RESUMEN
We report the complete genome sequence of Rhizobium leguminosarum bv. viciae SRDI969, an acid-tolerant, efficient nitrogen-fixing microorganism of Vicia faba. The 6.8 Mbp genome consists of a chromosome and four plasmids, with the symbiosis and nitrogen fixation genes encoded on the chromosome.
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The smo locus (sorbitol mannitol oxidation) is found on the chromosome of S. meliloti's tripartite genome. Mutations at the smo locus reduce or abolish the ability of the bacterium to grow on several carbon sources, including sorbitol, mannitol, galactitol, d-arabitol and maltitol. The contribution of the smo locus to the metabolism of these compounds has not been previously investigated. Genetic complementation of mutant strains revealed that smoS is responsible for growth on sorbitol and galactitol, while mtlK restores growth on mannitol and d-arabitol. Dehydrogenase assays demonstrate that SmoS and MtlK are NAD+-dependent dehydrogenases catalysing the oxidation of their specific substrates. Transport experiments using a radiolabeled substrate indicate that sorbitol, mannitol and d-arabitol are primarily transported into the cell by the ABC transporter encoded by smoEFGK. Additionally, it was found that a mutation in either frcK, which is found in an operon that encodes the fructose ABC transporter, or a mutation in frk, which encodes fructose kinase, leads to the induction of mannitol transport.
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Manitol , Sinorhizobium meliloti , Manitol/metabolismo , Fructosa/metabolismo , Sinorhizobium meliloti/genética , Sorbitol/metabolismo , Galactitol/metabolismo , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Transportadoras de Casetes de Unión a ATP/genéticaRESUMEN
Mesorhizobia are soil bacteria that establish nitrogen-fixing symbioses with various legumes. Novel symbiotic mesorhizobia frequently evolve following horizontal transfer of symbiosis-gene-carrying integrative and conjugative elements (ICESyms) to indigenous mesorhizobia in soils. Evolved symbionts exhibit a wide range in symbiotic effectiveness, with some fixing nitrogen poorly or not at all. Little is known about the genetic diversity and symbiotic potential of indigenous soil mesorhizobia prior to ICESym acquisition. Here we sequenced genomes of 144 Mesorhizobium spp. strains cultured directly from cultivated and uncultivated Australian soils. Of these, 126 lacked symbiosis genes. The only isolated symbiotic strains were either exotic strains used previously as legume inoculants, or indigenous mesorhizobia that had acquired exotic ICESyms. No native symbiotic strains were identified. Indigenous nonsymbiotic strains formed 22 genospecies with phylogenomic diversity overlapping the diversity of internationally isolated symbiotic Mesorhizobium spp. The genomes of indigenous mesorhizobia exhibited no evidence of prior involvement in nitrogen-fixing symbiosis, yet their core genomes were similar to symbiotic strains and they generally lacked genes for synthesis of biotin, nicotinate and thiamine. Genomes of nonsymbiotic mesorhizobia harboured similar mobile elements to those of symbiotic mesorhizobia, including ICESym-like elements carrying aforementioned vitamin-synthesis genes but lacking symbiosis genes. Diverse indigenous isolates receiving ICESyms through horizontal gene transfer formed effective symbioses with Lotus and Biserrula legumes, indicating most nonsymbiotic mesorhizobia have an innate capacity for nitrogen-fixing symbiosis following ICESym acquisition. Non-fixing ICESym-harbouring strains were isolated sporadically within species alongside effective symbionts, indicating chromosomal lineage does not predict symbiotic potential. Our observations suggest previously observed genomic diversity amongst symbiotic Mesorhizobium spp. represents a fraction of the extant diversity of nonsymbiotic strains. The overlapping phylogeny of symbiotic and nonsymbiotic clades suggests major clades of Mesorhizobium diverged prior to introduction of symbiosis genes and therefore chromosomal genes involved in symbiosis have evolved largely independent of nitrogen-fixing symbiosis.
