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1.
Plasmid ; 69(1): 67-71, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22982979

RESUMEN

Precise splicing pre-mRNA into correct mRNA is a tightly orchestrated process involving both cis and trans factors. However, the regulatory mechanism underlying alternative splicing remain elusive. An alternative splicing was revealed by comparing RT-PCR products (cDNA) of human adiponectin gene (ADPN) genes and sequencing the corresponding cDNA recovered from CHO-K1 cells transfected with a pIRES-neo vector carrying the cDNA. We determined that an 88-nt sequence in the original cDNA was missing from the adiponectin mRNA isolated from the transfected cells. After analyzing the flanking sequences and context of the 88-nt fragment, we discovered that it does have a typical intron configuration containing the splicing donor and acceptor, polypyrimidine tract, and branch site. A point mutation at the acceptor site (AG→TG) abolishes this splicing site indicating that it is a bona fide intron. The intron splicing defaulted again when the adjacent intervening sequence (IVS) of pIRES-neo was deleted or adiponectin 3'-UTR was present. We found that 3'-UTR segment contained several splicing silencers and IVS contained high density of splicing enhancers. It explained the reactivation of this silent intron. Our results elicited the possibility that a 3'-UTR-free cDNA may reactivate an otherwise silent intron in the coding region as it is cloned for expression in mammalian cells.


Asunto(s)
Adiponectina/genética , Vectores Genéticos/genética , Intrones , Sistemas de Lectura Abierta , Activación Transcripcional , Regiones no Traducidas 3' , Adiponectina/metabolismo , Empalme Alternativo , Animales , Secuencia de Bases , Sitios de Unión , Células CHO , Cricetinae , ADN Complementario/genética , Humanos , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Conformación de Ácido Nucleico , Mutación Puntual , Sitios de Empalme de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transfección
2.
PLoS One ; 18(11): e0288405, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38032998

RESUMEN

BACKGROUND: Individuals with chronic low back pain (CLBP) exhibit altered brain function and trunk muscle activation. AIM: This study examined the effects of sling exercises on pain, function, and corticomuscular coherence (CMC) in healthy adults and individuals with CLBP. METHODS: Eight individuals with CLBP and 15 healthy adults received sling exercise training for 6 weeks. Before and after training, participants performed two motor tasks: rapid arm lifts and repeated trunk flexion-extension tasks, and electromyography of the trunk muscles and electroencephalography of the sensorimotor cortex were recorded. Chi-squared test and Mann-Whitney U tests were used for between group comparison, and Wilcoxon signed-rank tests were used for pre- and post-training comparison. Spearman's Rank Correlation Coefficient (Rs) was used to identify for the relationship between motor performance and Corticomuscular coherence. RESULTS: Sling exercises significantly improved pain (median from 3 to 1, p = .01) and Oswestry Disability Index scores (median from 2.5 to 2, p = .03) in the CLBP group. During rapid arm lifts, individuals with CLBP showed lower beta CMC of the transverse abdominis and internal oblique (Tra/IO) (0.8 vs. 0.49, p = .01) and lumbar erector spinae (0.70 vs. 0.38, p = .04) than the control group at baseline. During trunk flexion-extension, the CLBP group showed higher gamma CMC of the left Tra/IO than the control group at baseline (0.28 vs. 0.16 , p = .001). After training, all CMC became statistically non-significant between groups. The training induced improvement in anticipatory activation of the Tra/IO was positively correlated with the beta CMC (rs = 0.7851, p = .02). CONCLUSION: A 6-week sling exercises diminished pain and disability in patients with CLBP and improved the anticipatory activation and CMC in some trunk muscles. These improvements were associated with training induced changes in corticomuscular connectivity in individuals with CLBP.


