RESUMEN
Peruvian and Chilean mummies and coprolites provide a source of population-based parasitological information. This is especially true of the fish tapeworm, Adenocephalus pacificus. Our analysis of Chinchorro and Chiribaya mummies and diversified coprolite samples from Chile and Peru show variation in infection. There is a statistically significant difference in prevalence between Chinchorro hunter-gatherer and Chiribaya mixed-subsistence contexts. Furthermore, the most pronounced differences occur between populations within these groups. Chinchorro differences in cemeteries at the same location can be related to El Niño-Southern Oscillation variations. Pronounced prevalence variations between 3 Chiribaya villages within 7 km of each other relate to fish distribution and preparation variation. As with other recent archaeoparasitology studies, eggs-per-gram data exhibit overdispersion.
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Cestodos , Difilobotriosis , Diphyllobothrium , Animales , Prevalencia , Difilobotriosis/epidemiología , Difilobotriosis/parasitología , Perú/epidemiologíaRESUMEN
Trees in the urban right-of-way areas have increasingly been considered part of a suite of green infrastructure practices used to manage stormwater runoff. A paired-catchment experimental design (with street tree removal as the treatment) was used to assess how street trees affect major hydrologic fluxes in a typical residential stormwater collection and conveyance network. The treatment consisted of removing 29 green ash (Fraxinus pennsylvanica) and two Norway maple (Acer platanoides) street trees from a medium-density residential area. Tree removal resulted in an estimated 198 m3 increase in surface runoff volume compared to the control catchment over the course of the study. This increase accounted for 4% of the total measured runoff after trees were removed. Despite significant changes to runoff volume (p ≤ 0.10), peak discharge was generally not affected by tree removal. On a per-tree basis, 66 L of rainfall per m2 of canopy was lost that would have otherwise been intercepted and stored. Runoff volume reduction benefit was estimated at 6376 L per tree. These values experimentally document per-capita retention services rendered by trees over a growing season with 42 storm events. These values are within the range reported by previous studies, which largely relied on simulation. This study provides catchment scale evidence that reducing stormwater runoff is one of many ecosystem services provided by street trees. This study quantifies these services, based on site conditions and a mix of deciduous species, and serves to improve our ability to account for this important yet otherwise poorly constrained hydrologic service. Engineers, city planners, urban foresters, and others involved with the management of urban stormwater can use this information to better understand tradeoffs involved in using green infrastructure to reduce urban runoff burden.
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Árboles , Movimientos del Agua , Ciudades , Ecosistema , Hidrología , LluviaRESUMEN
LESSONS LEARNED: Despite the compelling preclinical rationale of evaluating the genetically engineered heparin derivative, necuparanib, combined with standard therapy in metastatic pancreas adenocarcinoma, the results were ultimately disappointing.Safety was documented, although dose escalation was limited by the number of subcutaneous injections, the potential for skin toxicity (cellulitis), and low-level anticoagulant effect. Nonetheless, the hypothesis of targeting prothrombotic pathways in pancreas adenocarcinoma remains compelling. BACKGROUND: Necuparanib is derived from unfractionated heparin and engineered for reduced anticoagulant activity while preserving known heparin-associated antitumor properties. This trial assessed the safety, pharmacokinetics (PK), pharmacodynamics, and initial efficacy of necuparanib combined with gemcitabine ± nab-paclitaxel in patients with metastatic pancreatic cancer. METHODS: Patients received escalating daily subcutaneous doses of necuparanib plus 1,000 mg/m2 gemcitabine (days 1, 8, 15, and every 28 days). The protocol was amended to include 125 mg/m2 nab-paclitaxel after two cohorts (following release of the phase III MPACT data). The necuparanib starting dose was 0.5 mg/kg, with escalation via a modified 3 + 3 design until the maximum tolerated dose (MTD) was determined. RESULTS: Thirty-nine patients were enrolled into seven cohorts (necuparanib 0.5, 1 mg/kg + gemcitabine; necuparanib 1, 2, 4, 6, and 5 mg/kg + nab-paclitaxel + gemcitabine). The most common adverse events were anemia (56%), fatigue (51%), neutropenia (51%), leukopenia (41%), and thrombocytopenia (41%). No deaths and two serious adverse events were potentially related to necuparanib. Measurable levels of necuparanib were seen starting at the 2 mg/kg dose. Of 24 patients who received at least one dose of necuparanib + nab-paclitaxel + gemcitabine, 9 (38%) achieved a partial response and 6 (25%) achieved stable disease (63% disease control rate). Given a cellulitis event and mild activated partial thromboplastin time increases at 6 mg/kg, the 5 mg/kg dose was considered the MTD and selected for further assessment in phase II. CONCLUSION: Acceptable safety and encouraging signals of activity in patients with metastatic pancreatic cancer receiving necuparanib, nab-paclitaxel, and gemcitabine were demonstrated.
