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Objectives@#To compare the vector analysis, visual, and refractive outcomes of femtosecond-assisted laser insitu keratomileusis (LASIK) and small incision lenticule extraction (SMILE) among myopic patients with moderate myopic astigmatism.@*Methods@#This was a single-center, retrospective, cohort study that compared eyes that underwent femtosecond LASIK or SMILE for the correction of myopia and astigmatism of 0.75 to 3.0 diopters. Vector analysis and standard graphs for reporting visual and refractive outcomes were utilized for analysis.@*Results@#There were 82 femtosecond LASIK-treated eyes and 80 SMILE-treated eyes with similar preoperative characteristics except for slightly higher mean preoperative sphere refraction in the SMILE group (-4.2±2.4 D vs -4.9±1.6 D, p=0.03). At 3 months, femtosecond LASIK group had better mean uncorrected distance visual acuity (UDVA) (LogMAR 0.006±0.06 vs 0.06±0.09, p=0.00) and had more eyes achieving postoperative UDVA of 20/20 or better (88% versus 56%). Although there were similar postoperative spherical equivalents, residual astigmatism was higher in the SMILE group (0.11±0.22 D vs 0.32±0.30 D, p=0.00). Vector analyses showed significantly better outcomes for femtosecond LASIK than for SMILE in terms of difference vector (DV), index of success (IOS), torque, and flattening index (FI). A trend for undercorrection for higher astigmatism was seen in both groups that was greater in the SMILE group. Both groups showed high safety with the majority of eyes showing postoperative corrected distance VA (CDVA) within 1 line of preoperative CDVA (98.8% versus 91.2%). @*Conclusion@#Although femtosecond LASIK and SMILE have similar predictability at 3 months, femtosecond LASIK has relatively better efficacy and superior astigmatic outcomes than SMILE for the correction of moderate myopic astigmatism.
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AstigmatismoRESUMEN
Background Corticosteroids injected for the treatment of musculoskeletal pain are systemically absorbed and can affect the immune response to viral infections. Purpose To determine the incidence of symptomatic COVID-19 disease in individuals receiving image-guided corticosteroid injections for musculoskeletal pain compared with the general population during the pandemic recovery period. Materials and Methods In this prospective cohort multicenter study, adults with a history of musculoskeletal pain who underwent imaging-guided intra-articular and spine corticosteroid injections from April 2020 to February 2021 were consecutively enrolled. Participants were followed for a minimum of 28 days through their electronic medical record (EMR) or by direct phone communication to screen for COVID-19 test results or symptoms. Clinical data, including body mass index (BMI), were also obtained from the EMR. The incidence of COVID-19 in the state was obtained using the Massachusetts COVID-19 Response Reporting website. The Student t test was used for continuous variable comparisons. Univariable analyses were performed using the Fisher exact test. Results A total of 2714 corticosteroid injections were performed in 2190 adult participants (mean age, 59 years ± 15 [SD]; 1031 women). Follow-up was available for 1960 participants (89%) who received 2484 injections. Follow-up occurred a mean of 97 days ± 33 (range, 28-141 days) after the injection. Of the 1960 participants, 10 had COVID-19 within 28 days from the injection (0.5% [95% CI: 0.24, 0.94]) and 43 had COVID-19 up to 4 months after the injection (2.2% [95% CI: 1.6, 2.9]). These incidence rates were lower than that of the population of Massachusetts during the same period (519 195 of 6 892 503 [7.5%], P < .001 for both 28 days and 4 months). Participants diagnosed with COVID-19 (n = 10) within 28 days from the injection had a higher BMI than the entire cohort (n = 1960) (mean, 32 kg/m2 ± 10 vs 28 kg/m2 ± 6; P = .04). Conclusion Adults who received image-guided corticosteroid injections for pain management during the pandemic recovery period had a lower incidence of symptomatic COVID-19 compared with the general population. © RSNA, 2022 Online supplemental material is available for this article.
