RESUMEN
BACKGROUND: Immune checkpoint inhibitors targeting PD-1 or CTLA-4 individually have shown substantial clinical benefits in the treatment of malignancies. We aimed to assess the safety and antitumour activity of cadonilimab monotherapy, a bispecific PD-1/CTLA-4 antibody, in patients with advanced solid tumours. METHODS: This multicentre, open-label, phase 1b/2 trial was conducted across 30 hospitals in China. Patients aged 18 years or older with histologically or cytologically confirmed, unresectable advanced solid tumours, unsuccessful completion of at least one previous systemic therapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients who had previously received anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment were not eligible for inclusion. In the dose escalation phase of phase 1b, patients received intravenous cadonilimab at 6 mg/kg and 10 mg/kg every 2 weeks. In the dose expansion phase of phase 1b, cadonilimab at 6 mg/kg and a fixed dose of 450âmg were given intravenously every 2 weeks. In phase 2, cadonilimab at 6 mg/kg was administered intravenously every 2 weeks in three cohorts: patients with cervical cancer, oesophageal squamous cell carcinoma, and hepatocellular carcinoma. The primary endpoints were the safety of cadonilimab in phase 1b and objective response rate in phase 2, based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The safety analysis was done in all patients who received at least one dose of cadonilimab. Antitumour activity was assessed in the full analysis set for the cervical cancer cohort, and in all patients with measurable disease at baseline and who received at least one dose of cadonilimab in the oesophageal squamous cell carcinoma and hepatocellular carcinoma cohorts. The study is registered on ClinicalTrial.gov, NCT03852251, and closed to new participants; follow-up has been completed. FINDINGS: Between Jan 18, 2019, and Jan 8, 2021, 240 patients (83 [43 male and 40 female] in phase 1b and 157 in phase 2) were enrolled. Phase 2 enrolled 111 female patients with cervical cancer, 22 patients with oesophageal squamous cell carcinoma (15 male and seven female), and 24 patients with hepatocellular carcinoma (17 male and seven female). During dose escalation, no dose-limiting toxicities occurred. Grade 3-4 treatment-related adverse events occurred in 67 (28%) of 240 patients; the most frequent grade 3 or worse treatment-related adverse events were anaemia (seven [3%]), increased lipase (four [2%]), decreased bodyweight (three [1%]), decreased appetite (four [2%]), decreased neutrophil count (three [1%]), and infusion-related reaction (two [1%]). 17 (7%) patients discontinued treatment due to treatment-related adverse events. 54 (23%) of 240 patients reported serious treatment-related adverse events, including five patients who died (one due to myocardial infarction; cause unknown for four). In phase 2, in the cervical cancer cohort, with a median follow-up of 14·6 months (IQR 13·1-17·5), the objective response rate was 32·3% (32 of 99; 95% CI 23·3-42·5). In the oesophageal squamous cell carcinoma cohort, with a median follow-up of 17·9 months (IQR 4·0-15·1), the objective response rate was 18·2% (four of 22; 95% CI 5·2-40·3). In the hepatocellular carcinoma cohort, with a median follow-up of 19·6 months (IQR 8·7-19·8), the objective response rate was 16·7% (four of 24; 95% CI 4·7-37·4). INTERPRETATION: Cadonilimab showed an encouraging tumour response rate, with a manageable safety profile, suggesting the potential of cadonilimab for the treatment of advanced solid tumours. FUNDING: Akeso Biopharma. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
Asunto(s)
Antineoplásicos Inmunológicos , Carcinoma Hepatocelular , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Neoplasias Hepáticas , Neoplasias del Cuello Uterino , Humanos , Masculino , Femenino , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Antígeno CTLA-4 , Receptor de Muerte Celular Programada 1 , Empatía , Anticuerpos Monoclonales Humanizados , Antineoplásicos Inmunológicos/efectos adversos , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/inducido químicamente , Neoplasias Hepáticas/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
OBJECTIVE: To evaluate whether the effect of radiofrequency ablation can be improved by using sacubitril/valsartan (S/V) to control blood pressure in hypertensive patients with persistent atrial fibrillation. METHODS: A total of 63 and 67 hypertension patients with persistent atrial fibrillation were enrolled in an S/V group and ACEI/ARB group, respectively. All patients underwent radiofrequency catheter ablation (RFCA). The blood pressure of the two groups was controlled within the range of 100-140 mmHg (high pressure) and 60-90 mmHg (low pressure). The clinical outcomes of the two groups were observed after 12 months of follow-up. RESULTS: No significant differences in blood pressure were observed between the S/V and ACEI/ARB groups. In addition, the recurrence rate of atrial fibrillation between the two groups was not different. The left atrial diameter was an independent predictor of recurrence (HR = 1.063, P = 0.008). However, in the heart failure subgroup, the recurrence rate of S/V was significantly lower than that of the ACEI/ARB group (P = 0.005), and Cox regression analysis showed that the recurrence risk of atrial fibrillation of the S/V group was 0.302 lower than that of the ACEI/ARB group. NT-proBNP, LVEF, and LAD were significantly improved in hypertension patients with heart failure when comparing cases before and at the end of follow-up. CONCLUSIONS: S/V is better than ACEI/ARB in reducing the recurrence of persistent atrial fibrillation in patients with hypertension and heart failure after RFCA.
