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The advent of computed tomography (CT)-guided transthoracic needle biopsy has significantly advanced the diagnosis of lung lesions, offering a minimally invasive approach to obtaining tissue samples. However, the technique is not without risks, including pneumothorax and hemorrhage, and it demands high precision to ensure diagnostic accuracy while minimizing complications. This study introduces the Laser Angle Guide Assembly (LAGA), a novel device designed to enhance the accuracy and safety of CT-guided lung biopsies. We retrospectively analyzed 322 CT-guided lung biopsy cases performed with LAGA at a single center over seven years, aiming to evaluate its effectiveness in improving diagnostic yield and reducing procedural risks. The study achieved a diagnostic success rate of 94.3%, with a significant reduction in the need for multiple needle passes, demonstrating a majority of biopsies successfully completed with a single pass. The incidence of pneumothorax stood at 11.1%, which is markedly lower than the reported averages, and only 0.3% of cases necessitated chest tube placement, underscoring the safety benefits of the LAGA system. These findings underscore the potential of LAGA to revolutionize CT-guided lung biopsies by enhancing procedural precision and safety, making it a valuable addition to the diagnostic arsenal against pulmonary lesions.
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BACKGROUND: This retrospective study aimed to evaluate the precision and safety outcomes of image-guided lung percutaneous thermal ablation (LPTA) methods, focusing on radiofrequency ablation (RFA) and microwave ablation (MWA). The study utilized an innovative angle reference guide to facilitate these techniques in the treatment of lung tumors. METHODS: This study included individuals undergoing LPTA with the assistance of laser angle guide assembly (LAGA) at our hospital between April 2011 and March 2021. We analyzed patient demographics, tumor characteristics, procedure details, and complications. Logistic regressions were employed to assess risk factors associated with complications. RESULTS: A total of 202 patients underwent ablation for 375 lung tumors across 275 sessions involving 495 ablations. Most procedures used RFA, especially in the right upper lobe, and the majority of ablations were performed in the prone position (49.7%). Target lesions were at a median depth of 39.3 mm from the pleura surface, and remarkably, 91.9% required only a single puncture. Complications occurred in 31.0% of ablations, with pneumothorax being the most prevalent (18.3%), followed by pain (12.5%), sweating (6.5%), fever (5.0%), cough (4.8%), hemothorax (1.6%), hemoptysis (1.2%), pleural effusion (2.0%), skin burn (0.6%), and air emboli (0.2%). The median procedure time was 21 min. Notably, smoking/chronic obstructive pulmonary disease emerged as a significant risk factor for complications. CONCLUSION: The LAGA-assisted LPTA enhanced safety by improving accuracy and reducing risks. Overall, this investigation contributes to the ongoing efforts to refine and improve the clinical application of these thermal ablation techniques in the treatment of lung tumors.
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Ablación por Catéter , Hipertermia Inducida , Neoplasias Pulmonares , Humanos , Estudios Retrospectivos , Neoplasias Pulmonares/patología , Pulmón/patología , Tomografía Computarizada por Rayos X/métodos , Ablación por Catéter/métodos , Resultado del TratamientoRESUMEN
BACKGROUND: Iatrogenic pneumothorax is the most frequent complication in preoperative CT-guided localization (POCTGL) of lung nodules. We aimed to determine the predictive factors of iatrogenic pneumothorax. METHODS: We retrospectively analyzed data of consecutive POCTGL procedures in patients who received video-assisted thoracoscopic surgery (VATS) at our hospital between May 2015 and October 2019. All of our patients utilized laser angle guide assembly to aid in the localization procedures. RESULTS: In 610 consecutive POCTGL procedures, 40 (6.6%) patients developed iatrogenic pneumothorax, and complications occurred in 8.5%. Univariate analyses revealed that puncture frequency, male gender, puncture depth, left decubitus position, and nodule near fissure were factors associated with pneumothorax, while multivariate analysis showed that only male gender (odds ratio 3.58, p = 0.012) and puncture frequency (odds ratio 2.39/time, p = 0.0004) determined development of pneumothorax. Further collective analysis on puncture frequency revealed that tumor in a difficult zone (1.33 ± 0.71 vs. 1.19 ± 0.45, p = 0.002), especially adjacent to the mediastinum (1.41 ± 0.75 vs. 1.21 ± 0.52, p = 0.002), angle difference of plan-to-practice (r = 0.209, p = < 0.001), depth to skin (r = 0.152, p < 0.001), and depth to pleura (r = 0.164, p < 0.001) were factors related to increased puncture frequency in univariate analyses. Only angle difference of plan-to-practice was associated in multivariate analysis (odds ratio: 1.158, p = 0.008). CONCLUSIONS: Puncture frequency was the key factor in the development of iatrogenic pneumothorax from POCTGL. Other associated factors, especially angle difference, may have affected the puncture frequency and subsequently have some influence on the incidence of iatrogenic pneumothorax.
