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BACKGROUND: For severe anterior glenoid bone loss due to recurrent shoulder instability, the Latarjet procedure offers a dynamic sling effect in addition to bone augmentation. Yet, it heavily alters the surrounding anatomy, while fixation and graft union issues are also common. PURPOSE/HYPOTHESIS: The purpose of this study was to compare a novel printed 3-dimensional (3D) partial glenoid arthroplasty (PGA) implant with the classic Latarjet procedure. It was hypothesized that by replicating the original glenoid geometry and preserving soft tissue anatomy, PGA may better reproduce normal joint kinematics. In addition, the locking screw construct may offer stronger fixation. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 14 matched cadaveric shoulders were tested. The PGA implant was 3D printed in titanium based on preoperative computed tomography. The intact, 25% anterior glenoid bone loss, and postoperative states were tested in the scapular and coronal planes. The following parameters were measured: articular surface area and stepoff, rotational range of motion and the humeral head apex position during rotation, and load and linear stiffness at 25% anterior translation and at 2-mm construct displacement. RESULTS: The baseline dimensions of the glenoid articular surface were comparable between the groups. The articular surface area after PGA was significantly larger (P = .006) with less articular stepoff (P = .030). PGA better approximated the intact state's external (P = .006) and total (P = .019) rotational range of motion in the scapular plane. The course of the humeral head apex after PGA better followed that of the intact state (P < .001). Resistance against anterior translation after PGA was not significantly different compared with after the Latarjet procedure. Greater linear stiffness (P = .031) and loading (P = .002) at 2-mm construct displacement were demonstrated in the PGA group. CONCLUSION: In addressing anterior glenoid bone loss, PGA better approximated intact glenohumeral joint kinematics compared with the Latarjet procedure with less articular stepoff in a cadaveric model. PGA was comparable in resisting anterior translation while being significantly stronger against loading at 2-mm construct displacement. Further clinical studies are warranted to validate this novel procedure. CLINICAL RELEVANCE: A 3D-printed PGA implant may offer an alternative treatment option for severe glenoid bone loss due to shoulder instability, overcoming the previous drawbacks of the Latarjet procedure, including altered kinematics, fixation failure, and hardware issues.
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Inestabilidad de la Articulación , Articulación del Hombro , Humanos , Articulación del Hombro/diagnóstico por imagen , Articulación del Hombro/cirugía , Inestabilidad de la Articulación/cirugía , Cabeza Humeral/cirugía , Artroplastia , Fenómenos Biomecánicos , Rango del Movimiento Articular , CadáverRESUMEN
Background: Deltoid function critically influences the results of reverse total shoulder arthroplasty (RTSA), and spontaneous deltoid attrition tears are frequently detected in cuff tear arthropathy (CTA) patients; however, the clinical impacts of these tears on RTSA outcomes are undetermined. Our aim was to determine the effect of spontaneous deltoid attrition tears on postoperative outcomes after RTSA without an additional deltoid procedure. Methods: Seventy-two patients who underwent RTSA for CTA with preoperative magnetic resonance imaging (MRI) and a minimum clinical follow-up of 1 year (mean, 32 months) were retrospectively reviewed in the study. Patients with a history of previous shoulder surgery or injury were excluded. The presence and location of deltoid attrition tears were determined in preoperative MRI. Propensity score matching (1:1) was performed to construct tear and no-tear groups. Finally, 21 patients, matched with respect to age, sex, hand dominance, symptom duration, medical comorbidity (obesity, diabetes mellitus, and coronary artery disease), Hamada grade, and implant type, were assigned to each group. Clinical outcomes (functional scores, isometric power, and range of motion) in the two groups were compared. Results: Deltoid attrition tears were detected in 21 of the 72 enrolled cases (29.1%). Anterolateral deltoid was the most frequent location and no tear was detected in the posterior deltoid. The tear rate increased with disease severity (Hamada G2, 4.8%; G3, 23.8%; > G4, 71.4%). No pre- or postoperative clinical variables differed significantly between the tear and no tear groups. Conclusions: Deltoid attrition tears were detected in 29% of CTA patients who underwent RTSA. The most common site was the anterolateral region and tear prevalence tended to increase with CTA progression. However, RTSA was found to provide satisfactory outcomes regardless of the presence of a deltoid attrition tear.
