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BACKGROUND: There are limited real-world data to guide the sequencing of targeted therapies in patients with metastatic renal cell carcinoma (mRCC). The objective of this study was to characterize real-world treatment patterns (primarily second line [2L]) after prior vascular endothelial growth factor (VEGF) targeted therapy in an unselected mRCC population from Taiwan between 2013 and 2017. Treatment-related adverse events (TRAEs) and their management were also evaluated (NCT03633579). METHODS: This retrospective cohort study included patients who had received prior VEGF-targeted therapy and were treated at the National Taiwan University Hospital or the Taipei Veterans General Hospital between June 2013 and December 2017. Outcomes were characterized using descriptive statistics. RESULTS: Overall, 27 patients were included: 22 (81.5%) male; mean standard deviation (SD) age, 63.1 (11.1) years; 18 (66.7%) initiated targeted therapy during the year immediately following mRCC diagnosis. All patients received sunitinib as their first-line (1L) targeted therapy, with a median (range) treatment duration of 10 (1.8-65.8) months. The most common reason for discontinuing 1L sunitinib was disease progression (88.9% of patients). Everolimus was the most common 2L targeted therapy, in 23 patients (85.2%); 4 patients (14.8%) received 2L axitinib. Median (range) duration of 2L therapy was 4.0 (0.1-30.5) months for everolimus and 4.2 (0.5-9.2) months for axitinib. Ten TRAEs were reported among seven patients receiving 2L everolimus: hypertension (n = 5), hand-foot syndrome (n = 2), hyperglycemia (n = 1), renal failure (n = 1), and interstitial pneumonitis (n = 1). The majority (80%) of TRAEs were managed in the outpatient setting. No TRAEs were reported in the axitinib group. CONCLUSION: Real-world management of patients with mRCC in Taiwan broadly aligned with clinical guidelines and national reimbursement policy at the time of the study. These findings may be a useful reference for assessing the implications of evolving mRCC management approaches in Taiwan.
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Antineoplásicos , Carcinoma de Células Renales , Neoplasias Renales , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Taiwán , Resultado del Tratamiento , Factor A de Crecimiento Endotelial VascularRESUMEN
BACKGROUND: Limited brain metastasis is treated definitively with stereotactic radiosurgery when surgical resection is not indicated. Although this has historically been performed in a single fraction, multi-fraction approaches such as fraction radiosurgery (FSRS) and staged radiosurgery (SSRS) have been recently examined as alternative approaches for larger lesions to permit better tumor control without increased toxicity. CASE REPORT: We present the case of a patient who developed symptomatic radionecrosis in two brain metastasis, 2.3 cm and 2.1 cm in size, which were treated with 18 Gy in one fraction, but no radionecrosis in a 3.3 cm lesion treated in two fractions of 15 Gy nor in two punctate lesions that were treated in one fraction of 20 Gy. Although she did not respond to steroids, she responded to bevacizumab symptomatically and on neuroimaging. CONCLUSION: Congruent with other recent studies, our report suggests that large brain metastasis should be considered for FSRS/SSRS.
