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1.
Development ; 148(9)2021 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-33757991

RESUMEN

In the face, symmetry is established when bilateral streams of neural crest cells leave the neural tube at the same time, follow identical migration routes and then give rise to the facial prominences. However, developmental instability exists, particularly surrounding the steps of lip fusion. The causes of instability are unknown but inability to cope with developmental fluctuations are a likely cause of congenital malformations, such as non-syndromic orofacial clefts. Here, we tracked cell movements over time in the frontonasal mass, which forms the facial midline and participates in lip fusion, using live-cell imaging of chick embryos. Our mathematical examination of cell velocity vectors uncovered temporal fluctuations in several parameters, including order/disorder, symmetry/asymmetry and divergence/convergence. We found that treatment with a Rho GTPase inhibitor completely disrupted the temporal fluctuations in all measures and blocked morphogenesis. Thus, we discovered that genetic control of symmetry extends to mesenchymal cell movements and that these movements are of the type that could be perturbed in asymmetrical malformations, such as non-syndromic cleft lip. This article has an associated 'The people behind the papers' interview.


Asunto(s)
Movimiento Celular , Cara/fisiología , Mesodermo/crecimiento & desarrollo , Cresta Neural/fisiología , Actomiosina , Animales , Encéfalo/anatomía & histología , Encéfalo/crecimiento & desarrollo , División Celular , Proliferación Celular , Embrión de Pollo , Pollos , Labio Leporino/genética , Fisura del Paladar/genética , Ojo/anatomía & histología , Ojo/crecimiento & desarrollo , Cara/anomalías , Regulación del Desarrollo de la Expresión Génica , Mesodermo/anatomía & histología , Morfogénesis/genética , Cresta Neural/anatomía & histología
2.
Emerg Infect Dis ; 29(6): 1266-1267, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37209690

RESUMEN

Nocardia can cause systemic infections with varying manifestations. Resistance patterns vary by species. We describe N. otitidiscavarium infection with pulmonary and cutaneous manifestations in a man in the United States. He received multidrug treatment that included trimethoprim/sulfamethoxazole but died. Our case highlights the need to treat with combination therapy until drug susceptibilities are known.


Asunto(s)
Nocardiosis , Nocardia , Masculino , Humanos , Nocardiosis/diagnóstico , Nocardiosis/tratamiento farmacológico , Combinación Trimetoprim y Sulfametoxazol/uso terapéutico , Antibacterianos/farmacología , Antibacterianos/uso terapéutico
3.
Lung ; 200(6): 763-771, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36255519

RESUMEN

BACKGROUND: Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) caused by an immunological reaction to repeated inhalational exposure to antigens. The etiology and exact immunopathology are poorly understood. Autoimmunity overlapping with HP has been described but the role of concomitant autoimmunity in the clinical course and outcome of the HP is not clearly established. In this study, we examined patients diagnosed with HP and compare them to patients with concomitant HP and autoimmunity. METHODS: Patients were retrospectively screened from a single-center ILD registry. Patients > 18 years with an established multidisciplinary diagnosis of HP were included in the study. Patients with HP without autoimmune features and patients with HP with autoimmune features (HPAF) were assessed. We compared the demographics, clinical characteristics, treatment, and outcomes between the two groups. We used a Cox proportional hazards model to compare lung transplant-free survival outcomes of patients with HPAF to those with non-HPAF HP patients. RESULTS: Of 73 patients with HP, 43 were diagnosed with HPAF. Patients with HPAF had a higher echocardiographic probability of pulmonary hypertension as compared to non-HPAF HP patients [48.8 vs 23.3%, p = 0.028, Crude odds ratio (cOR) = 3.14]. Symptomatically, those with HPAF reported a higher prevalence of arthritis as compared to non-HPAF HP (20.9 vs 3.3%, p = 0.040, cOR = 7.68). No significant differences between pulmonary function tests, oxygen requirements, mortality, and lung transplantation rates were found between the two groups. There was no statistically significant difference in transplant-free survival (p = 0.836). CONCLUSION: Patients with HPAF had a higher echocardiographic probability of pulmonary hypertension as compared to patients with non-HPAF HP. The clinical characteristics and outcomes did not differ between the two groups and concomitant autoimmunity among the HP group did not portend a poorer prognosis.


