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1.
Occup Med (Lond) ; 74(4): 323-327, 2024 06 11.
Artículo en Inglés | MEDLINE | ID: mdl-38702919

RESUMEN

A 38-year-old woman experienced a persistent dry cough and progressively worsening dyspnoea for 2 years. Spirometry testing revealed a moderate-to-severe restrictive abnormality. High-resolution chest computed tomography showed diffuse reticulonodular opacities. A lung biopsy disclosed alveolar parenchymal inflammation and fibrosis with bronchiolocentric features, prompting consideration of interstitial pneumonia. Following a thorough investigation of her occupational history and an on-site inspection, it was discovered that the patient had been grinding drill bits designed for printed circuit boards for 8 years, exposing her to hard metals. Mineralogical analyses confirmed excessive tungsten in urine, serum and hair, leading to a diagnosis of hard metal lung disease due to tungsten carbide-cobalt exposure. After discontinuing exposure and commencing corticosteroid therapy, her symptoms, pulmonary function and imaging showed modest improvement. This case highlights the significance of assessing occupational history in patients with interstitial pneumonia and understanding industrial hazards for accurate diagnosis and care.


Asunto(s)
Enfermedades Pulmonares Intersticiales , Enfermedades Profesionales , Exposición Profesional , Humanos , Femenino , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/inducido químicamente , Adulto , Exposición Profesional/efectos adversos , Enfermedades Profesionales/diagnóstico , Tomografía Computarizada por Rayos X , Tungsteno/efectos adversos , Aleaciones/efectos adversos , Cobalto/efectos adversos , Pulmón/patología , Pulmón/diagnóstico por imagen
2.
Hernia ; 28(1): 17-24, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37676569

RESUMEN

PURPOSE: Unstructured data are an untapped source for surgical prediction. Modern image analysis and machine learning (ML) can harness unstructured data in medical imaging. Incisional hernia (IH) is a pervasive surgical disease, well-suited for prediction using image analysis. Our objective was to identify optimal biomarkers (OBMs) from preoperative abdominopelvic computed tomography (CT) imaging which are most predictive of IH development. METHODS: Two hundred and twelve rigorously matched colorectal surgery patients at our institution were included. Preoperative abdominopelvic CT scans were segmented to derive linear, volumetric, intensity-based, and textural features. These features were analyzed to find a small subset of OBMs, which are maximally predictive of IH. Three ML classifiers (Ensemble Boosting, Random Forest, SVM) trained on these OBMs were used for prediction of IH. RESULTS: Altogether, 279 features were extracted from each CT scan. The most predictive OBMs found were: (1) abdominopelvic visceral adipose tissue (VAT) volume, normalized for height; (2) abdominopelvic skeletal muscle tissue volume, normalized for height; and (3) pelvic VAT volume to pelvic outer aspect of body wall skeletal musculature (OAM) volume ratio. Among ML prediction models, Ensemble Boosting produced the best performance with an AUC of 0.85, accuracy of 0.83, sensitivity of 0.86, and specificity of 0.81. CONCLUSION: These OBMs suggest increased intra-abdominopelvic volume/pressure as the salient pathophysiologic driver and likely mechanism for IH formation. ML models using these OBMs are highly predictive for IH development. The next generation of surgical prediction will maximize the utility of unstructured data using advanced image analysis and ML.


Asunto(s)
Hernia Incisional , Humanos , Hernia Incisional/diagnóstico por imagen , Hernia Incisional/etiología , Hernia Incisional/cirugía , Herniorrafia/métodos , Tomografía Computarizada por Rayos X/métodos , Biomarcadores , Estudios Retrospectivos
3.
Hernia ; 26(5): 1355-1368, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-36006563