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Lotus , Mesorhizobium , Transferencia de Gen Horizontal , Mesorhizobium/genética , Simbiosis/genética , Metagenómica , Nitrógeno , Australia , Lotus/microbiología , SueloRESUMEN
Bacteriocins are narrow-spectrum antibiotics of bacterial origin that can affect competition in resource-limited environments, such as the rhizosphere. Therefore, bacteriocins may be good candidates for manipulation to generate more competitive inocula for soybean. In this study, Bradyrhizobium japonicum FN1, along with other Bradyrhizobia in our culture collection, was screened for bacteriocin-like activity. Five distinct inhibitory effects were observed. FN1 genes putatively involved in bacteriocin production were computationally identified. These genes were mutagenized, and the subsequent strains were screened for loss of inhibitory activity. Mutant strain BRJ-48, with an insert in bjfn1_01204, displayed a loss of ability to inhibit an indicator strain. This loss can be complemented by the introduction of a plasmid expressing bjfn1_01204 in trans. The strain carrying the mutation did not affect competition in broth cultures but was less competitive for nodule occupancy. Annotation suggests that bjfn1_01204 encodes a carboxymuconolactone decarboxylase; however, the direct contribution of how this enzyme contributes to inhibiting the tester strain remains unknown.
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Bradyrhizobium , Fabaceae , Bradyrhizobium/genética , Fabaceae/microbiología , Glycine max/microbiología , SimbiosisRESUMEN
BACKGROUND: 18F-fluciclovine is a synthetic amino acid positron emission tomography (PET) radiotracer that is approved for use in prostate cancer. In this clinical study, we characterised the kinetic model best describing the uptake of 18F-fluciclovine in breast cancer and assessed differences in tracer kinetics and static parameters for different breast cancer receptor subtypes and tumour grades. METHODS: Thirty-nine patients with pathologically proven breast cancer underwent 20-min dynamic PET/computed tomography imaging following the administration of 18F-fluciclovine. Uptake into primary breast tumours was evaluated using one- and two-tissue reversible compartmental kinetic models and static parameters. RESULTS: A reversible one-tissue compartment model was shown to best describe tracer uptake in breast cancer. No significant differences were seen in kinetic or static parameters for different tumour receptor subtypes or grades. Kinetic and static parameters showed a good correlation. CONCLUSIONS: 18F-fluciclovine has potential in the imaging of primary breast cancer, but kinetic analysis may not have additional value over static measures of tracer uptake. CLINICAL TRIAL REGISTRATION: NCT03036943.
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Neoplasias de la Mama/diagnóstico por imagen , Ácidos Carboxílicos/administración & dosificación , Ciclobutanos/administración & dosificación , Metformina/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Ácidos Carboxílicos/farmacocinética , Ciclobutanos/farmacocinética , Femenino , Humanos , Clasificación del Tumor , Tomografía Computarizada por Tomografía de Emisión de Positrones , Sensibilidad y Especificidad , Resultado del TratamientoRESUMEN
Sinorhizobium meliloti 1021 is a Gram-negative alphaproteobacterium with a robust capacity for carbohydrate metabolism. The enzymes that facilitate these reactions assist in the survival of the bacterium across a range of environmental niches, and they may also be suitable for use in industrial processes. SmoS is a dehydrogenase that catalyzes the oxidation of the commonly occurring sugar alcohols sorbitol and galactitol to fructose and tagatose, respectively, using NAD+ as a cofactor. The main objective of this study was to evaluate SmoS using biochemical techniques. The nucleotide sequence was codon-optimized for heterologous expression in Escherichia coli BL21 (DE3) Gold cells and the protein was subsequently overexpressed and purified. Size-exclusion chromatography and X-ray diffraction experiments suggest that SmoS is a tetramer. SmoS was crystallized, and crystals obtained in the absence of substrate diffracted to 2.1â Å resolution and those of a complex with sorbitol diffracted to 2.0â Å resolution. SmoS was characterized kinetically and shown to have a preference for sorbitol despite having a higher affinity for galactitol. Computational ligand-docking experiments suggest that tagatose binds the protein in a more energetically favourable complex than fructose, which is retained in the active site over a longer time frame following oxidation and reduces the rate of the reaction. These results supplement the inventory of biomolecules with potential for industrial applications and enhance the understanding of metabolism in the model organism S. meliloti.
