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1.
Proc Natl Acad Sci U S A ; 121(7): e2314346121, 2024 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-38315837

RESUMEN

Tobacco and alcohol are risk factors for human papillomavirus-negative head and neck squamous cell carcinoma (HPV- HNSCC), which arises from the mucosal epithelium of the upper aerodigestive tract. Notably, despite the mutagenic potential of smoking, HPV- HNSCC exhibits a low mutational load directly attributed to smoking, which implies an undefined role of smoking in HPV- HNSCC. Elevated YAP (Yes-associated protein) mRNA is prevalent in HPV- HNSCC, irrespective of the YAP gene amplification status, and the mechanism behind this upregulation remains elusive. Here, we report that oxidative stress, induced by major risk factors for HPV- HNSCC such as tobacco and alcohol, promotes YAP transcription via TM4SF19 (transmembrane 4 L six family member 19). TM4SF19 modulates YAP transcription by interacting with the GABP (Guanine and adenine-binding protein) transcription factor complex. Mechanistically, oxidative stress induces TM4SF19 dimerization and topology inversion in the endoplasmic reticulum membrane, which in turn protects the GABPß1 subunit from proteasomal degradation. Conversely, depletion of TM4SF19 impairs the survival, proliferation, and migration of HPV- HNSCC cells, highlighting the potential therapeutic relevance of targeting TM4SF19. Our findings reveal the roles of the key risk factors of HPV- HNSCC in tumor development via oxidative stress, offering implications for upcoming therapeutic approaches in HPV- HNSCC.


Asunto(s)
Neoplasias de Cabeza y Cuello , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Neoplasias de Cabeza y Cuello/genética , Papillomaviridae , Infecciones por Papillomavirus/patología , Factores de Riesgo , Carcinoma de Células Escamosas de Cabeza y Cuello/genética
2.
Ophthalmology ; 131(3): 322-332, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37739232

RESUMEN

PURPOSE: To evaluate the incidence of new retinal artery occlusion (RAO) and retinal vein occlusion (RVO) after the diagnosis of coronavirus disease 2019 (COVID-19) or vaccination against COVID-19 and compare the incidences with the population with neither. DESIGN: Nationwide population-based cohort study. PARTICIPANTS: From a nationwide population-based cohort, 8 418 590 patients were categorized into control (group 1), COVID-19 infection (group 2), and COVID-19 vaccination (group 3) groups. METHODS: The cumulative incidence of RAO and RVO was calculated in groups 1, 2, and 3 using the Kaplan-Meier method. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) based on the Poisson distribution for RAO and RVO according to each group and subgroup using Cox proportional hazards models, with group 1 as the reference. We conducted univariable and multivariable analyses for the risk factors of RAO and RVO according to each subgroup. MAIN OUTCOME MEASURES: Cumulative incidence and risks of incidence of RAO and RVO from the index date to day 60. RESULTS: In multivariable analysis, no significant increase in RAO and RVO risks after COVID-19 or COVID-19 vaccination were observed in either men or women. These results were observed consistently across various conditions in sensitivity analyses. In subgroup analysis, individuals who were vaccinated before infection showed no significant increase in RAO or RVO risks in both sexes compared with the control group. In the subgroup analysis of vaccinated patients, the HRs of RAO and RVO for different vaccine types did not show an increase compared with the control group; however, an exception was observed in women who received mRNA-1273 vaccines, who showed a higher RAO HR (4.65; 95% CI, 1.27-17.03; P = 0.021). CONCLUSIONS: Within 60 days of COVID-19 diagnosis or vaccination, RAO and RVO occurred rarely. We observed no increase in the HR of RVO and RAO relative to COVID-19 or COVID-19 vaccination except for a possible increase in the RAO HR in women who received mRNA-1273, for which the raw incidence was extremely low. Further investigation is required to validate this result. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.


Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Oclusión de la Arteria Retiniana , Oclusión de la Vena Retiniana , Femenino , Humanos , Masculino , Vacuna nCoV-2019 mRNA-1273 , Estudios de Cohortes , COVID-19/epidemiología , COVID-19/prevención & control , COVID-19/complicaciones , Prueba de COVID-19 , Vacunas contra la COVID-19/efectos adversos , Arteria Retiniana , Oclusión de la Arteria Retiniana/etiología , Oclusión de la Arteria Retiniana/complicaciones , Oclusión de la Vena Retiniana/epidemiología , Oclusión de la Vena Retiniana/etiología , Oclusión de la Vena Retiniana/diagnóstico , Vacunación/efectos adversos
3.
Proc Natl Acad Sci U S A ; 117(33): 19994-20003, 2020 08 18.
Artículo en Inglés | MEDLINE | ID: mdl-32747557

RESUMEN

The transcriptional regulator YAP, which plays important roles in the development, regeneration, and tumorigenesis, is activated when released from inhibition by the Hippo kinase cascade. The regulatory mechanism of YAP in Hippo-low contexts is poorly understood. Here, we performed a genome-wide RNA interference screen to identify genes whose loss of function in a Hippo-null background affects YAP activity. We discovered that the coatomer protein complex I (COPI) is required for YAP nuclear enrichment and that COPI dependency of YAP confers an intrinsic vulnerability to COPI disruption in YAP-driven cancer cells. We identified MAP2K3 as a YAP regulator involved in inhibitory YAP phosphorylation induced by COPI subunit depletion. The endoplasmic reticulum stress response pathway activated by COPI malfunction appears to connect COPI and MAP2K3. In addition, we provide evidence that YAP inhibition by COPI disruption may contribute to transcriptional up-regulation of PTGS2 and proinflammatory cytokines. Our study offers a resource for investigating Hippo-independent YAP regulation as a therapeutic target for cancers and suggests a link between YAP and COPI-associated inflammatory diseases.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteína Coat de Complejo I/metabolismo , MAP Quinasa Quinasa 3/metabolismo , Neoplasias/metabolismo , Interferencia de ARN , Factores de Transcripción/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Línea Celular Tumoral , Proteína Coat de Complejo I/genética , Regulación Neoplásica de la Expresión Génica , Genoma , Vía de Señalización Hippo , Humanos , MAP Quinasa Quinasa 3/genética , Ratones , Neoplasias/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Factores de Transcripción/genética , Proteínas Señalizadoras YAP
4.
Graefes Arch Clin Exp Ophthalmol ; 260(5): 1713-1721, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-34762167

RESUMEN

PURPOSE: This study aims to report complications, treatments, and visual prognosis of choroidal osteoma. METHODS: We retrospectively reviewed electronic medical records and multimodal images of 41 patients with choroidal osteoma. RESULTS: Visually significant complications included choroidal neovascularization (CNV) in 21 (47.7%) eyes and subretinal fluid (SRF) without CNV in 14 (31.8%) eyes. The most common treatment was intravitreal anti-vascular endothelial growth factor (VEGF) injection: 13 (61.9%) eyes with CNV received an average of 6.3 injections, and 6 (42.9%) eyes with SRF but without CNV received 1.8 injections. As the first-line treatment, intravitreal anti-VEGF injection induced complete or partial remission in 93.4% of eyes with CNV and 57.1% of eyes with SRF. The probability of legally low vision estimated at 3 and at 5 years was 29.1% and 34.2%, respectively. The presence of CNV and outer retinal tubulation (ORT) was independent risk factors for vision loss (adjusted odds ratio, 8.08 and 6.94, respectively). CONCLUSIONS: The development of CNV and ORT was strong risk factors for visual impairment. Due to the frequent recurrence of complications and poor visual prognosis, regular check-ups and appropriate treatment choices are warranted.