RESUMEN
Fibrosis serves a critical role in driving atrial remodelling-mediated atrial fibrillation (AF). Abnormal levels of the transcription factor PU.1, a key regulator of fibrosis, are associated with cardiac injury and dysfunction following acute viral myocarditis. However, the role of PU.1 in atrial fibrosis and vulnerability to AF remain unclear. Here, an in vivo atrial fibrosis model was developed by the continuous infusion of C57 mice with subcutaneous Ang-II, while the in vitro model comprised atrial fibroblasts that were isolated and cultured. The expression of PU.1 was significantly up-regulated in the Ang-II-induced group compared with the sham/control group in vivo and in vitro. Moreover, protein expression along the TGF-ß1/Smads pathway and the proliferation and differentiation of atrial fibroblasts induced by Ang-II were significantly higher in the Ang-II-induced group than in the sham/control group. These effects were attenuated by exposure to DB1976, a PU.1 inhibitor, both in vivo and in vitro. Importantly, in vitro treatment with small interfering RNA against Smad3 (key protein of TGF-ß1/Smads signalling pathway) diminished these Ang-II-mediated effects, and the si-Smad3-mediated effects were, in turn, antagonized by the addition of a PU.1-overexpression adenoviral vector. Finally, PU.1 inhibition reduced the atrial fibrosis induced by Ang-II and attenuated vulnerability to AF, at least in part through the TGF-ß1/Smads pathway. Overall, the study implicates PU.1 as a potential therapeutic target to inhibit Ang-II-induced atrial fibrosis and vulnerability to AF.
Asunto(s)
Fibrilación Atrial/metabolismo , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteína smad3/metabolismo , Transactivadores/antagonistas & inhibidores , Factor de Crecimiento Transformador beta/metabolismo , Angiotensina II/toxicidad , Animales , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/etiología , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Células Cultivadas , Fibrosis , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BL , Miocardio/metabolismo , Miocardio/patología , Miofibroblastos/efectos de los fármacos , Miofibroblastos/metabolismo , Miofibroblastos/patología , Proteínas Proto-Oncogénicas/metabolismo , Transducción de Señal , Transactivadores/metabolismoRESUMEN
AIM: We investigated the mechanisms by which N1-(ß-d-ribofuranosyl)-5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMP-activated protein kinase (AMPK), decreases lung injury and mortality when administered to mice post exposure to bromine gas (Br2). METHODS: We exposed male C57BL/6 mice and heme oxygenase-1 (HO-1)-deficient (HO-1-/-) and corresponding wild-type (WT) littermate mice to Br2 (600â ppm for 45 or 30â min, respectively) in environmental chambers and returned them to room air. AICAR was administered 6â h post exposure (10â mg·kg-1, intraperitoneal). We assessed survival, indices of lung injury, high mobility group box 1 (HMGB1) in the plasma, HO-1 levels in lung tissues and phosphorylation of AMPK and its upstream liver kinase B1 (LKB1). Rat alveolar type II epithelial (L2) cells and human club-like epithelial (H441) cells were also exposed to Br2 (100â ppm for 10â min). After 24â h we measured apoptosis and necrosis, AMPK and LKB1 phosphorylation, and HO-1 expression. RESULTS: There was a marked downregulation of phosphorylated AMPK and LKB1 in lung tissues and in L2 and H441 cells post exposure. AICAR increased survival in C57BL/6 but not in HO-1-/- mice. In WT mice, AICAR decreased lung injury and restored phosphorylated AMPK and phosphorylated LKB1 to control levels and increased HO-1 levels in both lung tissues and cells exposed to Br2. Treatment of L2 and H441 cells with small interfering RNAs against nuclear factor erythroid 2-related factor 2 or HO-1 abrogated the protective effects of AICAR. CONCLUSIONS: Our data indicate that the primary mechanism for the protective action of AICAR in toxic gas injury is the upregulation of lung HO-1 levels.