RESUMEN

PURPOSE: It is unknown whether the trend of rising incisional hernia (IH) repair (IHR) incidence and costs until 2011 currently persists. We aimed to evaluate how the IHR procedure incidence, cost and patient risk-profile have changed over the last decade relative to all abdominal surgeries (AS). METHODS: Repeated cross-sectional analysis of 38,512,737 patients undergoing inpatient 4AS including IHR within the 2008-2018 National Inpatient Sample. Yearly incidence (procedures/1,000,000 people [PMP]), hospital costs, surgical and patient characteristics were compared between IHR and AS using generalized linear and multinomial regression. RESULTS: Between 2008-2018, 3.1% of AS were IHR (1,200,568/38,512,737). There was a steeper decrease in the incidence of AS (356.5 PMP/year) compared to IHR procedures (12.0 PMP/year) which resulted in the IHR burden relative to AS (2008-2018: 12,576.3 to 9,113.4 PMP; trend difference P < 0.01). National costs averaged $47.9 and 1.7 billion/year for AS and IHR, respectively. From 2008-2018, procedure costs increased significantly for AS (68.2%) and IHR (74.6%; trends P < 0.01). Open IHR downtrended (42.2%), whereas laparoscopic (511.1%) and robotic (19,301%) uptrended significantly (trends P < 0.01). For both AS and IHR, the proportion of older (65-85y), Black and Hispanic, publicly-insured, and low-income patients, with higher comorbidity burden, undergoing elective procedures at small- and medium-sized hospitals uptrended significantly (all P < 0.01). CONCLUSION: IH persists as a healthcare burden as demonstrated by the increased proportion of IHR relative to all AS, disproportionate presence of high-risk patients that undergo these procedures, and increased costs. Targeted efforts for IH prevention have the potential of decreasing $17 M/year in costs for every 1% reduction.


Asunto(s)
Hernia Ventral , Hernia Incisional , Laparoscopía , Estudios Transversales , Gastos en Salud , Hernia Ventral/cirugía , Herniorrafia/métodos , Humanos , Incidencia , Hernia Incisional/epidemiología , Hernia Incisional/cirugía , Laparoscopía/métodos , Estudios Retrospectivos , Estados Unidos/epidemiología
4.
Hernia ; 25(6): 1667-1675, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-33835324

RESUMEN

BACKGROUND: Incisional hernias (IH) following abdominal surgery persist as morbid, costly, and multi-disciplinary surgical challenges. Using longitudinal, multi-state, administrative claims data (HCUP State Inpatient Databases (SID)); (HCUP State Ambulatory Surgery and Services Databases (SASD)), we aimed to characterize the epidemiology, outcomes, recurrence, and costs of IH. STUDY DESIGN: 529,108 patients undergoing abdominal surgery in 2010 across six specialties (colorectal, general/bariatric, hepatobiliary, obstetrics/gynecology, urology, and vascular) were identified within inpatient and ambulatory databases for Florida (FL), Iowa (IA), Nebraska (NE), New York (NY), and Utah (UT). IH repairs, complications, and expenditures were assessed through 2014. Predictive regression modeling was validated using a training set of 1000 bootstrapped repetitions. RESULTS: 16,169 (3.1%) patients developed hernias requiring repair (4.3-year mean follow-up), 3176 (20%) underwent recurrent repair, and 731 (23%) underwent re-recurrent repair. Patients with IH had increased readmissions (6.6 vs. 2.4), morbidity (39 vs. 8% surgical and 22 vs. 7% medical), and costs ($46,000 vs. $25,000) when compared to patients without IH (p < 0.001). IH expenditures totaled $875 million: initial ($687 million), recurrent ($155 million), and re-recurrent hernias ($33 million). IH predominated in colorectal (10%), hepatobiliary (8%), and vascular (5%) procedures. Of 31 significant independent IH risk factors (p < 0.001), obesity, age, smoking, open surgery, and prior surgery were pervasive across surgical specialties. CONCLUSION: IH represents an unremitting surgical epidemic associated with considerable morbidity, costs, and features consistent with a chronic disease state. We define critical pervasive risk factors (obesity, age, smoking open surgery, and prior surgery) independently associated with IH across surgical disciplines. With failed repairs, subsequent success becomes less likely, increasing morbidity and costs-underscoring the critical importance of optimal treatment and prevention.


