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1.
Proc Natl Acad Sci U S A ; 120(7): e2204434119, 2023 02 14.
Artículo en Inglés | MEDLINE | ID: mdl-36745800

RESUMEN

Motivated by declines in biodiversity exacerbated by climate change, we identified a network of conservation sites designed to provide resilient habitat for species, while supporting dynamic shifts in ranges and changes in ecosystem composition. Our 12-y study involved 289 scientists in 14 study regions across the conterminous United States (CONUS), and our intent was to support local-, regional-, and national-scale conservation decisions. To ensure that the network represented all species and ecosystems, we stratified CONUS into 68 ecoregions, and, within each, we comprehensively mapped the geophysical settings associated with current ecosystem and species distributions. To identify sites most resilient to climate change, we identified the portion of each geophysical setting with the most topoclimate variability (high landscape diversity) likely to be accessible to dispersers (high local connectedness). These "resilient sites" were overlaid with conservation priority maps from 104 independent assessments to indicate current value in supporting recognized biodiversity. To identify key connectivity areas for sustaining species movement in response to climate change, we codeveloped a fine-scale representation of human modification and ran a circuit-theory-based analysis that emphasized movement potential along geographic climate gradients. Integrating areas with high values for two or more factors, we identified a representative, resilient, and connected network of biodiverse lands covering 35% of CONUS. Because the network connects climatic gradients across 250,000 biodiversity elements and multiple resilient examples of all geophysical settings in every ecoregion, it could form the spatial foundation for targeted land protection and other conservation strategies to sustain a diverse, dynamic, and adaptive world.


Asunto(s)
Conservación de los Recursos Naturales , Ecosistema , Humanos , Estados Unidos , Biodiversidad , Cambio Climático , Movimiento
2.
BMC Cancer ; 21(1): 681, 2021 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-34107902

RESUMEN

BACKGROUND: Prolactin receptor (PRLR) is an attractive antibody therapeutic target with expression across a broad population of breast cancers. Antibody efficacy, however, may be limited to subtypes with either PRLR overexpression and/or those where estradiol no longer functions as a mitogen and are, therefore, reliant on PRLR signaling for growth. In contrast a potent PRLR antibody-drug conjugate (ADC) may provide improved therapeutic outcomes extending beyond either PRLR overexpressing or estradiol-insensitive breast cancer populations. METHODS: We derived a novel ADC targeting PRLR, ABBV-176, that delivers a pyrrolobenzodiazepine (PBD) dimer cytotoxin, an emerging class of warheads with enhanced potency and broader anticancer activity than the clinically validated auristatin or maytansine derivatives. This agent was tested in vitro and in vivo cell lines and patient derived xenograft models. RESULTS: In both in vitro and in vivo assays, ABBV-176 exhibits potent cytotoxicity against multiple cell line and patient-derived xenograft breast tumor models, including triple negative and low PRLR expressing models insensitive to monomethyl auristatin (MMAE) based PRLR ADCs. ABBV-176, which cross links DNA and causes DNA breaks by virtue of its PBD warhead, also demonstrates enhanced anti-tumor activity in several breast cancer models when combined with a poly-ADP ribose polymerase (PARP) inhibitor, a potentiator of DNA damage. CONCLUSIONS: Collectively the efficacy and safety profile of ABBV-176 suggest it may be an effective therapy across a broad range of breast cancers and other cancer types where PRLR is expressed with the potential to combine with other therapeutics including PARP inhibitors.


Asunto(s)
Citotoxinas/metabolismo , Inmunoconjugados/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Receptores de Prolactina/metabolismo , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunoconjugados/farmacología , Ratones , Ratones SCID , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología
3.
Pharmacology ; 100(5-6): 229-242, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28743107

RESUMEN

ABT-700 is a therapeutic antibody against the hepatocyte growth factor receptor (MET). At doses or regimens that lead to exposures exceeding optimum in vivo, the efficacy of ABT-700 is unexpectedly reduced. We hypothesized that this reduction in efficacy was due to a "prozone-like" effect in vivo. A prozone-like effect, which is a reduction in efficacy beyond optimum exposure, is caused due a mechanism similar to the generation of false negative flocculation tests by excessive antibody titres. In vitro, we demonstrate that at higher ABT-700 concentrations, this "prozone-like" effect is mediated by a progressive conversion from bivalent to ineffective monovalent binding of the antibody. In vivo, the efficacy of ABT-700 is dependent on an optimum range of exposure as well. Our data suggest that the "prozone-like" effect is operative and independent of target expression. ABT-700 dose, regimen, exposure, and tumor burden are interdependent variables influencing the "prozone-like" effect and mediating and in vivo efficacy. By optimization of dosage and regimen we demonstrate that the "prozone-like" effect can be alleviated and ABT-700 efficacy at varying tumor loads can be further extended in combination with cisplatin. Our results suggest that optimization of exposure taking tumor burden into account may alleviate "prozone-like" effects without compromising efficacy.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , Animales , Línea Celular , Cisplatino/administración & dosificación , Humanos , Ratones , Ratones Desnudos , Ratones SCID
5.
Conserv Biol ; 29(3): 618-29, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25922899