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COVID-19 , Dolor Musculoesquelético , Adulto , Humanos , Femenino , Persona de Mediana Edad , Incidencia , Pandemias , Estudios Prospectivos , Inyecciones Intraarticulares/métodos , CorticoesteroidesRESUMEN
BACKGROUND AND PURPOSE: Lumbar spine MRI can help guide the choice of corticosteroid injection in pain management. We investigated whether patient-reported symptom information from a questionnaire could improve agreement in the choice of type, level, and side of injection. MATERIALS AND METHODS: In this prospective observational study, 120 patients (median age 64, 70 men) were recruited from patients referred for pain management. After informed consent, they completed electronic questionnaires that obtained symptom information for later use during MRI reviews. In 3 research arms, 6 radiologists chose injections that would ideally deliver corticosteroid to the presumed sources of pain in (1) MRI studies reviewed with symptom information from questionnaires, (2) MRI studies reviewed without symptom information, and (3) MRI reports. Blinded to questionnaire results, radiologists providing clinical care and interviewing patients chose ideal therapeutic injections to establish reference standards. Injections were categorized by type, level, and side and compared using percent agreement and kappa statistics. Interreading agreement was analyzed. RESULTS: Compared to the reference standard, kappa agreements for injection types, levels, and sides were almost perfect when MRIs were reviewed knowing symptoms (0.85-0.93), fair without symptoms (0.23-0.35) (all P < .001) and fair in MRI reports (0.24-0.36) (all P < .001). Interreading kappa agreements were almost perfect knowing symptoms (0.82-0.90), but only moderate without symptoms (0.42-0.49) (all P < .001). CONCLUSIONS: Radiologists reviewing lumbar spine MRI converged on the type, level, and side of ideal therapeutic injection whether they obtained symptom information from direct patient interview or electronic questionnaire. Observer agreement was significantly lower without symptom information.
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Vértebras Lumbares , Manejo del Dolor , Humanos , Vértebras Lumbares/diagnóstico por imagen , Región Lumbosacra , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Estudios ProspectivosRESUMEN
OBJECTIVE. Imaging plays a critical role in the assessment of patients with femoroacetabular impingement (FAI). With better understanding of the underlying pathomechanics and advances in joint-preserving surgery, there is an increasing need to define the most appropriate imaging workup. The purpose of this article is to provide guidance on best practices for imaging of patients with FAI in light of recent advances in corrective FAI surgery. CONCLUSION. Pelvic radiography with dedicated hip projections is the basis of the diagnostic workup of patients with suspected FAI to assess arthritic changes and acetabular coverage and to screen for cam deformities. Chondrolabral lesions should be evaluated with unenhanced MRI or MR arthrography. The protocol should include a large-FOV fluid-sensitive sequence to exclude conditions that can mimic or coexist with FAI, radial imaging to accurately determine the presence of a cam deformity, and imaging of the distal femoral condyles for measurement of femoral torsion. CT remains a valuable tool for planning of complex surgical corrections. Advanced imaging, such as 3D simulation, biochemical MRI, and MR arthrography with application of leg traction, has great potential to improve surgical decision-making. Further research is needed to assess the added clinical value of these techniques.
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Artrografía/métodos , Pinzamiento Femoroacetabular/diagnóstico por imagen , Cuello Femoral/diagnóstico por imagen , Guías de Práctica Clínica como Asunto , Acetábulo/diagnóstico por imagen , Adulto , Diagnóstico Diferencial , Medicina Basada en la Evidencia , Femenino , Pinzamiento Femoroacetabular/complicaciones , Pinzamiento Femoroacetabular/cirugía , Cabeza Femoral/diagnóstico por imagen , Luxación Congénita de la Cadera/diagnóstico por imagen , Articulación de la Cadera/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Tratamientos Conservadores del Órgano/métodos , Osteoartritis de la Cadera/diagnóstico por imagen , Osteoartritis de la Cadera/etiología , Tomografía Computarizada por Rayos X/métodos , Anomalía Torsional/diagnóstico por imagen , Tracción/métodos , Adulto JovenRESUMEN