Asunto(s)
Neovascularización Coroidal , Osteoma , Inhibidores de la Angiogénesis/uso terapéutico , Neovascularización Coroidal/tratamiento farmacológico , Angiografía con Fluoresceína , Humanos , Inyecciones Intravítreas , Osteoma/complicaciones , Osteoma/diagnóstico , Osteoma/tratamiento farmacológico , Pronóstico , Ranibizumab , Estudios Retrospectivos , Tomografía de Coherencia Óptica , Factor A de Crecimiento Endotelial Vascular , Agudeza Visual
5.
Cancer Immunol Immunother ; 69(12): 2441-2452, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32556494

RESUMEN

Ocular adverse events (OAEs) including vision-threatening intraocular inflammation after immune checkpoint inhibitor (ICI) treatment have been increasingly reported; however, the risk factors associated with OAEs remain elusive. Here, we determined the factors associated with OAEs after ICI treatment. We analyzed 40 consecutive patients who experienced OAEs after ICI treatments. The OAEs included anterior uveitis, chorioretinitis, papillitis, foveal interdigitation zone thickening/serous retinal detachment (IZT/SRD), retinal vascular occlusion, and strabismus and ptosis. Of 40 patients, 18 (45%) were treated with atezolizumab, 13 (33%) with pembrolizumab, 7 (18%) with nivolumab, 1 (3%) with ipilimumab/nivolumab, and the other 1 (3%) with durvalumab/tremelimumab. BRAF/MEK inhibitors were concurrently used in 19 (48%) patients. Occurrence of intraocular inflammation was significantly associated with previous ocular surgery and trauma history (P = 0.015) and pembrolizumab use (P = 0.031). Neuro-ophthalmic complications and IZT/SRD were associated with brain metastasis (P = 0.005) and treatment with BRAF/MEK inhibitor (P < 0.001), respectively. In extensive literature review for clinical cases, we identified seven cases with intraocular inflammation, which were not observed with ipilimumab treatment, that occurred after a change of the drug to pembrolizumab. Collectively, these findings provide better understandings of OAEs after ICI treatment.


Asunto(s)
Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Oftalmopatías/epidemiología , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/inmunología , Sustitución de Medicamentos/efectos adversos , Oftalmopatías/inducido químicamente , Oftalmopatías/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Estudios Retrospectivos , Factores de Riesgo
6.
Cell Mol Life Sci ; 76(19): 3695-3709, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31147753

RESUMEN

Ciliopathies are a group of hereditary disorders that result from structural or functional abnormalities of cilia. Recent intense research efforts have uncovered the genetic bases of ciliopathies, and our understanding of the assembly and functions of cilia has been improved significantly. Although mechanism-specific therapies for ciliopathies have not yet received regulatory approval, the use of innovative therapeutic modalities such as oligonucleotide therapy, gene replacement therapy, and gene editing in addition to symptomatic treatments are expected to provide valid treatment options in the near future. Moreover, candidate chemical compounds for developing small molecule drugs to treat ciliopathies have been identified. This review introduces the key features of cilia and ciliopathies, and summarizes the advances as well as the challenges that remain with the development of therapies for treating ciliopathies.


Asunto(s)
Ciliopatías/terapia , Cilios/efectos de los fármacos , Ciliopatías/tratamiento farmacológico , Edición Génica , Terapia Genética , Humanos , Oligonucleótidos/uso terapéutico , Especificidad de Órganos
7.
Molecules ; 25(8)2020 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-32316426

RESUMEN

Ginkgo biloba leaf (GBL) is known as a potential source of bioactive flavonoids, such as quercetin, arresting the neuronal soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-zippering. Here, the GBL flavonoids were isolated in two different manners and then examined for their bioactivity, physicochemical stability, and biocompatibility. The majority of flavonoids in the non-hydrolyzed and acidolyzed isolates, termed non-hydrolyzed isolate (NI) and acidolyzed isolate (AI) hereafter, were rich in flavonol glycosides and aglycones, respectively. Glycosidic/aglyconic quercetin and kaempferol were abundant in both NI and AI, whereas a little of apigenin, luteolin, and isorhamnetin were found in AI. NI was more thermostable in all pH ranges than quercetin, kaempferol, and AI. NI and AI both inhibited neurotransmitter release from differentiated neuronal PC-12 cells. NI and AI showed 1/2-1/3 lower EC50/CC50 values than quercetin and kaempferol. The NI and AI exhibited no toxicity assessed by the tests on chorioallantoic membranes of hen's eggs, removing toxicological concerns of irritation potential. Moreover, GBL isolates, particularly AI, showed antioxidant and anti-inflammatory activities in the use below the CC50 levels. Taken together, these results suggest that GBL isolates that are rich in antioxidant flavonoids are effective anti-neuroexocytotic agents with high stability and low toxicity.