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Proteínas Bacterianas/química , L-Iditol 2-Deshidrogenasa/química , Sinorhizobium meliloti/enzimología , Dominio Catalítico , Cristalografía por Rayos X , Estabilidad de Enzimas , Fructosa/química , Galactitol/metabolismo , Concentración de Iones de Hidrógeno , Cinética , Modelos Moleculares , Sinorhizobium meliloti/crecimiento & desarrollo , Sorbitol/química , Sorbitol/metabolismoRESUMEN
The legume endosymbiont Sinorhizobium meliloti can utilize a broad range of carbon compounds to support its growth. The linear, six-carbon polyol galactitol is abundant in vascular plants and is metabolized in S. meliloti by the contribution of two loci SMb21372-SMb21377 and SMc01495-SMc01503 which are found on pSymB and the chromosome, respectively. The data suggest that several transport systems, including the chromosomal ATP-binding cassette (ABC) transporter smoEFGK, contribute to the uptake of galactitol, while the adjacent gene smoS encodes a protein for oxidation of galactitol into tagatose. Subsequently, genes SMb21374 and SMb21373, encode proteins that phosphorylate and epimerize tagatose into fructose-6-phosphate, which is further metabolized by the enzymes of the Entner-Doudoroff pathway. Of note, it was found that SMb21373, which was annotated as a 1,6-bis-phospho-aldolase, is homologous to the E. coli gene gatZ, which is annotated as encoding the non-catalytic subunit of a tagatose-1,6-bisphosphate aldolase heterodimer. When either of these genes was introduced into an Agrobacterium tumefaciens strain that carries a tagatose-6-phosphate epimerase mutation, they are capable of complementing the galactitol growth deficiency associated with this mutation, strongly suggesting that these genes are both epimerases. Phylogenetic analysis of the protein family (IPR012062) to which these enzymes belong, suggests that this misannotation is systemic throughout the family. S. meliloti galactitol catabolic mutants do not exhibit symbiotic deficiencies or the inability to compete for nodule occupancy.
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Proteínas Bacterianas/genética , Galactitol/metabolismo , Hexosas/metabolismo , L-Iditol 2-Deshidrogenasa/genética , Operón/genética , Sinorhizobium meliloti/genética , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Proteínas Bacterianas/clasificación , Proteínas Bacterianas/metabolismo , Cromosomas Bacterianos/genética , Fructosa-Bifosfato Aldolasa/clasificación , Fructosa-Bifosfato Aldolasa/genética , Fructosa-Bifosfato Aldolasa/metabolismo , Regulación Bacteriana de la Expresión Génica , L-Iditol 2-Deshidrogenasa/metabolismo , Filogenia , Plásmidos/genética , Sinorhizobium meliloti/clasificación , Sinorhizobium meliloti/metabolismoRESUMEN
Bradyrhizobium japonicum strain FN1 was found to produce bacteriocin-like zones of clearing when tested against other strains of bradyrhizbia. The genome was sequenced, and several putative bacteriocin-producing genes, in addition to the expected genes involved in nodulation and nitrogen fixation, were identified.