BACKGROUND. Lumbar spine MRI is associated with a high prevalence of interpretive errors by radiologists. Treating physicians can obtain symptom information, correlate symptoms with MRI findings, and distinguish presumptive pain generators from incidental abnormalities. OBJECTIVE. The purpose of this study was to capture symptom information using a patient questionnaire, review lumbar spine MRI examinations with and without symptom information, diagnose pain generators, and compare MRI diagnoses with clinical reference diagnoses. METHODS. In this prospective study, 120 participants (70 men and 50 women; median age, 64 years; interquartile range, 49.5-74 years) were recruited from patients referred for lumbar spine injections between February and June 2019. Participants completed electronic questionnaires regarding their symptoms before receiving the injections. For three research arms, six radiologists diagnosed pain generators in MRI studies reviewed with symptom information from questionnaires, MRI studies reviewed without symptom information, and MRI reports. Interreading agreement was analyzed. Blinded to the questionnaire results, the radiologists who performed injections obtained patient histories, correlated symptoms with MRI findings, and diagnosed presumptive pain generators. These diagnoses served as clinical reference standards. Pain generators were categorized by type, level, and side and were compared using kappa statistics. Diagnostic certainty was recorded using numeric values (0-100) and was compared using Wilcoxon rank-sum test RESULTS. When compared with the reference standard, agreement for the type, level, and side of pain generator was almost perfect in MRI examinations reviewed with symptom information (κ = 0.82-0.90), fair to moderate in MRI examinations reviewed without symptom information (κ = 0.28-0.51) (all p < .001), and fair to moderate in MRI reports (κ = 0.27-0.45) (all p < .001). Interreading agreement was almost perfect when MRI examinations were reviewed with symptom information (κ = 0.82-0.90) but was only moderate without symptom information (κ = 0.42-0.56) (all p < .001). Diagnostic certainty levels were highest for radiologists performing injections (mean [± SD], 90.0 ± 9.9) and were significantly higher for MRI review with symptom information versus without symptom information (means for reading 1, 84.6 ± 13.1 vs 62.9 ± 20.7; p < .001). CONCLUSION. In lumbar spine MRI, presumptive pain generators diagnosed using symptom information from electronic questionnaires showed almost perfect agreement with pain generators diagnosed using symptom information from direct patient interviews. CLINICAL IMPACT. Patient-reported symptom information from a brief questionnaire can be correlated with MRI findings to distinguish presumptive pain generators from incidental abnormalities.
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Dolor de la Región Lumbar/diagnóstico por imagen , Vértebras Lumbares/diagnóstico por imagen , Imagen por Resonancia Magnética , Cuestionario de Salud del Paciente , Anciano , Femenino , Humanos , Dolor de la Región Lumbar/etiología , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
BACKGROUND: Musculoskeletal pain is a debilitating problem treated with image-guided corticosteroid injections. During the COVID-19 pandemic, multiple societies issued caution statements because of the unknown effect of corticosteroids on the patient's immune system. The purpose is to determine if image-guided corticosteroid injections administered during the COVID-19 lockdown phase were associated with a higher infection rate compared to the general population. MATERIALS AND METHODS: In a prospective study, patients undergoing image-guided corticosteroid injections for pain management during the lockdown phase between April 15 and May 22, 2020, were enrolled. One month after the injection, patients were surveyed by telephone for any COVID-19-related symptoms, and the electronic medical record (EMR) was reviewed for symptoms and test results. RESULTS: Seventy-one subjects were recruited, 31 (44%) females, 40 (56%) males, ages 58 ± 17 (20-92) years. Follow-up was available in 66 (93%) of subjects, 60 (91%) by phone survey and EMR, 6 (9%) by EMR only, 45 ± 22 (19-83) days after injection. One (1/66, 1.52%; 95% CI 0.04-8.2%) 25-year-old male subject developed symptomatic infection 19 days after a tibiotalar injection. The prevalence of COVID-19 cases in the state of Massachusetts was 0.91% (62,726/6,892,503) during the study period. There was no significant difference in the rate of occurrence of new cases of COVID-19 infection between the corticosteroid injection group and the general population (p = 0.44). CONCLUSION: Image-guided corticosteroid injections for pain management performed during the lockdown phase of the COVID-19 pandemic were not associated with a higher infection rate compared to the general population.
