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2.
Eur J Radiol ; 163: 110834, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37080059

RESUMEN

PURPOSE: To assess the role of current imaging-based resectability criteria and the degree of radiological downsizing in locally advanced pancreatic adenocarcinoma (LAPC) after multiagent induction chemotherapy (ICT) in multicentre, open-label, randomized phase 2 trial. METHOD: LAPC patients were prospectively treated with multiagent ICT followed by surgical exploration within the NEOLAP trial. All patients underwent CT scan at baseline and after ICT to assess resectability status according to national comprehensive cancer network guidelines (NCCN) criteria and response evaluation criteria in solid tumors (RECIST) at the local study center and retrospectively in a central review. Imaging results were compared in terms of local and central staging, downsizing and pathological resection status. RESULTS: 83 patients were evaluable for central review of baseline and restaging imaging results. Downstaging by central review was rarely seen after multiagent ICT (7.7%), whereas tumor downsizing was documented frequently (any downsizing 90.4%, downsizing to partial response (PR) according to RECIST: 26.5%). Patients with any downsizing showed no significant different R0 resection rate (37.3%) as patients that fulfilled the criteria of PR (40.9%). The sensitivity of any downsizing for predicting R0 resection was 97% with a negative predictive value (NPV) of 0.88. ROC-analysis revealed that tumor downsizing was a predictor of R0 resection (AUC 0.647, p = 0.028) with a best cut-off value of 22.5% downsizing yielding a sensitivity of 65% and a specificity of 61%. CONCLUSIONS: Imaging-based tumor downsizing and not downstaging can guide the selection of patients with a realistic chance of R0-resection in LAPC after multi-agent ICT.


Asunto(s)
Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/cirugía , Estudios Prospectivos , Estudios Retrospectivos , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/cirugía , Terapia Neoadyuvante , Tomografía Computarizada por Rayos X/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estadificación de Neoplasias
3.
ESMO Open ; 7(4): 100552, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35970013

RESUMEN

BACKGROUND: The prognostic and predictive value of carbohydrate antigen 19-9 (CA 19-9) in locally advanced pancreatic cancer (LAPC) has not yet been defined from prospective randomized controlled trials (RCTs). PATIENTS AND METHODS: A total of 165 LAPC patients were treated within the NEOLAP RCT for 16 weeks with multiagent induction chemotherapy [ICT; either nab-paclitaxel/gemcitabine alone or nab-paclitaxel/gemcitabine followed by FOLFIRINOX (combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin)] followed by surgical exploration of all patients without evidence of disease progression. CA 19-9 was determined at baseline and after ICT and correlated with overall survival (OS) and secondary R0 resection rate. RESULTS: From the NEOLAP study population (N = 165) 133 patients (81%) were evaluable for CA 19-9 at baseline and 81/88 patients (92%) for post-ICT CA 19-9 response. Median OS (mOS) in the CA 19-9 cohort (n = 133) was 16.2 months [95% confidence interval (CI) 13.0-19.4] and R0 resection (n = 31; 23%) was associated with a significant survival benefit [40.8 months (95% CI 21.7-59.8)], while R1 resected patients (n = 14; 11%) had no survival benefit [14.0 (95% CI 11.7-16.3) months, hazard ratio (HR) 0.27; P = 0.001]. After ICT most patients showed a CA 19-9 response (median change from baseline: -82%; relative decrease ≥55%: 83%; absolute decrease to ≤50 U/ml: 43%). Robust CA 19-9 response (decrease to ≤50U/ml) was significantly associated with mOS [27.8 (95% CI 18.4-37.2) versus 16.5 (95% CI 11.7-21.2) months, HR 0.49; P = 0.013], whereas CA 19-9 baseline levels were not prognostic for OS. Multivariate analysis demonstrated that a robust CA 19-9 response was an independent predictive factor for R0 resection. Using a CA 19-9 decrease to ≤61 U/ml as optimal cut-off (by receiver operating characteristic analysis) yielded 72% sensitivity and 62% specificity for successful R0 resection, whereas CA 19-9 nonresponders (<20% decrease or increase) had no chance for successful R0 resection. CONCLUSIONS: CA 19-9 response after multiagent ICT provides relevant prognostic and predictive information and is useful in selecting LAPC patients for explorative surgery. CLINICAL TRIAL NUMBER: ClinicalTrials.govNCT02125136; https://clinicaltrials.gov/ct2/show/NCT02125136; EudraCT 2013-004796-12; https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-004796-12/results.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Antígeno CA-19-9 , Neoplasias Pancreáticas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno CA-19-9/uso terapéutico , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Pronóstico , Estudios Prospectivos
4.
Protein Eng Des Sel ; 21(8): 495-505, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18480090