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BACKGROUND: The primary aim was to compare long-term health-related quality of life (HRQoL) in patients undergoing sentinel lymph node biopsy (SLNB) alone versus axillary lymph node dissection (ALND), with or without axillary metastases. Secondary aims were to a) investigate agreement between objectively measured and self-reported lymphoedema and b) compare, with respect to HRQoL, women with objective arm lymphoedema without subjective ratings and those with no objective but subjective ratings of arm lymphoedema. METHODS: The three study groups were defined by axillary surgery: 1) SLNB alone (N = 140), 2) ALND in patients without axillary metastases (N = 125) and 3) ALND in patients with axillary metastases (N = 155). Preoperatively, one and three years postoperatively arm volume was measured and questionnaires regarding self-perceived symptoms of arm lymphoedema and HRQoL were completed (The Swedish Short Form-36 Health Survey, SF-36). RESULTS: Out of the original 516 who had axillary surgery, 420 (81%) completed the study. There were no statistically significant differences in HRQoL between the three study groups. No statistically significant agreement was found between self-perceived and objectively measured arm lymphoedema. Women without self-perceived arm lymphoedema, regardless of objective arm lymphoedema or not, scored higher on all eight SF-36 domains than those who reported self-perceived arm lymphoedema. CONCLUSION: Women reporting self-perceived arm lymphoedema, regardless of objective lymphoedema or not, have a decreased long-term health-related quality of life. This indicates that more attention should be given to the subjective reports of symptom in order to better help these women.
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Brazo/patología , Neoplasias de la Mama/patología , Escisión del Ganglio Linfático/efectos adversos , Ganglios Linfáticos/patología , Ganglios Linfáticos/cirugía , Linfedema/diagnóstico , Percepción , Calidad de Vida , Biopsia del Ganglio Linfático Centinela/efectos adversos , Anciano , Axila , Neoplasias de la Mama/cirugía , Femenino , Humanos , Metástasis Linfática , Linfedema/etiología , Linfedema/psicología , Persona de Mediana Edad , Tamaño de los Órganos , Encuestas y Cuestionarios , Factores de TiempoRESUMEN
Water clear cell hyperplasia (WCCH) and water clear cell adenomas (WCCA) of the parathyroid glands are rare causes of primary hyperparathyroidism. We report in this series one case of WCCH and two cases of WCCA representing 0.3% of patients with primary hyperparathyroidism presenting to our institution. Increased parathyroid cellular water content was responsible for relatively larger parathyroid gland sizes. However, this was not associated with higher biochemical markers or more severe clinical presentations. Histological distinction between WCCH and WCCA is difficult but important since patients with WCCH who have had a parathyroidectomy via a unilateral neck exploration may carry an increased risk of future disease recurrence.
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Adenoma/complicaciones , Hiperparatiroidismo Primario/patología , Glándulas Paratiroides/patología , Neoplasias de las Paratiroides/complicaciones , Adenoma/patología , Adenoma/cirugía , Anciano , Agua Corporal , Femenino , Humanos , Hiperparatiroidismo Primario/etiología , Hiperparatiroidismo Primario/cirugía , Hiperplasia/complicaciones , Hiperplasia/cirugía , Masculino , Persona de Mediana Edad , Neoplasias de las Paratiroides/patología , Neoplasias de las Paratiroides/cirugía , Resultado del TratamientoRESUMEN
PURPOSE: To test the hypothesis that cisplatin (CDDP) administered concurrently with standard radiotherapy (RT) would improve pelvic control and survival in patients with advanced squamous cell cancer of the cervix. PATIENTS AND METHODS: A total of 259 patients with International Federation of Gynecology and Obstetrics stage IB to IVA squamous cell cervical cancer with central disease greater-than-or-equal 5 cm or histologically confirmed pelvic lymph node involvement were randomized to receive RT (external-beam RT plus brachytherapy) plus weekly CDDP chemotherapy (40 mg/m(2)) (arm 1) or the same RT without chemotherapy (arm 2). RESULTS: A total of 253 patients were available for analysis. Median follow-up was 82 months. No significant difference was found in progression-free survival (P =.33). No significant difference in 3- and 5-year survival rates was found (69% v 66% and 62% v 58%, respectively; P =.42). The hazard ratio for survival (arm 2 to arm 1) was 1.10 (95% confidence interval, 0.75 to 1.62). CONCLUSION: This study did not show a benefit to either pelvic control or survival by adding concurrent weekly CDDP chemotherapy in a dose of 40 mg/m(2) to radical RT as given in this trial. Careful attention to RT details is important for achieving optimum outcome for patients with this disease.