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Corticoesteroides/administración & dosificación , COVID-19/epidemiología , Inyecciones/métodos , Manejo del Dolor , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pacientes Ambulatorios , Pandemias , Estudios ProspectivosRESUMEN
PURPOSE: Ischiofemoral impingement (IFI) is associated with abnormalities of the quadratus femoris muscle and narrowing of the ischiofemoral (IF) and quadratus femoris (QF) spaces. The hip abductors play an important role in pelvic stability and abductor tears might play a role in the pathophysiology of IFI. The purpose of our study was to assess the association between hip abductor tears and IFI on MRI. MATERIALS AND METHODS: The study was IRB approved and HIPAA compliant. Inclusion criteria were MRI findings of IFI (narrowing of the IF space ≤ 15 mm or QF space ≤ 10 mm with associated ipsilateral quadratus femoris edema or fatty infiltration/atrophy). Two MSK radiologists assessed hip/pelvic MRIs and integrity of the tensor fascia lata, gluteus medius, and minimus tendons. IFI and control groups were compared with a two-tailed Student t test or chi-squared test. RESULTS: We identified 140 patients with MRI findings of IFI (mean age 56 ± 13 years, 130 f, 10 m) and 140 controls of similar age and sex. Patients with IFI had a higher prevalence of gluteus medius/minimus partial tears (37 vs 21, p = 0.02) and full-thickness tears (24 vs 21, p = 0.03). Patients with IFI had a higher prevalence and higher grade of gluteal muscle atrophy compared with controls (p < 0.03). There were no tears of the tensor fascia lata in either group. CONCLUSION: Patients with IFI had a higher prevalence of abductor tears and abductor muscle atrophy compared with matched controls. This suggests that abductor tears might play a role in the pathophysiology of IFI.
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Imagen por Resonancia Magnética , Músculo Esquelético , Tendones , Adulto , Anciano , Nalgas/patología , Humanos , Persona de Mediana Edad , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , Atrofia Muscular/patología , Tendones/diagnóstico por imagenRESUMEN
PURPOSE: To determine the value of anesthetic injection during hip MR arthrography (anesthetic MRA) to differentiate between intra- and extra-articular pathology in patients with hip pain. MATERIALS AND METHODS: This retrospective study was IRB-approved and HIPAA-compliant. We included 75 consecutive adult patients (46 women, mean age 38 ± 13 years) who were referred for MRA. All patients underwent a focused hip examination including active flexion, passive flexion, and passive flexion with internal and external rotation, immediately prior to injection. Anesthetic MRA was performed following fluoroscopically guided intra-articular injection of contrast mixed with anesthetic. Following the injection, the hip examination was repeated, and the pain response was recorded. Clinical records, including response to corticosteroid injections, physical therapy notes, and operative reports were reviewed for verification of intra- and extra-articular pathology as the source of hip pain (gold standard). The positive (PPV) and negative predictive values (NPP) of anesthetic MRA to differentiate between intra- and extra-articular pathology were calculated. RESULTS: On MRI, 41 patients had only intra-articular and 5 patients only extra-articular pathology, while 29 patients had both, intra- and extra-articular pathology. Forty-three patients had pain relief and 32 patients had no pain relief after anesthetic injection. PPV of anesthetic MRA to detect intra-articular pathology was 91% and NPV was 67%. CONCLUSION: Anesthetic MRA can be used as an adjunct to define the origin of hip pain. A positive response suggests intra-articular pathology which can be helpful to localize the source of pain in equivocal cases where both intra- and extra-articular pathology are evident on MRI.
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Anestésicos Locales/uso terapéutico , Articulación de la Cadera/diagnóstico por imagen , Artropatías/diagnóstico por imagen , Artropatías/patología , Imagen por Resonancia Magnética/métodos , Dolor/tratamiento farmacológico , Examen Físico/métodos , Adulto , Anestésicos Locales/administración & dosificación , Artrografía/métodos , Enfermedades de los Cartílagos/diagnóstico por imagen , Enfermedades de los Cartílagos/patología , Diagnóstico Diferencial , Femenino , Fluoroscopía , Articulación de la Cadera/patología , Humanos , Inyecciones Intraarticulares , Masculino , Persona de Mediana Edad , Radiografía Intervencional , Rango del Movimiento Articular , Estudios Retrospectivos , Traumatismos de los Tendones/diagnóstico por imagen , Traumatismos de los Tendones/patologíaRESUMEN
Repetitive microtrauma in the elbow from chronic overuse occurs in athletes and nonathletes. Although the diagnosis is often made clinically, imaging is helpful to confirm the diagnosis, grade the injury, and guide treatment. MR imaging is particularly helpful in evaluating overuse injuries in the elbow, as tendons, ligaments, and bones/cartilage can be assessed. Tendinopathy can be distinguished from partial- or full-thickness tears, and reactive changes in the bone marrow can be easily identified. This article focuses on the MR imaging appearance of overuse injuries of the elbow involving tendons, ligaments, and bones.