Asunto(s)
Exocitosis/efectos de los fármacos , Flavonoides/química , Flavonoides/farmacología , Ginkgo biloba/química , Neuronas/efectos de los fármacos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Hojas de la Planta/química , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antioxidantes/química , Antioxidantes/farmacología , Supervivencia Celular , Cromatografía Líquida de Alta Presión , Flavonoides/aislamiento & purificación , Concentración de Iones de Hidrógeno , Ratones , Extractos Vegetales/aislamiento & purificación , Relación Estructura-Actividad , Transmisión Sináptica/efectos de los fármacos , Espectrometría de Masas en Tándem
8.
Ophthalmology ; 2024 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-38804993
10.
Retina ; 36(8): 1469-73, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26735562

RESUMEN

PURPOSE: To investigate the incidence of and risk factors for a dissociated optic nerve fiber layer (DONFL) after epiretinal membrane surgery. METHODS: Two hundred and ninety-six primary pars plana vitrectomy operations for epiretinal membrane that were eligible for inclusion in the study. All patients received a complete ophthalmologic examination and color fundus photography, optical coherence tomography preoperatively and postoperatively. DONFL group and non-DONFL group was compared. Univariate and multivariate analyses were performed to establish the risk factors for DONFL. RESULTS: A DONFL developed in 30 of the 296 eyes (incidence, 10.1%). Internal limiting membrane (ILM) peeling was performed in 29 of 30 eyes (96.7%) in the DONFL group and 126 of 266 eyes (47.4%) in the control group (P < 0.001). Intravitreal gas tamponade was performed in 21 eyes (70.0%) in the DONFL group and 133 eyes (50.0%) in the control group (P = 0.038). The ILM peeling (odds ratio, 32.22 [4.33-240.0]; P = 0.001) and intravitreal gas tamponade (odds ratio, 2.33 [1.03-5.28]; P = 0.042) were significantly associated with DONFL. CONCLUSION: It was found that ILM peeling and intravitreal gas tamponade were correlated with postoperative DONFL. The ILM peeling with intravitreal gas tamponade was more strongly correlated with postoperative DONFL formation than was ILM peeling alone.


Asunto(s)
Membrana Epirretinal/cirugía , Fibras Nerviosas/patología , Enfermedades del Nervio Óptico/epidemiología , Nervio Óptico/patología , Complicaciones Posoperatorias , Vitrectomía , Anciano , Colorantes/administración & dosificación , Endotaponamiento , Femenino , Fluorocarburos/administración & dosificación , Humanos , Incidencia , Verde de Indocianina/administración & dosificación , Masculino , Persona de Mediana Edad , Enfermedades del Nervio Óptico/diagnóstico , Factores de Riesgo , Hexafluoruro de Azufre/administración & dosificación , Tomografía de Coherencia Óptica , Agudeza Visual/fisiología
11.
Ophthalmic Plast Reconstr Surg ; 32(4): e81-3, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-25105523

RESUMEN

Granulicatella elegans is a normal component of the oral flora and is an unusual causative agent of infective endocarditis. A case of G. elegans periorbital infection of the eyelid after dental treatment is reported. A healthy 35-year-old man presented with painful swelling of the left upper eyelid. He was empirically treated with oral amoxicillin for 1 week. He presented 3 months later with the same clinical features. G. elegans and Staphylococcus epidermidis were identified in bacterial cultures from wound aspirates. Probable relapse of periorbital infection was successfully treated with a 6-week course of oral amoxicillin. This is the first reported case of a non-bloodstream infection caused by G. elegans. Clinicians should be aware of G. elegans as an unusual causative agent of periorbital infection. Within the limitations of this case report, prolonged antibiotic therapy is recommended for a G. elegans periorbital infection to minimize the risk of relapse.