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Neoplasias Pulmonares , Neumotórax , Lesiones Precancerosas , Nódulo Pulmonar Solitario , Humanos , Pulmón/patología , Neoplasias Pulmonares/patología , Masculino , Neumotórax/etiología , Neumotórax/cirugía , Punciones , Estudios Retrospectivos , Nódulo Pulmonar Solitario/patología , Cirugía Torácica Asistida por Video/efectos adversos , Cirugía Torácica Asistida por Video/métodos , Tomografía Computarizada por Rayos X/métodosRESUMEN
Oxygen pulse (O2P) is a function of stroke volume and cellular oxygen extraction and O2P curve pattern (O2PCP) can provide continuous measurements of O2P. However, measurements of these two components are difficult during incremental maximum exercise. As cardiac function is evaluated using ejection fraction (EF) according to the guidelines and EF can be obtained using first-pass radionuclide ventriculography, the aim of this study was to investigate associations of O2P%predicted and O2PCP with EF in patients with heart failure with reduced or mildly reduced ejection fraction (HFrEF/HFmrEF) and chronic obstructive pulmonary disease (COPD), and also in normal controls. This was a prospective observational cross-sectional study. Correlations of resting left ventricular EF, dynamic right and left ventricular EFs and outcomes with O2P% and O2PCP across the three participant groups were analyzed. A total of 237 male subjects were screened and 90 were enrolled (27 with HFrEF/HFmrEF, 30 with COPD and 33 normal controls). O2P% and the proportions of the three types of O2PCP were similar across the three groups. O2P% reflected dynamic right and left ventricular EFs in the control and HFrEF/HFmrEF groups, but did not reflect resting left ventricular EF in all participants. O2PCP did not reflect resting or dynamic ventricular EFs in any of the subjects. A decrease in O2PCP was significantly related to nonfatal cardiac events in the HFrEF/HFmrEF group (log rank test, p = 0.01), whereas O2P% and O2PCP did not predict severe acute exacerbations of COPD. The findings of this study may clarify the utility of O2P and O2PCP, and may contribute to the currently used interpretation algorithm and the strategy for managing patients, especially those with HFrEF/HFmrEF. (Trial registration number NCT05189301.).
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BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic neoplasm with high metastatic potential and poor clinical outcome. Like other solid tumors, PDAC in the early stages is often asymptomatic, and grows very slowly under a distinct acidic pHe (extracellular pH) microenvironment. However, most previous studies have only reported the fate of cancerous cells upon cursory exposure to acidic pHe conditions. Little is known about how solid tumors-such as the lethal PDAC originating within the pancreatic duct-acinar system that secretes alkaline fluids-evolve to withstand and adapt to the prolonged acidotic microenvironmental stress. METHODS: Representative PDAC cells were exposed to various biologically relevant periods of extracellular acidity. The time effects of acidic pHe stress were determined with respect to tumor cell proliferation, phenotypic regulation, autophagic control, metabolic plasticity, mitochondrial network dynamics, and metastatic potentials. RESULTS: Unlike previous short-term analyses, we found that the acidosis-mediated autophagy occurred mainly as an early stress response but not for later adaptation to microenvironmental acidification. Rather, PDAC cells use a distinct and lengthy process of reversible adaptive plasticity centered on the early fast and later slow mitochondrial network dynamics and metabolic adjustment. This regulates their acute responses and chronic adaptations to the acidic pHe microenvironment. A more malignant state with increased migratory and invasive potentials in long-term acidosis-adapted PDAC cells was obtained with key regulatory molecules being closely related to overall patient survival. Finally, the identification of 34 acidic pHe-related genes could be potential targets for the development of diagnosis and treatment against PDAC. CONCLUSIONS: Our study offers a novel mechanism of early rapid response and late reversible adaptation of PDAC cells to the stress of extracellular acidosis. The presence of this distinctive yet slow mode of machinery fills an important knowledge gap in how solid tumor cells sense, respond, reprogram, and ultimately adapt to the persistent microenvironmental acidification.