Asunto(s)
Proteínas Quinasas Activadas por AMP , Lesión Pulmonar Aguda , Lesión Pulmonar Aguda/inducido químicamente , Aminoimidazol Carboxamida/análogos & derivados , Animales , Hemo-Oxigenasa 1/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ribonucleótidos/farmacologíaRESUMEN
In this paper, environmental friendly magnetic composite adsorbent (MSAL), exhibited excellent adsorption capacity for lead ions in the solution, was successfully prepared using two non-biologically toxic materials including L-cysteine and sodium alginate. Batch experiments were carried out to discuss the influences of different parameters like pH, adsorbent dosing, initial concentration and contact time on adsorption performance. Results showed sorption process followed by pseudo-second-order kinetic model and Langmuir isotherm model, which suggested the adsorption was limited by the chemical process dominated by the molecular layer. Based on Langmuir isotherm model, the maximum Pb(â ¡) adsorption capacity was about 330 mg/g, which was better than a large amount of other lead adsorbents. Various analytical methods, such as SEM-EDS, FTIR, VSM, TGA, XPS and Zeta potential, were applied to characterize the performance of this adsorbent as well as exploring the adsorption mechanism. Characterization results found this adsorbent exhibited a large contact area, good thermal stability, sufficient adsorption sites and excellent magnetic responsiveness. It also has been found that the adsorption mechanism mainly included ion exchange and chelation between amino, carboxyl and lead ions. After 5 cycles, the adsorption capacity decreased from 98.04% to 87.40% and still maintained at high level. The average iron ions concentration in the adsorbed solution sample or in the regeneration solution were 0.34 mg/L and 0.15 mg/L. Overall, all above results imply that MSAL is a promising reusable adsorbent for removing Pb(â ¡) in solution.
Asunto(s)
Plomo/análisis , Nanopartículas de Magnetita/química , Contaminantes Químicos del Agua/análisis , Purificación del Agua/métodos , Adsorción , Alginatos/química , Cisteína/química , Óxido Ferrosoférrico/química , Concentración de Iones de Hidrógeno , Cinética , Fenómenos Magnéticos , Propiedades de SuperficieRESUMEN
Sodium sulfide (Na2S) was used as an inducer to regulate the components of Bacillus vallismortis sp. EPS (Extracellular Polymeric Substances). The main objective of this study was to improve the content of sulfhydryl protein and the adsorption property of EPS to Zn (â ¡) that as an typical heavy metal. The results showed that the maximum EPS production of 105.58â¯mg/g VSS coupling with doubled increase in protein in which the contant of -SH increased by 48.2% from 104.15 to 154.36⯵mol/L were recorded in the presence of 20â¯mg/L Na2S. Under this condition, the adsorption capacity of S-EPS (EPS with added exogenous Na2S) for Zn (â ¡) was highest. The kinetics of the adsorption process of Zn (â ¡) by the S-EPS can be well fitted by the Langmuir isotherm model and the theoretical maximum adsorption amount of 979.09â¯mg/g EPS could be obtained. The results of 3D-EEM and FTIR analyses, illustrated that -SH, CO, and N-H/C-N played major roles in the removal of Zn (â ¡) by S-EPS. The results obtained in this study demonstrated that the addition of sulfur source could increase the content of sulfhydryl protein, and effectively regulate the content of chemical composition, expecially for the sulfhydryl of EPS, and thereby greatly improving the removal efficiency of heavy metals, which showed a great application prospect in the prevention and control of heavy metal pollution.