RESUMEN

Using a comprehensive set of discovery and optimization tools, antibodies were produced with the ability to neutralize SARS coronavirus (SARS-CoV) infection in Vero E6 cells and in animal models. These anti-SARS antibodies were discovered using a novel DNA display method, which can identify new antibodies within days. Once neutralizing antibodies were identified, a comprehensive and effective means of converting the mouse sequences to human frameworks was accomplished using HuFR (human framework reassembly) technology. The best variant (61G4) from this screen showed a 3.5-4-fold improvement in neutralization of SARS-CoV infection in vitro. Finally, using a complete site-saturation mutagenesis methodology focused on the CDR (complementarity determining regions), a single point mutation (51E7) was identified that improved the 80% plaque reduction neutralization of the virus by greater than 8-fold. These discovery and evolution strategies can be applied to any emerging pathogen or toxin where a causative agent is known.


Asunto(s)
Anticuerpos Antivirales/aislamiento & purificación , Enfermedades Transmisibles Emergentes/terapia , Evolución Molecular Dirigida/métodos , Síndrome Respiratorio Agudo Grave/terapia , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/inmunología , Animales , Anticuerpos Antivirales/genética , Anticuerpos Antivirales/uso terapéutico , Especificidad de Anticuerpos/inmunología , Chlorocebus aethiops , Enfermedades Transmisibles Emergentes/prevención & control , Descubrimiento de Drogas , Humanos , Ratones , Ratones Endogámicos BALB C , Pruebas de Neutralización , Mutación Puntual/inmunología , Síndrome Respiratorio Agudo Grave/prevención & control , Células Vero
5.
Bone Marrow Transplant ; 41(7): 643-50, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18037935

RESUMEN

The ability to selectively deplete or enrich cells of specific phenotype by immunomagnetic selection to reduce the risk of GVHD holds significant promise for application in adoptive immunotherapy. Current clinical-scale approaches for T-cell depletion (e.g., CD34(+) selection, CD3(+) depletion), usually deplete gammadelta T cells, which may be advantageous in mediating graft-versus-tumor (GVT) effects and augmenting the innate immune response against infections. Here, we present a new method for depletion of T cells with potential GVHD reactivity by using a single-step immunomagnetic protocol, which efficiently depletes CD4(+) and CD8(+) alphabeta T cells under good manufacturing practice (GMP) conditions. Depletion from unstimulated leukapheresis products (n=6) containing up to 2.0 x 10(10) cells showed high efficiency (mean log depletion of CD4(+) cells: 4.12, CD8(+) cells: 3.77). In addition, immunomagnetic CD4/CD8 depletion resulted in passive enrichment of innate lymphocytes (mean recovery of natural killer (NK) cells: 38%, gammadelta T cells: 50%). We demonstrated that gammadelta/NK cells preserved their proliferative and cytotoxic capacity and conclude that simultaneous large-scale depletion of CD4(+)/CD8(+) T cells is feasible and can be performed under GMP conditions with high-depletion efficacy for alphabeta T cells and recovery of functionally intact innate effector lymphocytes for potential use in adoptive immunotherapy studies.