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Neoplasias Encefálicas/radioterapia , Encéfalo/efectos de la radiación , Fraccionamiento de la Dosis de Radiación , Radiocirugia/métodos , Adulto , Antineoplásicos Inmunológicos/uso terapéutico , Bevacizumab/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/patología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/secundario , Femenino , Humanos , Necrosis/radioterapia , Resultado del TratamientoAsunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Necrosis/etiología , Recurrencia Local de Neoplasia/complicaciones , Tomografía de Emisión de Positrones/métodos , Traumatismos por Radiación/etiología , Radiocirugia/métodos , Anciano , Neoplasias Encefálicas/secundario , Femenino , HumanosRESUMEN
Introduction Stereotactic radiosurgery (SRS) is effective and safe for the treatment of the vast majority of brain metastases (BMs). SRS is increasingly used for the simultaneous treatment of multiple lesions, retreatment of recurrence, or subsequent treatment of new lesions. Although radiation injury is relatively uncommon, with the increased utilization of SRS, it is imperative to develop approaches to assess and mitigate radiation-induced neurologic toxicity. Multiple factors influence the development of radiation injury, including patient age, genomic variations, prior treatment, dose and volume treated, and anatomic location. Functional neural structure proximity to SRS targets is a critical factor in developing a systematic integrated risk assessment for SRS patients. Methods We developed an approach for risk assessment based on the combinatorial application of i) the anatomic localization of target lesions using a reference neuroanatomical/functional imaging atlas merged with patient-specific imaging and ii) validation with functional MRI (fMRI) and diffusion tensor imaging MRI (DTI-MRI) to identify neural tracts. Results In the case of a thalamic/midbrain junction breast carcinoma metastasis, the reference image analysis revealed proximity to the corticospinal tract (CST), which was validated by functional DTI-MRI. Dose-volume exposure of the CST could be estimated and considered in the development of a final treatment plan. Conclusion Merging pretreatment MR imaging with neuroanatomical/functional reference MRIs and subsequent validation with fMRI or DTI-MRI may prove to be a valuable approach to screen for neural risks in individual SRS patients. Incorporating this approach in larger studies could further our understanding of dose tolerances in a broad range of neural structures.
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Neoplasias de la Mama/patología , Dolor de la Región Lumbar/terapia , Región Lumbosacra , Cuidados Paliativos/métodos , Neoplasias de la Columna Vertebral/radioterapia , Analgésicos Opioides/uso terapéutico , Neoplasias de la Mama/terapia , Quimioterapia Adyuvante/métodos , Femenino , Humanos , Dolor de la Región Lumbar/etiología , Escisión del Ganglio Linfático , Imagen por Resonancia Magnética , Mastectomía , Persona de Mediana Edad , Neoplasias de la Columna Vertebral/complicaciones , Neoplasias de la Columna Vertebral/diagnóstico por imagen , Neoplasias de la Columna Vertebral/secundario , Resultado del TratamientoRESUMEN
This corrects the article DOI: 10.1038/ncomms11947.
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OBJECTIVE: Bovine endometritis is one of the most common reproductive disorders in cattle. The aim of this study was to investigate the anti-inflammation potential of punicalagin in lipopolysaccharide (LPS)-induced bovine endometrial epithelial cells (bEECs) and to uncover the underlying mechanisms. METHODS: bEECs were stimulated with different concentrations (1, 10, 30, 50, and 100 µg/ml) of LPS for 3, 6, 9, 12, and 18 h. MTT assay was used to assess cell viability and to identify the conditions for inflammatory injury and effective concentrations of punicalagin. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to assess gene expression of pro-inflammatory cytokines. Western blotting was used to assess levels of inflammation-related proteins. RESULTS: Treatment of bEECs with 30 µg/ml LPS for 12 h induced cell injury and reduced cell viability. Punicalagin (5, 10, or 20 µg/ml) pretreatment significantly decreased LPS-induced productions of interleukin (IL)-1ß, IL-6, IL-8, and tumor necrosis factor-α (TNF-α) in bEECs. Molecular research showed that punicalagin inhibited the activation of the upstream mediator nuclear factor-κB (NF-κB) by suppressing the production of inhibitor κBα (IκBα) and phosphorylation of p65. Results also indicated that punicalagin can suppress the phosphorylation of mitogen-activated protein kinases (MAPKs) including p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK). CONCLUSIONS: Punicalagin may attenuate LPS-induced inflammatory injury and provide a potential option for the treatment of dairy cows with Escherichia coli endometritis.