Asunto(s)
Dolor Crónico , Dolor de la Región Lumbar , Adulto , Humanos , Dolor de la Región Lumbar/terapia , Terapia por Ejercicio , Torso , Electromiografía , Ejercicio Físico , Músculos Paraespinales , Dolor Crónico/terapia
3.
Can J Anaesth ; 58(1): 55-61, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21042903

RESUMEN

PURPOSE: Dextrorphan, a major metabolite of dextromethorphan, produces the duration of spinal and cutaneous anesthesia similar to bupivacaine. The purpose of this study was to test the central nervous system and cardiovascular toxicity of bupivacaine, dextromethorphan, and dextrorphan. METHODS: First, dose-response curves for dextromethorphan, dextrorphan, and bupivacaine (n = 8 at each testing point) were determined for cutaneous analgesia on the rat back, and equipotent doses were calculated. Next, during continuous intravenous infusion of equipotent doses of bupivacaine, dextromethorphan, and dextrorphan (n = 8 in each group), we observed the time to seizure, apnea, and complete cardiac arrest. A saline group (n = 7) was used for comparison. Mean arterial blood pressure (MAP), heart rate (HR), stroke volume (SV), and cardiac output (CO) were also monitored. RESULTS: Bupivacaine, dextromethorphan, and dextrorphan produced dose-dependent cutaneous anesthesia. A longer duration of equipotent infusion doses was required to produce seizures in the dextromethorphan group (10.6 ± 1.3 min) than in the bupivacaine group (7.6 ± 2.1 min) (P = 0.005). Dextrorphan did not produce any seizures. Compared with bupivacaine, time to apnea and complete cardiac arrest was longer with dextrorphan (P < 0.001) and with dextromethorphan (P = 0.001). Cardiovascular collapse, defined as a decline in MAP, HR, CO, and SV, was slower in the dextromethorphan and dextrorphan groups than in the bupivacaine group (P < 0.001 for both comparisons). CONCLUSION: At equipotent doses for local anesthesia, dextromethorphan and dextrorphan were less likely than bupivacaine to induce central nervous system and cardiovascular toxicity.


Asunto(s)
Anestésicos Locales/toxicidad , Bupivacaína/toxicidad , Dextrometorfano/toxicidad , Dextrorfano/toxicidad , Anestésicos Locales/administración & dosificación , Animales , Apnea/inducido químicamente , Bupivacaína/administración & dosificación , Dextrometorfano/administración & dosificación , Dextrorfano/administración & dosificación , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Antagonistas de Aminoácidos Excitadores/toxicidad , Paro Cardíaco/inducido químicamente , Infusiones Intravenosas , Masculino , Ratas , Ratas Sprague-Dawley , Convulsiones/inducido químicamente , Factores de Tiempo
4.
PLoS One ; 16(12): e0260620, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34855821

RESUMEN

The purpose of this study was to identify individual and residency program factors associated with increased suicide risk, as measured by suicidal ideation. We utilized a prospective, longitudinal cohort study design to assess the prevalence and predictors of suicidal ideation in 6,691 (2012-2014 cohorts, training data set) and 4,904 (2015 cohort, test data set) first-year training physicians (interns) at hospital systems across the United States. We assessed suicidal ideation two months before internship and then quarterly through intern year. The prevalence of reported suicidal ideation in the study population increased from 3.0% at baseline to a mean of 6.9% during internship. 16.4% of interns reported suicidal ideation at least once during their internship. In the training dataset, a series of baseline demographic (male gender) and psychological factors (high neuroticism, depressive symptoms and suicidal ideation) were associated with increased risk of suicidal ideation during internship. Further, prior quarter psychiatric symptoms (depressive symptoms and suicidal ideation) and concurrent work-related factors (increase in self-reported work hours and medical errors) were associated with increased risk of suicidal ideation. A model derived from the training dataset had a predicted area under the Receiver Operating Characteristic curve (AUC) of 0.83 in the test dataset. The suicidal ideation risk predictors analyzed in this study can help programs and interns identify those at risk for suicidal ideation before the onset of training. Further, increases in self-reported work hours and environments associated with increased medical errors are potentially modifiable factors for residency programs to target to reduce suicide risk.