Asunto(s)
Inmunoterapia Adoptiva/métodos , Células Asesinas Naturales/citología , Depleción Linfocítica/métodos , Linfocitos T CD4-Positivos/citología , Linfocitos T CD8-positivos/citología , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Separación Inmunomagnética , Leucaféresis/métodos , Transfusión de Linfocitos/métodos
6.
Phys Med Biol ; 49(20): 4799-809, 2004 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-15566176

RESUMEN

Ultraviolet light can affect the appearance and medical condition of the human skin by triggering biophysical processes such as erythema, melanogenesis, photoaging and carcinogenesis. The evolution of these processes is related to the amount of ultraviolet light absorbed by skin pigments. This amount may vary with the wavelength and path length of the radiation that is propagated within the skin tissues. For many years, biomedical researchers have been investigating the propagation of ultraviolet light in skin tissues through Monte Carlo simulations. The scattering of the incident radiation by tissue internal structures, a key component in this process, is usually approximated by functions without a plausible connection with the underlying physical phenomena. In this paper, we examine the origins of such an approach, and question its generalized use with respect to wavelengths and biological materials for which there is no supporting data available. Furthermore, we perform comparisons to demonstrate that the accuracy and predictability of Monte Carlo simulations of ultraviolet propagation in skin tissues can be improved by using a data-driven approach to represent the scattering profile of these tissues.


Asunto(s)
Modelos Biológicos , Radiometría/métodos , Dispersión de Radiación , Fenómenos Fisiológicos de la Piel/efectos de la radiación , Rayos Ultravioleta , Animales , Carga Corporal (Radioterapia) , Simulación por Computador , Humanos , Modelos Estadísticos , Método de Montecarlo , Especificidad de Órganos , Dosis de Radiación , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Estadística como Asunto
7.
J Bacteriol ; 183(16): 4771-8, 2001 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-11466280

RESUMEN

We previously described a bacteriophage of the Lyme disease agent Borrelia burgdorferi designated phiBB-1. This phage packages the host complement of the 32-kb circular plasmids (cp32s), a group of homologous molecules found throughout the genus Borrelia. To demonstrate the ability of phiBB-1 to package and transduce DNA, a kanamycin resistance cassette was inserted into a cloned fragment of phage DNA, and the resulting construct was transformed into B. burgdorferi CA-11.2A cells. The kan cassette recombined into a resident cp32 and was stably maintained. The cp32 containing the kan cassette was packaged by phiBB-1 released from this B. burgdorferi strain. phiBB-1 has been used to transduce this antibiotic resistance marker into naive CA-11.2A cells, as well as two other strains of B. burgdorferi. This is the first direct evidence of a mechanism for lateral gene transfer in B. burgdorferi.


Asunto(s)
Bacteriófagos/genética , Bacteriófagos/fisiología , Grupo Borrelia Burgdorferi/genética , Grupo Borrelia Burgdorferi/virología , Resistencia a la Kanamicina/genética , Bacteriófagos/ultraestructura , Clonación Molecular , Elementos Transponibles de ADN , ADN Bacteriano/genética , ADN Viral/genética , Prueba de Complementación Genética , Plásmidos , Reacción en Cadena de la Polimerasa , Mapeo Restrictivo , Transducción Genética , Transformación Genética
8.
Control Clin Trials ; 22(1): 29-41, 2001 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11165421