Asunto(s)
Carnobacteriaceae/aislamiento & purificación , Infecciones Bacterianas del Ojo/microbiología , Enfermedades de los Párpados/microbiología , Órbita/microbiología , Ortodoncia/métodos , Adulto , Infecciones Bacterianas del Ojo/diagnóstico , Infecciones Bacterianas del Ojo/terapia , Enfermedades de los Párpados/diagnóstico , Enfermedades de los Párpados/terapia , Estudios de Seguimiento , Humanos , Masculino , Órbita/diagnóstico por imagen , Tomografía Computarizada por Rayos X
12.
Retina ; 35(12): 2529-36, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26035515

RESUMEN

PURPOSE: To measure fluctuations in infusion pressure and intraocular pressure (IOP) during vitrectomy performed using a flow-based IOP control system. METHODS: Using 3 vitrectomized porcine eyes, the authors simultaneously measured infusion pressure and IOP during vitreous cutting and aspiration and after extraction of operative instruments in 23-gauge and 25-gauge system. The measurements were performed with the "IOP control" setting turned on or off. The efficacy of valved cannula and a built-in "IOP control limit" module in attenuation of infusion pressure fluctuation was evaluated. RESULTS: At set pressure of 30 mmHg and 60 mmHg, the mean infusion pressure levels were 43.7 mmHg and 78.7 mmHg in the vitreous cutting mode, 67.4 mmHg and 101.2 mmHg in the aspiration mode, and 72.8 mmHg and 115.8 mmHg after extraction of the operative instrument, respectively, when the 23-gauge system was used. Use of valved cannulas effectively attenuated fluctuations in both infusion pressure and IOP. When the IOP control limit setting was "on," the compensatory infusion pressure increase was markedly limited and similar to the set pressure level when the IOP control limit was set at Level 2. Similar results were obtained when a 25-gauge system was used. CONCLUSION: Infusion pressure increased markedly during vitrectomy using a flow-based IOP control system.


Asunto(s)
Presión Intraocular/fisiología , Microcirugia/métodos , Vitrectomía/métodos , Cuerpo Vítreo/cirugía , Animales , Bombas de Infusión , Periodo Intraoperatorio , Modelos Animales , Monitoreo Intraoperatorio , Presión , Enfermedades de la Retina/cirugía , Porcinos
13.
Retina ; 35(5): 935-43, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25574784

RESUMEN

PURPOSE: To assess the changes in diabetic retinopathy (DR) in Type 2 diabetes (T2DM) patients after bariatric surgery. METHODS: Consecutive 20 patients with T2DM who underwent bariatric surgery and were followed for at least 12 months were enrolled. The case history was reviewed retrospectively, and laboratory data were assessed at baseline and every 3 months postoperatively. Two retinal specialists evaluated the severity of DR with dilated fundus examination preoperatively and postoperatively. Factors associated with DR progression were assessed. RESULTS: During the follow-up period, 2 of 12 patients without DR and 2 of 3 patients with mild nonproliferative DR before surgery developed moderate nonproliferative DR. All five patients with moderate nonproliferative DR or worse preoperatively had progression requiring intervention. Preexisting DR (P = 0.005) and albuminuria (P = 0.01) were identified as associated with DR progression. Six patients (30%) entered remission of T2DM, but remission of T2DM could not halt the DR progression. CONCLUSION: Diabetic retinopathy progression can occur in patients with or without before DR after bariatric surgery, regardless of remission of T2DM. All patients with T2DM should be examined regularly by an ophthalmologist postoperatively, and more carefully patients with previous DR or albuminuria.


Asunto(s)
Cirugía Bariátrica , Diabetes Mellitus Tipo 2/fisiopatología , Diabetes Mellitus Tipo 2/cirugía , Retinopatía Diabética/fisiopatología , Adulto , Pueblo Asiatico/etnología , Creatinina/sangre , Diabetes Mellitus Tipo 2/etnología , Retinopatía Diabética/diagnóstico , Retinopatía Diabética/etnología , Progresión de la Enfermedad , Femenino , Angiografía con Fluoresceína , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , República de Corea , Estudios Retrospectivos , Factores de Riesgo , Tomografía de Coherencia Óptica , Agudeza Visual/fisiología
14.
Molecules ; 20(1): 249-92, 2014 Dec 24.
Artículo en Inglés | MEDLINE | ID: mdl-25547726