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Enfermedades de los Bovinos/prevención & control , Endometritis/veterinaria , Endometrio/efectos de los fármacos , Taninos Hidrolizables/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacología , Bovinos , Enfermedades de los Bovinos/metabolismo , Enfermedades de los Bovinos/patología , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Citocinas/biosíntesis , Endometritis/patología , Endometritis/prevención & control , Endometrio/metabolismo , Endometrio/patología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Femenino , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/toxicidad , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , FN-kappa B/metabolismoRESUMEN
Blood pressure is maintained within a normal physiological range by a sophisticated regulatory mechanism. Baroreceptors serve as a frontline sensor to detect the change in blood pressure. Nerve signals are then sent to the cardiovascular control centre in the brain in order to stimulate baroreflex responses. Here, we identify TRPC5 channels as a mechanical sensor in aortic baroreceptors. In Trpc5 knockout mice, the pressure-induced action potential firings in the afferent nerve and the baroreflex-mediated heart rate reduction are attenuated. Telemetric measurements of blood pressure demonstrate that Trpc5 knockout mice display severe daily blood pressure fluctuation. Our results suggest that TRPC5 channels represent a key pressure transducer in the baroreceptors and play an important role in maintaining blood pressure stability. Because baroreceptor dysfunction contributes to a variety of cardiovascular diseases including hypertension, heart failure and myocardial infarction, our findings may have important future clinical implications.
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Aorta/fisiología , Presión Sanguínea/fisiología , Presorreceptores/metabolismo , Canales Catiónicos TRPC/metabolismo , Animales , Frecuencia Cardíaca/fisiología , Activación del Canal Iónico , Masculino , Mecanotransducción Celular , Ratones Noqueados , Neuronas/metabolismo , Concentración Osmolar , Ratas Sprague-Dawley , Estrés MecánicoRESUMEN
BACKGROUND: Alpinia oxyphylla is a common remedy in traditional Chinese medicine. Yakuchinone A is a major constituent of A. oxyphylla and exhibits anti-inflammatory, antitumor, antibacterial, and gastric protective activities. METHODS: Antioxidant and antitumor characteristics of yakuchinone A in skin cancer cells as well as novel mechanisms for the inhibition of adipocyte differentiation, cestocidal activities against Hymenolepis nana adults, and nematocidal activities against Anisakis simplex larvae are investigated. RESULTS: Yakuchinone A presents the ability of the removal of DPPH·and ABTS+ free radicals and inhibition of lipid peroxidation. Yakuchinone A suppresses intracellular lipid accumulation during adipocyte differentiation in 3 T3-L1 cells and the expressions of leptin and peroxisome proliferator-activated receptor γ (PPARγ). Yakuchinone A induces apoptosis and inhibits cell proliferation in skin cancer cells. The inhibition of cell growth by yakuchinone A is more significant for non-melanoma skin cancer (NMSC) cells than for melanoma (A375 and B16) and noncancerous (HaCaT and BNLCL2) cells. Treatment BCC cells with yakuchinone A shows down-regulation of Bcl-2, up-regulation of Bax, and an increase in cleavage poly (ADP-ribose) polymerase (PARP). This suggests that yakuchinone A induces BCC cells apoptosis through the Bcl-2-mediated signaling pathway. The anthelmintic activities of yakuchinone A for A. simplex are better than for H. nana. CONCLUSIONS: In this work, yakuchinone A exhibits antioxidative properties, anti-adipocyte differentiation, antitumor activity, and anthelmintic activities against A. simplex and H. nana.