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Acidosis , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Adaptación Fisiológica , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Humanos , Concentración de Iones de Hidrógeno , Conductos Pancreáticos/metabolismo , Conductos Pancreáticos/patología , Neoplasias Pancreáticas/patología , Microambiente Tumoral/genética , Neoplasias PancreáticasRESUMEN
Tidal volume at peak exercise and vital capacity ratio (VTpeak/VC) and VTpeak/inspiratory capacity (IC) were used to differentiate lung expansion in subjects with normal health and chronic obstructive pulmonary disease (COPD) from that in subjects with restrictive ventilation. However, VC and IC variably change due to pseudorestriction of lung volumes. Thus, these variables are currently not recommended. In contrast, total lung capacity (TLC) does little change during exercise. The aims of the study investigated whether VTpeak/TLC is more significantly correlated with static air trapping and lung hyperinflation in patients with COPD than VTpeak/IC, VTpeak/FVC, and VTpeak/SVC (study 1), and developed a marker to replace dynamic IC maneuvers by evaluation of the relationship between end-expiratory lung volume (EELV) and VTpeak/TLC and identification of a cutoff value for VTpeak/TLC (study 2). One hundred adults with COPD (study 1) and 23 with COPD and 19 controls (study 2) were analyzed. Spirometry, lung volume, diffusing capacity, incremental cardiopulmonary exercise tests with dynamic IC maneuvers were compared between groups. An ROC curve was generated to identify a cut off value for VTpeak/TLC. In study 1, VTpeak/TLC was more significantly associated with airflow obstruction, static air trapping and hyperinflation. In study 2, VTpeak/TLC was highly correlated with EELV in the patients (r = -0.83), and VTpeak/TLC ≥ 0.27 predicted that 18% of the patients with static air trapping and hyperinflation can expand their VT equivalent to the controls. In conclusions, VTpeak/TLC was superior to other VTpeak/capacities. VTpeak/TLC may be a marker of dynamic hyperinflation in subjects with COPD, thereby avoiding the need for dynamic IC maneuvers. VTpeak/TLC < 0.27 identified approximately 82% of subjects with COPD who could not adequately expand their tidal volume. As most of our participants were male, further studies are required to elucidate whether the results of this study can be applied to female patients with COPD.
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Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Pruebas de Función Respiratoria/métodos , Volumen de Ventilación Pulmonar/fisiología , Capacidad Pulmonar Total/fisiología , Adulto , Anciano , Estudios de Casos y Controles , Estudios Transversales , Prueba de Esfuerzo , Femenino , Voluntarios Sanos , Humanos , Capacidad Inspiratoria/fisiología , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Pruebas de Función Respiratoria/estadística & datos numéricos , Capacidad Vital/fisiologíaRESUMEN
BACKGROUND: There is an increasing need for thoracic medicine specialists to master preoperative localizations after high rates of sub-centimeter nodules have been positively screened by low-dose CT. The Laser Angle Guide Assembly® (LAGA), an innovative angle reference device for CT-guided pulmonary invasive procedures, has been developed to safely and efficiently aid in the performance of preoperative CT-guided localizations (POCTGL). METHODS: The clinical and localization data of patients who received LAGA-assisted POCTGL for pulmonary nodules between May 2015 and June 2018 were collected and analyzed. RESULTS: One hundred and eighty-seven patients with 266 pulmonary nodules received LAGA-assisted POCTGL. The number of lung nodules localized for one surgery ranged from 1 to 5, with >1 for 22.1% of the surgeries. The median nodule size was 6 mm. A hookwire was inserted in 32 (12%) of the nodules. Most (83.1%) of the localizations were completed with a single puncture. The median angle was 18 degrees. The median and maximum depths of the nodule to pleura were 12 and 60 mm, respectively. The median procedure time was 19 minutes. The successful targeting and field targeting rates were 100% and 98.1%, respectively. Pneumothorax was noted in 17 (6.4%) localizations that did not require chest drainage. The multivariable analyses for pneumothorax showed odds ratios of 2.4 (95% confidence interval, 1.2-4.9) for puncture times/nodule and 10.1 (95% confidence interval, 2.3-41.7) for tumors adjacent to the fissure, respectively. There was no incidence of hookwire migration. CONCLUSIONS: LAGA enhanced the precision of POCTGL by optimizing targeting precision and decreasing repeated punctures, which minimized complications, such as pneumothorax.
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Computed tomography (CT)-guided lung procedures such as preoperative localizations, biopsies, and ablations are associated with morbidity even mortality. Often, the puncture angle is determined by the 'experienced hand' without a precise guide. We describe here the Laser Angle Guide Assembly® to direct and steer the puncture angles precisely. It decreases procedure-related complications, saves time, reduces costs, avoids repeated punctures, and minimizes radiation exposures.