RESUMEN

Curcumin is a natural product with several thousand years of heritage. Its traditional Asian application to human ailments has been subjected in recent decades to worldwide pharmacological, biochemical and clinical investigations. Curcumin's Achilles heel lies in its poor aqueous solubility and rapid degradation at pH ~ 7.4. Researchers have sought to unlock curcumin's assets by chemical manipulation. One class of molecules under scrutiny are the monocarbonyl analogs of curcumin (MACs). A thousand plus such agents have been created and tested primarily against cancer and inflammation. The outcome is clear. In vitro, MACs furnish a 10-20 fold potency gain vs. curcumin for numerous cancer cell lines and cellular proteins. Similarly, MACs have successfully demonstrated better pharmacokinetic (PK) profiles in mice and greater tumor regression in cancer xenografts in vivo than curcumin. The compounds reveal limited toxicity as measured by murine weight gain and histopathological assessment. To our knowledge, MAC members have not yet been monitored in larger animals or humans. However, Phase 1 clinical trials are certainly on the horizon. The present review focuses on the large and evolving body of work in cancer and inflammation, but also covers MAC structural diversity and early discovery for treatment of bacteria, tuberculosis, Alzheimer's disease and malaria.


Asunto(s)
Curcumina/química , Imitación Molecular , Animales , Cristalografía por Rayos X , Curcumina/farmacocinética , Curcumina/farmacología , Curcumina/uso terapéutico , Humanos , Inflamación/tratamiento farmacológico , Ratones , Neoplasias/tratamiento farmacológico
15.
Am J Ophthalmol ; 258: 22-31, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37739204

RESUMEN

PURPOSE: To investigate the incidence and risk of noninfectious uveitis (NIU) following COVID-19 vaccination compared with an unvaccinated, uninfected control group. DESIGN: Retrospective population-based cohort study. METHODS: We included 5,185,153 individuals who received the first vaccine dose in the exposed group and 2,680,164 individuals in the unexposed, uninfected control group. The study observed for 180 days from their index date. Cumulative incidence and risk of NIU following COVID-19 vaccination, and attributable risk factors were assessed. RESULTS: Multivariable analysis showed elevated risk of nonanterior NIU within 60 days (hazard ratio [HR] 1.27 [95% confidence interval {CI} 1.03-1.55] and 61-180 days (HR 1.39 [95% CI 1.20-1.62]). Subgroup analysis highlighted an increased risk in females for early and delayed nonanterior uveitis (HR 1.44 [95% CI 1.08-1.92]; HR 1.78 [95% CI 1.43-2.20], respectively). Regardless of the location and onset timing of uveitis, a history of NIU was identified as the most significant risk factor, with a high hazard ratio ranging from 100 to 200. CONCLUSIONS: COVID-19 vaccination may modestly increase the risk of nonanterior uveitis especially in females. Despite adjustments, bias may persist in the exposed group, owing to significant differences between unexposed and exposed groups and low incidence of nonanterior uveitis in the unexposed group. Future research should aim to refine these findings by assessing uveitis risk in prior NIU patients and by enlarging the sample size or cohort matching.


Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Uveítis , Femenino , Humanos , Estudios de Cohortes , COVID-19/epidemiología , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Estudios Retrospectivos , Uveítis/epidemiología , Uveítis/etiología , Vacunación/efectos adversos
16.
Am J Ophthalmol ; 2024 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-38977151