Asunto(s)
Bacillus/metabolismo , Contaminantes Ambientales/metabolismo , Matriz Extracelular de Sustancias Poliméricas/metabolismo , Metales Pesados/metabolismo , Sulfuros/farmacología , Adsorción , CinéticaRESUMEN
Contemporary studies have identified rs10494366 in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene as a new genetic marker in modulating the QT interval and sudden cardiac death (SCD) in general populations. However, the conclusions were not coincident. Therefore, we conducted for the first time a system evaluation of the relativity of rs10494366, the QT interval, and sudden death by meta-analysis. In our study, the meta-analysis displayed the GG genotype of rs10494366 correlated with the QT interval in women with no heterogeneity, and in diabetes mellitus (DM) patients with minor heterogeneity. In the Caucasian population, the correlation of rs10494366 and sudden death was significant. The heterogeneity referred to the relevance between rs10494366 and sudden death in the Asian population. In conclusion, the minor allele of rs10494366 may have an impact on the QT interval in women or DM patients and may have a potential role in sudden death in the Caucasian population.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Muerte Súbita Cardíaca/epidemiología , Predisposición Genética a la Enfermedad/epidemiología , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/mortalidad , Polimorfismo de Nucleótido Simple/genética , Alelos , Pueblo Asiatico/genética , China , Muerte Súbita Cardíaca/etnología , Electrocardiografía , Femenino , Genotipo , Humanos , Masculino , Análisis de SupervivenciaRESUMEN
Acid (HCl) aspiration during anesthesia may lead to acute lung injury. There is no effective therapy. We hypothesized that HCl instilled intratracheally in C57BL/6 mice results in the formation of low-molecular weight hyaluronan (L-HA), which activates RhoA and Rho kinase (ROCK), causing airway hyperresponsiveness (AHR) and increased permeability. Furthermore, instillation of high-molecular weight hyaluronan (H-HA; Yabro) will reverse lung injury. We instilled HCl in C57BL/6 wild-type (WT), myeloperoxidase gene-deficient (MPO-/-) mice, and CD44 gene-deficient (CD44-/-) mice. WT mice were also instilled intranasally with H-HA (Yabro) at 1 and 23 h post-HCl. All measurements were performed at 1, 5, or 24 h post-HCl. Instillation of HCl in WT but not in CD44-/- resulted in increased inflammation, AHR, lung injury, and L-HA in the bronchoalveolar lavage fluid (BALF) 24 h post-HCl; L-HA levels and lung injury were significantly lower in HCl-instilled MPO-/- mice. Isolated perfused lungs of HCl instilled WT but not of CD44-/- mice had elevated values of the filtration coefficient ( Kf). Addition of L-HA on the apical surface of human primary bronchial epithelial cell monolayer decreased barrier resistance ( RT). H-HA significantly mitigated inflammation, AHR, and pulmonary vascular leakage at 24 h after HCl instillation and mitigated the increase of Kf and RT, as well as ROCK2 phosphorylation. Increased H- and L-HA levels were found in the BALF of mechanically ventilated patients but not in healthy volunteers. HCl instillation-induced lung injury is mediated by the L-HA-CD44-RhoA-ROCK2 signaling pathway, and H-HA is a potential novel therapeutic agent for acid aspiration-induced lung injury.
Asunto(s)
Lesión Pulmonar Aguda/tratamiento farmacológico , Barrera Alveolocapilar/efectos de los fármacos , Receptores de Hialuranos/fisiología , Ácido Hialurónico/farmacología , Ácido Clorhídrico/toxicidad , Peroxidasa/fisiología , Neumonía/tratamiento farmacológico , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Animales , Barrera Alveolocapilar/metabolismo , Barrera Alveolocapilar/patología , Líquido del Lavado Bronquioalveolar/química , Células Cultivadas , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neumonía/inducido químicamente , Neumonía/metabolismo , Neumonía/patología , Intercambio Gaseoso Pulmonar , Viscosuplementos/farmacologíaRESUMEN
Bacillus vallismortis (B. vallismortis), an aerobic heterotrophic bacteria, was screened in a laboratory pilot study, to assess the interaction between the heavy metal Zn(II) and extracellular polymeric substances (EPS). The influence of Zn(II) stress on EPS production, component variation, and sorption performance, was investigated. The characteristics of B. vallismortis EPS formed under stress were analyzed using FTIR, 3D-EEM and XPS. EPS was used as an adsorbent and the adsorption capacity and adsorption behavior of EPS formed with and without Zn(II) stress, were compared and assessed. Results showed that the production of polysaccharides and proteins, the main components of EPS, were promoted under Zn(II) stress. The types of EPS functional groups observed remained the same with and without heavy metal stress, but their concentrations were increased. Due to stress-induction, the adsorption capacity of Zn-EPS was significantly enhanced compared with the control-EPS. Specific EPS produced by B. vallismortis in the presence of Zn(II) stress, could have a wide range of potential applications, allowing optimization and improvement of the capacity of EPS to remove heavy metals from effluent.