Asunto(s)
Neoplasias Colorrectales , Hernia Incisional , Neoplasias Colorrectales/cirugía , Costos de la Atención en Salud , Herniorrafia/métodos , Humanos , Hernia Incisional/epidemiología , Hernia Incisional/etiología , Hernia Incisional/cirugía , Obesidad/complicaciones , Obesidad/epidemiología , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/cirugía , Recurrencia , Estudios Retrospectivos
5.
Ann Oncol ; 32(2): 197-207, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33186740

RESUMEN

BACKGROUND: The phase III SANDPIPER study assessed taselisib (GDC-0032), a potent, selective PI3K inhibitor, plus fulvestrant in estrogen receptor-positive, HER2-negative, PIK3CA-mutant locally advanced or metastatic breast cancer. PATIENTS AND METHODS: Postmenopausal women with disease recurrence/progression during/after an aromatase inhibitor were randomized 2 : 1 to receive taselisib (4 mg; taselisib arm) or placebo (placebo arm) plus fulvestrant (500 mg). Stratification factors were visceral disease, endocrine sensitivity, and geographic region. Patients with PIK3CA-mutant tumors (central cobas® PIK3CA Mutation Test) were randomized separately from those without detectable mutations. The primary endpoint was investigator-assessed progression-free survival (INV-PFS) in patients with PIK3CA-mutant tumors. Secondary endpoints included objective response rate, overall survival, clinical benefit rate, duration of objective response, PFS by blinded independent central review (BICR-PFS), safety, and time to deterioration in health-related quality of life. RESULTS: The PIK3CA-mutant intention-to-treat population comprised 516 patients (placebo arm: n = 176; taselisib arm: n = 340). INV-PFS was significantly improved in the taselisib {7.4 months [95% confidence interval (CI), 7.26-9.07]} versus placebo arm (5.4 months [95% CI, 3.68-7.29]) (stratified hazard ratio [HR] 0.70; 95% CI, 0.56-0.89; P = 0.0037) and confirmed by BICR-PFS (HR 0.66). Secondary endpoints, including objective response rate, clinical benefit rate, and duration of objective response, showed consistent improvements in the taselisib arm. Safety was assessed in all randomized patients who received at least one dose of taselisib/placebo or fulvestrant regardless of PIK3CA-mutation status (n = 629). Serious adverse events were lower in the placebo versus taselisib arm (8.9% versus 32.0%). There were more discontinuations (placebo arm: 2.3%; taselisib arm: 16.8%) and dose reductions (placebo arm: 2.3%; taselisib arm: 36.5%) in the taselisib arm. CONCLUSION: SANDPIPER met its primary endpoint; however, the combination of taselisib plus fulvestrant has no clinical utility given its safety profile and modest clinical benefit.


Asunto(s)
Neoplasias de la Mama , Receptores de Estrógenos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Fosfatidilinositol 3-Quinasa Clase I/genética , Femenino , Fulvestrant , Humanos , Imidazoles , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Oxazepinas , Fosfatidilinositol 3-Quinasas , Calidad de Vida , Receptor ErbB-2/genética
6.
Neth J Med ; 76(2): 65-71, 2018 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-29515003

RESUMEN

BACKGROUND: Osteoporosis is a major public health problem because of its associated fractures and the resulting complications. The objective of this study was to identify the association between the severity of type 2 diabetes mellitus (T2DM) and the risk of hip fracture in osteoporotic patients. METHODS: The patients who received a diagnosis of osteoporosis between 2006 and 2010, with an adequate follow-up between 2006 and 2015, were enrolled in this study. Among patients with T2DM, the severity of the disease was evaluated using the Diabetes Complication Severity Index (DCSI). Logistic regression models were used to calculate the odds ratios and to predict the risk of hip fracture in diabetic osteoporotic patients. RESULTS: A total of 1188 patients were enrolled in the final study, 87 patients had hip fractures in the follow-up period between 2006 and 2015. Among the diabetic patients, each level of the continuous DCSI was associated with a 1.56-fold greater risk of hip fracture. In further stratification, patients with a DCSI > 3 had a significantly higher risk of hip fracture in comparison with those with a DCSI ≤ 1. The categorical DCSI (DCSI > 3), HbA1c level on the diagnosis of T2DM and duration of diabetes, facilitate predicting the risk of hip fracture. CONCLUSION: The severity of T2DM reflects the risk of hip fracture in osteoporotic patients. Physicians should pay attention to osteoporotic patients presenting with a high HbA1c level on diagnosis of T2DM and a higher DCSI because of their vulnerability to hip fracture.