RESUMEN

The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized, practice-based trial sponsored by the National Heart, Lung, and Blood Institute (NHLBI). The double-blind, active-controlled component of ALLHAT was designed to determine whether the rate of the primary outcome-a composite of fatal coronary heart disease and nonfatal myocardial infarction-differs between diuretic (chlorthalidone) treatment and each of three other classes of antihypertensive drugs: a calcium antagonist (amlodipine), an angiotensin-converting enzyme inhibitor (lisinopril), and an alpha-adrenergic blocker (doxazosin) in high-risk hypertensive persons ages 55 years and older. In addition, 10,377 ALLHAT participants with mild to moderate hypercholesterolemia were also enrolled in a randomized, open-label trial designed to determine whether lowering serum LDL cholesterol with an HMG CoA reductase inhibitor (pravastatin) will reduce all-cause mortality as compared to a control group receiving "usual care." In January 2000, an independent data review committee recommended discontinuing the doxazosin treatment arm. The NHLBI director promptly accepted the recommendation. This article discusses the steps involved in the orderly closeout of one arm of ALLHAT and the dissemination of trial results. These steps included provisional preparations; the actual decision process; establishing a timetable; forming a transition committee; preparing materials and instructions; informing 65 trial officers and coordinators, 628 active clinics and satellite locations, 313 institutional review boards, over 42,000 patients, and the general public; reporting detailed trial results; and monitoring the closeout process. Control Clin Trials 2001;22:29-41


Asunto(s)
Sistemas de Registro de Reacción Adversa a Medicamentos , Antihipertensivos/efectos adversos , Enfermedad Coronaria/prevención & control , Doxazosina/efectos adversos , Hipercolesterolemia/prevención & control , Hipertensión/tratamiento farmacológico , Infarto del Miocardio/prevención & control , Antihipertensivos/uso terapéutico , Causas de Muerte , Enfermedad Coronaria/mortalidad , Bases de Datos Factuales , Método Doble Ciego , Doxazosina/uso terapéutico , Femenino , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/mortalidad , Humanos , Hipercolesterolemia/mortalidad , Hipertensión/mortalidad , Masculino , Persona de Mediana Edad , Infarto del Miocardio/mortalidad , Pravastatina/efectos adversos , Pravastatina/uso terapéutico , Medición de Riesgo , Tasa de Supervivencia , Resultado del Tratamiento , Estados Unidos
9.
J Bacteriol ; 182(7): 2048-51, 2000 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-10715016

RESUMEN

The C-terminal domain of the A subunit of DNA gyrase, which we term Gac, is naturally synthesized in Borrelia burgdorferi as an abundant DNA-binding protein. Full-length GyrA, which includes the C-terminal domain, is also synthesized by the spirochete and functions as a subunit of DNA gyrase. We have disrupted synthesis of Gac as an independent protein and demonstrated that it is not essential for growth in a coumarin-resistant background. We detected no alterations in DNA maintenance, condensation, or topology in B. burgdorferi lacking this small DNA-binding protein.


Asunto(s)
Grupo Borrelia Burgdorferi/enzimología , Grupo Borrelia Burgdorferi/genética , ADN-Topoisomerasas de Tipo II/química , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Mutación/genética , Secuencia de Aminoácidos , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Secuencia de Bases , Grupo Borrelia Burgdorferi/efectos de los fármacos , Grupo Borrelia Burgdorferi/crecimiento & desarrollo , Cumarinas/farmacología , Girasa de ADN , ADN-Topoisomerasas de Tipo II/genética , ADN-Topoisomerasas de Tipo II/metabolismo , ADN Bacteriano/genética , Proteínas de Unión al ADN/química , Farmacorresistencia Microbiana/genética , Genes Bacterianos/genética , Genes Bacterianos/fisiología , Fenotipo , Plásmidos/genética , Estructura Terciaria de Proteína/genética
10.
Infect Immun ; 68(2): 915-20, 2000 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-10639463

RESUMEN

Colonization of the gastric mucosa by Helicobacter pylori is the major cause of gastroduodenal pathologies in humans. Studying the outcome of the humoral immune response directed against this gastric pathogen may contribute substantially to vaccine development and to the improvement of diagnostic techniques based on serology. By using two-dimensional gel electrophoresis, 29 proteins from H. pylori G27 were identified which strongly react with sera derived from H. pylori-infected patients suffering from different gastroduodenal pathologies. These antigens were characterized by mass spectrometry and proved to correspond to products of open reading frames predicted by the H. pylori genome sequence. The comparison of the antigenic patterns recognized by these sera revealed no association of specific H. pylori antigens with antibodies in patients with particular gastroduodenal pathologies.