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Alpinia/química , Antihelmínticos/farmacología , Antioxidantes/farmacología , Diferenciación Celular/efectos de los fármacos , Guayacol/análogos & derivados , Adipocitos/citología , Adipocitos/efectos de los fármacos , Adipogénesis/efectos de los fármacos , Animales , Anisakis/efectos de los fármacos , Antihelmínticos/química , Antioxidantes/química , Apoptosis/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Guayacol/química , Guayacol/farmacología , Humanos , Hymenolepis nana/efectos de los fármacos , Larva/efectos de los fármacos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
Understanding molecular determinants of protein mechanical stability is important not only for elucidating how elastomeric proteins are designed and functioning in biological systems but also for designing protein building blocks with defined nanomechanical properties for constructing novel biomaterials. GB1 is a small α/ß protein and exhibits significant mechanical stability. It is thought that the shear topology of GB1 plays an important role in determining its mechanical stability. Here, we combine single molecule atomic force microscopy and protein engineering techniques to investigate the effect of side chain reduction and hydrophobic core packing on the mechanical stability of GB1. We engineered seven point mutants and carried out mechanical φ-value analysis of the mechanical unfolding of GB1. We found that three mutations, which are across the surfaces of two subdomains that are to be sheared by the applied stretching force, in the hydrophobic core (F30L, Y45L, and F52L) result in significant decrease in mechanical unfolding force of GB1. The mechanical unfolding force of these mutants drop by 50-90 pN compared with wild-type GB1, which unfolds at around 180 pN at a pulling speed of 400 nm/s. These results indicate that hydrophobic core packing plays an important role in determining the mechanical stability of GB1 and suggest that optimizing hydrophobic interactions across the surfaces that are to be sheared will likely be an efficient method to enhance the mechanical stability of GB1 and GB1 homologues.
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Proteínas Bacterianas/química , Interacciones Hidrofóbicas e Hidrofílicas , Microscopía de Fuerza Atómica , Proteínas Bacterianas/genética , Fenómenos Biomecánicos , Fenómenos Mecánicos , Modelos Moleculares , Mutagénesis Sitio-Dirigida , Mutación Puntual , Conformación Proteica , Estabilidad Proteica , Desplegamiento ProteicoRESUMEN
Synthetic/artificial protein switches provide an efficient means of controlling protein functions using chemical signals and stimuli. Mutually exclusive proteins, in which only the host or guest domain can remain folded at a given time owing to conformational strain, have been used to engineer novel protein switches that can switch enzymatic functions on and off in response to ligand binding. To further explore the potential of mutually exclusive proteins as protein switches and sensors, we report here a new redox-based approach to engineer a mutually exclusive folding-based protein switch. By introducing a disulfide bond into the host domain of a mutually exclusive protein, we demonstrate that it is feasible to use redox potential to switch the host domain between its folded and unfolded conformations via the mutually exclusive folding mechanism, and thus switching the functionality of the host domain on and off. Our study opens a new and potentially general avenue that uses mutually exclusive proteins to design novel switches able to control the function of a variety of proteins.
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Disulfuros/química , Ingeniería de Proteínas , Pliegue de Proteína , Proteínas/química , Proteínas/genética , Secuencia de Aminoácidos , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Conectina , Humanos , Inmunoglobulina G/metabolismo , Modelos Moleculares , Datos de Secuencia Molecular , Proteínas Musculares/química , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Mutación , Oxidación-Reducción , Conformación Proteica , Proteínas Quinasas/química , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Estabilidad Proteica , Estructura Terciaria de Proteína , Proteínas/metabolismo , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Streptococcus/química , Streptococcus/genética , Streptococcus/metabolismo , TermodinámicaRESUMEN
Configurational entropy plays important roles in defining the thermodynamic stability as well as the folding/unfolding kinetics of proteins. Here we combine single-molecule atomic force microscopy and protein engineering techniques to directly examine the role of configurational entropy in the mechanical unfolding kinetics and mechanical stability of proteins. We used a small protein, GB1, as a model system and constructed four mutants that elongate loop 2 of GB1 by 2, 5, 24 and 46 flexible residues, respectively. These loop elongation mutants fold properly as determined by far-UV circular dichroism spectroscopy, suggesting that loop 2 is well tolerant of loop insertions without affecting GB1's native structure. Our single-molecule atomic force microscopy results reveal that loop elongation decreases the mechanical stability of GB1 and accelerates the mechanical unfolding kinetics. These results can be explained by the loss of configurational entropy upon closing an unstructured flexible loop using classical polymer theory, highlighting the important role of loop regions in the mechanical unfolding of proteins. This study not only demonstrates a general approach to investigating the structural deformation of the loop regions in mechanical unfolding transition state, but also provides the foundation to use configurational entropy as an effective means to modulate the mechanical stability of proteins, which is of critical importance towards engineering artificial elastomeric proteins with tailored nanomechanical properties.