Asunto(s)
Complicaciones de la Diabetes/epidemiología , Diabetes Mellitus Tipo 2/epidemiología , Fracturas de Cadera/etiología , Osteoporosis/complicaciones , Osteoporosis/epidemiología , Anciano , Anciano de 80 o más Años , Comorbilidad , Complicaciones de la Diabetes/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Taiwán/epidemiología
7.
J Asthma ; 51(6): 652-9, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24580369

RESUMEN

OBJECTIVES: To identify patients' beliefs or behaviors related to treatment adherence and to assess association between asthma control and adherence in Asian patients with asthma. METHODS: We conducted a cross-sectional observational study of adult patients with asthma from specialist clinics in six Asian countries. Patients who were deemed by their treating physicians to require a maintenance treatment with an inhaler for at least 1 year were recruited. Patients completed a 12-item questionnaire related to health beliefs and behaviors, the 8-item Morisky Medication Adherence Scale (MMAS-8), the Asthma Control Test (ACT™), and the Standardized Asthma Quality of Life Questionnaire (AQLQ-S). RESULTS: Of the 1054 patients recruited, 99% were current users of inhaled corticosteroids. The mean ACT score was 20.0 ± 4.5 and 64% had well-controlled asthma. The mean MMAS-8 score was 5.5 ± 2.0 and 53% were adherent. Adherence was significantly associated with patients' understanding of the disease and inhaler techniques, and with patients' acceptance of inhaler medicines in terms of benefits, safety, convenience, and cost (p < 0.01 for all). In multivariate analysis, three questions related to patients' acceptance of inhaler medicines remained significantly associated with poor adherence, after adjusting for potential confounders: "I am not sure inhaler type medicines work well" (p = 0.001), "Taking medicines more than once a day is inconvenient" (p = 0.002), and "Sometimes I skip my inhaler to use it over a longer period" (p < 0.001). CONCLUSIONS: Our study showed that patients' acceptance of the benefits, convenience and cost of inhaler medications have a significant impact on treatment adherence in the participating Asian countries.


Asunto(s)
Antiasmáticos/administración & dosificación , Asma/tratamiento farmacológico , Asma/psicología , Conocimientos, Actitudes y Práctica en Salud , Cumplimiento de la Medicación/psicología , Adulto , Factores de Edad , Anciano , Antiasmáticos/uso terapéutico , Índice de Masa Corporal , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nebulizadores y Vaporizadores , Aceptación de la Atención de Salud/psicología , Calidad de Vida , Factores Sexuales , Factores Socioeconómicos
9.
Allergy ; 68(4): 524-30, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23414255

RESUMEN

BACKGROUND: We conducted Phase 2 of the Asthma Insights and Reality in the Asia-Pacific (AIRIAP 2) survey in 2006 to determine the level of asthma control in this region and the validity of the Asthma Control Test (ACT) and childhood ACT (C-ACT) in relation to asthma control. METHODS: Pediatric participants (0 to <16 years; N = 988) with diagnosed asthma and current asthma symptoms or taking anti-asthma medications were recruited from 12 geographic areas in Asia. The survey consisted of the AIRIAP 2 questionnaire (asthma symptoms, use of urgent healthcare services and anti-asthma medication) and the ACT or C-ACT (English or Chinese translations only), both administered in the participant's preferred language. A symptom control index based on the Global Initiative for Asthma criteria (except lung function) was used to classify asthma control status. RESULTS: Most participants had inadequately controlled asthma ('uncontrolled' = 53.4%, 528/988; 'partly controlled' = 44.0%, 435/988). Only 2.5% (25/988) had 'controlled' asthma. Demand for urgent healthcare services (51.7%, 511/988) and use of short-acting beta-agonists (55.2%, 545/988) was high. The optimal ACT and C-ACT cutoff score for detecting uncontrolled asthma (compared with controlled or partly controlled asthma) was determined to be ≤19 (receiver operating characteristic analysis) with good agreement between the ACT and C-ACT and the symptom control index. CONCLUSIONS: Findings from this survey show that asthma control is suboptimal in many children in the Asia-Pacific region. Practical tools, such as the ACT or C-ACT, may help clinicians assess asthma control and facilitate adjustment of asthma medication.