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Nickel exposure promotes the invasive potential of human lung cancer cells. Polyphenols such as quercetin, curcumin, chrysin, apigenin, and luteolin, present in many plant foods may suppress the development of cancers. However, whether these compounds inhibit the promoting effects of Nickel on cancer cell invasion and migration as well as the possible mechanisms are unclear. In the present study, we first showed that quercetin, curcumin, chrysin, apigenin, and luteolin at 5⯵M, significantly suppressed the promoting effects of NiCl2 (Ni) on migration and invasion in H1975 and A549 human lung cancer cells. The five phytochemicals also significantly suppressed the secretion of cytokines, IL-1ß, IL-6, TNF-α and IL-10, induced by Ni in A549â¯cells. The overall efficiency of quercetin was the best, followed by chrysin and the other compounds. Furthermore, we found that quercetin and chrysin suppressed the mRNA and protein expression of TLR4 and Myd88. Consistently, quercetin and chrysin also decreased the phosphorylation of IKKß and IκB, the nuclear level of p65 (NF-κB) as well as the expression of MMP-9 in A549â¯cells exposed to Ni. In conclusion, these results suggest the potential preventive effects of the five phytochemicals on the promoting effect of Ni on human lung cancer cell invasion. In addition, the preventive effects are associated with downregulation of the TLR4/NF-κB signaling pathway, especially for quercetin and chrysin.
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Regulación hacia Abajo/efectos de los fármacos , Flavonoides/farmacología , FN-kappa B/genética , Níquel , Quercetina/farmacología , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/genética , Células A549 , Antineoplásicos/farmacología , Western Blotting , Movimiento Celular/efectos de los fármacos , Humanos , Níquel/toxicidad , Reacción en Cadena de la PolimerasaRESUMEN
Resistance to tyrosine kinase inhibitors (TKIs) results in tumor relapse and poor prognosis in patients with lung adenocarcinoma. TKI resistance caused by epidermal growth factor receptor (EGFR) mutations at T790M and c-Met amplification occurs through persistent activation of the MEK/ERK and PI3K/AKT signaling pathways. We therefore expected that dual inhibitors of both signaling pathways could overcome TKI resistance in lung adenocarcinoma. Here, dioscin was selected from a product library of Chinese naturally occurring compounds and overcame TKI resistance in EGFR-mutated lung adenocarcinoma cells. Mechanistically, dioscin may down-regulate the expression of SH2 domain-containing phosphatase-2 (SHP2) at the transcription level by increasing p53 binding to the SHP2 promoter due to reactive oxygen species (ROS). Simultaneous inhibition of MEK/ERK and PI3K/AKT activation via decreased SHP2 expression and its interaction with GAB1 may be responsible for dioscin-mediated TKI sensitivity. A higher unfavorable response to TKI therapy occurred more commonly in patients with high SHP2 mRNA expression than in patients with low SHP2 mRNA expression. Therefore, we suggest that dioscin may act as a dual inhibitor of the MEK/ERK and PI3K/AKT signaling pathways to overcome TKI resistance via dysregulation of SHP2 expression in lung adenocarcinoma.
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Adenocarcinoma del Pulmón/genética , Diosgenina/análogos & derivados , Resistencia a Antineoplásicos/efectos de los fármacos , Receptores ErbB/genética , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Neoplasias Pulmonares/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adenocarcinoma del Pulmón/tratamiento farmacológico , Apoptosis/genética , Apoptosis/fisiología , Western Blotting , Línea Celular Tumoral , Inmunoprecipitación de Cromatina , Diosgenina/farmacología , Diosgenina/uso terapéutico , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Mutación/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Major blunt chest injury usually leads to the development of retained hemothorax and pneumothorax, and needs further intervention. However, since blunt chest injury may be combined with blunt head injury that typically requires patient observation for 3-4 days, other critical surgical interventions may be delayed. The purpose of this study is to analyze the outcomes of head injury patients who received early, versus delayed thoracic surgeries. MATERIALS AND METHODS: From May 2005 to February 2012, 61 patients with major blunt injuries to the chest and head were prospectively enrolled. These patients had an intracranial hemorrhage without indications of craniotomy. All the patients received video-assisted thoracoscopic surgery (VATS) due to retained hemothorax or pneumothorax. Patients were divided into two groups according to the time from trauma to operation, this being within 4 days for Group 1 and more than 4 days for Group 2. The clinical outcomes included hospital length of stay (LOS), intensive care unit (ICU) LOS, infection rates, and the time period of ventilator use and chest tube intubation. RESULT: All demographics, including age, gender, and trauma severity between the two groups showed no statistical differences. The average time from trauma to operation was 5.8 days. The ventilator usage period, the hospital and ICU length of stay were longer in Group 2 (6.77 vs. 18.55, p = 0.016; 20.63 vs. 35.13, p = 0.003; 8.97 vs. 17.65, p = 0.035). The rates of positive microbial cultures in pleural effusion collected during VATS were higher in Group 2 (6.7 vs. 29.0%, p = 0.043). The Glasgow Coma Scale score for all patients improved when patients were discharged (11.74 vs. 14.10, p < 0.05). DISCUSSION: In this study, early VATS could be performed safely in brain hemorrhage patients without indication of surgical decompression. The clinical outcomes were much better in patients receiving early intervention within 4 days after trauma.