Asunto(s)
Anticuerpos Antibacterianos/inmunología , Antígenos Bacterianos/análisis , Helicobacter pylori/inmunología , Antígenos Bacterianos/inmunología , Proteínas Bacterianas/análisis , Proteínas Bacterianas/inmunología , Gastritis/inmunología , Humanos , Immunoblotting , Linfoma de Células B de la Zona Marginal/inmunología , Úlcera Péptica/inmunología , Neoplasias Gástricas/inmunología
11.
J Laparoendosc Adv Surg Tech A ; 8(2): 65-8, 1998 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-9617964

RESUMEN

We report a case of fatal mesenteric artery thrombosis following laparoscopic cholecystectomy in a 60-year-old hypertensive woman, whose preoperative complaints were not typical of calculous biliary disease. Two previous case reports have associated laparoscopic cholecystectomy and acute intestinal ischemia; one of these patients died. Experimental and clinical data indicate that carbon dioxide pneumoperitoneum reduces splanchnic blood flow through several mechanical and physiologic mechanisms. Consequently, we believe that, when laparoscopic surgery is contemplated, physicians and patients should be aware of the risk of splanchnic vessel thrombosis, especially when certain pre-existing conditions are present (e.g., impairment of splanchnic vessel flow, hypercoagulable states, etc.). For such high-risk patients, especially when the planned laparoscopic procedure may be lengthy, gasless or low-pressure laparoscopic surgery, or even reversion to traditional open surgery should be considered.


Asunto(s)
Colecistectomía Laparoscópica , Oclusión Vascular Mesentérica/etiología , Neumoperitoneo Artificial/efectos adversos , Complicaciones Posoperatorias/etiología , Trombosis/etiología , Dióxido de Carbono , Resultado Fatal , Femenino , Humanos , Arteria Mesentérica Superior , Oclusión Vascular Mesentérica/epidemiología , Persona de Mediana Edad , Complicaciones Posoperatorias/epidemiología , Factores de Riesgo , Trombosis/epidemiología
12.
Mol Microbiol ; 27(5): 875-87, 1998 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-9535079

RESUMEN

Despite the presence of highly conserved signalling modules, significant cross-communication between different two-component systems has only rarely been observed. Domain swapping and the characterization of liberated signalling modules enabled us to characterize in vitro the protein domains that mediate specificity and are responsible for the high fidelity in the phosphorelay of the unorthodox Bvg and Evg two-component systems. Under equimolar conditions, significant in vitro phosphorylation of purified BvgA and EvgA proteins was only obtained by their histidine kinases, BvgS and EvgS respectively. One hybrid histidine kinase consisting of the BvgS transmitter and HPt domains and of the EvgS receiver domain (BvgS-TO-EvgS-R) was able to phosphorylate BvgA but not EvgA. In contrast, the hybrid protein consisting of the BvgS transmitter and the EvgS receiver and HPt domains (BvgS-T-EvgS-RO) was unable to phosphorylate BvgA but efficiently phosphorylated EvgA. These results demonstrate that the C-terminal HPt domains of the sensor proteins endow the unorthodox two-component systems with a high specificity for the corresponding regulator protein. In the case of the response regulators, the receiver but not the output domains contribute to the specific interaction with the histidine kinases, because a hybrid protein consisting of the EvgA receiver and the BvgA output domain could only be phosphorylated by the EvgS protein.