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Trastornos de Traumas Acumulados/diagnóstico por imagen , Diagnóstico por Imagen/métodos , Lesiones de Codo , Articulación del Codo/diagnóstico por imagen , Humanos , Ligamentos Articulares/diagnóstico por imagen , Ligamentos Articulares/lesiones , Imagen por Resonancia Magnética , Radiografía , Traumatismos de los Tendones/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
The unfolded protein response (UPR) is induced by proteotoxic stress of the endoplasmic reticulum (ER). Here we report that ATF6, a major mammalian UPR sensor, is also activated by specific sphingolipids, dihydrosphingosine (DHS) and dihydroceramide (DHC). Single mutations in a previously undefined transmembrane domain motif that we identify in ATF6 incapacitate DHS/DHC activation while still allowing proteotoxic stress activation via the luminal domain. ATF6 thus possesses two activation mechanisms: DHS/DHC activation and proteotoxic stress activation. Reporters constructed to monitor each mechanism show that phenobarbital-induced ER membrane expansion depends on transmembrane domain-induced ATF6. DHS/DHC addition preferentially induces transcription of ATF6 target lipid biosynthetic and metabolic genes over target ER chaperone genes. Importantly, ATF6 containing a luminal achromatopsia eye disease mutation, unresponsive to proteotoxic stress, can be activated by fenretinide, a drug that upregulates DHC, suggesting a potential therapy for this and other ATF6-related diseases including heart disease and stroke.
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Factor de Transcripción Activador 6/efectos de los fármacos , Retículo Endoplásmico/efectos de los fármacos , Respuesta de Proteína Desplegada/genética , Factor de Transcripción Activador 6/metabolismo , Línea Celular , Retículo Endoplásmico/metabolismo , Estrés del Retículo Endoplásmico/efectos de los fármacos , Fenretinida/farmacología , Humanos , Proteínas Serina-Treonina Quinasas/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Esfingosina/análogos & derivados , Esfingosina/farmacología , Transcripción Genética/efectos de los fármacosRESUMEN
OBJECTIVE: To study anatomical variations on MRI of the first extensor compartment of the wrist in DeQuervain tenosynovitis (DQT). MATERIALS AND METHODS: A retrospective search for DQT patients yielded 47 subjects (51 ± 15 years, 36 female, 11 male). The age-matched control group (normal first extensor compartment) was 49 ± 15 years (29 female, 18 male). Two independent readers reviewed: the number of abductor pollicis longus (APL) tendon slips, tendon sheath septations (compartmentalization), and APL and EPB cross-sectional area (CSA) at the radial styloid. A tendon slip was defined as a discrete structure for ≥5 contiguous slices with its own insertion. RESULTS: The distribution of APL tendon slips was different for the DQT and control groups (Reader 1/Reader 2: P = 0.0001 and 0.001). The most common arrangement for both groups was two APL tendon slips. One tendon slip was less common (P = 0.03 and 0.1) and compartmentalization was more common (P = 0.003; < 0.0001) for the DQT group than the control group. There was no difference in tendon slip insertions on one or multiple bones (P = 0.1; 0.7). APL and EPB compartment CSAs were also higher for the DQT group (combined first extensor compartment area: 21.3 ± 7.6 mm2; 21.0 ± 7.1) than the control group (17.2 ± 3.8; 17.1 ± 3.9) (P = 0.002; 0.002). CONCLUSION: We found a statistically significantly increased proportion of supernumerary tendon slips and compartmentalization of the first extensor compartment in patients with DQT and greater CSA of the first extensor compartment at the radial styloid, consistent with previous anatomical, surgical, and ultrasound studies.
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Enfermedad de De Quervain/diagnóstico por imagen , Enfermedad de De Quervain/patología , Imagen por Resonancia Magnética/métodos , Articulación de la Muñeca/anatomía & histología , Articulación de la Muñeca/diagnóstico por imagen , Puntos Anatómicos de Referencia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
In this study, we used cre-lox techniques to generate mice selectively deficient in ORMDL3 in airway epithelium (Ormdl3Δ2-3/Δ2-3/CC10) to simulate an inhaled therapy that effectively inhibited ORMDL3 expression in the airway. In contrast to the anticipated reduction in airway hyperresponsiveness (AHR), OVA allergen-challenged Ormdl3Δ2-3/Δ2-3/CC10 mice had a significant increase in AHR compared with wild-type mice. Levels of airway inflammation, mucus, fibrosis, and airway smooth muscle were no different in Ormdl3Δ2-3/Δ2-3/CC10 and wild-type mice. However, levels of sphingosine-1-phosphate (S1P) were significantly increased in Ormdl3Δ2-3/Δ2-3/CC10 mice as well as in airway epithelial cells in which ORMDL3 was inhibited with small interfering RNA. Incubation of S1P with airway smooth muscle cells significantly increased contractility. Overall, Ormdl3Δ2-3/Δ2-3/CC10 mice exhibit increased allergen-induced AHR independent of inflammation and associated with increased S1P generation. These studies raise concerns for inhaled therapies that selectively and effectively inhibit ORMDL3 in airway epithelium in asthma.