RESUMEN

PURPOSE: To compare the incidence of noninfectious uveitis in skin melanoma or lung cancer patients who received BRAF inhibitors with that in those who received immune checkpoint inhibitors (ICIs) or conventional cytotoxic chemotherapy. DESIGN: Nationwide population-based retrospective clinical cohort study METHODS: From the Health Insurance Review and Assessment Service database of South Korea, we retrospectively defined 77,323 patients with skin melanoma or lung cancer who received BRAF inhibitor therapy (BRAF inhibitor-exposed group; n = 396), ICIs (ICI-exposed group; n = 22,474), or conventional cytotoxic chemotherapy (unexposed group; n = 54,453). We calculated the 1-year cumulative incidence of noninfectious uveitis in each group from the first day of BRAF inhibitor, ICI, or cytotoxic agent administration. RESULTS: During the first year of treatment initiation, the cumulative incidence of uveitis was 0.33%, 0.35%, and 2.27% in the unexposed, ICI-exposed, and BRAF inhibitor-exposed groups, respectively. Adjusted hazard ratios (aHR) indicated a 7.52-fold and 5.68-fold increased risk of uveitis in the BRAF inhibitor-exposed group compared with that in the unexposed and ICI-exposed groups (95% confidence interval [CI] 3.83-14.75, P < 0.001 and 95% CI 2.81-11.47, P < 0.001, respectively). After 1:4 propensity score matching, aHRs showed a 35.51-fold and 15.80-fold increased risk (95% CI 4.49-280.48, P = 0.001 and 95% CI 1.76-141.00, P = 0.014) of uveitis and severe uveitis, respectively, in the BRAF inhibitor-exposed versus unexposed patients. Crossover analysis within the BRAF inhibitor-exposed group showed a 3.71-fold increase in uveitis risk during 1-year post index date in comparison with 1-year prior to index date (95% CI 1.03-13.40, P = 0.046). In the BRAF inhibitor-exposed group, female sex, chronic kidney disease, and melanoma were associated with a trend of increased, albeit nonsignificant, risk of uveitis. CONCLUSIONS: Melanoma or lung cancer patients treated with BRAF inhibitors showed significantly higher risk of noninfectious uveitis than patients treated with conventional cytotoxic drugs or ICIs. These findings emphasize the importance of pretreatment patient education on BRAF-inhibitor-associated uveitis risk to enable prompt ophthalmic evaluation and treatment if symptoms arise during drug administration.

17.
Am J Ophthalmol ; 262: 125-133, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38341167

RESUMEN

PURPOSE: To investigate the risk of noninfectious uveitis following the first dose of coronavirus disease 2019 (COVID-19) vaccination based on the uveitis history. DESIGN: Retrospective matched cohort and crossover case series study. METHODS: A random sample of 7 917 457 individuals who received COVID-19 vaccine between January 2021 and March 2022 in Korea, and had no recorded history of COVID-19 were categorized into the control and uveitis groups based on their uveitis history. After performing 3:1 propensity score matching, we assessed the cumulative incidence and risk of noninfectious uveitis in the 180 days after COVID-19 vaccination. Additionally, we performed a crossover case series analysis to compare the pre- and postvaccination incidence rate ratios (IRRs) of uveitis in individuals with and without a history of uveitis. RESULTS: In the matched cohort analysis, uveitis group had a significantly higher cumulative incidence of uveitis (15.4%) than control group (0.10%). The uveitis group exhibited increased risks of all uveitis types, anterior, and nonanterior uveitis in the first 60 days (hazard ratio [HR]: 169, 158, and 253, respectively) and in days 61 to 180 (HR: 166, 164, and 143, respectively) after vaccination. In the crossover case series analysis, uveitis occurred with relatively equal frequency in 20-day intervals during the 180 days before and after vaccination, regardless of uveitis history. For uveitis group, the adjusted IRRs for early and late postvaccination events were 0.92 (95% CI, 0.88-0.96) and 0.83 (95% CI, 0.80-0.85), respectively. CONCLUSIONS: COVID-19 vaccination did not increase the risk of uveitis, regardless of uveitis history.


Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Estudios Cruzados , SARS-CoV-2 , Uveítis , Vacunación , Humanos , Masculino , Femenino , Estudios Retrospectivos , Incidencia , Persona de Mediana Edad , COVID-19/prevención & control , COVID-19/epidemiología , Adulto , Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/administración & dosificación , Vacunación/efectos adversos , República de Corea/epidemiología , Factores de Riesgo , Anciano , Adulto Joven
18.
Cancer Lett ; 596: 216998, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-38830470