Asunto(s)
Proteínas Bacterianas/metabolismo , Bordetella pertussis/metabolismo , Proteínas de Escherichia coli , Escherichia coli/metabolismo , Proteínas Quinasas/metabolismo , Transducción de Señal , Proteínas Bacterianas/genética , Proteínas Bacterianas/aislamiento & purificación , Histidina Quinasa , Cinética , Fosforilación , Fosfotransferasas/química , Fosfotransferasas/metabolismo , Proteínas Quinasas/química , Sensibilidad y Especificidad , Factores de Transcripción/genética , Factores de Transcripción/aislamiento & purificación , Factores de Transcripción/metabolismo
13.
Cell ; 91(2): 161-9, 1997 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-9346234

RESUMEN

Different olfactory cues elicit distinct behaviors such as attraction, avoidance, feeding, or mating. In the nematode C. elegans, these cues are sensed by a small number of olfactory neurons, each of which expresses several different odorant receptors. The type of behavioral response elicited by an odorant could be specified by the olfactory receptor or by the olfactory neuron in which the receptor is activated. The attractive odorant diacetyl is detected by the receptor protein ODR-10, which is normally expressed in the AWA olfactory neurons. The repulsive odorant 2-nonanone is detected by the AWB olfactory neurons. Transgenic animals that express ODR-10 in AWB rather than AWA avoid diacetyl, while maintaining qualitatively normal responses to other attractive and repulsive odorants. Animals that express ODR-10 simultaneously in AWA and AWB have a defective response to diacetyl, possibly because of conflicting olfactory inputs. Thus, an animal's preference for an odor is defined by the sensory neurons that express a given odorant receptor molecule.


Asunto(s)
Caenorhabditis elegans/genética , Quimiotaxis/fisiología , Neuronas Receptoras Olfatorias/fisiología , Olfato/fisiología , Animales , Animales Modificados Genéticamente , Conducta Animal/fisiología , Caenorhabditis elegans/citología , Diacetil , Reacción de Fuga/efectos de los fármacos , Expresión Génica/fisiología , Genes de Helminto/fisiología , Cetonas , Transducción de Señal/fisiología , Transgenes/fisiología
14.
Gene ; 183(1-2): 103-8, 1996 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-8996093

RESUMEN

rough (ro) encodes a homeobox transcription factor required for proper specification of photoreceptor cells R2 and R5 in Drosophila eye development. To identify the transcriptional targets through which ro acts to specify the R2/R5 neuronal sub-type, we screened enhancer trap lines expressed in developing photoreceptors for those whose expression patterns were altered when ro function was inactivated. In this way we identified two potential ro targets, which are also targets of the zinc finger transcription factor glass (gl). We also identified an enhancer trap line that exhibits altered morphogenetic furrow expression in a ro mutant background. Finally, we have molecularly characterized an enhancer trap line, AE33, that was identified in earlier screens as a target of both ro and gl (freeman et al., 1992; Treisman and Rubin, 1996). The transcript interrupted by AE33 shares similarity with the mammalian vasodilator-stimulated phosphoprotein (VASP), a substrate for cAMP- and cGMP-dependent protein kinases that is associated with actin filaments, focal adhesions, and dynamic membrane regions (Haffner et al., 1995) with enabled (ena), a substrate of the Drosophila Abl tyrosine kinase (Gertler et al. 1995) and with two human Expressed Sequence Tags (ESTs).


Asunto(s)
Proteínas de Ciclo Celular , Proteínas de Unión al ADN/fisiología , Proteínas de Drosophila , Drosophila melanogaster/genética , Regulación del Desarrollo de la Expresión Génica , Proteínas Asociadas a Microtúbulos , Células Fotorreceptoras de Invertebrados/crecimiento & desarrollo , Factores de Transcripción/fisiología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Moléculas de Adhesión Celular/genética , ADN Complementario/genética , Proteínas de Unión al ADN/genética , Drosophila melanogaster/crecimiento & desarrollo , Elementos de Facilitación Genéticos/genética , Genes de Insecto/genética , Proteínas de Microfilamentos , Datos de Secuencia Molecular , Sistemas de Lectura Abierta/genética , Fosfoproteínas/genética , Mapeo Restrictivo , Análisis de Secuencia de ADN , Homología de Secuencia de Aminoácido , Transducción de Señal/genética , Factores de Transcripción/genética , Dedos de Zinc/genética
15.
Nat Genet ; 13(4): 399-408, 1996 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-8696333