Asunto(s)
Asma/prevención & control , Encuestas Epidemiológicas , Adolescente , Antiasmáticos/uso terapéutico , Asia , Asma/diagnóstico , Asma/tratamiento farmacológico , Niño , Preescolar , Estudios Transversales , Humanos , Lactante , Recién Nacido , Servicios Preventivos de Salud , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios
10.
Aliment Pharmacol Ther ; 33(1): 89-98, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21083591

RESUMEN

BACKGROUND: Gastro-oesophageal reflux disease (GERD) has been associated with reflux laryngitis. AIMS: To investigate the risk factors and the predictors of pharyngeal acid reflux (PAR) in Taiwanese patients with suspected reflux laryngitis. METHODS: With referral from ENT physicians, 104 patients with symptoms and signs suggestive of reflux laryngitis completed a validated symptom questionnaire, an upper endoscopy exam and ambulatory 24-h pH tests with three sensors located at the hypopharynx, proximal and distal oesophagus. Patients with one or more episodes of PAR were considered abnormal. RESULTS: Pharyngeal acid reflux was identified in 17% (18/104) of patients. In multivariate logistic regression analysis, PAR was independently associated with classical reflux symptoms [adjusted odds ratio (aOR) = 3.5, 95% confidence interval (CI): 1.0-12.8], hiatus hernia (aOR = 6.7, 95% CI: 1.5-30.2) and overweight (aOR = 3.4, 95% CI: 1.0-11.0). In predicting PAR, classical reflux symptoms had a sensitivity of 78% and hiatus hernia had a specificity of 95%. With all three factors, the positive predictive value for PAR was 80%. Classical reflux symptoms included heartburn, chest pain, dyspepsia and acid regurgitation. CONCLUSIONS: Classical reflux symptoms, hiatus hernia and overweight are independent risk factors that may predict pharyngeal acid reflux in patients with suspected reflux laryngitis.


Asunto(s)
Reflujo Biliar , Reflujo Gastroesofágico/complicaciones , Hernia Hiatal/complicaciones , Laringitis/complicaciones , Faringe/fisiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Métodos Epidemiológicos , Femenino , Reflujo Gastroesofágico/fisiopatología , Hernia Hiatal/fisiopatología , Humanos , Laringitis/fisiopatología , Masculino , Persona de Mediana Edad , Sobrepeso/complicaciones , Factores de Riesgo , Adulto Joven
11.
J Med Virol ; 81(8): 1444-9, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19551818

RESUMEN

Cutaneous human papillomavirus (HPV) types are commonly found in normal skin, and some of them have been suspected to play a role in the development of non-melanoma skin cancer. This present study is divided into three sections, the aims of this study were to examine if certain HPV-types persist over time and if HPV-types are shared within families. From the first part of the study, swab samples from foreheads were collected for three longitudinal studies from one family with a newborn baby. Five specific HPV-types were isolated from the family with a newborn, with HPV-5 and FA67 being found at various time points and prevalence rates in all four members of the family. Part 2 consisted of a followed up study from two families with a 6 years interval. Six of the family members were found to have at least one of the HPV-types identified in the family 6 years earlier. Many of the HPV-types identified were shared within the families studied. Part 3 of this study involved weekly samples from four healthy females for 4 months. Among the four healthy individuals, 11%, 65%, and 56% of the weekly samples were HPV-DNA positive with one individual HPV-negative. All specimens were tested for HPV-DNA by PCR using the broad range HPV-type primer pair FAP59/64. The positive samples were HPV-type determined by cloning and sequencing. Specific cutaneous HPV-types persist over long periods of time in healthy skin in most individuals investigated and certain HPVs are shared between family members.