Asunto(s)
Bacillus/metabolismo , Proteínas Bacterianas/biosíntesis , Polisacáridos Bacterianos/biosíntesis , Estrés Fisiológico/efectos de los fármacos , Zinc/farmacologíaRESUMEN
Primary cilia (PC) are solitary cellular organelles that play critical roles in development, homeostasis, and disease pathogenesis by modulating key signaling pathways such as Sonic Hedgehog and calcium flux. The antenna-like shape of PC enables them also to facilitate sensing of extracellular and mechanical stimuli into the cell, and a critical role for PC has been described for mesenchymal cells such as chondrocytes. However, nothing is known about the role of PC in airway smooth muscle cells (ASMCs) in the context of airway remodeling. We hypothesized that PC on ASMCs mediate cell contraction and are thus integral in the remodeling process. We found that PC are expressed on ASMCs in asthmatic lungs. Using pharmacological and genetic methods, we demonstrated that PC are necessary for ASMC contraction in a collagen gel three-dimensional model both in the absence of external stimulus and in response to the extracellular component hyaluronan. Mechanistically, we demonstrate that the effect of PC on ASMC contraction is, to a small extent, due to their effect on Sonic Hedgehog signaling and, to a larger extent, due to their effect on calcium influx and membrane depolarization. In conclusion, PC are necessary for the development of airway remodeling by mediating calcium flux and Sonic Hedgehog signaling.
Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias)/fisiología , Bronquios/patología , Cilios/patología , Asma/metabolismo , Asma/patología , Bronquios/metabolismo , Membrana Celular/metabolismo , Membrana Celular/patología , Células Cultivadas , Cilios/metabolismo , Células HEK293 , Proteínas Hedgehog/metabolismo , Humanos , Potenciales de la Membrana/fisiología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Transducción de Señal/fisiologíaRESUMEN
Acute ozone (O3) inhalation has been shown to cause airway and pulmonary epithelial injury with accompanying inflammation responses. Robust evidence exists that O3 induces airway hyperresponsiveness (AHR) in humans and in animal models. Several pathways exist that culminate in airway smooth muscle contraction, but the mechanism(s) by which O3 elicits AHR are unclear. Here, we review the recent report by Kasahara et al. (Kasahara DI, Mathews JA, Park CY, Cho Y, Hunt G, Wurmbrand AP, Liao JK, Shore SA. Am J Physiol Lung Cell Mol Physiol 309: L736-L746, 2015.) describing the role of two Rho kinase (ROCK) isoforms in O3-induced AHR utilizing a murine haploinsufficiency model. Compared with wild-type (WT) mice, the authors report that ROCK1(+/-) and ROCK2(+/-) mice exhibited significantly reduced AHR following acute exposure to O3. Additionally, WT mice treated with fasudil, an FDA-approved ROCK1/2 inhibitor, recapitulated reduction in AHR as seen in ROCK haplotypes. It was suggested that, although the two ROCK isoforms are both induced by Rho, they have different mechanisms by which they mediate O3-induced AHR: ROCK1 via hyaluronan signaling vs. ROCK2 acting downstream of inflammation at the level of airway smooth muscle contraction. These observations provide an important framework to develop novel ROCK-targeting therapies for acute O3-induced AHR.
Asunto(s)
Ozono/efectos adversos , Isoformas de Proteínas/metabolismo , Hipersensibilidad Respiratoria/inducido químicamente , Hipersensibilidad Respiratoria/metabolismo , Quinasas Asociadas a rho/metabolismo , Animales , Hiperreactividad Bronquial/inducido químicamente , Hiperreactividad Bronquial/metabolismo , Humanos , Pulmón/efectos de los fármacos , Pulmón/metabolismoRESUMEN
Exposure to chlorine (Cl2) damages airway and alveolar epithelia resulting in acute lung injury and reactive airway hyperresponsiveness (AHR) to methacholine. However, little is known about the effect of preexisting respiratory disease on Cl2-induced lung injury. By using a murine respiratory syncytial virus (RSV) infection model, we found that preexisting RSV infection increases Cl2 (187 ppm for 30 min)-induced lung inflammation and airway AHR at 24 h after exposure (5 days after infection). RSV infection and Cl2 exposure synergistically induced oxygen desaturation and neutrophil infiltration and increased MCP-1, MIP-1ß, IL-10, IFN-γ, and RANTES concentrations in the bronchoalveolar lavage fluid (BALF). In contrast, levels of type 2 cytokines (i.e., IL-4, IL-5, IL-9, and IL-13) were not significantly affected by either RSV infection or Cl2 exposure. Cl2 exposure, but not RSV infection, induced AHR to methacholine challenge as measured by flexiVent. Moreover, preexisting RSV infection amplified BALF levels of hyaluronan (HA) and AHR. The Cl2-induced AHR was mitigated by treatment with inter-α-trypsin inhibitor antibody, which inhibits HA signaling, suggesting a mechanism of HA-mediated AHR from exacerbated oxidative injury. Our results show for the first time that preexisting RSV infection predisposes the lung to Cl2-induced injury. These data emphasize the necessity for further research on the effects of Cl2 in vulnerable populations and the development of appropriate treatments.