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Albúminas/administración & dosificación , Desoxicitidina/análogos & derivados , Heparina , Paclitaxel/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Adulto , Anciano , Albúminas/efectos adversos , Albúminas/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica , Celulitis (Flemón)/inducido químicamente , Celulitis (Flemón)/patología , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/farmacocinética , Supervivencia sin Enfermedad , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/clasificación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Metástasis de la Neoplasia , Paclitaxel/efectos adversos , Paclitaxel/farmacocinética , Neoplasias Pancreáticas/patología , Resultado del Tratamiento , GemcitabinaRESUMEN
Despite the beneficial therapeutic effects of intravenous immunoglobulin (IVIg) in inflammatory diseases, consistent therapeutic efficacy and potency remain major limitations for patients and physicians using IVIg. These limitations have stimulated a desire to generate therapeutic alternatives that could leverage the broad mechanisms of action of IVIg while improving therapeutic consistency and potency. The identification of the important anti-inflammatory role of fragment crystallizable domain (Fc) sialylation has presented an opportunity to develop more potent Ig therapies. However, translating this concept to potent anti-inflammatory therapeutics has been hampered by the difficulty of generating suitable sialylated products for clinical use. Therefore, we set out to develop the first, to our knowledge, robust and scalable process for generating a well-qualified sialylated IVIg drug candidate with maximum Fc sialylation devoid of unwanted alterations to the IVIg mixture. Here, we describe a controlled enzymatic, scalable process to produce a tetra-Fc-sialylated (s4-IVIg) IVIg drug candidate and its qualification across a wide panel of analytic assays, including physicochemical, pharmacokinetic, biodistribution, and in vivo animal models of inflammation. Our in vivo characterization of this drug candidate revealed consistent, enhanced anti-inflammatory activity up to 10-fold higher than IVIg across different animal models. To our knowledge, this candidate represents the first s4-IVIg suitable for clinical use; it is also a valuable therapeutic alternative with more consistent and potent anti-inflammatory activity.
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Antiinflamatorios/uso terapéutico , Diseño de Fármacos , Inmunoglobulinas Intravenosas/uso terapéutico , Ácido N-Acetilneuramínico/metabolismo , Receptores Fc/metabolismo , Animales , Antiinflamatorios/farmacocinética , Antiinflamatorios/farmacología , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/patología , Vesícula/complicaciones , Vesícula/tratamiento farmacológico , Vesícula/patología , Modelos Animales de Enfermedad , Epidermólisis Ampollosa Adquirida/complicaciones , Epidermólisis Ampollosa Adquirida/tratamiento farmacológico , Epidermólisis Ampollosa Adquirida/patología , Glicosilación/efectos de los fármacos , Células HEK293 , Humanos , Fragmentos Fab de Inmunoglobulinas/metabolismo , Inmunoglobulinas Intravenosas/farmacocinética , Inmunoglobulinas Intravenosas/farmacología , Ratones , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/patología , Distribución Tisular/efectos de los fármacos , Resultado del TratamientoRESUMEN
The use of combination drug regimens has dramatically improved the clinical outcome for patients with multiple myeloma. However, to date, combination treatments have been limited to approved drugs and a small number of emerging agents. Using a systematic approach to identify synergistic drug combinations, combination high-throughput screening (cHTS) technology, adenosine A2A and ß-2 adrenergic receptor (ß2AR) agonists were shown to be highly synergistic, selective, and novel agents that enhance glucocorticoid activity in B-cell malignancies. Unexpectedly, A2A and ß2AR agonists also synergize with melphalan, lenalidomide, bortezomib, and doxorubicin. An analysis of agonists, in combination with dexamethasone or melphalan in 83 cell lines, reveals substantial activity in multiple myeloma and diffuse large B-cell lymphoma cell lines. Combination effects are also observed with dexamethasone as well as bortezomib, using multiple myeloma patient samples and mouse multiple myeloma xenograft assays. Our results provide compelling evidence in support of development of A2A and ß2AR agonists for use in multi-drug combination therapy for multiple myeloma. Furthermore, use of cHTS for the discovery and evaluation of new targets and combination therapies has the potential to improve cancer treatment paradigms and patient outcomes.