Asunto(s)
Alveolitis Alérgica Extrínseca , Hipertensión Pulmonar , Enfermedades Pulmonares Intersticiales , Humanos , Hipertensión Pulmonar/complicaciones , Estudios Retrospectivos , Alveolitis Alérgica Extrínseca/diagnóstico , Alveolitis Alérgica Extrínseca/epidemiología , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/epidemiología , Enfermedades Pulmonares Intersticiales/etiología , Pulmón
4.
Hum Mol Genet ; 28(14): 2395-2414, 2019 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-31032853

RESUMEN

Heterozygous missense mutations in several genes in the WNT5A signaling pathway cause autosomal dominant Robinow syndrome 1 (DRS1). Our objective was to clarify the functional impact of a missense mutation in WNT5A on the skeleton, one of the main affected tissues in RS. We delivered avian replication competent retroviruses (RCAS) containing human wild-type WNT5A (wtWNT5A), WNT5AC83S variant or GFP/AlkPO4 control genes to the chicken embryo limb. Strikingly, WNT5AC83S consistently caused a delay in ossification and bones were more than 50% shorter and 200% wider than controls. In contrast, bone dimensions in wtWNT5A limbs were slightly affected (20% shorter, 25% wider) but ossification occurred on schedule. The dysmorphology of bones was established during cartilage differentiation. Instead of stereotypical stacking of chondrocytes, the WNT5AC83S-infected cartilage was composed of randomly oriented chondrocytes and that had diffuse, rather than concentrated Prickle staining, both signs of disrupted planar cell polarity (PCP) mechanisms. Biochemical assays revealed that C83S variant was able to activate the Jun N-terminal kinase-PCP pathway similar to wtWNT5A; however, the activity of the variant ligand was influenced by receptor availability. Unexpectedly, the C83S change caused a reduction in the amount of protein being synthesized and secreted, compared to wtWNT5A. Thus, in the chicken and human, RS phenotypes are produced from the C83S mutation, even though the variant protein is less abundant than wtWNT5A. We conclude the variant protein has dominant-negative effects on chondrogenesis leading to limb abnormalities.


Asunto(s)
Condrocitos/citología , Condrogénesis , Anomalías Craneofaciales/metabolismo , Enanismo/metabolismo , Extremidades/embriología , Deformidades Congénitas de las Extremidades/metabolismo , Anomalías Urogenitales/metabolismo , Proteína Wnt-5a/genética , Animales , Animales Modificados Genéticamente , Cartílago/metabolismo , Polaridad Celular/fisiología , Embrión de Pollo , Pollos , Condrogénesis/genética , Anomalías Craneofaciales/genética , Modelos Animales de Enfermedad , Enanismo/genética , Células HEK293 , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Deformidades Congénitas de las Extremidades/genética , Mutación Missense , Fenotipo , Anomalías Urogenitales/genética , Vía de Señalización Wnt , Proteína Wnt-5a/metabolismo
5.
Cytotherapy ; 20(1): 108-125, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29056548

RESUMEN

BACKGROUND AIMS: Bronchopulmonary dysplasia (BPD), a chronic lung disease characterized by disrupted lung growth, is the most common complication in extreme premature infants. BPD leads to persistent pulmonary disease later in life. Alveolar epithelial type 2 cells (AEC2s), a subset of which represent distal lung progenitor cells (LPCs), promote normal lung growth and repair. AEC2 depletion may contribute to persistent lung injury in BPD. We hypothesized that induced pluripotent stem cell (iPSC)-derived AECs prevent lung damage in experimental oxygen-induced BPD. METHODS: Mouse AECs (mAECs), miPSCs/mouse embryonic stem sells, human umbilical cord mesenchymal stromal cells (hUCMSCs), human (h)iPSCs, hiPSC-derived LPCs and hiPSC-derived AECs were delivered intratracheally to hyperoxia-exposed newborn mice. Cells were pre-labeled with a red fluorescent dye for in vivo tracking. RESULTS: Airway delivery of primary mAECs and undifferentiated murine pluripotent cells prevented hyperoxia-induced impairment in lung function and alveolar growth in neonatal mice. Similar to hUCMSC therapy, undifferentiated hiPSCs also preserved lung function and alveolar growth in hyperoxia-exposed neonatal NOD/SCID mice. Long-term assessment of hiPSC administration revealed local teratoma formation and cellular infiltration in various organs. To develop a clinically relevant cell therapy, we used a highly efficient method to differentiate hiPSCs into a homogenous population of AEC2s. Airway delivery of hiPSC-derived AEC2s and hiPSC-derived LPCs, improved lung function and structure and resulted in long-term engraftment without evidence of tumor formation. CONCLUSIONS: hiPSC-derived AEC2 therapy appears effective and safe in this model and warrants further exploration as a therapeutic option for BPD and other lung diseases characterized by AEC injury.