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Antineoplásicos/farmacología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Cisplatino/farmacología , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Braquiterapia , Carcinoma de Células Escamosas/patología , Cisplatino/administración & dosificación , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Resultado del Tratamiento , Neoplasias del Cuello Uterino/patologíaRESUMEN
We compare the relative activities of surface-bound and fluid-phase thrombin and their inhibition by heparin and Intimatan, a novel heparin cofactor II (HCII) agonist. In vitro, we compared the observed amidolytic activities of fluid-phase and surface-bound thrombin with the expected activities based upon 125I-specific activity. In vivo, we compared the inhibitory effects of heparin and Intimatan on thrombin activity bound to injured vessel walls. In vitro, the correlations between observed and expected activities of fluid-phase and surface-bound thrombin, were: r = 0.9974, p < 0.001; and r = 0.9678, p < 0.001; respectively. In vivo, injured vessel wall surface-bound thrombin activity persisted for > 24 h. This activity was not inhibited by heparin, but was inhibited by Intimatan, p < 0.001. We conclude that surface-bound thrombin is as active as fluid-phase thrombin and remains protected from inhibition by heparin, thereby contributing to vessel wall thrombogenicity following injury. In contrast, surface-bound thrombin is inhibited by Intimatan, thereby effectively decreasing vessel wall thrombogenicity following injury in vivo.
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Anticoagulantes/farmacología , Pruebas de Coagulación Sanguínea , Dermatán Sulfato/análogos & derivados , Dermatán Sulfato/farmacología , Cofactor II de Heparina/farmacología , Trombina/antagonistas & inhibidores , Trombosis/etiología , Animales , Traumatismos de las Arterias Carótidas/sangre , Membrana Celular/química , Evaluación Preclínica de Medicamentos , Endotelio Vascular/química , Endotelio Vascular/efectos de los fármacos , Femenino , Cofactor II de Heparina/agonistas , Humanos , Masculino , Tiempo de Tromboplastina Parcial , Protrombina/análisis , ConejosRESUMEN
Tight regulation of retinoic acid (RA) distribution in the embryo is critical for normal morphogenesis. The RA-metabolizing enzymes Cyp26A1 and Cyp26B1 are believed to play important roles in protecting certain embryonic tissues from inappropriate RA signaling. We have cloned the murine Cyp26B1 cDNA and compared its expression pattern to that of Cyp26A1 from embryonic day (E) E7-E11.5 using in situ hybridization. Northern blot analysis shows the presence of two Cyp26B1 transcripts of approximately 2.3 and 3.5 kb in embryonic limb bud. Whereas Cyp26A1 is expressed in gastrulating embryos by E7, Cyp26B1 is first expressed at E8.0 in prospective rhombomeres 3 and 5. Cyp26B1 expression expands to specific dorso-ventral locations in rhombomeres 2-6 between E8.5 and E9.5, whereas Cyp26A1 hindbrain expression is limited to rhombomere 2 at E8.5. No (or very weak) Cyp26B1 expression is observed in the tail bud, a major site of Cyp26A1 expression. Differential expression is seen in branchial arches, with Cyp26A1 being mainly expressed in neural crest-derived mesenchyme, and Cyp26B1 in specific ectodermal and endodermal areas. Cyp26B1 is markedly expressed in the ectoderm and distal mesoderm of the limb buds from the beginning of their outgrowth. Cyp26A1 transcripts are seen later and at lower levels in limb ectoderm, and both transcripts are excluded from the apical ectodermal ridge.