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Traumatismos Cerrados de la Cabeza/complicaciones , Hemotórax/cirugía , Traumatismo Múltiple/complicaciones , Traumatismos Torácicos/complicaciones , Cirugía Torácica Asistida por Video , Heridas no Penetrantes/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Traumatismos Cerrados de la Cabeza/cirugía , Hemotórax/etiología , Humanos , Masculino , Persona de Mediana Edad , Traumatismo Múltiple/cirugía , Estudios Prospectivos , Traumatismos Torácicos/cirugía , Factores de Tiempo , Heridas no Penetrantes/cirugía , Adulto JovenRESUMEN
High programmed cell death 1 ligand 1 (PD-L1) expression in tumour tissues was associated with poor outcomes in non-small cell lung cancer (NSCLC) due to evasion of tumour immune surveillance. However, the role of PD-L1 in tumour invasion and resistance to tyrosine kinase inhibitor (TKI) treatments is not fully understood. Here, we provide evidence to support the involvement of PD-L1 expression in the invasiveness and TKI resistance in NSCLC cells by increased Bcl-2-associated athanogene-1 (BAG-1) expression. The upregulation of BAG-1 transcription by PD-L1 was verified by constructing the BAG-1 promoters using the polymerase chain reaction (PCR) and deletion mutations for luciferase reporter assays. The results indicated that C/EBPß phosphorylation by extracellular signal-regulated kinase (ERK) signalling was responsible for PD-L1-mediated BAG-1 transcription. Mechanistically, the PD-L1-induced BAG-1 expression reciprocally increased PD-L1 expression due to persistent activation of ERK signalling, and it consequently conferred TKI resistance in NSCLC cells. The mechanistic action of this cell model was further confirmed by an animal model, affirming that PD-L1 conferred tumour invasiveness and TKI resistance via persistent activation of ERK signalling by the PD-L1/BAG-1 axis. We therefore suggest a combination of an ERK inhibitor with a TKI as a potential strategy for conquering PD-L1-mediated tumour invasion and TKI resistance in NSCLC patients whose tumours harbour high PD-L1/high BAG-1 expression.
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Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Proteínas de Unión al ADN/metabolismo , Resistencia a Antineoplásicos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/metabolismo , Células A549 , Animales , Anticuerpos Monoclonales/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Proteína 11 Similar a Bcl2/metabolismo , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Movimiento Celular/efectos de los fármacos , Proteínas de Unión al ADN/genética , Supervivencia sin Enfermedad , Activación Enzimática , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Gefitinib , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Fosforilación , Regiones Promotoras Genéticas , Unión Proteica , Estabilidad Proteica , Interferencia de ARN , Factores de Tiempo , Factores de Transcripción/genética , Transcripción Genética , Transfección , Regulación hacia Arriba , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Proteinopathy in the heart which often manifests excessive misfolded/aggregated proteins in cardiac myocytes can result in severe fibrosis and heart failure. Here we developed a mouse model, which transgenically express tetrameric DsRed, a red fluorescent protein (RFP), in an attempt to mimic the pathological mechanisms ofcardiac fibrosis. Whilst DsRed is expressed and forms aggregation in most mouse organs, certain pathological defects are specifically recapitulated in cardiac muscle cells including mitochondria damages, aggresome-like residual bodies, excessive ubiquitinated proteins, and the induction of autophagy. The proteinopathy and cellular injuries caused by DsRed aggregates may be due to impaired or overburdened ubiquitin-proteasome system and autophagy-lysosome systems. We further identified that DsRed can be ubiquitinated and associated with MuRF1, a muscle-specific E3 ligase. Concomitantly, an activation of NF-κB signaling and a strong TIMP1 induction were noted, suggesting that RFP-induced fibrosis was augmented by a skewed balance between TIMP1 and MMPs. Taken together, our study highlights the molecular consequences of uncontrolled protein aggregation leading to congestive heart failure, and provides novel insights into fibrosis formation that can be exploited for improved therapy.