Asunto(s)
Células Epiteliales Alveolares/citología , Hiperoxia/complicaciones , Células Madre Pluripotentes Inducidas/citología , Lesión Pulmonar/etiología , Lesión Pulmonar/terapia , Animales , Animales Recién Nacidos , Diferenciación Celular , Modelos Animales de Enfermedad , Humanos , Células Madre Pluripotentes Inducidas/ultraestructura , Lesión Pulmonar/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Oxígeno , Teratoma/patología
6.
J Environ Sci (China) ; 58: 239-249, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28774615

RESUMEN

Human neural stem cells (hNSCs) are a useful tool to assess the developmental effects of various environmental contaminants; however, the application of hNSCs to evaluate water disinfection byproducts (DBPs) is scarce. Comprehensive toxicological results are essential to the prioritization of DBPs for further testing and regulation. Therefore, this study examines the effects of DBPs on the proliferation and differentiation of hNSCs. Prior to DBP treatment, characteristic protein markers of hNSCs from passages 3 to 6 were carefully examined and it was determined that hNSCs passaged 3 or 4 times maintained stem cell characteristics and can be used for DBP analysis. Two regulated DBPs, monobromoacetic acid (BAA) and monochloroacetic acid (CAA), and two emerging DBPs, 2,6-dibromo-1,4-benzoquinone (2,6-DBBQ) and 2,6-dichloro-1,4-benzoquinone (2,6-DCBQ), were chosen for hNSC treatment. Both 2,6-DBBQ and 2,6-DCBQ induced cell cycle arrest at S-phase at concentrations up to 1µmol/L. Comparatively, BAA and CAA at 0.5µmol/L affected neural differentiation. These results suggest DBP-dependent effects on hNSC proliferation and differentiation. The DBP-induced cell cycle arrest and inhibition of normal hNSC differentiation demonstrate the need to assess the developmental neurotoxicity of DBPs.


Asunto(s)
Ácido Acético/toxicidad , Benzoquinonas/toxicidad , Desinfectantes/toxicidad , Contaminantes Químicos del Agua/toxicidad , Desinfección , Agua Potable , Humanos , Células-Madre Neurales , Purificación del Agua
7.
Dev Biol ; 407(2): 275-88, 2015 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-26385749

RESUMEN

Cranial neural crest cells form the majority of the facial skeleton. However exactly when the pattering information and hence jaw identity is established is not clear. We know that premigratory neural crest cells contain a limited amount of information about the lower jaw but the upper jaw and facial midline are specified later by local tissue interactions. The environmental signals leading to frontonasal identity have been explored by our group in the past. Altering the levels of two signaling pathways (Bone Morphogenetic Protein) and retinoic acid (RA) in the chicken embryo creates a duplicated midline on the side of the upper beak complete with egg tooth in place of maxillary derivatives (Lee et al., 2001). Here we analyze the transcriptome 16 h after bead placement in order to identify potential mediators of the identity change in the maxillary prominence. The gene list included RA, BMP and WNT signaling pathway genes as well as transcription factors expressed in craniofacial development. There was also cross talk between Noggin and RA such that Noggin activated the RA pathway. We also observed expression changes in several poorly characterized genes including the upregulation of Peptidase Inhibitor-15 (PI15). We tested the functional effects of PI15 overexpression with a retroviral misexpression strategy. PI15 virus induced a cleft beak analogous to human cleft lip. We next asked whether PI15 effects were mediated by changes in expression of major clefting genes and genes in the retinoid signaling pathway. Expression of TP63, TBX22, BMP4 and FOXE1, all human clefting genes, were upregulated. In addition, ALDH1A2, ALDH1A3 and RA target, RARß were increased while the degradation enzyme CYP26A1 was decreased. Together these changes were consistent with activation of the RA pathway. Furthermore, PI15 retrovirus injected into the face was able to replace RA and synergize with Noggin to induce beak transformations. We conclude that the microarrays have generated a rich dataset containing genes with important roles in facial morphogenesis. Moreover, one of these facial genes, PI15 is a putative clefting gene and is in a positive feedback loop with RA.