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Sistema Enzimático del Citocromo P-450/genética , Embrión de Mamíferos/metabolismo , Expresión Génica , Oxigenasas de Función Mixta/genética , Secuencia de Aminoácidos , Animales , Región Branquial/embriología , Región Branquial/metabolismo , Sistema Nervioso Central/embriología , Sistema Nervioso Central/metabolismo , Clonación Molecular , Sistema Enzimático del Citocromo P-450/química , Endodermo/metabolismo , Gástrula/metabolismo , Perfilación de la Expresión Génica , Esbozos de los Miembros/embriología , Esbozos de los Miembros/metabolismo , Mesodermo/metabolismo , Ratones , Oxigenasas de Función Mixta/química , Datos de Secuencia Molecular , Ácido Retinoico 4-Hidroxilasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Alineación de Secuencia , Cola (estructura animal)/embriología , Cola (estructura animal)/metabolismoRESUMEN
BACKGROUND/PURPOSE: Portoenterostomy is an accepted method of achieving bile drainage in biliary atresia, but there is a paucity of data, including formal quality-of-life (QoL) studies, on long-term survivors. This report includes survival analysis and QoL studies from the world's largest series of cases treated in Japan (1951 to 1998). The Japanese QoL results are compared with a matched group of UK patients from King's College Hospital, London. METHODS: One hundred fifteen Japanese surviving portoenterostomy patients were studied and comparison of trends in survival calculated from 6-year period cohorts. Liver function and hematologic status in a group of 30 long-term survivors (14 to 24 years) were compared with 25 patients from England, (14 to 23 years). Twenty-five Japanese and 21 UK patients (SF-36) completed a QoL questionnaire. RESULTS: Median survival times in Japanese patients before 1975 were less than 1 year but increased to 18 years after 1975. Hematologic and liver function test results did not show any significant differences between the Japanese and UK patients. QoL studies in the UK patients showed no significant difference from normative, general population data. Japanese patients underperformed in general health (P = .01), role emotional (P = .05) and role physical (P = .07) but, overall, there was no significant difference between the Japanese and UK patients except for marginal differences in indices of general health and vitality (P = .06 and .04, respectively). CONCLUSIONS: Long-term survival rate in the Japanese patients increased dramatically from 1 year to 17 years after 1975. The QoL of survivors was comparable in Japan and England. The satisfactory comparison with normative population data suggests that we should continue to use portoenterostomy as the primary treatment for biliary atresia. J Pediatr Surg 36:892-897.
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Atresia Biliar/mortalidad , Atresia Biliar/cirugía , Portoenterostomía Hepática/mortalidad , Calidad de Vida , Sobrevivientes , Adolescente , Adulto , Inglaterra/epidemiología , Femenino , Estudios de Seguimiento , Estado de Salud , Humanos , Japón/epidemiología , Tablas de Vida , Pruebas de Función Hepática , Masculino , Portoenterostomía Hepática/psicología , Tasa de Supervivencia/tendenciasRESUMEN
Active specific immunotherapy with liposomal vaccines targeted to the mucinous carcinoma-associated glycoprotein MUC1 have shown promising results in animal models. The aim of this phase I study was to evaluate the safety and immunogenicity of 2 dose levels of the MUC1 liposomal vaccine preparation BLP25. Patients with stage IIIB or IV non-small-cell lung cancer received either 20 microg or 200 microg of the liposomal BLP25 vaccine preparation. Injections were administered subcutaneously at weeks 0, 2, 5, and 9. Immunological responses to vaccination were measured by antibody production, cytotoxic T lymphocytes (CTL), and proliferative T-helper cells. Seventeen patients were entered on study; 12 patients completed the vaccination protocol. Two patients, 1 in each dose group, developed clinically insignificant grade 3 lymphopenia during the study. Nonhematologic toxicities were mild and self-limiting, and there were no significant long-term injection site reactions. Immunological assays revealed the generation of CTLs against MUC1-positive tumor cell lines in 5 of 12 evaluable patients. These patients did not have CTLs prior to receiving the vaccine. No significant humoral response to the vaccination was observed. No objective antitumor responses were observed. Of the 12 patients completing all the vaccinations, 4 had stable disease. Median survival time was 5.4 months in the 20 microg group and 14.6 months in the 200 microg group. In summary, the BLP25 liposomal vaccine was well tolerated and elicited a primarily cellular immune response in these lung cancer patients. This study forms the basis for further clinical exploration of the MUC1 liposomal vaccine, BLP25.