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Asma/metabolismo , Proteínas de la Membrana/antagonistas & inhibidores , Hipersensibilidad Respiratoria/metabolismo , Animales , Asma/inmunología , Modelos Animales de Enfermedad , Lisofosfolípidos/inmunología , Lisofosfolípidos/metabolismo , Proteínas de la Membrana/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Reacción en Cadena de la Polimerasa , Hipersensibilidad Respiratoria/inmunología , Esfingosina/análogos & derivados , Esfingosina/inmunología , Esfingosina/metabolismoRESUMEN
Activation of the IRE1α-XBP1 branch of the unfolded protein response (UPR) has been implicated in multiple types of human cancers, including multiple myeloma (MM). Through an in silico drug discovery approach based on protein-compound virtual docking, we identified the anthracycline antibiotic doxorubicin as an in vitro and in vivo inhibitor of XBP1 activation, a previously unknown activity for this widely utilized cancer chemotherapeutic drug. Through a series of mechanistic and phenotypic studies, we showed that this novel activity of doxorubicin was not due to inhibition of topoisomerase II (Topo II). Consistent with its inhibitory activity on the IRE1α-XBP1 branch of the UPR, doxorubicin displayed more potent cytotoxicity against MM cell lines than other cancer cell lines that have lower basal IRE1α-XBP1 activity. In addition, doxorubicin significantly inhibited XBP1 activation in CD138(+) tumor cells isolated from MM patients. Our findings suggest that the UPR-modulating activity of doxorubicin may be utilized clinically to target IRE1α-XBP1-dependent tumors such as MM.
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Doxorrubicina/farmacología , Endorribonucleasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Respuesta de Proteína Desplegada/efectos de los fármacos , Proteína 1 de Unión a la X-Box/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Doxorrubicina/química , Etopósido/química , Etopósido/farmacología , Humanos , Empalme del ARN/genética , Inhibidores de Topoisomerasa/farmacologíaRESUMEN
Using a luciferase reporter-based high-throughput chemical library screen and topological data analysis, we identified N-acridine-9-yl-N',N'-dimethylpropane-1,3-diamine (DAPA) as an inhibitor of the inositol requiring kinase 1α (IRE1α)-X-box binding protein-1 (XBP1) pathway of the unfolded protein response. We designed a collection of analogues based on the structure of DAPA to explore structure-activity relationships and identified N(9)-(3-(dimethylamino)propyl)-N(3),N(3),N(6),N(6)-tetramethylacridine-3,6,9-triamine (3,6-DMAD), with 3,6-dimethylamino substitution on the chromophore, as a potent inhibitor. 3,6-DMAD inhibited both IRE1α oligomerization and in vitro endoribonuclease (RNase) activity, whereas the other analogues only blocked IRE1α oligomerization. Consistent with the inhibition of IRE1α-mediated XBP1 splicing, which is critical for multiple myeloma cell survival, these analogues were cytotoxic to multiple myeloma cell lines. Furthermore, 3,6-DMAD inhibited XBP1 splicing in vivo and the growth of multiple myeloma tumor xenografts. Our study not only confirmed the utilization of topological data analysis in drug discovery but also identified a class of compounds with a unique mechanism of action as potent IRE1α-XBP1 inhibitors in the treatment of multiple myeloma. Mol Cancer Ther; 15(9); 2055-65. ©2016 AACR.