RESUMEN

Most conservation planning to date has focused on protecting today's biodiversity with the assumption that it will be tomorrow's biodiversity. However, modern climate change has already resulted in distributional shifts of some species and is projected to result in many more shifts in the coming decades. As species redistribute and biotic communities reorganize, conservation plans based on current patterns of biodiversity may fail to adequately protect species in the future. One approach for addressing this issue is to focus on conserving a range of abiotic conditions in the conservation-planning process. By doing so, it may be possible to conserve an abiotically diverse "stage" upon which evolution will play out and support many actors (biodiversity). We reviewed the fundamental underpinnings of the concept of conserving the abiotic stage, starting with the early observations of von Humboldt, who mapped the concordance of abiotic conditions and vegetation, and progressing to the concept of the ecological niche. We discuss challenges posed by issues of spatial and temporal scale, the role of biotic drivers of species distributions, and latitudinal and topographic variation in relationships between climate and landform. For example, abiotic conditions are not static, but change through time-albeit at different and often relatively slow rates. In some places, biotic interactions play a substantial role in structuring patterns of biodiversity, meaning that patterns of biodiversity may be less tightly linked to the abiotic stage. Furthermore, abiotic drivers of biodiversity can change with latitude and topographic position, meaning that the abiotic stage may need to be defined differently in different places. We conclude that protecting a diversity of abiotic conditions will likely best conserve biodiversity into the future in places where abiotic drivers of species distributions are strong relative to biotic drivers, where the diversity of abiotic settings will be conserved through time, and where connectivity allows for movement among areas providing different abiotic conditions.


Asunto(s)
Biodiversidad , Conservación de los Recursos Naturales/métodos , Fenómenos Geológicos , Ecología/tendencias
6.
Conserv Biol ; 28(4): 959-70, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24673543

RESUMEN

Conservationists need methods to conserve biological diversity while allowing species and communities to rearrange in response to a changing climate. We developed and tested such a method for northeastern North America that we based on physical features associated with ecological diversity and site resilience to climate change. We comprehensively mapped 30 distinct geophysical settings based on geology and elevation. Within each geophysical setting, we identified sites that were both connected by natural cover and that had relatively more microclimates indicated by diverse topography and elevation gradients. We did this by scoring every 405 ha hexagon in the region for these two characteristics and selecting those that scored >SD 0.5 above the mean combined score for each setting. We hypothesized that these high-scoring sites had the greatest resilience to climate change, and we compared them with sites selected by The Nature Conservancy for their high-quality rare species populations and natural community occurrences. High-scoring sites captured significantly more of the biodiversity sites than expected by chance (p < 0.0001): 75% of the 414 target species, 49% of the 4592 target species locations, and 53% of the 2170 target community locations. Calcareous bedrock, coarse sand, and fine silt settings scored markedly lower for estimated resilience and had low levels of permanent land protection (average 7%). Because our method identifies-for every geophysical setting-sites that are the most likely to retain species and functions longer under a changing climate, it reveals natural strongholds for future conservation that would also capture substantial existing biodiversity and correct the bias in current secured lands.


Asunto(s)
Cambio Climático , Clima , Conservación de los Recursos Naturales , Animales , Biodiversidad , Geografía , América del Norte , Especificidad de la Especie
8.
Proc Natl Acad Sci U S A ; 107(28): 12634-9, 2010 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-20616035

RESUMEN

Aurora kinase B inhibitors induce apoptosis secondary to polyploidization and have entered clinical trials as an emerging class of neocytotoxic chemotherapeutics. We demonstrate here that polyploidization neutralizes Mcl-1 function, rendering cancer cells exquisitely dependent on Bcl-XL/-2. This "addiction" can be exploited therapeutically by combining aurora kinase inhibitors and the orally bioavailable BH3 mimetic, ABT-263, which inhibits Bcl-XL, Bcl-2, and Bcl-w. The combination of ABT-263 with aurora B inhibitors produces a synergistic loss of viability in a range of cell lines of divergent tumor origin and exhibits more sustained tumor growth inhibition in vivo compared with aurora B inhibitor monotherapy. These data demonstrate that Bcl-XL/-2 is necessary to support viability during polyploidization in a variety of tumor models and represents a druggable molecular vulnerability with potential therapeutic utility.


Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Neoplasias/tratamiento farmacológico , Compuestos de Anilina , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/genética , Aurora Quinasa B , Aurora Quinasas , Inhibidores Enzimáticos/uso terapéutico , Masculino , Ratones , Neoplasias/genética , Proteínas Serina-Treonina Quinasas , Sulfonamidas
9.
Neurooncol Adv ; 5(1): vdac183, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36814898

RESUMEN

Background: Serclutamab talirine (Ser-T, formerly ABBV-321) is an antibody-drug conjugate consisting of an antibody (AM-1-ABT-806) directed against activated epidermal growth factor receptor (EGFR) and a pyrrolobenzodiazepine dimer. We investigated Ser-T monotherapy in a phase I, first-in-human, dose-escalation, and dose-expansion study in patients with advanced solid tumors associated with EGFR overexpression. Methods: Eligible patients (≥18 years) had advanced, histologically confirmed solid tumors associated with EGFR overexpression (centralized testing). Patients received Ser-T intravenously once every 4 weeks (Q4W; 5-50 µg/kg) in the dose-escalation phase. Herein, preliminary antitumor activity at the recommended phase II dose (RP2D) is reported only for patients with glioblastoma (n = 24); additional assessments included all treated patients. Results: Sixty-two patients (median age: 58 years) were enrolled within the dose-escalation (n = 43) and dose-expansion (n = 19) phases. One dose-limiting toxicity, grade 3 aspartate aminotransferase and alanine aminotransferase elevation, occurred at 20 µg/kg during dose escalation. The Ser-T RP2D regimen of 50 µg/kg × 1 (loading dose) followed by 25 µg/kg Q4W (maintenance dose) was administered during dose expansion. Fatigue (37%) was the only treatment-emergent adverse event (AE) occurring in >25% of patients. Two patients (3%) reported mild treatment-related ocular AEs (eye pruritus). Responses in patients with glioblastoma included 1 partial response (~33 months), 6 stable disease, and 14 progressive disease (not evaluable: n = 3). Conclusions: Ser-T monotherapy at doses up to 50 µg/kg initial dose, followed by 25 µg/kg Q4W demonstrated a tolerable safety profile with minimal antitumor activity observed in patients with glioblastoma. The glioblastoma dose-expansion cohort was closed due to a lack of efficacy (NCT03234712).

10.
Genomics ; 94(5): 341-8, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19660539

RESUMEN

Formalin-fixed paraffin-embedded (FFPE) tissue samples are a potentially valuable resource of expression information for medical research, but are under-utilized due to degradation and modification of the RNA. Using a random primer-based RNA amplification strategy, we have evaluated multiple protocols for the extraction and isolation of RNA from FFPE samples. We found that the RecoverAll RNA isolation procedure with three or four slices (ten-microns in thickness), supplemented with additional DNAse, gave optimal results. RNA integrity as assessed by Agilent Bioanalyzer, and amplification of the 28S ribosomal RNA, were predictive for the number of genes detected on Affymetrix arrays. We obtained expression data for colon and lung tumor and normal FFPE samples and matched frozen samples and found a high correlation between frozen and matched FFPE samples (R(2) between 0.82 and 0.89), while the signature sets in tumor versus normal comparisons were also quite similar. QPCR confirmed all 16 of the differential expression results from the microarrays that we tested. Differentially expressed signature genes from tumor versus matched normal FFPE tissue from colon and lung were identified as cancer-related, with 95 colon tumor and 67 lung tumor genes identified, respectively.


Asunto(s)
Formaldehído , Perfilación de la Expresión Génica , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Adhesión en Parafina/métodos , ARN/aislamiento & purificación , Fijación del Tejido/métodos , Neoplasias del Colon/metabolismo , Congelación , Humanos , Neoplasias Pulmonares/metabolismo , ARN/análisis , ARN Neoplásico/análisis , ARN Neoplásico/aislamiento & purificación , ARN Ribosómico 28S/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
11.
Mol Cancer Ther ; 19(10): 2117-2125, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32847977