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Antagonistas del Receptor de Adenosina A2/farmacología , Antagonistas de Receptores Adrenérgicos beta 2/farmacología , Antineoplásicos/farmacología , Mieloma Múltiple/metabolismo , Animales , Línea Celular Tumoral , Análisis por Conglomerados , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Femenino , Perfilación de la Expresión Génica , Ensayos Analíticos de Alto Rendimiento , Humanos , Masculino , Ratones , Ratones SCID , Mieloma Múltiple/genética , Transcriptoma , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Drug combinations are a promising strategy to overcome the compensatory mechanisms and unwanted off-target effects that limit the utility of many potential drugs. However, enthusiasm for this approach is tempered by concerns that the therapeutic synergy of a combination will be accompanied by synergistic side effects. Using large scale simulations of bacterial metabolism and 94,110 multi-dose experiments relevant to diverse diseases, we provide evidence that synergistic drug combinations are generally more specific to particular cellular contexts than are single agent activities. We highlight six combinations whose selective synergy depends on multitarget drug activity. For one anti-inflammatory example, we show how such selectivity is achieved through differential expression of the drugs' targets in cell types associated with therapeutic, but not toxic, effects and validate its therapeutic relevance in a rat model of asthma. The context specificity of synergistic combinations creates many opportunities for therapeutically relevant selectivity and enables improved control of complex biological systems.
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Sinergismo Farmacológico , Quimioterapia Combinada , Preparaciones Farmacéuticas/administración & dosificación , Farmacología , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Escherichia coli/efectos de los fármacos , Escherichia coli/crecimiento & desarrollo , Humanos , Masculino , Modelos Biológicos , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los ResultadosRESUMEN
INTRODUCTION: Glucocorticoids are a mainstay of anti-inflammatory therapy, but significant adverse effects ultimately limit their utility. Previous efforts to design glucocorticoid structures with an increased therapeutic window have focused on dissociating anti-inflammatory transcriptional repression from adverse effects primarily driven by transcriptional activation. An alternative to this medicinal chemistry approach is a systems biology based strategy that seeks to amplify selectively the anti-inflammatory activity of very low dose glucocorticoid in immune cells without modulating alternative cellular networks that mediate glucocorticoid toxicity. METHODS: The combination of prednisolone and the antithrombotic drug dipyridamole was profiled using in vitro and in vivo models of anti-inflammatory activity and glucocorticoid-induced adverse effects to demonstrate a dissociated activity profile. RESULTS: The combination synergistically suppresses release of proinflammatory mediators, including tumour necrosis factor-alpha, IL-6, chemokine (C-C motif) ligand 5 (RANTES), matrix metalloproteinase-9, and others, from human peripheral blood mononuclear cells and mouse macrophages. In rat models of acute lipopolysaccharide-induced endotoxemia and delayed-type hypersensitivity, and in chronic models of collagen-induced and adjuvant-induced arthritis, the combination produced anti-inflammatory activity that required only a subtherapeutic dose of prednisolone. The immune-specific amplification of prednisolone anti-inflammatory activity by dipyridamole did not extend to glucocorticoid-mediated adverse effects, including corticosterone suppression or increased expression of tyrosine aminotransferase, in vivo after repeat dosing in rats. After 8 weeks of oral dosing in mice, treatment with the combination did not alter prednisolone-induced reduction in osteocalcin and mid-femur bone density, which are markers of steroid-induced osteoporosis. Additionally, amplification was not observed in the cellular network of corticotroph AtT-20/D16v-F2 cells in vitro, as measured by pro-opiomelanocortin expression and adrenocorticotropic hormone secretion. CONCLUSIONS: These data suggest that the multi-target mechanism of low-dose prednisolone and dipyridamole creates a dissociated activity profile with an increased therapeutic window through cellular network selective amplification of glucocorticoid-mediated anti-inflammatory signaling.
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Antiinflamatorios/farmacología , Dipiridamol/farmacología , Glucocorticoides/farmacología , Inflamación/tratamiento farmacológico , Prednisolona/farmacología , Animales , Quimioterapia Combinada , Humanos , Mediadores de Inflamación/inmunología , Ratones , Ratas , Ratas Endogámicas LewRESUMEN
Combination therapy has proven successful in treating a wide variety of aggressive human cancers. Historically, combination treatments have been discovered through serendipity or lengthy trials using known anticancer agents with similar indications. We have used combination high-throughput screening to discover the unexpected synergistic combination of an antiparasitic agent, pentamidine, and a phenothiazine antipsychotic, chlorpromazine. This combination, CRx-026, inhibits the growth of tumor cell lines in vivo more effectively than either pentamidine or chlorpromazine alone. Here, we report that CRx-026 exerts its antiproliferative effect through synergistic dual mitotic action. Chlorpromazine is a potent and specific inhibitor of the mitotic kinesin KSP/Eg5 and inhibits tumor cell proliferation through mitotic arrest and accumulation of monopolar spindles. Pentamidine treatment results in chromosomal segregation defects and delayed progression through mitosis, consistent with inhibition of the phosphatase of regenerating liver family of phosphatases. We also show that CRx-026 synergizes in vitro and in vivo with the microtubule-binding agents paclitaxel and vinorelbine. These data support a model where dual action of pentamidine and chlorpromazine in mitosis results in synergistic antitumor effects and show the importance of systematic screening for combinations of targeted agents.