Asunto(s)
Lesión Pulmonar Aguda/inducido químicamente , Contaminantes Atmosféricos/toxicidad , Cloro/toxicidad , Hipersensibilidad Respiratoria/inducido químicamente , Infecciones por Virus Sincitial Respiratorio/inmunología , Lesión Pulmonar Aguda/inmunología , Lesión Pulmonar Aguda/virología , Animales , Quimiocinas/metabolismo , Ácido Hialurónico/metabolismo , Masculino , Ratones Endogámicos BALB C , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/virología , Virus Sincitiales RespiratoriosRESUMEN
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal primary tumors in humans, with undetermined tumorigenesis. Although previous work by us, and by others, has clearly demonstrated an involvement of miR-21 in the growth of PDAC, the underlying mechanism has not been clarified. METHODS: Here we analyzed the regulation of FoxO1 by miR-21 in vitro and in vivo, using luciferase-reporter assay and pancreatic intraductal infusion of antisense of miR-21, respectively. RESULTS: We found that overexpression of miR-21 in PDAC cells decreased FoxO1 protein levels, whereas inhibition of miR-21 increased FoxO1 levels. Further, miR-21 bound to FoxO1 mRNA to prevent its translation through its 3'UTR. Moreover, administration of antisense of miR-21 through an intraductal infusion system significantly decreased miR-21 levels and increased FoxO1 levels in implanted PDAC, resulting in a significant decrease in PDAC growth. CONCLUSION: Taken together, our data highlight miR-21/FoxO1 axis as a novel therapeutic target for inhibiting the growth of PDAC.
Asunto(s)
Carcinoma Ductal Pancreático/diagnóstico por imagen , Factores de Transcripción Forkhead/metabolismo , Regulación Neoplásica de la Expresión Génica , MicroARNs/metabolismo , Neoplasias Pancreáticas/diagnóstico por imagen , Regiones no Traducidas 3' , Animales , Secuencia de Bases , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Proliferación Celular , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/química , Factores de Transcripción Forkhead/genética , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , MicroARNs/antagonistas & inhibidores , Oligonucleótidos Antisentido/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Radiografía , Alineación de Secuencia , Transfección , Trasplante Heterólogo , Neoplasias PancreáticasRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant primary tumors in humans, with extremely high lethality. Although great efforts have been made to understand the molecular regulation of the tumorigenesis of PDAC, our current knowledge remains very limited. Previous work has shown a possible involvement of miR-21 in the growth of PDAC, whereas the underlying mechanism has not been clarified. Here, we show significant higher levels of miR-21 in PDAC, compared to the adjacent normal pancreatic tissue. Moreover, overexpression of miR-21 in PDAC cells increased cell growth, whereas inhibition of miR-21 decreased cell growth. Furthermore, miR-21 was found to inhibit nuclear retention of FoxO1 to augment the growth of PDAC cells. Thus, miR-21/FoxO1 axis appears to be a novel therapeutic target for inhibiting the growth of PDAC.