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The purpose of this study was to evaluate the toxicity and potential efficacy of administering the THERATOPE STn-KLH cancer vaccine to ovarian and breast cancer patients after an autologous stem cell transplant. Forty patients (11 high-risk stage II/III breast cancer, 22 stage IV breast cancer, and seven stage III/IV ovarian cancer patients) were treated with high-dose chemotherapy followed by autologous/syngeneic stem cell rescue and vaccination with THERATOPE STn-KLH (Sialyl-Tn-KLH with Detox-B Stable Emulsion). Each patient was scheduled to receive a total of five vaccinations beginning on days 30-151 after stem cell infusion. The vaccine was well tolerated. Induration and erythema at the site of injection were the most common side-effects. When one compares the outcome of patients vaccinated with 66 breast and ovarian cancer patients who were not, following risk-adjustment analysis, vaccinated patients appeared more likely to survive (P = 0.07) and less likely to relapse (P = 0. 10). Vaccinated patients with the greatest specific lytic activity against STn+OVCAR tumor cells relative to nonspecific killing of Daudi cells tended to remain in remission longer than patients who displayed less specific immune activity (P = 0.057). We conclude that the THERATOPE STn-KLH cancer vaccine is well tolerated in breast and ovarian cancer patients after autologous transplant and, while not statistically significant, the trends in data support the concept that THERATOPE vaccine may decrease the risk for relapse and death and thus warrants further study. Bone Marrow Transplantation (2000) 25, 1233-1241.
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Antígenos de Carbohidratos Asociados a Tumores/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/terapia , Vacunas contra el Cáncer/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Hemocianinas/administración & dosificación , Neoplasias Ováricas/terapia , Adulto , Neoplasias de la Mama/patología , Terapia Combinada , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/patología , Trasplante Autólogo , Resultado del TratamientoRESUMEN
Seven ovarian and 33 breast high-risk stage II/III and stage IV cancer patients received high-dose chemotherapy followed by stem cell rescue. Thirty to 151 days after stem cell transplantation, the patients received their first immunotherapy treatment with Theratope STn-KLH cancer vaccine. Most patients developed increasing IgG anti-STn titers to a sustained peak after the fourth or fifth immunizations. Only one patient had elevated CA27.29 (MUC1 mucin) serum levels at trial entry. Five of the seven patients with preimmunotherapy elevated serum CA125 levels demonstrated decreasing CA125 levels during immunotherapy, consistent with an antitumor response. Evidence of STn antigen-specific T-cell proliferation was obtained from 17 of the 27 evaluable patients who received at least three immunotherapy treatments. Eleven of the 26 patients tested had evidence of an anti-STn TH1 antigen-specific T-cell response as determined by interferon-gamma, but not interleukin (IL)-4, production. After immunization, lytic activity of peripheral blood lymphocytes (PBLs) tested against a lymphokine activated killer (LAK)-sensitive cell line, a natural killer (NK)-sensitive cell line, and an STn-expressing cancer cell line (OVCAR) increased significantly. In vitro IL-2 treatment of the PBLs after vaccination greatly enhanced killing of the STn+ cancer cell line. Evidence of the development of OVCAR specific killing activity, over and above that seen due to LAK or NK killing, is presented. These studies provide the strongest evidence in humans of the development of an antitumor T-cell response after immunization with a cancer-associated carbohydrate antigen.