RESUMEN

Immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) are rare but fatal, requiring systemic steroid use. Therefore, to examine the outcomes, incidence, timing, and risk factors of ICI-associated steroid-requiring severe irAEs, we conducted a nationwide, retrospective, cohort study utilizing the Korean Health Insurance and Review Assessment database. We identified 357,010 patients with lung cancer, bladder cancer, or skin melanoma, eligible for ICI reimbursement in Korea between January 2012 to June 2020. Steroid-requiring severe irAEs following ICI treatment or treatment-emergent AEs following cytotoxic chemotherapy were defined as moderate- or high-dose steroid administration for over 2 consecutive days, along with corresponding ICD-10 codes indicating affected organ systems. The ICI-exposed group (N = 10,118) was compared to a matched cohort of 55,436 ICI-unexposed patients treated with cytotoxic chemotherapy. Incidences of acute severe irAEs requiring moderate- and high-dose steroids were higher in the ICI-exposed group (1.95% and 6.42%, respectively). The ICI-exposed group also had a higher risk of developing delayed severe irAEs requiring moderate- and high-dose steroid use (3.89% and 7.39%). Male sex, high comorbidity index, or previously diagnosed autoimmune diseases were associated with an increased risk of severe irAEs. Notably, 27.4-38.8% of the patients experienced recurrent severe irAEs after re-challenge with ICIs following moderate- or high-dose steroid use, with the severity matching the initial episode. Steroid-requiring severe irAEs were significantly more prevalent among patients exposed to ICIs than among those treated with chemotherapy in acute and delayed periods.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Estudios Retrospectivos , Masculino , Femenino , Factores de Riesgo , Incidencia , Persona de Mediana Edad , Anciano , República de Corea/epidemiología , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Adulto , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/inmunología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/inmunología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Esteroides/uso terapéutico , Esteroides/administración & dosificación
19.
Protein Sci ; 33(4): e4938, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38533551

RESUMEN

Regulation of SIRT1 activity is vital to energy homeostasis and plays important roles in many diseases. We previously showed that insulin triggers the epigenetic regulator DBC1 to prime SIRT1 for repression by the multifunctional trafficking protein PACS-2. Here, we show that liver DBC1/PACS-2 regulates the diurnal inhibition of SIRT1, which is critically important for insulin-dependent switch in fuel metabolism from fat to glucose oxidation. We present the x-ray structure of the DBC1 S1-like domain that binds SIRT1 and an NMR characterization of how the SIRT1 N-terminal region engages DBC1. This interaction is inhibited by acetylation of K112 of DBC1 and stimulated by the insulin-dependent phosphorylation of human SIRT1 at S162 and S172, catalyzed sequentially by CK2 and GSK3, resulting in the PACS-2-dependent inhibition of nuclear SIRT1 enzymatic activity and translocation of the deacetylase in the cytoplasm. Finally, we discuss how defects in the DBC1/PACS-2-controlled SIRT1 inhibitory pathway are associated with disease, including obesity and non-alcoholic fatty liver disease.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Sirtuina 1 , Humanos , Sirtuina 1/genética , Sirtuina 1/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Glucógeno Sintasa Quinasa 3/metabolismo , Procesamiento Proteico-Postraduccional , Insulina/metabolismo
20.
J Neuroophthalmol ; 33(2): 151-2, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23535570

RESUMEN

A healthy 46-year-old man presented with decreased vision in the right eye after ingestion of raw meat. On funduscopic examination, a cystic lesion was found on an edematous right optic disc with adjacent serous retinal detachment. Optical coherence tomography confirmed a peripapillary serous retinal detachment and a well-demarcated cystic lesion (200 × 200 × 500 µm) in the right eye. The patient had moderate eosinophilia and was seropositive for anti-Toxocara IgG antibody. Diagnosed with ocular toxocariasis, he was treated with systemic corticosteroids and albendazole with improvement in vision and fundus appearance.


Asunto(s)
Disco Óptico/patología , Disco Óptico/parasitología , Desprendimiento de Retina/complicaciones , Desprendimiento de Retina/parasitología , Toxocariasis/complicaciones , Toxocariasis/patología , Animales , Recuento de Células Sanguíneas , Ensayo de Inmunoadsorción Enzimática , Angiografía con Fluoresceína , Humanos , Inmunoglobulina G/sangre , Masculino , Persona de Mediana Edad , Tomografía de Coherencia Óptica , Toxocara/inmunología , Agudeza Visual/fisiología
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