Asunto(s)
Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Factores de Transcripción Forkhead/biosíntesis , MicroARNs/biosíntesis , Adenocarcinoma/patología , Carcinogénesis/genética , Carcinoma Ductal Pancreático/patología , Proliferación Celular/genética , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/genética , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genéticaRESUMEN
The relative efficacy and safety of first-line metastatic colorectal cancer (mCRC) treatment regimens, capecitabine with irinotecan (CAPIRI) and 5-fluorouracil/leucovorin plus irinotecan (FOLFIRI), are not well defined. We identified and subsequently examined seven independent, randomized controlled clinical trials, performing a meta-analysis to compare these two treatment regimens. Using Medline, EMBASE, Cochrane Library (CENTRAL), and the American Society of Clinical Oncology Annual Meeting to search available literature until February 2014, we identified seven studies comparing safety and efficacy of CAPIRI and FOLFIRI in mCRC patients. These studies were pooled and evaluated for rates of progression-free survival (PFS), objective response rate (ORR), overall survival (OS), and diarrhea. CAPIRI and FOLFIRI demonstrated similar efficacy outcomes, though CAPIRI was associated with a higher incidence of diarrhea. CAPIRI and FOLFIRI are equally effective options for first-line treatment of mCRC.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Capecitabina , Neoplasias Colorrectales/patología , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Irinotecán , Leucovorina/administración & dosificación , Metástasis de la Neoplasia , Sesgo de PublicaciónRESUMEN
The treatment of acute lung injury caused by exposure to reactive chemicals remains challenging because of the lack of mechanism-based therapeutic approaches. Recent studies have shown that transient receptor potential vanilloid 4 (TRPV4), an ion channel expressed in pulmonary tissues, is a crucial mediator of pressure-induced damage associated with ventilator-induced lung injury, heart failure, and infarction. Here, we examined the effects of two novel TRPV4 inhibitors in mice exposed to hydrochloric acid, mimicking acid exposure and acid aspiration injury, and to chlorine gas, a severe chemical threat with frequent exposures in domestic and occupational environments and in transportation accidents. Postexposure treatment with a TRPV4 inhibitor suppressed acid-induced pulmonary inflammation by diminishing neutrophils, macrophages, and associated chemokines and cytokines, while improving tissue pathology. These effects were recapitulated in TRPV4-deficient mice. TRPV4 inhibitors had similar anti-inflammatory effects in chlorine-exposed mice and inhibited vascular leakage, airway hyperreactivity, and increase in elastance, while improving blood oxygen saturation. In both models of lung injury we detected increased concentrations of N-acylamides, a class of endogenous TRP channel agonists. Taken together, we demonstrate that TRPV4 inhibitors are potent and efficacious countermeasures against severe chemical exposures, acting against exaggerated inflammatory responses, and protecting tissue barriers and cardiovascular function.
Asunto(s)
Lesión Pulmonar Aguda/inducido químicamente , Canales Catiónicos TRPV/antagonistas & inhibidores , Lesión Pulmonar Aguda/tratamiento farmacológico , Animales , Antiinflamatorios/farmacología , Líquido del Lavado Bronquioalveolar/química , Cloro/toxicidad , Células HEK293 , Humanos , Ácido Clorhídrico/toxicidad , Masculino , Ratones , Neumonía/tratamiento farmacológico , Ratas , Canales Catiónicos TRPV/agonistas , Canales Catiónicos TRPV/deficienciaRESUMEN
A versatile nickel catalyst allowed for C-H alkylations of unactivated arenes with challenging secondary alkyl bromides and chlorides. The high catalytic efficacy also set the stage for direct secondary alkylations of indoles as well as C-H trifluoroethylations with ample substrate scope.
RESUMEN
BACKGROUND: ADP-glucose pyrophosphorylase (AGPase) is the key rate-limiting enzyme in starch biosynthesis pathway, and has been identified as a potential target for manipulation strategies aimed at improving crop yield and quality. OBJECTIVE: To identify the AGPase gene family members in soybean, and explore the potential implications of GmAGPS2 in drought stress tolerance. METHODS: The genome-wide identification and sequence analysis of soybean AGPase gene family was carried out by bioinformatics methods. The GmAGP gene expression was analyzed using transcriptome data and quantitative real-time PCR (qRT-PCR). Furthermore, transgenic yeast strains overexpressing GmAGPS2 were generated, and their growth was observed under drought stress. RESULTS: In this study, we searched for AGPase genes (GmAGP) in the soybean genome and identified a total of 14 GmAGP genes. The GmAGP proteins had a unique conserved NTP_transferase domain and were mainly located in the chloroplast and cytosol. Evolutionarily, the GmAGP proteins can be clustered into two distinct subgroups; within the same subgroup, they displayed a similar distribution pattern of conserved motifs. The GmAGP genes exhibited an uneven distribution on 10 chromosomes, and segmental duplication contributed to AGPase gene family expansion in soybean. The GmAGP genes presented different tissue expression pattern, in which GmAGPL6, GmAGPL9, and GmAGPL10 mainly exhibited tissue-specific expression pattern. The promoter of GmAGP genes had multiple cis-acting elements related to phytohormones and stress responses, and 8 GmAGP genes contained drought-responsive cis-acting elements. qRTâPCR analysis demonstrated a significant upregulation expression of GmAGPL6, GmAGPL10, and GmAGPS2 in response to drought stress. Further functional analysis indicated that GmAGPS2 gene could improve yeast growth under drought stress conditions and enhance the drought tolerance of yeast. CONCLUSION: These results will contribute to further elucidation of the function of GmAGP genes, and offer important candidate genes for the genetic improvement of starch and yield-related traits and the breeding of high drought stress tolerance varieties in soybean.