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Acridinas/farmacología , Antineoplásicos/farmacología , Endorribonucleasas/metabolismo , Mieloma Múltiple/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína 1 de Unión a la X-Box/metabolismo , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Análisis por Conglomerados , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Ensayos de Selección de Medicamentos Antitumorales , Endorribonucleasas/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ensayos Analíticos de Alto Rendimiento , Humanos , Ratones , Mieloma Múltiple/genética , Proteínas Serina-Treonina Quinasas/genética , Proteína 1 de Unión a la X-Box/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
An evolutionarily conserved unfolded protein response (UPR) component, IRE1, cleaves XBP1/HAC1 introns in order to generate spliced mRNAs that are translated into potent transcription factors. IRE1 also cleaves endoplasmic-reticulum-associated RNAs leading to their decay, an activity termed regulated IRE1-dependent decay (RIDD); however, the mechanism by which IRE1 differentiates intron cleavage from RIDD is not well understood. Using in vitro experiments, we found that IRE1 has two different modes of action: XBP1/HAC1 is cleaved by IRE1 subunits acting cooperatively within IRE1 oligomers, whereas a single subunit of IRE1 performs RIDD without cooperativity. Furthermore, these distinct activities can be separated by complementation of catalytically inactive IRE1 RNase and mutations at oligomerization interfaces. Using an IRE1 RNase inhibitor, STF-083010, selective inhibition of XBP1 splicing indicates that XBP1 promotes cell survival, whereas RIDD leads to cell death, revealing modulation of IRE1 activities as a drug-development strategy.
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Biocatálisis , Proteínas de Unión al ADN/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Empalme del ARN , Estabilidad del ARN , Proteínas de Saccharomyces cerevisiae/metabolismo , Factores de Transcripción/metabolismo , Animales , Muerte Celular , Linaje de la Célula , Endorribonucleasas , Glicoproteínas de Membrana/química , Ratones , Modelos Moleculares , Multimerización de Proteína , Proteínas Serina-Treonina Quinasas/química , Estructura Terciaria de Proteína , ARN de Hongos/metabolismo , Factores de Transcripción del Factor Regulador X , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Relación Estructura-Actividad , Especificidad por Sustrato , Proteína 1 de Unión a la X-BoxRESUMEN
Orosomucoid-like (ORMDL)3 has been strongly linked with asthma in genetic association studies. Because allergen challenge induces lung ORMDL3 expression in wild-type mice, we have generated human ORMDL3 zona pellucida 3 Cre (hORMDL3(zp3-Cre)) mice that overexpress human ORMDL3 universally to investigate the role of ORMDL3 in regulating airway inflammation and remodeling. These hORMDL3(zp3-Cre) mice have significantly increased levels of airway remodeling, including increased airway smooth muscle, subepithelial fibrosis, and mucus. hORMDL3(zp3-Cre) mice had spontaneously increased airway responsiveness to methacholine compared to wild-type mice. This increased airway remodeling was associated with selective activation of the unfolded protein response pathway transcription factor ATF6 (but not Ire1 or PERK). The ATF6 target gene SERCA2b, implicated in airway remodeling in asthma, was strongly induced in the lungs of hORMDL3(zp3-Cre) mice. Additionally, increased levels of expression of genes associated with airway remodeling (TGF-ß1, ADAM8) were detected in airway epithelium of these mice. Increased levels of airway remodeling preceded increased levels of airway inflammation in hORMDL3(zp3-Cre) mice. hORMDL3(zp3-Cre) mice had increased levels of IgE, with no change in levels of IgG, IgM, and IgA. These studies provide evidence that ORMDL3 plays an important role in vivo in airway remodeling potentially through ATF6 target genes such as SERCA2b and/or through ATF6-independent genes (TGF-ß1, ADAM8).