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Autofagia , Proteínas Luminiscentes/química , Miocardio/patología , Complejo de la Endopetidasa Proteasomal/metabolismo , Animales , Fibrosis , Insuficiencia Cardíaca/etiología , Ratones , Músculo Esquelético/patología , Agregado de Proteínas , Inhibidor Tisular de Metaloproteinasa-1/fisiología , Ubiquitina-Proteína Ligasas/fisiología , UbiquitinaciónRESUMEN
PURPOSE: EGFR mutation as a biomarker has documented that EGFR-mutant patients will derive clinical benefit from tyrosine kinase inhibitor (TKI) treatment. Unfortunately, most patients show TKI resistance and tumor recurrence after therapy. Therefore, we expected that an adjuvant biomarker other than EGFR mutation is needed for predicting TKI resistance. EXPERIMENTAL DESIGN: Molecular manipulations were performed to verify whether TKI resistance mediated by p21-activated kinase (PAK1) could be through increasing Mcl-1 protein stability via the PI3K/AKT/C/EBP-ß/miR-145 cascade. Xenograft mouse models were used to confirm the mechanistic action of PAK1 on TKI resistance. Forty-six tumor tissues from patients with lung adenocarcinoma who received TKI therapy were collected to evaluate PAK1 and E-cadherin mRNA expressions by real-time PCR. The association of PAK1 and E-cadherin mRNA expressions with tumor response to TKI treatment and outcomes was evaluated. RESULTS: We demonstrate that PAK1 confers TKI resistance in EGFR-mutant cells as well as in EGFR-wild-type cells. Mechanistically, the positive feedback loop of PAK1/PI3K/AKT/C/EBP-ß/miR-145 cascades persistently activates the PI3K/AKT signaling pathway to protect Mcl-1 degradation by Fbw7, which results, in turn, in TKI resistance and cell invasion via epithelial-to-mesenchymal transition due to a decrease in E-cadherin expression. The mechanism underlying the cell model is further confirmed in xenograft tumors. Among patients, high-PAK1 or low-E-cadherin tumors more commonly exhibited an unfavorable response to TKI and poorer outcome compared with low-PAK1 or low-E-cadherin tumors. CONCLUSIONS: The combination of TKI with AKT inhibitor might confer TKI sensitivity and in turn improve outcomes in patients with lung adenocarcinoma who harbored high PAK1 mRNA-expressing tumors. Clin Cancer Res; 22(21); 5370-82. ©2016 AACR.
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Adenocarcinoma/metabolismo , Receptores ErbB/metabolismo , Neoplasias Pulmonares/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Quinasas p21 Activadas/metabolismo , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma del Pulmón , Animales , Biomarcadores de Tumor/metabolismo , Cadherinas/metabolismo , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Mutación/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/metabolismo , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Genistein has been shown to enhance the antitumor activity of trichostatin A (TSA) in human lung carcinoma A549 cells. However, whether the combined treatment exerts the same effect in other lung cancer cells is unclear. In the present study we first compared the enhancing effect of genistein on the antitumor effect of TSA in ABC-1, NCI-H460 (H460) and A549 cells. Second, we investigated whether the effects of genistein are associated with increased histone/non-histone protein acetylation. We found that the enhancing effect of genistein on cell-growth-arrest in ABC-1 cells (p53 mutant) was less than in A549 and H460 cells. Genistein enhanced TSA induced apoptosis in A549 and H460 cells rather than in ABC-1 cells. After silencing p53 expression in A549 and H460 cells, the enhancing effect of genistein was diminished. In addition, genistein increased TSA-induced histone H3/H4 acetylation in A549 and H460 cells. Genistein also increased p53 acetylation in H460 cells. The inhibitor of acetyltransferase, anacardic acid, diminished the enhancing effect of genistein on all TSA-induced histone/p53 acetylation and apoptosis. Genistein in combination with TSA increased the expression of p300 protein, an acetyltransferase, in A549 and NCI-H460 cells. Furthermore, we demonstrated that genistein also enhanced the antitumor effect of genistein in A549-tumor-bearing mice. Taken together, these results suggest that the enhancing effects of genistein on TSA-induced apoptosis in lung cancer cells were p53-dependent and were associated with histone/non-histone protein acetylation.