RESUMEN
Myocardial infarction (MI) is an extremely severe cardiovascular disease, which ranks as the leading cause of sudden death worldwide. Studies have proved that cardiac injury following MI can cause cardiomyocyte apoptosis and myocardial fibrosis. Bilobalide (Bilo) from Ginkgo biloba leaves have been widely reported to possess excellent cardioprotective effects. However, concrete roles of Bilo in MI have not been investigated yet. We here designed both in vitro and in vivo experiments to explore the effects of Bilo on MI-induced cardiac injury and the underlying mechanisms of its action. We conducted in vitro experiments using oxygen-glucose deprivation (OGD)-treated H9c2 cells. Cell apoptosis in H9c2 cells was assessed by conducting flow cytometry assay and evaluating apoptosis-related proteins with western blotting. MI mouse model was established by performing left anterior descending artery (LAD) ligation. Cardiac function of MI mice was determined by assessing ejection fraction (EF), fractional shortening (FS), left ventricular end-systolic diameter (LVESD), and left ventricular end-diastolic diameter (LVEDD). Histological changes were analyzed, infarct size and myocardial fibrosis were measured by hematoxylin and eosin (H&E) and Masson staining in cardiac tissues from the mice. The apoptosis of cardiomyocytes in MI mice was assessed by TUNEL staining. Western blotting was applied to detect the effect of Bilo on c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinases (p38 MAPK) signaling both in vitro and in vivo. Bilo inhibited OGD-induced cell apoptosis and lactate dehydrogenase (LDH) release in H9c2 cells. The protein levels of p-JNK and p-p38 were significantly downregulated by Bilo treatment. SB20358 (inhibitor of p38) and SP600125 (inhibitor of JNK) suppressed OGD-induced cell apoptosis as Bilo did. In MI mouse model, Bilo improved the cardiac function and significantly reduced the infarct size and myocardial fibrosis. Bilo inhibited MI-induced cardiomyocytes apoptosis in mice. Bilo suppressed the protein levels of p-JNK and p-p38 in cardiac tissues from MI mice. Bilo alleviated OGD-induced cell apoptosis in H9c2 cells and suppressed MI-induced cardiomyocyte apoptosis and myocardial fibrosis in mice via the inactivation of JNK/p38 MAPK signaling pathways. Thus, Bilo may be an effective anti-MI agent.
Asunto(s)
Bilobálidos , Infarto del Miocardio , Ratones , Animales , Bilobálidos/farmacología , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/farmacología , Apoptosis , FibrosisRESUMEN
In this study, we investigated the adsorption of Cd(II) and the biosynthesis of CdS quantum dots (QDs) mediated by cells of sulfate-reducing bacteria before and after the removal of EPS to determine whether EPS or the cell wall plays a major role. Potentiometric titration revealed that the concentration of proton-active binding sites on cells with EPS (EPS-intact) was notably higher than that on cells without EPS (EPS-free) and that the sites were predominantly carboxyl, phosphoryl, hydroxyl, and amine groups. The protein content in EPS-intact cells was higher, and thus the Cd(II) adsorption capacity was stronger. The CdS QDs biosynthesized using EPS-intact possessed better properties, including uniform size distribution, good crystallinity, small particle size, high fluorescence, and strong antimicrobial activity, and the yields were significantly higher than those of EPS-free by a factor of about 1.5-3.7. Further studies revealed that alkaline amino acids in EPS play a major role and serve as templates in the biosynthesis of QDs, whereas they were rarely detected in the cell wall. This study emphasizes the important role of EPS in the bacterial binding of metals and efficient recycling of hazardous waste in water.