Asunto(s)
Papillomaviridae/clasificación , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/virología , Enfermedades Cutáneas Virales/virología , Piel/virología , Adulto , Niño , Preescolar , Salud de la Familia , Femenino , Experimentación Humana , Humanos , Recién Nacido , Masculino , Datos de Secuencia Molecular , Papillomaviridae/genética , Adulto Joven
12.
Biochem Soc Trans ; 34(Pt 6): 1047-50, 2006 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-17073747

RESUMEN

The RNA polymerase II core promoter is a critical yet often overlooked component in the transcription process. The core promoter is defined as the stretch of DNA, which encompasses the RNA start site and is typically approx. 40-50 nt in length, that directs the initiation of gene transcription. In the past, it has been generally presumed that core promoters are general in function and that transcription initiation occurs via a common shared mechanism. Recent studies have revealed, however, that there is considerable diversity in core promoter structure and function. There are a number of DNA elements that contribute to core promoter activity, and the specific properties of a given core promoter are dictated by the presence or absence of these core promoter motifs. The known core promoter elements include the TATA box, Inr (initiator), BRE(u) {BRE [TFIIB (transcription factor for RNA polymerase IIB) recognition element] upstream of the TATA box} and BRE(d) (BRE downstream of the TATA box), MTE (motif ten element), DCE (downstream core element) and DPE (downstream core promoter element). In this paper, we will provide some perspectives on current and future issues that pertain to the RNA polymerase II core promoter.


Asunto(s)
Regiones Promotoras Genéticas , ARN Polimerasa II/genética , Modelos Genéticos , Factores de Transcripción/metabolismo , Transcripción Genética
13.
Opt Lett ; 29(18): 2157-9, 2004 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-15460888

RESUMEN

Parametric decay of electromagnetic waves into two Langmuir oscillations near the quarter critical density is suggested as being attributable to an enhanced electric field and to surface-enhanced Raman scattering in near-field optics. A nanolayer of silver aggregates localizes the wave in the evanescent region to a one-wavelength span and results in a wave-number mismatch as well as in a reduced growth rate. The fastest-growing mode has a growth rate that scales with the square root of the nanolayer's thickness.

14.
Phys Rev Lett ; 91(13): 133001, 2003 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-14525301

RESUMEN

The density functional theory is derived from a cluster expansion by truncating the higher-order correlations in one and only one term in the kinetic energy. The formulation allows self-consistent calculation of the exchange correlation effect without imposing additional assumptions to generalize the local density approximation. The pair correlation is described as a two-body collision of bound-state electrons, and modifies the electron- electron interaction energy as well as the kinetic energy. The theory admits excited states, and has no self-interaction energy.

15.
Cell ; 105(5): 645-55, 2001 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-11389834

RESUMEN

We have discovered an early mitotic inhibitor, Emi1, which regulates mitosis by inhibiting the anaphase promoting complex/cyclosome (APC). Emi1 is a conserved F box protein containing a zinc binding region essential for APC inhibition. Emi1 accumulates before mitosis and is ubiquitylated and destroyed in mitosis, independent of the APC. Emi1 immunodepletion from cycling Xenopus extracts strongly delays cyclin B accumulation and mitotic entry, whereas nondestructible Emi1 stabilizes APC substrates and causes a mitotic block. Emi1 binds the APC activator Cdc20, and Cdc20 can rescue an Emi1-induced block to cyclin B destruction. Our results suggest that Emi1 regulates progression through early mitosis by preventing premature APC activation, and may help explain the well-known delay between cyclin B/Cdc2 activation and cyclin B destruction.


