RESUMEN
Extensive damage of the tibialis anterior tendon is rare and mainly caused by trauma. Surgical treatment of these injuries can become challenging owing to the limited availability of autogenous graft resources for reconstruction of the defect. In the present case report, we describe a large defect in the midfoot soft tissue after a traffic injury, which included complete loss of the tibialis anterior tendon. The tendon was reconstructed by split tendon transfer of the tibialis posterior tendon without sacrificing function, which was confirmed by the follow-up examination at 6 years after injury. We believe split tendon transfer of the tibialis posterior tendon can be one of the treatment options for patients with extensive disruption of the tibialis anterior tendon.
Asunto(s)
Procedimientos de Cirugía Plástica/métodos , Traumatismos de los Tendones/cirugía , Transferencia Tendinosa/métodos , Cicatrización de Heridas/fisiología , Accidentes de Tránsito , Niño , Femenino , Estudios de Seguimiento , Humanos , Puntaje de Gravedad del Traumatismo , Traumatismos de la Pierna/diagnóstico por imagen , Traumatismos de la Pierna/cirugía , Imagen por Resonancia Magnética/métodos , Fuerza Muscular/fisiología , Músculo Esquelético/cirugía , Radiografía/métodos , Recuperación de la Función , Medición de Riesgo , Traumatismos de los Tendones/diagnóstico por imagen , Tibia , Factores de Tiempo , Resultado del TratamientoRESUMEN
Activated microglia are involved in secondary injury after acute spinal cord injury (SCI) and in development of spinal cord-related neuropathic pain (NeP). The aim of the study was to assess expression of translocator protein 18 kDa (TSPO) as an indicator of microglial activation and to investigate visualization of the dynamics of activated microglia in the injured spinal cord using PET imaging with (R)-[11C]PK11195, a specific ligand for TSPO. In SCI chimeric animal models, TSPO was expressed mainly in activated microglia. Accumulation of (R)-[3H]PK11195 was confirmed in autoradiography and its dynamics in the injured spinal cord were visualized by (R)-[11C]PK11195 PET imaging in the acute phase after SCI. In clinical application of (R)-[11C]PK11195 PET/MRI of the cervical spinal cord in patients with NeP related to cervical disorders, uptake was found in cases up to 10 months after injury or surgery. No uptake could be visualized in the injured spinal cord in patients with chronic NeP at more than 1 year after injury or surgery, regardless of the degree of NeP. However, a positive correlation was found between standardized uptake value ratio and the severity of NeP, suggesting the potential of clinical application for objective evaluation of chronic NeP.
RESUMEN
The cytosolic Hsp90-selective inhibitor TAS-116 has an acceptable safety profile and promising antitumor activity in clinical trials. We examined the binding characteristics of TAS-116 and its analogs to determine the impact of the ligand binding mode on selectivity for cytosolic Hsp90. Analyses of the co-crystal structure of Hsp90 and inhibitor TAS-116 suggest that TAS-116 interacts with the ATP-binding pocket, the ATP lid region, and the hydrophobic pocket. A competitive isothermal titration calorimetry analysis confirmed that a small fragment of TAS-116 (THS-510) docks into the lid region and hydrophobic pockets without binding to the ATP-binding pocket. THS-510 exhibited enthalpy-driven binding to Hsp90α and selectively inhibited cytosolic Hsp90 activity. The heat capacity change of THS-510 binding was positive, likely due to the induced conformational rearrangement of Hsp90. Thus, we concluded that interactions with the hydrophobic pocket of Hsp90 determine potency and selectivity of TAS-116 and derivatives for the cytosolic Hsp90 isoform.