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Artroplastía de Reemplazo de Hombro , Lesiones del Manguito de los Rotadores , Artropatía por Desgarro del Manguito de los Rotadores , Articulación del Hombro , Humanos , Artroplastía de Reemplazo de Hombro/métodos , Artropatía por Desgarro del Manguito de los Rotadores/cirugía , Estudios Retrospectivos , Puntaje de Propensión , Resultado del Tratamiento , Rotura/cirugía , Articulación del Hombro/cirugía , Lesiones del Manguito de los Rotadores/diagnóstico por imagen , Lesiones del Manguito de los Rotadores/cirugía , Rango del Movimiento ArticularRESUMEN
Background: Synovial osteochondromatosis (SOC) of the shoulder is a rare condition with unclear characteristics. This study evaluated the clinical features and postoperative functional outcomes of SOC of the shoulder that are distinct from SOC of other joints. Methods: The characteristics of 28 shoulders with SOC that underwent arthroscopy were retrospectively assessed. Ten shoulders (35.7%) had rotator cuff tears (RCTs) and underwent concomitant arthroscopic rotator cuff repair. The mean follow-up period was 83.6 months (range, 24-154 months). Demographic characteristics and loose bodies localized under arthroscopy were compared between cases with and without concomitant RCTs. Radiography, ultrasonography, or magnetic resonance imaging were performed preoperatively and postoperatively. Visual analog scale (VAS) scores for pain and satisfaction were evaluated for all cases, and functional scores were assessed in shoulders with concomitant RCTs. Results: The average age was 36.2 ± 15.6 years among patients without RCTs and 58.3 ± 7.2 years among patients with RCTs. Seven shoulders (7%) had osteoarthritis. Arthroscopy revealed loose bodies in multiple spaces, including the glenohumeral joint, subacromial (SA) space, and biceps tendon sheath. Overall, loose bodies were found in multiple spaces in 12 shoulders (42.9%). Loose bodies were found in the SA space only in 4 shoulders (22.2%) without RCTs and in 7 shoulders (70.0%) with RCTs. VAS for pain decreased significantly from 3.9 ± 2.3 to 1.1 ± 1.3 (p < 0.001). The functional scores increased significantly after arthroscopic management for patients with concurrent RCTs (all p < 0.05). Recurrence of SOC occurred in 3 of the 22 shoulders (13.6%) who underwent postoperative imaging, but no patient had a recurrent RCT. Conclusions: Pain relief and patient satisfaction were achieved via arthroscopic management. Unlike in other joints, loose bodies can occur simultaneously in several spaces in the shoulder, including the glenohumeral joint, SA space, and biceps tendon sheath. Early diagnosis of SOC of the SA space can help prevent osteoarthritis and RCT progression.
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Condromatosis Sinovial , Osteoartritis , Lesiones del Manguito de los Rotadores , Articulación del Hombro , Humanos , Adulto Joven , Adulto , Persona de Mediana Edad , Hombro/cirugía , Manguito de los Rotadores/cirugía , Condromatosis Sinovial/diagnóstico por imagen , Condromatosis Sinovial/cirugía , Resultado del Tratamiento , Lesiones del Manguito de los Rotadores/cirugía , Articulación del Hombro/cirugía , Artroscopía/métodos , DolorRESUMEN
BACKGROUND: Baseplate screws have been suggested to be a possible cause of suprascapular neuropathy after reverse total shoulder arthroplasty (RTSA). Three-dimensional analyses of screw penetration and confirmation of its clinical impacts are relevant. The study aims to investigate the association between screw penetration and the clinical outcomes. MATERIALS AND METHODS: Eighty-two patients who underwent RTSA for a massive rotator cuff tear, cuff tear arthropathy, or osteoarthritis with rotator cuff tear were retrospectively enrolled. They were followed up for a minimum of 12 months, and all underwent computed tomography at 1 year postoperatively. The lengths of the superior and posterior baseplate screws were documented. Postoperative computed tomography images were subjected to 3-dimensional analysis to determine whether superior or posterior screws penetrated the glenoid vault and the location to which they penetrated, and screw-to-nerve distances were measured to estimate risks of screw nerve violation and iatrogenic suprascapular neuropathy. Patients with any screw <5 mm from the suprascapular nerve were deemed to have a high risk. Clinical outcomes (functional scores, ranges of motion, and isometric strengths) of patients in the high- and lower-risk groups were compared. RESULTS: The mean lengths of the superior and posterior screws were 28 ± 4 mm and 18 ± 3 mm, respectively. Penetration was detected for 13% of superior screws and 64% of posterior screws. Sixty-three percent of penetrating superior screws and 5% of penetrating posterior screws were <5 mm from the suprascapular nerve, and therefore, 12% of patients who received RTSA were assessed to have a high risk of iatrogenic suprascapular neuropathy. However, no significant difference was detected in clinical outcomes between the high- and lower-risk patients after a mean follow-up period of 20 months. CONCLUSION: Twelve percent of patients who received RTSA were assessed to be at high risk of iatrogenic suprascapular neuropathy by baseplate screw penetration. However, the clinical outcomes of RTSA at a minimum follow-up of 1 year were similar in the high- and lower-risk groups.