Asunto(s)
Internado y Residencia , Adulto , Humanos , Masculino , Ideación Suicida , Estados Unidos
5.
Nat Genet ; 50(6): 814-824, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29808028

RESUMEN

The androgen receptor (AR) plays a critical role in the development of the normal prostate as well as prostate cancer. Using an integrative transcriptomic analysis of prostate cancer cell lines and tissues, we identified ARLNC1 (AR-regulated long noncoding RNA 1) as an important long noncoding RNA that is strongly associated with AR signaling in prostate cancer progression. Not only was ARLNC1 induced by the AR protein, but ARLNC1 stabilized the AR transcript via RNA-RNA interaction. ARLNC1 knockdown suppressed AR expression, global AR signaling and prostate cancer growth in vitro and in vivo. Taken together, these data support a role for ARLNC1 in maintaining a positive feedback loop that potentiates AR signaling during prostate cancer progression and identify ARLNC1 as a novel therapeutic target.


Asunto(s)
Neoplasias de la Próstata/genética , ARN Largo no Codificante/genética , Receptores Androgénicos/genética , Andrógenos/genética , Andrógenos/metabolismo , Línea Celular Tumoral , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Próstata/fisiología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , ARN Largo no Codificante/metabolismo , Receptores Androgénicos/metabolismo , Transducción de Señal
6.
Eur Urol Focus ; 3(4-5): 502-509, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28753826

RESUMEN

BACKGROUND: Urothelial carcinoma (UC) is the most common malignancy of the urinary tract. Upper tract (renal pelvis and ureter) urothelial carcinomas (UTUC) account for approximately 5% of UCs but a significant subset are invasive and associated with poor clinical outcomes. OBJECTIVE: To evaluate programmed death-ligand 1 (PD-L1) expression in UTUC. DESIGN, SETTING, AND PARTICIPANTS: UTUC cases from 1997-2016 were retrospectively identified from the surgical pathology database at a single large academic institution. The cohort included 149 cases: 27 low-grade and 24 high-grade pathologic T (pT)a, 29 pT1, 23 pT2, 38 pT3, and eight pT4. PD-L1 immunohistochemistry (IHC) was performed on representative whole tumor sections using anti-PD-L1 primary antibody clone 5H1. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PD-L1 expression was evaluated using a previously established cut-off for positivity (≥ 5% membranous staining). Association between PD-L1 IHC expression and clinicopathologic parameters was examined with Fisher's exact test; the effect of PD-L1 expression on cancer-specific mortality was assessed using the Cox proportional hazard model. RESULTS AND LIMITATIONS: Approximately one-third (32.7%) of invasive primary UTUC and 23.5% of all primary UTUC (invasive and noninvasive tumors) demonstrated positive PD-L1 expression. Positive PD-L1 expression was associated with high histologic grade, high pathologic stage, and angiolymphatic invasion. Cancer-specific survival was not significantly associated with positive PD-L1 expression using a 5% cut-off. Study limitations include the retrospective nature and the fact that PD-L1 expression by IHC is an imperfect surrogate for response to therapy. CONCLUSIONS: Positive PD-L1 expression in approximately one-third of primary invasive UTUC and association with high-risk clinicopathologic features provide a rational basis for further investigation of PD-L1-based immunotherapeutics in these patients. PATIENT SUMMARY: Upper tract urothelial carcinoma is often associated with poor clinical outcome. While current treatment options for advanced upper tract urothelial carcinoma are limited, programmed death-ligand 1 positivity in approximately one-third of invasive tumors provides a rational basis for further investigation of programmed death-ligand 1-based immunotherapeutics in these patients.


Asunto(s)
Antígeno B7-H1/metabolismo , Carcinoma de Células Transicionales/metabolismo , Neoplasias Urológicas/metabolismo , Urotelio/patología , Anciano , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/epidemiología , Carcinoma de Células Transicionales/mortalidad , Femenino , Humanos , Inmunohistoquímica/métodos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Prevalencia , Estudios Retrospectivos , Neoplasias Urológicas/patología
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