Asunto(s)
Pico/anomalías , Pico/metabolismo , Tipificación del Cuerpo/genética , Regulación del Desarrollo de la Expresión Génica , Animales , Animales Modificados Genéticamente , Tipificación del Cuerpo/efectos de los fármacos , Proteínas Morfogenéticas Óseas/metabolismo , Proteínas Portadoras/metabolismo , Embrión de Pollo , Bases de Datos Genéticas , Cara , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Hibridación in Situ , Maxilar/efectos de los fármacos , Maxilar/embriología , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Inhibidoras de Proteinasas Secretoras/genética , Proteínas Inhibidoras de Proteinasas Secretoras/metabolismo , Control de Calidad , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Tretinoina/metabolismo , Tretinoina/farmacología
8.
Nutr Neurosci ; 19(9): 406-413, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26098738

RESUMEN

OBJECTIVE: To determine the association in amount of daily coffee consumption with incidence of stroke in a broad cohort, considering other vascular risk factors. METHODS: We utilized the Third National Health and Nutrition Examination Survey (1988-1994; NHANES III) data on participants aged ≥17 years old to examine coffee consumption and stroke. Multivariate logistic regression models related the amount of coffee use reported in a food frequency questionnaire with stroke, controlling for other vascular risk factors. RESULTS: Of 33 994 NHANES III subjects, coffee consumption and stroke data in adults ≥17 years old were available in 19 994. Daily coffee consumption ranged from 0 to 20 (median 1) cups and 644 (3.2%) participants had a stroke diagnosed by a physician. Coffee intake varied with age, gender, and ethnicity (P < 0.001). Interestingly, heart failure, diabetes, and hypertension were less frequent, and high cholesterol more frequent in those consuming ≥3 cups per day (P < 0.001). Smoking was more frequent in all coffee drinkers (P < 0.0001). Multivariate analyses revealed an independent effect of heavier coffee consumption (≥3 cups/day) on reduced stroke (OR 0.44, 95% CI 0.22-0.87, P < 0.02) in healthy subjects that was attenuated by vascular risk factors (OR 0.78, 95% CI 0.58-1.07, P ≈ 0.12). CONCLUSION: Heavier daily coffee consumption is associated with decreased stroke prevalence, despite smoking tendency in heavy coffee drinkers.


Asunto(s)
Café , Alimentos Funcionales , Accidente Cerebrovascular/prevención & control , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Café/efectos adversos , Comorbilidad , Factores de Confusión Epidemiológicos , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/prevención & control , Femenino , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/prevención & control , Humanos , Hipercolesterolemia/epidemiología , Hipercolesterolemia/etiología , Hipertensión/epidemiología , Hipertensión/etiología , Hipertensión/prevención & control , Incidencia , Masculino , Persona de Mediana Edad , Encuestas Nutricionales , Prevalencia , Factores de Riesgo , Fumar/efectos adversos , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Estados Unidos/epidemiología , Adulto Joven
9.
Ann Plast Surg ; 77(5): 577-582, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26418799

RESUMEN

Botulinum toxin has increasingly become a prevalent treatment option for a wide range of conditions, many of which have their roots in plastic surgery and have been well studied. In adults, chronic headache, hyperhidrosis, and facial muscular hypertrophy have been effectively treated with botulinum toxin, and emerging studies have begun looking at its efficacy in children, as well. Successful treatment of spasticity and muscular contraction has allowed for the creation of safety profiles and dosage guidelines for botulinum toxin usage in children. The expanded indications for its use have since flourished in all arenas of pediatric care, including plastic surgery. Recent studies have described the use of botulinum toxin as an adjunct to the treatment of congenital torticollis and cleft lip. This review discusses the various applications of botulinum toxin for pediatric patients in the field of plastic surgery.


Asunto(s)
Toxinas Botulínicas Tipo A/uso terapéutico , Fármacos Neuromusculares/uso terapéutico , Procedimientos de Cirugía Plástica , Niño , Labio Leporino/terapia , Terapia Combinada , Humanos , Hiperhidrosis/terapia , Trastornos Migrañosos/terapia , Pediatría , Cirugía Plástica , Tortícolis/terapia , Resultado del Tratamiento
10.
J Craniofac Surg ; 27(3): 593-7, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-27035597