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Artroplastía de Reemplazo de Hombro , Traumatismos de los Nervios Periféricos , Lesiones del Manguito de los Rotadores , Articulación del Hombro , Artroplastía de Reemplazo de Hombro/efectos adversos , Artroplastía de Reemplazo de Hombro/métodos , Tornillos Óseos/efectos adversos , Humanos , Enfermedad Iatrogénica , Traumatismos de los Nervios Periféricos/etiología , Estudios Retrospectivos , Lesiones del Manguito de los Rotadores/complicaciones , Lesiones del Manguito de los Rotadores/diagnóstico por imagen , Lesiones del Manguito de los Rotadores/cirugía , Articulación del Hombro/diagnóstico por imagen , Articulación del Hombro/inervación , Articulación del Hombro/cirugía , Resultado del TratamientoRESUMEN
BACKGROUND: Although the effectiveness of acromioplasty is controversial, it is commonly performed during rotator cuff repair to reduce external impingement. During follow-up, osteolysis under the acromion (acromial cupping) could be observed. However, this phenomenon has been rarely addressed in the literature. The purpose of this study was to compare the prevalence and severity of acromial cupping after rotator cuff repair depending on the concomitant performance of acromioplasty and evaluate the influence of acromial cupping on clinical and radiological outcome. METHODS: This is a retrospective study involving patients who underwent arthroscopic rotator cuff repair for small-to-large full-thickness rotator cuff tears from October 2015 to March 2019 and clinical follow-up and magnetic resonance imaging at least 1 year postoperatively. A total of 110 patients were enrolled and divided into two groups depending on whether acromioplasty had been performed (group A) or not (group N). The prevalence of acromial cupping was evaluated in each group. In addition, we stratified patients according to the severity of acromial cupping to investigate its influence on healing and functional scores (visual analog scale [VAS], American Shoulder and Elbow Surgeons [ASES] score, simple shoulder test [SST], and Constant-Murley score). RESULTS: There were 85 patients in group A and 25 patients in group N. The prevalence of acromial cupping and acromial cysts was as follows: 36.4% (40 patients) and 6.4% (7 patients), respectively, in the total subjects; 43.5% (37/85) and 5.9% (5/85), respectively, in group A; and 12.0% (3/25) and 8.0% (2/25), respectively, in group N. The prevalence of acromial cupping was significantly different between the two groups (p = 0.012). However, functional outcomes were not significantly different between groups stratified by the severity of acromial cupping (VAS, p = 0.464; ASES score, p = 0.902; SST, p = 0.816; and Constant-Murley score, p = 0.117). The difference in healing rate was statistically insignificant between groups (p = 0.726). CONCLUSIONS: The incidence and severity of acromial cupping were significantly greater in patients who underwent rotator cuff repair with acromioplasty. It was a relatively common phenomenon, especially after acromioplasty. However, neither the existence nor the severity of acromial cupping affected functional outcomes or healing.
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Acromion , Lesiones del Manguito de los Rotadores , Acromion/diagnóstico por imagen , Acromion/cirugía , Artroscopía , Humanos , Prevalencia , Estudios Retrospectivos , Manguito de los Rotadores/diagnóstico por imagen , Manguito de los Rotadores/cirugía , Lesiones del Manguito de los Rotadores/diagnóstico por imagen , Lesiones del Manguito de los Rotadores/epidemiología , Lesiones del Manguito de los Rotadores/cirugía , Resultado del TratamientoRESUMEN
Managing information at city level has become increasingly important owing to the introduction of smart cities and the increasing severity of disasters due to climate change. A data collection framework, model construction, and information management must be established to systematically manage information at the city level. This study developed an urban model generation method using detailed attributes within the City Geography Markup Language (CityGML), a standard data schema for 3D representation of cities based on different types of publicly available information within Korea. The generated model was used to develop a method for simulating flooding status, degree of flooding, and level of building damage after heavy rainfall, in Korea. Furthermore, we developed a method to estimate the loss of human life and property damage by combining the results of the flood analysis with the city model. The proposed methodology supports the creation of standard-based models for flood analysis and exhibits strong interoperability for application to different areas of analysis.