RESUMEN

Hereditary haemochromatosis (HH), which affects some 1 in 400 and has an estimated carrier frequency of 1 in 10 individuals of Northern European descent, results in multi-organ dysfunction caused by increased iron deposition, and is treatable if detected early. Using linkage-disequilibrium and full haplotype analysis, we have identified a 250-kilobase region more than 3 megabases telomeric of the major histocompatibility complex (MHC) that is identical-by-descent in 85% of patient chromosomes. Within this region, we have identified a gene related to the MHC class I family, termed HLA-H, containing two missense alterations. One of these is predicted to inactivate this class of proteins and was found homozygous in 83% of 178 patients. A role of this gene in haemochromatosis is supported by the frequency and nature of the major mutation and prior studies implicating MHC class I-like proteins in iron metabolism.


Asunto(s)
Antígenos HLA/genética , Hemocromatosis/genética , Antígenos de Histocompatibilidad Clase I/genética , Proteínas de la Membrana , Alelos , Secuencia de Aminoácidos , Secuencia de Bases , Evolución Biológica , Cromosomas Artificiales de Levadura , Cromosomas Humanos Par 6 , Clonación Molecular/métodos , Cisteína , Cartilla de ADN/química , Expresión Génica , Genes MHC Clase I , Marcadores Genéticos , Haplotipos , Proteína de la Hemocromatosis , Humanos , Desequilibrio de Ligamiento , Complejo Mayor de Histocompatibilidad , Datos de Secuencia Molecular , ARN Mensajero/genética , Alineación de Secuencia , Homología de Secuencia de Aminoácido
16.
Hum Genet ; 96(2): 237-8, 1995 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-7635480

RESUMEN

Three human chromosome 9-specific cosmid recombinants containing (CA)n microsatellites are described. Three microsatellite loci, D9S970, D9S971, and D9S972, were observed to have heterozygosities of 0.78, 0.84, and 0.82, respectively. Subchromosomal localizations were determined by R-banding and fluorescence in situ hybridization.


Asunto(s)
Cromosomas Humanos Par 9/genética , Polimorfismo Genético , Secuencias Repetitivas de Ácidos Nucleicos , Secuencia de Bases , Bandeo Cromosómico , Mapeo Cromosómico , Cósmidos , Frecuencia de los Genes , Biblioteca Genómica , Humanos , Células Híbridas , Hibridación Fluorescente in Situ , Datos de Secuencia Molecular , Oligodesoxirribonucleótidos , Linaje , Reacción en Cadena de la Polimerasa
17.
Hum Mol Genet ; 2(9): 1407-11, 1993 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-7902161

RESUMEN

A panel of 18 superficial or invasive transitional cell carcinomas (TCCs) was analyzed for chromosome 9 deletions by performing a high-density loss of heterozygosity (LOH) analysis. Twenty-five microsatellite loci were assayed by the polymerase chain reaction (PCR) and 7 restriction fragment length polymorphism (RFLP) loci were analyzed by Southern blotting. Concordant results were obtained with these methods, including direct comparisons at 2 loci. Chromosome 9 LOH was observed in 13 (72%) of 18 informative cases, including 10 superficial lesions. In contrast, LOH on chromosomes 10, 15, 20 and 21 was < or = 8%. Evidence for missing copies of chromosome 9 was observed in 7 of 13 LOH cases. Comparison of cases with subchromosomal LOH implicated the region between the D9S55 locus on 9p12 and the argininosuccinate synthetase (ASS) locus on 9q34.1 as the location of a tumor suppressor gene relevant to TCC.