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Apoptosis/efectos de los fármacos , Genes p53/efectos de los fármacos , Genisteína/administración & dosificación , Histona Acetiltransferasas/biosíntesis , Ácidos Hidroxámicos/administración & dosificación , Neoplasias Pulmonares/enzimología , Animales , Apoptosis/fisiología , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Genes p53/fisiología , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Ratones , Ratones Desnudos , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiología , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
BACKGROUND: Blunt chest injuries are usually combined with multiple rib fractures and severe lung contusions. This can occasionally induce acute respiratory failure and prolong ventilations. In order to reduce the periods of ventilator dependency, we propose a less invasive method of fixing multiple rib fractures. METHODS: Since October 2009, we have developed a new method to fix fractured ribs caused by blunt trauma. Rib fixations were performed using 2.0- or 2.5-mm intramedullary titanium elastic nails (TEN), with the help of video-assisted thoracoscopic surgery (VATS) and minimal thoracic incisions. All the patients' demographics and postoperative data were collected. RESULTS: From January 2010 to December 2012, a total of 65 patients presenting with multiple rib fractures resulting in acute respiratory failure were included in the study. Twelve patients received the new surgical fixation. Rib fixations were performed at an average of 4 days after trauma. Patients were successfully weaned off ventilators after an average of 3 days. The average length of stay in the hospital and the intensive care unit (ICU) was shorter for the patients with fixation than for nonsurgical patients. All twelve patients returned to normal daily activities and work. CONCLUSIONS: In the reconstruction of an injured chest wall, the VATS with TENs fixation in multiple rib fractures is feasible. This method is also effective in decreasing the length of the surgical wound. Because the structure of the chest cage is protected, the period of mechanical ventilation is shortened and the length of stay in the hospital and the ICU can be reduced.
Asunto(s)
Fijación Intramedular de Fracturas/instrumentación , Fracturas de las Costillas/cirugía , Heridas no Penetrantes/complicaciones , Femenino , Humanos , Tiempo de Internación/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Respiración Artificial , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/terapia , Fracturas de las Costillas/etiología , Cirugía Torácica Asistida por Video , Titanio , Centros Traumatológicos , Desconexión del VentiladorRESUMEN
The objective of this study was to investigate the associations among lung cancer location, and epidermal growth factor receptor (EGFR) mutation status. Treatment-naive, pathologically confirmed lung adenocarcinomas with tumor specimens available for genetic analysis were included from 2011 through 2014. Overall, 1771 patients with lung adenocarcinoma were included for analysis, after excluding those with carcinoma not otherwise specified, or synchronous multiple primary lung cancers. The median age was 64 years, and the female:male and never smoker:ever smoker ratios were 930:855 (52:48%) and 1167:604 (65:35%), respectively. The EGFR mutation rate was 56%. Among patients, 1093 (62%) had primary tumors in the upper lobes. Compared with the characteristics of the EGFR wild-type, tumors with EGFR activating mutations were more common in women (P < 0.001), never smokers (P < 0.001), and in the upper lobes (P = 0.004). Among EGFR activating mutations, compared with the EGFR exon 19 deletion, L858R mutation were more common in women (P = 0.002), never smokers (P = 0.038), and the upper lobes P < 0.0005). The present study is the first to address that different pulmonary lobar locations might harbor different EGFR mutation subtypes. We demonstrated that adenocarcinomas with L858R mutation, rather than exon 19 deletion or wild-type EGFR gene, prefer to locate over the upper lungs. This phenomenon was more significant in females and never-smokers, implying the result of complex interactions between genetic susceptibility and environmental factors. Therefore, EGFR L858R mutation and exon 19 deletion may not be identical disease entity from the point of carcinogenesis.