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Inundaciones , Lenguaje , Ciudades , Geografía , Humanos , República de CoreaRESUMEN
AIMS: Scapular notching is thought to have an adverse effect on the outcome of reverse total shoulder arthroplasty (RTSA). However, the matter is still controversial. The aim of this study was to determine the clinical impact of scapular notching on outcomes after RTSA. METHODS: Three electronic databases (PubMed, Cochrane Database, and EMBASE) were searched for studies which evaluated the influence of scapular notching on clinical outcome after RTSA. The quality of each study was assessed. Functional outcome scores (the Constant-Murley scores (CMS), and the American Shoulder and Elbow Surgeons (ASES) scores), and postoperative range of movement (forward flexion (FF), abduction, and external rotation (ER)) were extracted and subjected to meta-analysis. Effect sizes were expressed as weighted mean differences (WMD). RESULTS: In all, 11 studies (two level III and nine level IV) were included in the meta-analysis. All analyzed variables indicated that scapular notching has a negative effect on the outcome of RTSA . Statistical significance was found for the CMS (WMD -3.11; 95% confidence interval (CI) -4.98 to -1.23), the ASES score (WMD -6.50; 95% CI -10.80 to -2.19), FF (WMD -6.3°; 95% CI -9.9° to -2.6°), and abduction (WMD -9.4°; 95% CI -17.8° to -1.0°), but not for ER (WMD -0.6°; 95% CI -3.7° to 2.5°). CONCLUSION: The current literature suggests that patients with scapular notching after RTSA have significantly worse results when evaluated by the CMS, ASES score, and range of movement in flexion and abduction. Cite this article: Bone Joint J 2020;102-B(11):1438-1445.
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Artroplastía de Reemplazo de Hombro/efectos adversos , Enfermedades Óseas/etiología , Artropatías/cirugía , Escápula/lesiones , Articulación del Hombro/cirugía , Artroplastía de Reemplazo de Hombro/métodos , Humanos , Rango del Movimiento Articular , Rotación , Resultado del TratamientoRESUMEN
BACKGROUND: The preoperative status of the teres minor (Tm) can affect the outcome of reverse total shoulder arthroplasty (RTSA). The effect of preoperative Tm hypertrophy on the outcome of RTSA is unclear. METHODS: A total of 86 shoulders that underwent RTSA were retrospectively enrolled. Of these, 48 cases with a Tm occupation ratio (OR) of >0.288 in the preoperative magnetic resonance image were assigned to the hypertrophic group, and 38 cases to the control group. The two groups were compared with respect to preoperative rotator cuff tear involvement, fatty infiltration, pre- and postoperative rotator cuff ORs, pain scores, functional scores, range of motion, and muscle strength. Postoperative Tm ORs in 1-year follow-up multidetector computed tomography were compared with preoperative Tm ORs. RESULTS: Preoperatively, integrities of infraspinatus (ISP) and supraspinatus were significantly different between the 2 groups (P = .001, 0.009, each). Preoperative ISP ORs were significantly related to preoperative Tm ORs (r = -0.534, P < .001). The mean pre- to postoperative change of Tm ORs in the hypertrophic group decreased (-0.029 ± 0.068), whereas that of the control group increased (+0.047 ± 0.092). Postoperative pain scores, functional scores, range of motion, and muscle strength were not different between groups. CONCLUSIONS: In cases of advanced rotator cuff tear requiring RTSA, Tm hypertrophy is found to be related to tear and atrophy of the ISP, suggesting that Tm hypertrophy is a compensatory change for ISP dysfunction. However, Tm hypertrophy was observed to diminish after RTSA. Preoperative Tm hypertrophy appears to have no beneficial effect on the outcomes of RTSA.