Asunto(s)
Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Drosophila , Ligasas/metabolismo , Mitosis/fisiología , Proteínas/metabolismo , Complejos de Ubiquitina-Proteína Ligasa , Adenosina Trifosfatasas/genética , Secuencia de Aminoácidos , Ciclosoma-Complejo Promotor de la Anafase , Animales , Proteínas Cdc20 , Secuencia Conservada , Ciclina A/metabolismo , Ciclina B/metabolismo , Drosophila , Técnicas In Vitro , Proteínas de la Membrana/genética , Ratones , Datos de Secuencia Molecular , Oocitos/citología , Oocitos/fisiología , Conejos , Ubiquitina-Proteína Ligasas , Xenopus , Proteínas de Xenopus
16.
Cancer Res ; 61(7): 2852-6, 2001 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-11306457

RESUMEN

Evidence from epidemiological, molecular, and genetic studies suggests a role for vitamin D in the development and/or progression of prostate cancer. In experimental models and clinical trials, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] was shown to exert antiproliferative, prodifferentiating, and antimetastatic/invasive effects on prostatic epithelial cells. Because the direct clinical application of 1,25(OH)2D3 is limited by the major side effect of hypercalcemia, we investigated the potential therapeutic utility of its less calcemic precursor, 25-hydroxyvitamin D3 [25(OH)D3], which is converted locally within the prostate to 1,25(OH)2D3 by 1alpha-hydroxylase. Quantification of 1alpha-hydroxylase activity in human prostatic epithelial cells by enzyme-substrate reaction analyses revealed a significantly decreased activity in cells derived from adenocarcinomas compared with cells derived from normal tissues or benign prostatic hyperplasia (BPH). In growth assays, we found that 25(OH)D3 inhibited growth of normal or BPH cells similarly to 1,25(OH)2D3. In contrast, in primary cultures of cancer cells and established cell lines, the antiproliferative action of 25(OH)D3 was significantly less pronounced than that of 1,25(OH)2D3. Our results indicate that growth inhibition by 25(OH)D3 depends on endogenous 1alpha-hydroxylase activity, and that this activity is deficient in prostate cancer cells. This finding has ramifications for both the prevention and therapy of prostate cancer with vitamin D compounds.


Asunto(s)
25-Hidroxivitamina D3 1-alfa-Hidroxilasa/metabolismo , Calcifediol/farmacología , Neoplasias de la Próstata/enzimología , División Celular/efectos de los fármacos , Células Epiteliales/enzimología , Inhibidores de Crecimiento/farmacología , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología
17.
Dig Surg ; 17(5): 528-31, 2000.
Artículo en Inglés | MEDLINE | ID: mdl-11124564

RESUMEN

BACKGROUND: Leiomyomas are rare esophagus neoplasms. They are usually solitary, and the diffuse lesion is extremely rare. CASE REPORT: A 19-year-old male presented with a 3-year history of occasional dysphagia and postprandial regurgitation. The chest radiographs showed a huge mass in the posterior mediastinum. Barium esophagograms showed narrowing of the middle third esophagus with proximal dilatation. The fibroesophagoscopy demonstrated multiple submucosal nodules below a level 22 cm from the incisor and covered with intact mucosa. CT scans of the chest showed a long segment of circumferential soft tissue in the posterior mediastinum which encircled and involved the upper two thirds of the esophagus. An intrathoracic esophagectomy with cervical esophagogastrostomy via the substernal route was performed. Grossly, multiple confluent myomatous nodules circumferentially involved the upper and middle third of the esophagus. Histologic findings showed diffuse leiomyomatosis of the esophagus. CONCLUSION: Esophageal leiomyomatosis should be considered in a young patient with long-standing dysphagia in whom smooth, tapered esophageal narrowing on barium study and circumferential esophageal wall thickening on CT scan are seen. An esophagectomy combined with a reconstruction procedure is indicated.


Asunto(s)
Neoplasias Esofágicas/cirugía , Esofagectomía , Leiomiomatosis/cirugía , Adulto , Neoplasias Esofágicas/diagnóstico por imagen , Esofagostomía , Gastrostomía , Humanos , Leiomiomatosis/diagnóstico por imagen , Masculino , Tomografía Computarizada por Rayos X
18.
Trends Cell Biol ; 10(10): 429-39, 2000 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-10998601

RESUMEN

Recently, many new examples of E3 ubiquitin ligases or E3 enzymes have been found to regulate a host of cellular processes. These E3 enzymes direct the formation of multiubiquitin chains on specific protein substrates, and - typically - the subsequent destruction of those proteins. We discuss how the modular architecture of E3 enzymes connects one of two distinct classes of catalytic domains to a wide range of substrate-binding domains. In one catalytic class, a HECT domain transfers ubiquitin directly to substrate bound to a non-catalytic domain. Members of the other catalytic class, found in the SCF, VBC and APC complexes, use a RING finger domain to facilitate ubiquitylation. The separable substrate-recognition domains of E3 enzymes provides a flexible means of linking a conserved ubiquitylation function to potentially thousands of ubiquitylated substrates in eukaryotic cells.