Asunto(s)
Adenocarcinoma/genética , Adenocarcinoma/patología , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
INTRODUCTION: Severe sepsis and septic shock are associated with substantial mortality. However, few studies have assessed the risk of septic shock among patients who suffered from urinary tract infection (UTI). MATERIALS AND METHODS: This retrospective study recruited UTI cases from an acute care hospital between January 2006 and October 2012 with prospective data collection. RESULTS: Of the 710 participants admitted for UTI, 80 patients (11.3%) had septic shock. The rate of bacteremia is 27.9%; acute kidney injury is 12.7%, and the mortality rate is 0.28%. Multivariable logistic regression analyses indicated that coronary artery disease (CAD) (OR: 2.521, 95% CI: 1.129-5.628, P = 0.024), congestive heart failure (CHF) (OR: 4.638, 95% CI: 1.908-11.273, P = 0.001), and acute kidney injury (AKI) (OR: 2.992, 95% CI: 1.610-5.561, P = 0.001) were independently associated with septic shock in patients admitted with UTI. In addition, congestive heart failure (female, OR: 4.076, 95% CI: 1.355-12.262, P = 0.012; male, OR: 5.676, 95% CI: 1.103-29.220, P = 0.038, resp.) and AKI (female, OR: 2.995, 95% CI: 1.355-6.621, P = 0.007; male, OR: 3.359, 95% CI: 1.158-9.747, P = 0.026, resp.) were significantly associated with risk of septic shock in both gender groups. CONCLUSION: This study showed that patients with a medical history of CAD or CHF have a higher risk of shock when admitted for UTI treatment. AKI, a complication of UTI, was also associated with septic shock. Therefore, prompt and aggressive management is recommended for those with higher risks to prevent subsequent treatment failure in UTI patients.
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Lesión Renal Aguda/epidemiología , Choque Séptico/epidemiología , Infecciones Urinarias/epidemiología , Lesión Renal Aguda/complicaciones , Lesión Renal Aguda/patología , Adulto , Anciano , Bacteriemia/complicaciones , Bacteriemia/epidemiología , Bacteriemia/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Choque Séptico/complicaciones , Choque Séptico/patología , Infecciones Urinarias/complicaciones , Infecciones Urinarias/patologíaRESUMEN
UNLABELLED: Chronic obstructive pulmonary disease (COPD) is a low grade systemic inflammatory disease characterized by dyspnea and exercise intolerance even under standard therapy. Rhodiola crenulata (RC) has been shown to exert anti-inflammatory effects and to enhance exercise endurance, thereby having the potential to treat COPD. In this 12-week, randomized, double-blind, placebo-controlled clinical trial, 57 patients with stable moderate-to-severe COPD aged 70±8.8 years were given RC (250 mg twice/day) (n=38) or a placebo (250 mg twice/day) (n=19) in addition to their standard regimen. There were no significant differences in anthropometrics, quality of life, lung function, six-minute walk and incremental exercise tests between the two groups at enrollment. Over the 12 weeks, RC was well tolerated, significantly reduced triceps skin thickness (Δ=-1 mm, p=.04), change of FEV1 (4.5%, p=.03), and improved workload (Δ=10%, p=.01); although there were no significant differences in these factors between the two groups. However, there were significant between-group differences in tidal volume and ventilation-CO2-output ratio at peak exercise (both p=.05), which were significantly related to peak work rate (both p<.0001). RC tended to protect against acute exacerbation of COPD (p=.1) but not other measurements. RC did not improve the six-minute walk test distance but significantly improved tidal breathing and ventilation efficiency, most likely through improvements in work rate. Further studies with a larger patient population are needed in order to confirm these findings. TRIAL REGISTRATION: ClinicalTrials.gov number NCT02242461.
Asunto(s)
Antiinflamatorios/uso terapéutico , Extractos Vegetales/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Ventilación Pulmonar/efectos de los fármacos , Rhodiola/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Método Doble Ciego , Tolerancia al Ejercicio/efectos de los fármacos , Humanos , Persona de Mediana Edad , Placebos , Extractos Vegetales/efectos adversos , Calidad de Vida , Encuestas y Cuestionarios , Volumen de Ventilación Pulmonar/efectos de los fármacos , Resultado del TratamientoRESUMEN
PURPOSE OF REVIEW: In the last decade, video-assisted thoracoscopic surgery (VATS) has become a popular method in diagnosis and treatment of acute chest injuries. Except for patients with unstable vital signs who require larger surgical incisions to check bleeding, this endoscopic surgery could be employed in the majority of thoracic injury patients with stable vital signs. RECENT FINDINGS: In the past, VATS was used to evacuate traumatic-retained hemothorax. Recent study has revealed further that lung repair during VATS could decrease complications after trauma. Management of fractured ribs could also be assisted by VATS. Early VATS intervention within 7 days after injury can decrease the rate of posttraumatic infection and length of hospital stay. In studies of the pathophysiology of animal models, N-acetylcysteine and methylene blue were used in animals with blunt chest trauma and found to improve clinical outcomes. SUMMARY: Retained hemothorax derived from blunt chest trauma should be managed carefully and rapidly. Early VATS intervention is a well tolerated and reliable procedure that can be applied to manage this complication cost effectively.