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Artroplastía de Reemplazo de Hombro , Manguito de los Rotadores/diagnóstico por imagen , Manguito de los Rotadores/patología , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Hipertrofia , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Fuerza Muscular , Periodo Preoperatorio , Rango del Movimiento Articular , Estudios Retrospectivos , Lesiones del Manguito de los Rotadores/cirugía , Escala Visual AnalógicaRESUMEN
BACKGROUND: Reversibility of rotator cuff atrophy after surgical repair is controversial. Traditionally, the cross-sectional area (CSA) of the rotator cuff was measured in conventional Y-view (CYV) via magnetic resonance imaging (MRI) to evaluate reversibility. However, it has been suggested that scanning axis inconsistency in CYV was overlooked and that the CSA in CYV reflects not only atrophy but also rotator cuff retraction. HYPOTHESIS: Discrepancies between scanning axes in CYV cause significant errors when one is evaluating changes in the CSA of the supraspinatus (SS) using preoperative and postoperative MRI scans. A more medial section than the Y-view is not influenced as much by retraction recovery after repair. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 3. METHODS: The study included 36 patients with full-thickness SS tear and retraction who underwent arthroscopic complete repair with preoperative MRI and immediate postoperative MRI (within 5 days after rotator cuff repair). Angles between CYV planes in the preoperative and immediate postoperative MRI scans were measured. MRI scans were reconstructed perpendicular to the scapular axes by multiplanar reconstruction. Differences between the CSAs of the SS in preoperative and postoperative Y-view on the original and reconstructed MRI scans were compared, and changes in CSAs of the SS muscles after repair in 2 sections medial to the reconstructed Y-view (RYV) were compared. RESULTS: The mean angle between CYV planes in preoperative and postoperative MRI scans was 13.1° ± 7.1°. Mean pre- to postoperative increase in the CSA of the SS was greater in CYV than in RYV (95 ± 72 vs 75 ± 62 mm2; P = .024). Furthermore, pre- to postoperative CSA differences in the 2 medial sections were less than in RYV. For the most medial section, crossing the omohyoid origin, the CSA differences were not significant (434 ± 98 vs 448 ± 98 mm2; P = .061). CONCLUSION: Scanning axes inconsistencies in CYV cause unacceptable errors in CSA measurements of the SS after repair. We recommend reconstruction along a consistent axis by multiplanar reconstruction when evaluating postoperative changes in SS atrophy and the use of sections more medial than the scapular Y-view to reduce errors caused by tendon retraction.
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BACKGROUND: Repair tension of a torn rotator cuff can affect healing after repair. However, a measurement of the actual tension during arthroscopic rotator cuff repair is not feasible. The relationship between repair tension and healing of a rotator cuff repair remains unclear. PURPOSE/HYPOTHESIS: The purpose of this study was to evaluate the effect of repair tension on healing at the repair site. The hypothesis was that repair tension would be a major factor in determining the anatomic outcome of rotator cuff repair. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Arthroscopic rotator cuff repairs (132 patients) for full-thickness rotator cuff tears were analyzed. An intraoperative model was designed for the estimation of repair tension using a tensiometer. Magnetic resonance imaging (MRI) was performed approximately 1 year (mean [±SD], 12.7 ± 3.2 months) postoperatively for the evaluation of healing at the repair site. Multivariable analysis was performed for tear size, amount of retraction, and fatty degeneration (FD) of rotator cuff muscles. RESULTS: The mean repair tension measured during the arthroscopic procedure was 28.5 ± 23.1 N. There was a statistically significant correlation between tension and tear size (Pearson correlation coefficient [PCC], 0.529; P < .001), amount of retraction (PCC, 0.619; P < .001), and FD of the supraspinatus (Spearman correlation coefficient [SCC], 0.308; P < .001) and infraspinatus (SCC, 0.332; P < .001). At the final follow-up (12.7 ± 3.2 months), healing failure was observed in 18.2% (24/132), and repair tension also showed a significant inverse correlation with healing at the repair site (SCC, 0.195; P = .025). However, when sex, age, tear size, amount of retraction, tendon quality, and FD of rotator cuff muscles were included for multivariable logistic regression analysis, only FD of the infraspinatus showed an association with the anatomic outcome of repair (Exp(B) = 0.596; P = .010). CONCLUSION: Our intraoperative model for the estimation of rotator cuff repair tension showed an inverse correlation of repair tension with healing at the repair site, suggesting that complete healing is less likely with high-tension repairs. A significant association was observed on MRI between a high level of FD of the infraspinatus and repaired tendon integrity.