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Antígenos de Carbohidratos Asociados a Tumores/inmunología , Neoplasias de la Mama/terapia , Vacunas contra el Cáncer/inmunología , Hemocianinas/inmunología , Neoplasias Ováricas/terapia , Linfocitos T/inmunología , Antígenos de Carbohidratos Asociados a Tumores/administración & dosificación , Antígenos de Carbohidratos Asociados a Tumores/uso terapéutico , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/inmunología , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/uso terapéutico , Terapia Combinada , Citotoxicidad Inmunológica/efectos de los fármacos , Femenino , Trasplante de Células Madre Hematopoyéticas , Hemocianinas/administración & dosificación , Hemocianinas/uso terapéutico , Humanos , Inmunoglobulinas/sangre , Inmunoterapia , Interferón gamma/biosíntesis , Interleucina-2/farmacología , Activación de Linfocitos/efectos de los fármacos , Mucinas/inmunología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/inmunología , Células Tumorales CultivadasRESUMEN
Se describe el desempeño de la planta de tratamiento de agua durante el evento de contaminacion de agua en Sydney. Este consiste en realidad en una serie de eventos en donde la cantidad de patogenos aumenta notablemente en el agua cruda
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Australia , Plantas de Tratamiento , Purificación del AguaRESUMEN
Sixteen metastatic breast cancer patients were immunized with a low dose (5 micrograms) of a 16 amino acid MUC1 peptide (GVTSAPDTRPAPGSTA) conjugated to KLH (BP16-KLH) plus DETOX adjuvant and evaluated for antibody titers against MUC1 peptide and KLH and for cytotoxic lymphocyte (CTL) activity using class 1 HLA-matched MUC1-positive tumor targets. All patients generated strong anti-KLH IgG responses. Only 3 patients developed an anti-MUC1 IgG response, which was weak in magnitude. As it is controversial whether human cancer patients generate class-1-restricted CTL against MUC1, we examined anti-MUC1 CTL activity of PBLs following 4 immunizations with BP16-KLH. The generation of MUC1-specific CTLs required only a 6-day in vitro stimulation of patients' T-cells with synthetic MUC1-peptide-pulsed autologous APCs. The assay for CTL activity was a 4 hour 51Cr release from labeled adenocarcinoma target cells. Eleven of the 16 immunized patients were tested for CTL activity using class-1-matched adenocarcinoma target cell lines. Evidence for class-1-restricted killing of MUC1-expressing tumor cell lines was obtained in 7 of these 11 patients.
Asunto(s)
Neoplasias de la Mama/inmunología , Antígenos de Histocompatibilidad Clase I/fisiología , Mucina-1/inmunología , Linfocitos T Citotóxicos/fisiología , Femenino , Humanos , Inmunización , Inmunoglobulina G/sangre , Metástasis de la NeoplasiaRESUMEN
UNLABELLED: PURPOSE. This article reports the pharmacokinetics, radiation dosimetry and radioimmunoscintigraphy (RIS) of two (99m)Tc-labelled monoclonal antibodies (MAb) used to detect cancer. METHODS: The effects of circulating antigen in female cancer patients are explored and their effects on the ability of these MAbs to effectively perform as RIS agents noted. To illustrate the effects of circulating antigen, data using MAb B43.13 (OVAREX, AltaRex Corp., Waltham, MA, USA) from a Pilot study in ovarian cancer patients are presented. The results from a Phase II study of MAb 170H.82 (Tru-Scint AD, BIOMIRA INC., Edmonton, Alberta, Canada) in patients with primary and locally recurrent breast cancer were used to portray the biodistribution patterns when no circulating antigen is present. Data from planar gamma camera images were obtained for both groups and used for pharmacokinetic and radiation dosimetry analyses. RESULTS: A pharmacokinetic analysis indicated a shorter residence time and higher clearance of (99m)Tc-MAb-B43.13 that was ascribed in part to the circulating CA 125 antigen in this group of ovarian cancer patients. CONCLUSION: These clearance patterns resulted in acceptable, though higher radiation doses to the spleen and urinary bladder wall for these patients when compared to the MAb-170H.82 group. Both MAbs were found to produce acceptable radioimmunoscintigraphic images