RESUMEN

BACKGROUND: The use of alloplastic material in cranial reconstruction has been well described in the adult population, especially when a paucity of autologous tissue exists. In children it is unknown how long-term growth, however, may be affected by the implantation of nonexpansible alloplastic material. Therefore, the authors sought to compare the outcomes of pediatric patients undergoing alloplastic versus autologous cranial reconstruction. METHODS: To assess the safety and long-term outcomes of alloplastic cranioplasty in children, an institutional review board-approved, retrospective, single institution review of pediatric patients undergoing cranioplasty was performed from 2000 to 2014. The age at surgery, cause of the cranial defect, defect size, time since initial surgery to reconstruction, implant type, and complications were assessed. Postreconstruction imaging was reviewed if available. RESULTS: A reconstructive cranioplasty was performed in 41 pediatric patients (ages 1-19 years, average 7.35 years). Thirty patients underwent alloplastic reconstruction (age 4.37 ±â€Š5.57 years), and 11 underwent autologous reconstruction (age 2.00 ±â€Š3.74 years). The size of the cranial defects was 144.01 ±â€Š393.04 cm for autologous and 405.31 ±â€Š572.96 cm for alloplastic reconstructions. Follow-up for all patients was an average of 2.33 ±â€Š2.76 years (0.1-9 years). No patients in either group showed evidence of elevated intracranial pressure after cranioplasty. In long-term follow-up, none of the implants were exposed or lost because of infection. Computed tomography and physical examination demonstrated that there was no skull growth restriction in either group. CONCLUSIONS: Our data show that alloplastic cranioplasty in the pediatric population is a safe alternative, when autologous cranial bone is not available.


Asunto(s)
Procedimientos de Cirugía Plástica/métodos , Prótesis e Implantes , Cráneo/cirugía , Adolescente , Trasplante Óseo , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Estudios Retrospectivos , Cráneo/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Trasplante Autólogo , Adulto Joven
11.
J Biol Chem ; 289(35): 24153-67, 2014 Aug 29.
Artículo en Inglés | MEDLINE | ID: mdl-25008326

RESUMEN

Wingless-related proteins (WNTs) regulate extension of the central axis of the vertebrate embryo (convergent extension) as well as morphogenesis of organs such as limbs and kidneys. Here, we asked whether WNT signaling directs facial morphogenesis using a targeted approach in chicken embryos. WNT11 is thought to mainly act via ß-catenin-independent pathways, and little is known about its role in craniofacial development. RCAS::WNT11 retrovirus was injected into the maxillary prominence, and the majority of embryos developed notches in the upper beak or the equivalent of cleft lip. Three-dimensional morphometric analysis revealed that WNT11 prevented lengthening of the maxillary prominence, which was due in part to decreased proliferation. We next determined, using a series of luciferase reporters, that WNT11 strongly induced JNK/planar cell polarity signaling while repressing the ß-catenin-mediated pathway. The activation of the JNK-ATF2 reporter was mediated by the DEP domain of Dishevelled. The impacts of altered signaling on the mesenchyme were assessed by implanted Wnt11- or Wnt3a-expressing cells (activates ß-catenin pathway) into the maxillary prominence or by knocking down endogenous WNT11 with RNAi. Host cells were attracted to Wnt11 donor cells. In contrast, cells exposed to Wnt3a or the control cells did not migrate. Cells in which endogenous WNT11 was knocked down were more oriented and shorter than those exposed to exogenous WNT11. The data suggest that JNK/planar cell polarity WNT signaling operates in the face to regulate several morphogenetic events leading to lip fusion.


Asunto(s)
Polaridad Celular , Cara , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Morfogénesis , Transducción de Señal , Proteínas Wnt/metabolismo , Animales , Secuencia de Bases , Embrión de Pollo , Cartilla de ADN , Reacción en Cadena en Tiempo Real de la Polimerasa
12.
BMC Cancer ; 15: 649, 2015 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-26438152