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Artroscopía/métodos , Lesiones del Manguito de los Rotadores/cirugía , Manguito de los Rotadores/cirugía , Adulto , Anciano , Estudios de Cohortes , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Manguito de los Rotadores/diagnóstico por imagen , Manguito de los Rotadores/fisiología , Lesiones del Manguito de los Rotadores/diagnóstico por imagen , Rotura/cirugía , Resultado del Tratamiento , Cicatrización de Heridas/fisiologíaRESUMEN
Ribosomal protein S6 is a key regulator of 40S ribosome biogenesis, and its phosphorylation is closely related to cell growth capacity. However, as a downstream target of S6 kinases, the clinical significance and the roles of S6 and S6 phosphorylation in cell viability and motility of esophageal squamous cell carcinoma remain unclear. Here, we show that high level of phosphorylated-ribosomal protein S6 (p-S6) (immunohistochemistry score ≥5) and an increased ratio of p-S6/S6 (immunohistochemistry score ≥0.75) were significantly associated with shortened disease-free survival in patients with esophageal squamous cell carcinoma in univariate analysis (P=0.049 and P<0.001, respectively). After adjusting for age, tumor-nodes-metastasis stage, chemotherapy, and radiation therapy in multivariate analysis, both p-S6 (hazard ratio 2.21, P=0.005) and p-S6/S6 (hazard ratio 2.40, P<0.001) remained independent adverse prognostic factors. In addition, S6 and S6 kinase 1 knockdown resulted in attenuation of viability by suppressing cyclin D1 expression in esophageal cancer cells. Furthermore, depletion of S6 and S6 kinase 1 resulted in a reduction in esophageal cancer cell migration and invasion. This was paralleled by a reduction in focal adhesion and by suppression of extracellular signal-regulated kinase and c-jun N-terminal kinase phosphorylation, which control cell motility. Collectively, these findings suggest that p-S6 and the ratio of p-S6/S6 are closely relevant to tumor progression and have prognostic significance in esophageal squamous cell carcinoma.
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Carcinoma de Células Escamosas/enzimología , Neoplasias Esofágicas/enzimología , Proteína S6 Ribosómica/metabolismo , Anciano , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Línea Celular Tumoral , Movimiento Celular , Supervivencia Celular , Ciclina D1/metabolismo , Supervivencia sin Enfermedad , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/terapia , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Adhesiones Focales/enzimología , Humanos , Inmunohistoquímica , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Invasividad Neoplásica , Fosforilación , Pronóstico , Modelos de Riesgos Proporcionales , Interferencia de ARN , Proteína S6 Ribosómica/genética , Proteínas Quinasas S6 Ribosómicas/metabolismo , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , TransfecciónRESUMEN
Mammalian target of rapamycin (mTOR) has emerged as a key regulator of cell metabolism, growth, and proliferation. Despite the increasing significance of mTOR signaling in cancer cell cycle and proliferation, the clinical significance of activated mTOR in esophageal squamous cell carcinoma and its role in esophageal cancer cell proliferation and invasion remain unclear. Here, we show that both high levels of phosphorylated-mTOR and an increased ratio of phosphorylated-mTOR/mTOR (ratio ≥0.2) were significantly associated with shortened disease-specific survival in 165 patients with esophageal squamous cell carcinoma in univariate analysis (P = .047 for phosphorylated-mTOR, P = .021 for phosphorylated-mTOR/mTOR); phosphorylated-mTOR and phosphorylated-mTOR/mTOR remained independent prognostic factors after adjusting for age, TNM stage, chemotherapy, and radiation therapy in multivariate analysis (hazard ratio, 1.67, P = .025 for phosphorylated-mTOR; hazard ratio, 1.95, P = .006 for phosphorylated-mTOR/mTOR). Moreover, down-regulation of mTOR or mTOR complex components led to attenuation of proliferation, migration, and invasion of esophageal squamous cell carcinoma cell lines through suppression of cyclin D1 expression. Collectively, our findings suggest that phosphorylated-mTOR and the ratio of phosphorylated-mTOR/mTOR are closely linked to tumor progression and represent independent prognostic factors in esophageal squamous cell carcinoma, thereby providing a potential therapeutic target for this malignancy.
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Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Adolescente , Adulto , Anciano , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Niño , Preescolar , Ciclina D1/metabolismo , Progresión de la Enfermedad , Regulación hacia Abajo , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas de Esófago , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Lactante , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Fosforilación , Pronóstico , Transducción de Señal , Adulto JovenRESUMEN
Phospholipase D (PLD) catalyzes the hydrolysis of phosphatidylcholine to generate the lipid second messenger, phosphatidic acid. PLD is localized in most cellular organelles, where it is likely to play different roles in signal transduction. PLD1 is primarily localized in vesicular structures such as endosomes, lysosomes and autophagosomes. However, the factors defining its localization are less clear. In this study, we found that four hydrophobic residues present in the N-terminal HKD catalytic motif of PLD1, which is involved in intramolecular association, are responsible for vesicular localization. Site-directed mutagenesis of the residues dramatically disrupted vesicular localization of PLD1. Interestingly, the hydrophobic residues of PLD1 are also involved in the interruption of its nuclear localization. Mutation of the residues increased the association of PLD1 with importin-ß, which is known to mediate nuclear importation, and induced the localization of PLD1 from vesicles into the nucleus. Taken together, these data suggest that the hydrophobic amino acids involved in the interdomain association of PLD1 are required for vesicular localization and disturbance of its nuclear localization.