Asunto(s)
Antineoplásicos/metabolismo , Benzamidas/metabolismo , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Pirazoles/metabolismo , Sitios de Unión , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Unión Proteica , TermodinámicaRESUMEN
The molecular chaperone heat shock protein 90 (HSP90) is a promising target for cancer therapy, as it assists in the stabilization of cancer-related proteins, promoting cancer cell growth, and survival. A novel series of HSP90 inhibitors were discovered by structure-activity relationship (SAR)-based optimization of an initial hit compound 11a having a 4-(4-(quinolin-3-yl)-1 H-indol-1-yl)benzamide structure. The pyrazolo[3,4- b]pyridine derivative, 16e (TAS-116), is a selective inhibitor of HSP90α and HSP90ß among the HSP90 family proteins and exhibits oral availability in mice. The X-ray cocrystal structure of the 16e analogue 16d demonstrated a unique binding mode at the N-terminal ATP binding site. Oral administration of 16e demonstrated potent antitumor effects in an NCI-H1975 xenograft mouse model without significant body weight loss.
Asunto(s)
Benzamidas/química , Diseño de Fármacos , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Pirazoles/química , Administración Oral , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/uso terapéutico , Benzamidas/metabolismo , Benzamidas/uso terapéutico , Sitios de Unión , Línea Celular Tumoral , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Proteínas HSP90 de Choque Térmico/genética , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Ratones , Ratones Desnudos , Conformación Molecular , Simulación de Dinámica Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Pirazoles/metabolismo , Pirazoles/uso terapéutico , Quinolinas/química , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/aislamiento & purificación , Solubilidad , Relación Estructura-ActividadRESUMEN
The use of mesenchymal stromal cell (MSC) transplantation to repair the injured spinal cord has shown consistent benefits in preclinical models. However, the low survival rate of grafted MSC is one of the most important problems. In the injured spinal cord, transplanted cells are exposed to hypoxic conditions and exposed to nutritional deficiency caused by poor vascular supply. Also, the transplanted MSCs face cytotoxic stressors that cause cell death. The aim of this study was to compare adipose-derived MSCs (AD-MSCs) and bone marrow-derived MSCs (BM-MSCs) isolated from individual C57BL6/J mice in relation to: (i) cellular characteristics, (ii) tolerance to hypoxia, oxidative stress and serum-free conditions, and (iii) cellular survival rates after transplantation. AD-MSCs and BM-MSCs exhibited a similar cell surface marker profile, but expressed different levels of growth factors and cytokines. To research their relative stress tolerance, both types of stromal cells were incubated at 20.5% O2 or 1.0% O2 for 7 days. Results showed that AD-MSCs were more proliferative with greater culture viability under these hypoxic conditions than BM-MSCs. The MSCs were also incubated under H2O2-induced oxidative stress and in serum-free culture medium to induce stress. AD-MSCs were better able to tolerate these stress conditions than BM-MSCs; similarly when transplanted into the spinal cord injury region in vivo, AD-MSCs demonstrated a higher survival rate post transplantation Furthermore, this increased AD-MSC survival post transplantation was associated with preservation of axons and enhanced vascularization, as delineated by increases in anti-gamma isotype of protein kinase C and CD31 immunoreactivity, compared with the BM-MSC transplanted group. Hence, our results indicate that AD-MSCs are an attractive alternative to BM-MSCs for the treatment of severe spinal cord injury. However, it should be noted that the motor function was equally improved following moderate spinal cord injury in both groups, but with no significant improvement seen unfortunately following severe spinal cord injury in either group.