RESUMEN

BACKGROUND: ATM and ATR are kinases implicated in a myriad of DNA-damage responses. ATM kinase inhibition radiosensitizes cells and selectively kills cells with Fanconi anemia (FA) gene mutations. ATR kinase inhibition sensitizes cells to agents that induce replication stress and selectively kills cells with ATM and TP53 mutations. ATM mutations and FANCF promoter-methylation are reported in lung carcinomas. METHODS: We undertook functional analyses of ATM, ATR, Chk1 and FA proteins in lung cancer cell lines. We included Calu6 that is reported to be FANCL-deficient. In addition, the cancer genome atlas (TCGA) database was interrogated for alterations in: 1) ATM, MRE11A, RAD50 and NBN; 2) ATR, ATRIP and TOPBP1; and 3) 15 FA genes. RESULTS: No defects in ATM, ATR or Chk1 kinase activation, or FANCD2 monoubiquitination were identified in the lung cancer cell lines examined, including Calu6, and major alterations in these pathways were not identified in the TCGA database. Cell lines were radiosensitized by ATM kinase inhibitor KU60019, but no cell killing by ATM kinase inhibitor alone was observed. While no synergy between gemcitabine or carboplatin and ATR kinase inhibitor ETP-46464 was observed, synergy between gemcitabine and Chk1 kinase inhibitor UCN-01 was observed in 54 T, 201 T and H460, and synergy between carboplatin and Chk1 kinase inhibitor was identified in 201 T and 239 T. No interactions between ATM, ATR and FA activation were observed by either ATM or ATR kinase inhibition in the lung cancer cell lines. CONCLUSIONS: Analyses of ATM serine 1981 and Chk1 serine 345 phosphorylation, and FANCD2 monoubiquitination revealed that ATM and ATR kinase activation and FA pathway signaling are intact in the lung cancer cell lines examined. As such, these posttranslational modifications may have utility as biomarkers for the integrity of DNA damage signaling pathways in lung cancer. Different sensitization profiles between gemcitabine and carboplatin and ATR kinase inhibitor ETP-46464 and Chk1 kinase inhibitor UCN-01 were observed and this should be considered in the rationale for Phase I clinical trial design with ATR kinase inhibitors.


Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Carcinoma/metabolismo , Proteínas del Grupo de Complementación de la Anemia de Fanconi/metabolismo , Neoplasias Pulmonares/metabolismo , Antineoplásicos/farmacología , Carcinoma/genética , Muerte Celular/efectos de los fármacos , Muerte Celular/efectos de la radiación , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Activación Enzimática , Humanos , Neoplasias Pulmonares/genética , Inhibidores de Proteínas Quinasas/farmacología , Radiación Ionizante , Transducción de Señal
13.
Pathophysiology ; 22(1): 15-29, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25466606

RESUMEN

The pathogenesis and pathophysiology of a disease determine how it should be diagnosed and treated. Yet, understanding the cause and mechanisms of progression often requires intensive human efforts, especially for diseases with complex etiology. The latest genomic technology coupled with advanced, large-scale data analysis in the field known as bioinformatics has promised a high-throughput approach that can quickly identify disease-affected genes and pathways by examining tissue samples collected from patients and control subjects. Furthermore, significant biological themes indicative of genomic events can be recognized on the basis of affected genes. However, given identified biological themes, it is not clear how to organize genomic events to arrive at a coherent pathophysiological explanation about the disease. To address this important issue, we have developed an innovative method named "Expression Data Up-Stream Analysis" (EDUSA) that can perform a bioinformatics analysis to identify and rank upstream processes effectively. We applied it to Parkinson's disease (PD) using a genomic data set available at a public data repository known as Gene Expression Omnibus (GEO). In this study, disease-affected genes were identified using GEO2R software, and disease-pertinent processes were identified using EASE software. Then the EDUSA program was used to determine the upstream versus downstream hierarchy of the processes. The results confirmed the current misfolded protein theory about the pathogenesis of PD, and provided new insights as well. Particularly, our program discovered that RNA (ribonucleic acid) metabolism pathology was a potential cause of PD, which in fact, is an emerging theory of neurodegenerative disorders. In addition, it was found that the dysfunction of the transport system seemed to occur in the early phase of neurodegeneration, whereas mitochondrial dysfunction appeared at a later stage. Using this methodology, we have demonstrated how to determine the stages of disease development with single-point data collection.

14.
Int J Psychiatry Med ; 55(1): 30-34, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-30080108
15.
Dis Model Mech ; 17(6)2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38967226

RESUMEN

Robinow syndrome is a rare disease caused by variants of seven WNT pathway genes. Craniofacial features include widening of the nasal bridge and jaw hypoplasia. We used the chicken embryo to test whether two missense human FZD2 variants (1301G>T, p.Gly434Val; 425C>T, p.Pro142Lys) were sufficient to change frontonasal mass development. In vivo, the overexpression of retroviruses with wild-type or variant human FZD2 inhibited upper beak ossification. In primary cultures, wild-type and variant human FZD2 significantly inhibited chondrogenesis, with the 425C>T variant significantly decreasing activity of a SOX9 luciferase reporter compared to that for the wild type or 1301G>T. Both variants also increased nuclear shuttling of ß-catenin (CTNNB1) and increased the expression of TWIST1, which are inhibitory to chondrogenesis. In canonical WNT luciferase assays using frontonasal mass cells, the variants had dominant-negative effects on wild-type FZD2. In non-canonical assays, the 425C>T variant failed to activate the reporter above control levels and was unresponsive to exogenous WNT5A. This is the first single amino acid change to selectively alter ligand binding in a FZD receptor. Therefore, FZD2 missense variants are pathogenic and could lead to the altered craniofacial morphogenesis seen in Robinow syndrome.