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Núcleo Celular/enzimología , Fosfolipasa D/metabolismo , Vesículas Transportadoras/enzimología , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Aminoácidos/química , Endosomas/enzimología , Células HEK293 , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Lisosomas/enzimología , Fagosomas/enzimología , Fosfolipasa D/química , Dominios y Motivos de Interacción de Proteínas , Transporte de ProteínasRESUMEN
Phospholipase D plays an anti-apoptotic role but little is known about dynamics of phospholipase D turnover during apoptosis. We have recently identified phospholipase D1 as a new substrate of caspases which generates the N-terminal and C-terminal fragment of phospholipase D1. In the present study, we tried to investigate whether association of the caspase cleavage fragments may be involved in regulation of apoptosis. Ectopically expressed C-terminal fragment, but not N-terminal fragment of phospholipase D1, is exclusively imported into the nucleus via a nuclear localization sequence; however, endogenous C-terminal fragment of phospholipase D1 from etoposide-induced apoptotic cells and Alzheimer's disease brain tissues with active caspase-3, was localized in the cytosolic fraction as well as the nuclear fraction. Intermolecular association between the two fragments of phospholipase D1 through hydrophobic residues within the catalytic motif inhibited nuclear localization of C-terminal fragment of phospholipase D1, and two catalytic motif and nuclear localization sequence regulated nuclocytoplasmic shuttling of phospholipase D1. Moreover, hydrophobic residues involved in the intermolecular association are also required for both its enzymatic activity and anti-apoptotic function. Taken together, we demonstrate that interdomain association and dissociation of phospholipase D1 might provide new insights into modulation of apoptosis.
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Apoptosis/fisiología , Caspasas/metabolismo , Fosfolipasa D/metabolismo , Encéfalo/enzimología , Línea Celular Tumoral , Citosol/metabolismo , Etopósido/farmacología , Células HEK293 , Humanos , Fosfolipasa D/químicaRESUMEN
Binding of N-formyl-methionyl-leucyl-phenylalanine (fMLP) to its specific cell surface receptor, N-formyl peptide receptor (FPR), triggers different cascades of biochemical events, eventually leading to cellular activation. However, the physiological role of fMLP and FPR during differentiation of mesenchymal stem cells is unknown. In this study, we attempted to determine whether fMLP regulates differentiation of mesenchymal stem cells derived from bone marrow. Analysis by quantitative-PCR and flow cytometry showed significantly increased expression of FPR1, but not FPR2 and FPR3, during osteoblastic differentiation. fMLP, a specific ligand of FPR1, promotes osteoblastic commitment and suppresses adipogenic commitment under differentiation conditions. Remarkably, fMLP-stimulated osteogenesis is associated with increased expression of osteogenic markers and mineralization, which were blocked by cyclosporine H, a selective FPR1 antagonist. In addition, fMLP inhibited expression of peroxisome proliferator-activated receptor-γ1, a major regulator of adipocytic differentiation. fMLP-stimulated osteogenic differentiation was mediated via FPR1-phospholipase C/phospholipase D-Ca(2+)-calmodulin-dependent kinase II-ERK-CREB signaling pathways. Finally, fMLP promoted bone formation in zebrafish and rabbits, suggesting its physiological relevance in vivo. Collectively, our findings provide novel insight into the functional role of fMLP in bone biology, with important implications for its potential use as a therapeutic agent for treatment of bone-related disorders.