Asunto(s)
Ligasas/metabolismo , Animales , Dominio Catalítico , Células Eucariotas/enzimología , Humanos , Ligasas/química , Especificidad por Sustrato/fisiología , Ubiquitina-Proteína Ligasas
19.
Cell ; 102(3): 279-91, 2000 Aug 04.
Artículo en Inglés | MEDLINE | ID: mdl-10975519

RESUMEN

Phosphorylation of histone H3 at serine 10 occurs during mitosis and meiosis in a wide range of eukaryotes and has been shown to be required for proper chromosome transmission in Tetrahymena. Here we report that Ipl1/aurora kinase and its genetically interacting phosphatase, Glc7/PP1, are responsible for the balance of H3 phosphorylation during mitosis in Saccharomyces cerevisiae and Caenorhabditis elegans. In these models, both enzymes are required for H3 phosphorylation and chromosome segregation, although a causal link between the two processes has not been demonstrated. Deregulation of human aurora kinases has been implicated in oncogenesis as a consequence of chromosome missegregation. Our findings reveal an enzyme system that regulates chromosome dynamics and controls histone phosphorylation that is conserved among diverse eukaryotes.


Asunto(s)
Caenorhabditis elegans/citología , Proteínas Fúngicas/metabolismo , Histonas/metabolismo , Mitosis , Fosfoproteínas Fosfatasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Saccharomyces cerevisiae/citología , Animales , Aurora Quinasas , Caenorhabditis elegans/metabolismo , Genoma , Proteínas del Helminto/metabolismo , Fenotipo , Fosforilación , ARN sin Sentido , ARN Interferente Pequeño , Saccharomyces cerevisiae/metabolismo , Serina/metabolismo , Especificidad de la Especie
20.
Mol Cell ; 5(6): 917-26, 2000 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-10911986

RESUMEN

Multiple covalent modifications exist in the amino-terminal tails of core histones, but whether a relationship exists between them is unknown. We examined the relationship between serine 10 phosphorylation and lysine 14 acetylation in histone H3 and have found that, in vitro, several HAT enzymes displayed increased activity on H3 peptides bearing phospho-Ser-10. This augmenting effect of Ser-10 phosphorylation on acetylation by yGcn5 was lost by substitution of alanine for arginine 164 [Gcn5(R164A)], a residue close to Ser-10 in the structure of the ternary tGcn5/CoA/histone H3 complex. Gcn5(R164A) had reduced activity in vivo at a subset of Gcn5-dependent promoters, and, strikingly, transcription of this same subset of genes was also impaired by substitution of serine 10 to alanine in the histone H3 tail. These observations suggest that transcriptional regulation occurs by multiple mechanistically linked covalent modifications of histones.


Asunto(s)
Proteínas de Unión al ADN , Histonas/metabolismo , Lisina/metabolismo , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae/metabolismo , Serina/metabolismo , Acetilación , Acetiltransferasas/química , Acetiltransferasas/genética , Acetiltransferasas/metabolismo , Secuencia de Aminoácidos , Arginina/genética , Arginina/metabolismo , División Celular , Proteínas Fúngicas/química , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Histona Acetiltransferasas , Histonas/genética , Sustancias Macromoleculares , Modelos Biológicos , Modelos Moleculares , Datos de Secuencia Molecular , Mutación , Fragmentos de Péptidos/metabolismo , Fosforilación , Fosfoserina/metabolismo , Regiones Promotoras Genéticas , Proteínas Quinasas/química , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Proteínas Recombinantes , Saccharomyces cerevisiae/citología , Saccharomyces cerevisiae/enzimología , Saccharomyces cerevisiae/genética , Especificidad por Sustrato , Activación Transcripcional/genética
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