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Proteínas Bacterianas/química , Secuencia de Aminoácidos , Proteínas Bacterianas/genética , Fenómenos Biomecánicos , Dicroismo Circular , Entropía , Microscopía de Fuerza Atómica , Modelos Moleculares , Datos de Secuencia Molecular , Mutagénesis Insercional , Desnaturalización Proteica , Ingeniería de Proteínas , Estructura Secundaria de Proteína , Streptococcus/química , Streptococcus/genéticaRESUMEN
Hepatocellular carcinoma (HCC) is a common and rapidly progressing malignancy. Current treatment options for advanced HCC are limited. This clinical study of dendritic cell (DC)-based immunotherapy for HCC enrolled 31 patients with advanced HCC. DCs, propagated from peripheral blood monocytes, were pulsed with autologous tumor lysates to treat HCC. The first 14 patients underwent pulsed therapy with five courses of DC vaccination intravenously at weekly intervals. The other 17 patients underwent monthly boost vaccinations after the initial pulsed therapy. Among the 31 patients, 4 (12.9%) exhibited partial response to DC vaccination. Seventeen patients (54.8%) had stable disease. Ten patients (32.3%) had progressive disease. The overall 1-year survival rate of all 31 patients was 40.1 +/- 9.1%. The patients treated with pulsed and boosted therapy had better 1-year survival rates than those treated by pulsed therapy alone (63.3 +/- 12.0% vs. 10.7 +/- 9.4%; P < 0.001). In this trial, DC vaccinations for advanced HCC were safe. Liver function tests showed no difference before and after DC vaccinations. The results of this clinical trial indicate that DC vaccination is a safe treatment for HCC. Pulsed DC vaccination followed by boosters can provide better clinical survival for advanced HCC patients than pulsed DC vaccination only. Further studies are needed to increase the efficacy of this therapeutic approach.
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Carcinoma Hepatocelular/terapia , Células Dendríticas/citología , Inmunoterapia/métodos , Adulto , Anciano , Anciano de 80 o más Años , Vacunas contra el Cáncer , Membrana Celular/metabolismo , Citocinas/metabolismo , Células Dendríticas/metabolismo , Progresión de la Enfermedad , Femenino , Humanos , Hipersensibilidad Tardía , Inmunoterapia Adoptiva/métodos , Linfocitos/metabolismo , Masculino , Persona de Mediana Edad , Monocitos/citología , Fenotipo , Factores de Tiempo , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Immunosuppression in tumor-bearing hosts may be a major obstacle in eradicating tumors. This study investigated whether hepatocellular carcinoma suppressed the functions of dendritic cells to escape tumor surveillance. Dendritic cells (DC), propagated from C57BL/10J mice, were cocultured with or without murine hepatoma Hepa1-6 cells to examine the influence of hepatocellular carcinoma on dendritic cells. The results revealed that dendritic cells cocultured with hepatoma cells expressed low levels of costimulatory molecules, and the stimulatory capacity was decreased. The antigen-specific cytotoxic effects of T cells activated by the DC cocultured with hepatoma cells were also decreased. In ex vivo studies, the maturation and function of dendritic cells propagated from tumor-bearing mice were suppressed. The suppressive effect of Hepa1-6 cells on dendritic cells could be partially reversed by neutralizing IL-10. In conclusion, the maturation and stimulatory function of DC are suppressed by hepatocellular carcinoma. IL-10 release may be one of the mechanisms employed by hepatocellular carcinoma to suppress dendritic cells.