptor function in rats with isoproterenol-induced heart failure. METHODS: Wistar rats were divided randomly into control and heart failure groups. The heart failure groups were further divided into the following groups: castration; castration+testosterone replacement; and sham castration. Echocardiography and haemodynamic measurements were used to evaluate cardiac function. Cardiocyte apoptosis and fibrosis were determined using terminal deoxyribonucleotide transferase-mediated dUTP nick-end labelling (TUNEL) staining and Masson's Trichrome staining, respectively. Angiotensin II receptor (AT1 and AT2) messenger ribonucleic acid (mRNA) expression levels were assayed using real-time reverse transcriptase-polymerase chain reactions, while Western immunoblotting was used to estimate Bcl-2 protein expression levels. RESULTS: Castration significantly increased cardiomyocyte apoptosis and fibrosis that was normally induced by isoproterenol (P<0.05). AT2 receptor mRNA expression in the castration group was increased and Bcl-2 protein expression was decreased compared with the castration+testosterone replacement group (P<0.05). CONCLUSION: These data suggest that androgen therapy could play an important role in pathophysiological changes in heart failure and have beneficial effects for its treatment.