Asunto(s)
Tejido Adiposo/citología , Células de la Médula Ósea/citología , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/citología , Traumatismos de la Médula Espinal/terapia , Animales , Axones/patología , Separación Celular/métodos , Células Cultivadas , Locomoción , Masculino , Ratones Endogámicos C57BL , Médula Espinal/patología , Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/patología , Traumatismos de la Médula Espinal/fisiopatologíaRESUMEN
OBJECTIVE: Low lumbar osteoporotic vertebral collapse (OVC) has not been well documented compared with OVC of the thoracolumbar spine. The differences between low lumbar and thoracolumbar lesions should be studied to provide better treatment. The aim of this study was to clarify the clinical and imaging features as well as outcomes of low lumbar OVC and to discuss the appropriate surgical treatment. METHODS: Thirty patients (10 men; 20 women; mean age 79.3 ± 4.7 years [range 70-88 years]) with low lumbar OVC affecting levels below L-3 underwent surgical treatment. The clinical symptoms, morphological features of affected vertebra, sagittal spinopelvic alignment, neurological status before and after surgery, and surgical procedures were reviewed at a mean follow-up period of 2.4 years. RESULTS: The main clinical symptom was radicular leg pain. Most patients had old compression fractures at the thoracolumbar level. The affected vertebra was flat-type and concave or H-shaped type, not wedge type as often found in thoracolumbar OVC. There were mismatches between pelvic incidence and lumbar lordosis on plain radiographs. On CT and MR images, foraminal stenosis was seen in 18 patients (60%) and canal stenosis in 24 patients (80%). Decompression with short fusion using a posterior approach was performed. Augmentations of vertebroplasty, posterolateral fusion, and posterior lumbar interbody fusion were performed based on the presence/absence of local kyphosis of lumbar spine, cleft formation, and/or intervertebral instability. Although the neurological and visual analog scale scores improved postoperatively, 8 patients (26.7%) developed postoperative complications mainly related to instrumentation failure. In patients with postoperative complications, lumbar spine bone mineral density was significantly low, but the spinopelvic alignment showed no correlation when compared with those without complications. CONCLUSIONS: The main types of low lumbar OVC were flat-type and concave type, which resulted in neurological symptoms by retropulsed bony fragments generating foraminal stenosis and/or canal stenosis. For patients with low lumbar OVC, decompression of the foraminal and canal stenosis with short fusion surgery via posterior approach can improve neurological symptoms. Since these patients are elderly with poor bone quality and other complications, treatments for both OVC and osteoporosis should be provided to achieve good clinical outcome.
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Vértebras Lumbares/cirugía , Osteoporosis/cirugía , Fracturas Osteoporóticas/cirugía , Fracturas de la Columna Vertebral/cirugía , Espondilolistesis/cirugía , Anciano , Anciano de 80 o más Años , Descompresión Quirúrgica/métodos , Femenino , Humanos , Masculino , Estudios Retrospectivos , Fusión Vertebral/métodos , Resultado del TratamientoRESUMEN
The molecular chaperone HSP90 plays a crucial role in cancer cell growth and survival by stabilizing cancer-related proteins. A number of HSP90 inhibitors have been developed clinically for cancer therapy; however, potential off-target and/or HSP90-related toxicities have proved problematic. The 4-(1H-pyrazolo[3,4-b]pyridine-1-yl)benzamide TAS-116 is a selective inhibitor of cytosolic HSP90α and ß that does not inhibit HSP90 paralogs such as endoplasmic reticulum GRP94 or mitochondrial TRAP1. Oral administration of TAS-116 led to tumor shrinkage in human tumor xenograft mouse models accompanied by depletion of multiple HSP90 clients, demonstrating that the inhibition of HSP90α and ß alone was sufficient to exert antitumor activity in certain tumor models. One of the most notable HSP90-related adverse events universally observed to differing degrees in the clinical setting is visual disturbance. A two-week administration of the isoxazole resorcinol NVP-AUY922, an HSP90 inhibitor, caused marked degeneration and disarrangement of the outer nuclear layer of the retina and induced photoreceptor cell death in rats. In contrast, TAS-116 did not produce detectable photoreceptor injury in rats, probably due to its lower distribution in retinal tissue. Importantly, in a rat model, the antitumor activity of TAS-116 was accompanied by a higher distribution of the compound in subcutaneously xenografted NCI-H1975 non-small cell lung carcinoma tumors than in retina. Moreover, TAS-116 showed activity against orthotopically transplanted NCI-H1975 lung tumors. Together, these data suggest that TAS-116 has a potential to maximize antitumor activity while minimizing adverse effects such as visual disturbances that are observed with other compounds of this class.