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Antiprotozoarios/farmacología , Antipsicóticos/farmacología , Proliferación Celular/efectos de los fármacos , Clorpromazina/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Mitosis/efectos de los fármacos , Pentamidina/farmacología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Sinergismo Farmacológico , Quimioterapia Combinada , Femenino , Técnica del Anticuerpo Fluorescente , Células HCT116/efectos de los fármacos , Humanos , Cinesinas/antagonistas & inhibidores , Cinesinas/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones SCID , Microtúbulos/efectos de los fármacos , Paclitaxel/administración & dosificación , Huso Acromático , Vinblastina/administración & dosificación , Vinblastina/análogos & derivados , Vinorelbina , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The Mixed-Lineage Leukemia (MLL) gene encodes a Trithorax-related chromatin-modifying protooncogene that positively regulates Hox genes. In addition to their well-characterized roles in axial patterning, Trithorax and Polycomb family proteins perform less-understood functions in vertebrate hematopoiesis. To define the role of MLL in the development of the hematopoietic system, we examined the potential of cells lacking MLL. Mll-deficient cells could not develop into lymphocytes in adult RAG-2 chimeric animals. Similarly, in vitro differentiation of B cells required MLL. In chimeric embryos, Mll-deficient cells failed to contribute to fetal liver hematopoietic stem cell/progenitor populations. Moreover, we show that aorta-gonad-mesonephros (AGM) cells from Mll-deficient embryos lacked hematopoietic stem cell (HSC) activity despite their ability to generate hematopoietic progeny in vitro. These results demonstrate an intrinsic requirement for MLL in definitive hematopoiesis, where it is essential for the generation of HSCs in the embryo.
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Proteínas de Unión al ADN/fisiología , Regulación del Desarrollo de la Expresión Génica , Hematopoyesis/fisiología , Proto-Oncogenes , Células Madre/fisiología , Animales , Antígenos CD/metabolismo , Antígenos CD34/metabolismo , Aorta/citología , Aorta/embriología , Aorta/metabolismo , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Células Cultivadas , Técnicas de Cocultivo/métodos , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Embrión de Mamíferos , Citometría de Flujo/métodos , Galactósidos/metabolismo , Hematopoyesis/genética , Trasplante de Células Madre Hematopoyéticas , N-Metiltransferasa de Histona-Lisina , Inmunohistoquímica/métodos , Hibridación in Situ/métodos , Indoles/metabolismo , Células Asesinas Naturales/fisiología , Antígenos Comunes de Leucocito/metabolismo , Hígado/citología , Hígado/metabolismo , Linfopoyesis/efectos de los fármacos , Linfopoyesis/fisiología , Mesonefro/citología , Mesonefro/embriología , Mesonefro/metabolismo , Ratones , Ratones Transgénicos , Proteína de la Leucemia Mieloide-Linfoide , Fenotipo , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Trasplante de Células Madre/métodos , Células Madre/citología , Factores de Tiempo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Kit/SCF signaling and Mitf-dependent transcription are both essential for melanocyte development and pigmentation. To identify Mitf-dependent Kit transcriptional targets in primary melanocytes, microarray studies were undertaken. Among identified targets was BCL2, whose germline deletion produces melanocyte loss and which exhibited phenotypic synergy with Mitf in mice. BCL2's regulation by Mitf was verified in melanocytes and melanoma cells and by chromatin immunoprecipitation of the BCL2 promoter. Mitf also regulates BCL2 in osteoclasts, and both Mitf(mi/mi) and Bcl2(-/-) mice exhibit severe osteopetrosis. Disruption of Mitf in melanocytes or melanoma triggered profound apoptosis susceptible to rescue by BCL2 overexpression. Clinically, primary human melanoma expression microarrays revealed tight nearest neighbor linkage for MITF and BCL2. This linkage helps explain the vital roles of both Mitf and Bcl2 in the melanocyte lineage and the well-known treatment resistance of melanoma.