Asunto(s)
Carcinoma de Células Transicionales/genética , Deleción Cromosómica , Cromosomas Humanos Par 9 , Neoplasias de la Vejiga Urinaria/genética , Argininosuccinato Sintasa/genética , Secuencia de Bases , Cartilla de ADN/genética , ADN de Neoplasias/genética , ADN Satélite/genética , Marcadores Genéticos , Humanos , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción
18.
Ciba Found Symp ; 179: 235-44; discussion 244-50, 1993.
Artículo en Inglés | MEDLINE | ID: mdl-8168378

RESUMEN

The small soil nematode Caenorhabditis elegans has only 302 neurons in its entire nervous system, so it is possible to analyse the functions of individual neurons in the animal's behaviour. We are using behavioural, cellular and genetic analyses of chemotactic responses to find out how olfactory behaviour patterns are generated and regulated. Single chemosensory neurons in C. elegans can recognize several different attractive odorants that are distinguished by the animal. Distinct sets of chemosensory neurons detect high and low concentrations of a single odorant. Odorant responses adapt after prolonged exposure to an odorant; this adaptation is odorant specific and reversible. Mutants with defects in odorant responses have been identified. Some genes appear to be necessary for the development or function of particular kinds of sensory neurons. Other genes have effects that suggest that they participate in odorant reception or signal transduction.


Asunto(s)
Caenorhabditis elegans/fisiología , Mutación , Vías Olfatorias/fisiología , Neuronas Receptoras Olfatorias/fisiología , Adaptación Fisiológica , Animales , Caenorhabditis elegans/genética
19.
Development ; 116(2): 335-46, 1992 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-1363086

RESUMEN

In order to identify potential target genes of the rough homeodomain protein, which is known to specify some aspects of the R2/R5 photoreceptor subtype in the Drosophila eye, we have carried out a search for enhancer trap lines whose expression is rough-dependent. We crossed 101 enhancer traps that are expressed in the developing eye into a rough mutant background, and have identified seven lines that have altered expression patterns. One of these putative rough target genes is rhomboid, a gene known to be required for dorsoventral patterning and development of some of the nervous system in the embryo. We have examined the role of rhomboid in eye development and find that, while mutant clones have only a subtle phenotype, ectopic expression of the gene causes the non-neuronal mystery cells to be transformed into photoreceptors. We propose that rhomboid is a part of a partially redundant network of genes that specify photoreceptor cell fate.


Asunto(s)
Drosophila/genética , Ojo/embriología , Expresión Génica/fisiología , Genes Homeobox/fisiología , Células Fotorreceptoras/embriología , Animales , Elementos de Facilitación Genéticos/fisiología , Fenotipo , Retina/embriología , Retina/ultraestructura
20.
J Comput Assist Tomogr ; 16(1): 3-6, 1992.
Artículo en Inglés | MEDLINE | ID: mdl-1729302

RESUMEN

Adequate sedation remains one of the most important parts of performing high quality cross-sectional imaging in children. This is a noncomparative retrospective analysis of existing sedation protocols used in 1,158 children between the ages of 1 day and 18 years, checking for safety and efficacy. The most commonly used drugs were chloral hydrate (60-120 mg/kg) by mouth for infants less than 18 months and intravenous Nembutal (2-6 mg/kg) for older children. Sedation was successful in 97% of patients.


Asunto(s)
Sedación Consciente , Imagen por Resonancia Magnética , Tomografía Computarizada por Rayos X , Administración Oral , Adolescente , Niño , Preescolar , Hidrato de Cloral/administración & dosificación , Hidrato de Cloral/efectos adversos , Sedación Consciente/efectos adversos , Humanos , Lactante , Inyecciones Intravenosas , Pentobarbital/administración & dosificación , Pentobarbital/efectos adversos
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