Asunto(s)
Condrogénesis , Anomalías Craneofaciales , Receptores Frizzled , Animales , Embrión de Pollo , Humanos , Pico , beta Catenina/metabolismo , Núcleo Celular/metabolismo , Condrogénesis/genética , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/patología , Enanismo , Receptores Frizzled/genética , Receptores Frizzled/metabolismo , Deformidades Congénitas de las Extremidades , Cráneo/patología , Cráneo/embriología , Proteína 1 Relacionada con Twist/metabolismo , Proteína 1 Relacionada con Twist/genética , Anomalías Urogenitales , Vía de Señalización Wnt
16.
Neurohospitalist ; 14(1): 5-12, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38235019

RESUMEN

Background and Purpose: Clinical documentation of patient acuity is a major determinant of payer reimbursement. This project aimed to improve case mix index (CMI) by incorporating a novel electronic health record (EHR) discharge documentation tool into the inpatient general neurology service at the University of California, Los Angeles (UCLA) Medical Center. Methods: We used data from Vizient AMC Hospital: Risk Model Summary for Clinical Data Base (CBD) 2017 to create a discharge diagnosis documentation tool consisting of dropdown menus to better capture relevant secondary diagnoses and comorbidities. After implementation of this tool, we compared pre- (July 2017-June 2019) and post-intervention (July 2019-June 2021) time periods on mean expected length of stay (LOS) and mean CMI with two sample T-tests and the percentage of encounters classified as having Major Complications/Comorbidities (MCC), with Complication/Comorbidity (CC), and without CC/MCC with tests of proportions. Results: Mean CMI increased significantly from 1.2 pre-intervention to 1.4 post-intervention implementation (P < .01). There was a pattern of increased MCC percentages for "Bacterial infections," "Other Disorders of Nervous System", "Multiple Sclerosis," and "Nervous System Neoplasms" diagnosis related groups post-intervention. Conclusions: This pilot study describes the creation of an innovative EHR discharge diagnosis documentation tool in collaboration with neurology healthcare providers, the clinical documentation improvement team, and neuro-informaticists. This novel discharge diagnosis documentation tool demonstrates promise in increasing CMI, shifting diagnosis related groups to a greater proportion of those with MCC, and improving the quality of clinical documentation.

17.
J Thorac Dis ; 16(7): 4340-4349, 2024 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-39144357

RESUMEN

Background: Interstitial lung diseases (ILDs) are a group of pulmonary disorders affecting the lung's structure. Acute exacerbation of ILD (AE-ILD) following medical procedures is a significant clinical concern. Lung cryoprobe transbronchial biopsy (cryobiopsy) is a relatively new diagnostic technique for ILD, but data on AE-ILD post-cryobiopsy is limited. This study aims to fill this gap by examining the prevalence, risk factors, and outcomes of AE-ILD following cryobiopsy. Methods: This multicenter retrospective study analyzed data from patients who underwent cryobiopsy for ILD diagnosis at three U.S. institutions between January 2014 and August 2022. The study included patients over 18 years with confirmed or suspected ILD, categorized into those who experienced AE-ILD post-cryobiopsy and those who did not. Results: Out of 111 patients, 3.6% experienced AE-ILD, with a 50% mortality rate in these cases. The study cohort was predominantly white, with a median age of 69.0 years. Common comorbidities included tobacco use and hypertension. Patients who developed AE-ILD had an increased median number of biopsies. The overall 30-day mortality was 1.8%. Overall complication rate was 32%, including pneumonia, pneumothorax, AE-ILD, and bleeding requiring intervention. The study findings suggest that bronchoscopic cryobiopsy may be associated with lower overall mortality, particularly in patients with compromised lung function. Conclusions: This study provides significant insights into AE-ILD following cryobiopsy, underscoring the need for careful patient selection and procedural assessment. While cryobiopsy may offer a safer alternative to surgical lung biopsy in specific patient cohorts, the elevated risk of AE-ILD necessitates further research to optimize patient outcomes and procedural safety.