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Remodelación de las Vías Aéreas (Respiratorias)/genética , Remodelación de las Vías Aéreas (Respiratorias)/inmunología , Asma/genética , Asma/inmunología , Proteínas de la Membrana/genética , Factor de Transcripción Activador 6/metabolismo , Alérgenos/inmunología , Animales , Especificidad de Anticuerpos/inmunología , Asma/patología , Hiperreactividad Bronquial/inducido químicamente , Quimiocinas CC/metabolismo , Quimiocinas CXC/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Eosinófilos/inmunología , Eosinófilos/metabolismo , Expresión Génica , Orden Génico , Marcación de Gen , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Cloruro de Metacolina/administración & dosificación , Ratones , Ratones Transgénicos , Ovalbúmina/inmunología , Células Th2/inmunología , Células Th2/metabolismo , Transgenes , Respuesta de Proteína Desplegada , eIF-2 Quinasa/metabolismoRESUMEN
The objective of this study is to determine whether presbycusis occurs much earlier than previously believed if the high frequency (above 8 kHz) are included. Tertiary referral center (a teaching University). This is a cross-sectional observational study. Healthy adults from 20 to 49 years of age who had essentially normal hearing were included into the study. They were subjected to high frequency pure tone audiometry (until 16 kHz). Participants were grouped based on age ranges of 10 years (e.g., 20-29, 30-39, and 40-49) and the presence of symmetrical high frequency sensor neural hearing loss were documented. There is a significant presence of symmetrical high frequency sensor neural hearing loss (not attributed to any known risk factors) as early as from the age group of 40 to 49 years. Seven of 43 participants (16%) from age group of 20 to 29 years and 12 of 24 participants (50%) from age group of 30 to 39 years had significant high frequency hearing loss. High frequency hearing loss (high frequency Presbycusis) may occur much earlier than previously believed.
RESUMEN
NF-κB, a transcription factor, becomes activated during the Unfolded Protein Response (UPR), an endoplasmic reticulum (ER) stress response pathway. NF-κB is normally held inactive by its inhibitor, IκBα. Multiple cellular pathways activate IKK (IκBα Kinase) which phosphorylate IκBα leading to its degradation and NF-κB activation. Here, we find that IKK is required for maximum activation of NF-κB in response to ER stress. However, unlike canonical NFκB activation, IKK activity does not increase during ER stress, but rather the level of basal IKK activity is critical for determining the extent of NF-κB activation. Furthermore, a key UPR initiator, IRE1, acts to maintain IKK basal activity through IRE1's kinase, but not RNase, activity. Inputs from IRE1 and IKK, in combination with translation repression by PERK, another UPR initiator, lead to maximal NF-κB activation during the UPR. These interdependencies have a significant impact in cancer cells with elevated IKK/NF-κB activity such as renal cell carcinoma cells (786-0). Inhibition of IKK by an IKK inhibitor, which significantly decreases NF-κB activity, is overridden by UPR induction, arguing for the importance of considering UPR activation in cancer treatment.
Asunto(s)
Estrés del Retículo Endoplásmico/fisiología , Quinasa I-kappa B/metabolismo , FN-kappa B/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , eIF-2 Quinasa/metabolismo , Animales , Western Blotting , Células CHO , Línea Celular , Inmunoprecipitación de Cromatina , Cricetinae , Ensayo de Cambio de Movilidad Electroforética , Estrés del Retículo Endoplásmico/genética , Endorribonucleasas/genética , Endorribonucleasas/metabolismo , Humanos , Quinasa I-kappa B/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , FN-kappa B/genética , Células 3T3 NIH , Proteínas Serina-Treonina Quinasas/genética , eIF-2 Quinasa/genéticaRESUMEN
Orosomucoid like 3 (ORMDL3) has been strongly linked with asthma in genetic association studies, but its function in asthma is unknown. We demonstrate that in mice ORMDL3 is an allergen and cytokine (IL-4 or IL-13) inducible endoplasmic reticulum (ER) gene expressed predominantly in airway epithelial cells. Allergen challenge induces a 127-fold increase in ORMDL3 mRNA in bronchial epithelium in WT mice, with lesser 15-fold increases in ORMDL-2 and no changes in ORMDL-1. Studies of STAT-6-deficient mice demonstrated that ORMDL3 mRNA induction highly depends on STAT-6. Transfection of ORMDL3 in human bronchial epithelial cells in vitro induced expression of metalloproteases (MMP-9, ADAM-8), CC chemokines (CCL-20), CXC chemokines (IL-8, CXCL-10, CXCL-11), oligoadenylate synthetases (OAS) genes, and selectively activated activating transcription factor 6 (ATF6), an unfolded protein response (UPR) pathway transcription factor. siRNA knockdown of ATF-6α in lung epithelial cells inhibited expression of SERCA2b, which has been implicated in airway remodeling in asthma. In addition, transfection of ORMDL3 in lung epithelial cells activated ATF6α and induced SERCA2b. These studies provide evidence of the inducible nature of ORMDL3 ER expression in particular in bronchial epithelial cells and suggest an ER UPR pathway through which ORMDL3 may be linked to asthma.