Asunto(s)
Antineoplásicos/farmacocinética , Benzamidas/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Pirazoles/farmacología , Retina/patología , Animales , Antineoplásicos/efectos adversos , Benzamidas/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Ratones , Células Fotorreceptoras/efectos de los fármacos , Pirazoles/efectos adversos , Ratas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The solid-phase synthesis of a combinatorial cross-conjugated dienone library based on the structure of clavulones and their biological activity are reported. Clavulones are a family of marine prostanoids, and are composed of a cross-conjugated dienone system bearing two alkyl side-chains. The cross-conjugated dienone system irreversibly reacted with two nucleophiles. Our strategy for the solid-phase synthesis of the cross-conjugated dienones involves the Sonogashira-coupling reaction of a solid-supported cyclopentenone 10 bearing an acetylene group, followed by aldol condensation with aldehydes. The diphenyl derivative 7 aA was prepared from the solid-supported cyclopentenone 10 in 56% total yield. Combinatorial synthesis of a small library using twelve halides and eight aldehydes resulted in the production of 74 desired compounds from 98 candidates, and were detected by their mass spectra. Antiproliferative effects of the crude compounds against HeLaS3 cells showed that eleven samples showed strong antitumor activity (IC50<0.05 microM). Further biological examination of four purified compounds by using five tumor cell lines (A549, HeLaS3, MCF7, TMF1, and P388) revealed strong cytotoxicity comparable to that of adriamycin.
Asunto(s)
Antibióticos Antineoplásicos/química , Técnicas Químicas Combinatorias , Prostaglandinas A/química , Antibióticos Antineoplásicos/síntesis química , Antibióticos Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Doxorrubicina/farmacología , Humanos , Estructura Molecular , Prostaglandinas A/síntesis química , Prostaglandinas A/farmacologíaRESUMEN
The Cdc25 dual-specificity phosphatases are key regulators of cell cycle progression through activation of cyclin-dependent kinases (Cdk). Three homologs exist in humans: Cdc25A, Cdc25B, and Cdc25C. Cdc25A and Cdc25B have oncogenic properties and are overexpressed in some types of tumors. Compounds that inhibit Cdc25 dual-specificity phosphatase activity might thus be potent anticancer agents. We screened several hundred compounds in a library using an in vitro phosphatase assay, with colorimetric measurement of the conversion of p-nitrophenyl phosphate (pNPP) to p-nitrophenol by the catalytic domain of recombinant human Cdc25, and discovered TPY-835, which inhibits Cdc25A and Cdc25B activity (IC50 = 5.1 and 5.7 microM, respectively). TPY-835 had mixed inhibition kinetics for Cdc25A and Cdc25B. TPY-835 caused cell cycle arrest in the G1 phase in human lung cancer cells (A549 and SBC-5) but not cell cycle arrest in the G2/M phase. After treatment with TPY-835, the activation of Cdk2 was suppressed and phosphorylation of the retinoblastoma (Rb) protein was decreased in SBC-5 cells. In addition, TPY-835 induced an increase of the sub-G1 phase cell population after 48-72 h treatment. The growth inhibitory effects of TPY-835 against cisplatin (CDDP)-, camptothecin- and 5-FU-resistant cell lines are comparable to the growth inhibitory effect on their parental lines, thus indicating that TPY-835 did not show cross-resistance to these cell lines. These results suggest that TPY-835 is a promising candidate for constructing a novel class of antitumor agents that can control the cell cycle progression of cancer cells.
Asunto(s)
Fase G1/efectos de los fármacos , Fase G1/fisiología , Neoplasias Pulmonares/patología , Pirazoles/farmacología , Fosfatasas cdc25/antagonistas & inhibidores , Fosfatasas cdc25/metabolismo , Proteínas de Ciclo Celular/fisiología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Resistencia a Antineoplásicos , Humanos , Cinética , Fosforilación , Proteína de Retinoblastoma/metabolismo , Células Tumorales CultivadasRESUMEN
We describe the design and synthesis of alkylating reagents based on the structure of clavulones. They are composed of cross-conjugated dienone system and irreversibly reacted with two nucleophiles under mildly basic conditions via beta-elimination. Hydroxyl derivative 7b showed the highest reactivity toward thiols and showed the strongest cytotoxicity in Hela S3 cells among the three derivatives having a different protecting group at the tert-hydroxyl group.