18.
Neurology ; 100(11): 537-539, 2023 03 14.
Artículo en Inglés | MEDLINE | ID: mdl-36526424

RESUMEN

A patient with probable Creutzfeldt Jakob disease (CJD) who was previously a high-functioning financial analyst remains fiercely independent despite her family's concerns about her safety. As a trainee with limited experience in leading these difficult conversations, this neurology resident describes her experience reconciling the viewpoints of herself, the patient, and her family. She reflects on the ability to reframe this delicate conversation from one of loss of independence in a patient with a rapidly progressive, neurodegenerative condition to one of safety, security, and the care of her family.


Asunto(s)
Síndrome de Creutzfeldt-Jakob , Humanos , Femenino , Síndrome de Creutzfeldt-Jakob/complicaciones , Síndrome de Creutzfeldt-Jakob/diagnóstico por imagen , Encéfalo
19.
Dis Model Mech ; 16(4)2023 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-36916233

RESUMEN

The study of rare genetic diseases provides valuable insights into human gene function. The autosomal dominant or autosomal recessive forms of Robinow syndrome are genetically heterogeneous, and the common theme is that all the mutations lie in genes in Wnt signaling pathways. Cases diagnosed with Robinow syndrome do survive to adulthood with distinct skeletal phenotypes, including limb shortening and craniofacial abnormalities. Here, we focus on mutations in dishevelled 1 (DVL1), an intracellular adaptor protein that is required for both canonical (ß-catenin-dependent) or non-canonical (requiring small GTPases and JNK) Wnt signaling. We expressed human wild-type DVL1 or DVL1 variants alongside the endogenous genome of chicken and Drosophila. This design is strategically suited to test for functional differences between mutant and wild-type human proteins in relevant developmental contexts. The expression of variant forms of DVL1 produced a major disorganization of cartilage and Drosophila wing morphology compared to expression of wild-type DVL1. Moreover, the variants caused a loss of canonical and gain of non-canonical Wnt signaling in several assays. Our data point to future therapies that might correct the levels of Wnt signaling, thus improving skeletal growth.


Asunto(s)
Pollos , Anomalías Craneofaciales , Proteínas Dishevelled , Drosophila , Animales , Humanos , Pollos/metabolismo , Anomalías Craneofaciales/genética , Proteínas Dishevelled/genética , Proteínas Dishevelled/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Vía de Señalización Wnt/genética
20.
ACS Biomater Sci Eng ; 9(5): 2277-2291, 2023 05 08.
Artículo en Inglés | MEDLINE | ID: mdl-37094361

RESUMEN

The chemical characterization of extractables and leachables (E&Ls) is an important aspect of biosafety and biocompatibility assessment in medical device industry. The advent of the body-contact use of medical devices in patient treatment has introduced a potential source for extractables and leachables as these medical devices are comprised of various polymeric materials. Several industry working groups, the FDA and USP, have recognized the guidance for chemical characterizations and nontargeted analysis of medical device extracts, such as ISO 10993-18:2020. The MS application of nontargeted analysis has played a critical role in understanding the E&Ls from medical device extracts. However, there have been very few reports about the MS based workflow with nontargeted analysis for medical device extracts and there is little guidance about the exact methodologies which should be used, even though there is an urgent need for a clearly defined process for the identification of medical device extracts. In this study, we demonstrated an analytical LC/MS (liquid chromatography/mass spectrometry) workflow using high resolution Exploris120 Orbitrap instrument for data acquisition and Compound Discoverer 3.3 intelligent software for data processing to profile the polymer related E&Ls from a balloon dilation catheter device extracted with 40% ethanol. An E&L ID workflow combining LC separation, data-informed MS acquisition strategy, MS information mining (including adduct ions, MS information from both electrospray ionization (ESI) (+) and ESI (-), in-source fragmentation, common fragment ions (CFIs), common neutral losses (CNLs), and in silico MS simulation was described with intelligent software processing and manual data interpretation. The workflow developed in this study was proven to be effective to provide a comprehensive profile of polymer related degradation products, polymer impurities and additives including surfactants, UV curing agent, antioxidants, and plasticizers for the device analyzed. The classification of E&L compounds using CFIs and CNLs was very effective to facilitate the identification of polymer related impurities and extract the polymer related impurities with common structures in a large data result set.


Asunto(s)
Mezclas Complejas , Polímeros , Humanos , Flujo de Trabajo , Espectrometría de Masas , Cromatografía Liquida
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