Asunto(s)
Células de la Médula Ósea/citología , Células Madre Mesenquimatosas/citología , N-Formilmetionina Leucil-Fenilalanina/farmacología , Osteoblastos/citología , Receptores de Formil Péptido/fisiología , Adipocitos/citología , Animales , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Diferenciación Celular , Ciclosporina/farmacología , Humanos , PPAR gamma/metabolismo , Fosfolipasa D/metabolismo , Conejos , Receptores de Formil Péptido/química , Transducción de Señal , Fosfolipasas de Tipo C/metabolismoRESUMEN
Recent studies highlight the existence of a nuclear lipid metabolism related to cellular proliferation. However, the importance of nuclear phosphatidylcholine (PC) metabolism is poorly understood. Therefore, we were interested in nuclear PC as a source of second messengers and, particularly, nuclear localization of PC-specific phospholipase D (PLD). In the present study we have identified the nuclear localization sequence (NLS) of PLD1 whose mutation abolished its nuclear import. Recently, we reported that caspase-mediated cleavage of PLD1 generates the N-terminal fragment (NF-PLD1) and C-terminal fragment (CF-PLD1). Here we show that CF-PLD1 but not NF-PLD1, is exclusively imported into the nucleus via its functional NLS, whereas only some portions of intact PLD1 were localized into the nucleus. The NLS of intact PLD1 or CF-PLD1 is required for interaction with importin-ß, which is known to mediate nuclear import. The amount of intact PLD1 or CF-PLD1 translocated into nucleus is correlated with its binding affinity with importin-ß. Ultimately, nuclear localization of intact PLD1 but not CF-PLD1 mediates the activation of nuclear protein kinase Cα and extracellular signal-regulated kinase signaling pathways. Taken together, we propose that nuclear localization of PLD1 via the NLS and its interaction with importin-ß may provide new insights on the functional role of nuclear PLD1 signaling.
Asunto(s)
Núcleo Celular/enzimología , Señales de Localización Nuclear/metabolismo , Fosfolipasa D/metabolismo , Proteína Quinasa C-alfa/metabolismo , Transducción de Señal/fisiología , Transporte Activo de Núcleo Celular/fisiología , Núcleo Celular/genética , Activación Enzimática/fisiología , Células HEK293 , Humanos , Señales de Localización Nuclear/genética , Fosfolipasa D/genética , Proteína Quinasa C-alfa/genética , Estructura Terciaria de Proteína , beta Carioferinas/genética , beta Carioferinas/metabolismoRESUMEN
In spite of the importance of phospholipase D (PLD) in cell proliferation and tumorigenesis, little is known about the molecules regulating PLD expression. Thus, identification of small molecules inhibiting PLD expression would be an important advance for PLD- mediated physiology. We examined one such here, denoted Triptolide, which was identified in a chemical screen for inhibitors of PLD expression using cell assay system based on measurement of PLD promoter activity. Triptolide significantly suppressed the expression of both PLD1 and PLD2 with sub-mM potency in MDA-MB-231 breast cancer cells as analyzed by promoter assay and RT-PCR. Moreover, triptolide abolished the protein level of PLD in a time and dose-dependent manner. Triptolide-induced PLD1 downregulation was also observed in all the cancer cells examined, suggesting a general phenomenon detected in various cancer cells. Decrease of PLD expression by triptolide suppressed both basal and PMA-induced PLD activity. In addition, triptolide inhibited activation of NFkB which increased PLD1 expression. Ultimately, downregulation of PLD by triptolide inhibited proliferation of breast cancer cells. Taken together, we demonstrate that triptolide suppresses the expression of PLD via inhibition of NFkappaB activation and then decreases cell proliferation.
Asunto(s)
Antineoplásicos Alquilantes/farmacología , Diterpenos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Fenantrenos/farmacología , Fosfolipasa D/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/enzimología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Compuestos Epoxi/farmacología , Femenino , Humanos , FN-kappa B/genética , FN-kappa B/metabolismo , Fosfolipasa D/metabolismoRESUMEN
Phospholipase D (PLD) has been implicated in survival and anti-apoptosis, but the molecular mechanism by which it responds to apoptotic stimuli is poorly unknown. Here, we demonstrate that cleavage of PLD isozymes as specific substrates of caspase differentially regulates apoptosis. PLD1 is cleaved at one internal site (DDVD(545)S) and PLD2 is cleaved at two or three sites (PTGD(13)ELD(16)S and DEVD(28)T) in the front of N-terminus. Cleavage of PLD was endogenously detected in post-mortem Alzheimer brain together with activated caspase-3, suggesting the physiological relevance. The cleavage of PLD1 but not PLD2 might act as an inactivating process since PLD1 but not PLD2 activity is significantly decreased during apoptosis, suggesting that differential cleavage of PLD isozymes could affect its enzymatic activity. Moreover, caspase-resistant mutant of PLD1 showed more potent anti-apoptotic capacity than that of wild type PLD1, whereas PLD2 maintained anti-apoptotic potency in spite of its cleavage during apoptosis. Moreover, PLD2 showed more potent anti-apoptotic effect than that of PLD1 in overexpression and knockdown experiments, suggesting that difference in anti-apoptotic potency between PLD1 and PLD2 might be due to its intrinsic protein property. Taken together, our results demonstrate that differential cleavage pattern of PLD isozymes by caspase might affect its enzymatic activity and anti-apoptotic function.