RESUMEN

ABBV-321 (serclutamab talirine), a next-generation EGFR-targeted antibody-drug conjugate (ADC) incorporates a potent pyrrolobenzodiazepine (PBD) dimer toxin conjugated to the EGFR-targeting ABT-806 affinity-matured AM1 antibody. ABBV-321 follows the development of related EGFR-targeted ADCs including depatuxizumab mafodotin (depatux-m, ABT-414), ABT-806 conjugated to monomethyl auristatin F (MMAF), and ABBV-221 (losatuxizumab vedotin), AM1 antibody conjugated to monomethyl auristatin E (MMAE). The distinct tumor selectivity of ABBV-321 differentiates it from many previous highly active antibody PBD conjugates that lack a therapeutic window. Potency of the PBD dimer, combined with increased binding of AM1 to EGFR-positive tumor cells, opens the possibility to target a wide array of tumors beyond those with high levels of EGFR overexpression or amplification, including those insensitive to auristatin-based ADCs. ABBV-321 exhibits potent antitumor activity in cellular and in vivo studies including xenograft cell line and patient-derived xenograft glioblastoma, colorectal, lung, head and neck, and malignant mesothelioma tumor models that are less sensitive to depatux-m or ABBV-221. Combination studies with ABBV-321 and depatux-m suggest a promising treatment option permitting suboptimal, and potentially better tolerated, doses of both ADCs while providing improved potency. Collectively, these data suggest that ABBV-321 may offer an extended breadth of efficacy relative to other EGFR ADCs while extending utility to multiple EGFR-expressing tumor indications. Despite its highly potent PBD dimer payload, the tumor selectivity of ABBV-321, coupled with its pharmacology, toxicology, and pharmacokinetic profiles, support continuation of ongoing phase I clinical trials in patients with advanced EGFR-expressing malignancies.


Asunto(s)
Receptores ErbB/metabolismo , Inmunoconjugados/uso terapéutico , Animales , Línea Celular Tumoral , Femenino , Humanos , Inmunoconjugados/farmacología , Ratones , Ratones Desnudos
12.
Cancer Res ; 67(3): 1176-83, 2007 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-17283153

RESUMEN

ABT-737 is a novel and potent Bcl-2 antagonist with single-agent activity against small-cell lung cancer (SCLC) cell lines. Here, we evaluated the contribution of Bcl-2 family members to the in vitro cellular response of several SCLC cell lines to ABT-737. Relatively higher levels of Bcl-2, Bcl-X(L), Bim and Noxa, and lower levels of Mcl-1 characterized naïve SCLC cell lines that were sensitive to ABT-737. Conversely, a progressive decrease in the relative levels of Bcl-2 and Noxa and a progressive increase in Mcl-1 levels characterized the increased resistance of H146 cells following chronic exposure to ABT-737. Knockdown of Mcl-1 with small interfering RNA sensitized two resistant SCLC cell lines H196 and DMS114 to ABT-737 by enhancing the induction of apoptosis. Likewise, up-regulation of Noxa sensitized H196 cells to ABT-737. Combination treatment with DNA-damaging agents was extremely synergistic with ABT-737 and was associated with the down-regulation of Mcl-1 and the up-regulation of Noxa, Puma, and Bim in H196 cells. Thus, SCLC cells sensitive to ABT-737 expressed the target proteins Bcl-2 and Bcl-X(L), whereas Mcl-1 and factors regulating Mcl-1 function seem to contribute to the overall resistance of SCLC cells to ABT-737. Overall, these observations provide further insight as to the mechanistic bases for ABT-737 efficacy in SCLC and will be helpful for profiling patients and aiding in the rational design of combination therapies.


Asunto(s)
Compuestos de Bifenilo/farmacología , Carcinoma de Células Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Nitrofenoles/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Sulfonamidas/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/biosíntesis , Proteínas Reguladoras de la Apoptosis/genética , Proteína 11 Similar a Bcl2 , Compuestos de Bifenilo/administración & dosificación , Carboplatino/administración & dosificación , Carcinoma de Células Pequeñas/patología , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Regulación hacia Abajo , Sinergismo Farmacológico , Etopósido/administración & dosificación , Humanos , Neoplasias Pulmonares/patología , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Nitrofenoles/administración & dosificación , Piperazinas/administración & dosificación , Piperazinas/farmacología , Proteínas Proto-Oncogénicas/biosíntesis , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Proteínas Proto-Oncogénicas c-bcl-2/genética , ARN Interferente Pequeño/genética , Sulfonamidas/administración & dosificación , Transfección , Regulación hacia Arriba
13.
Mol Cancer Res ; 5(4): 331-9, 2007 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-17426248

RESUMEN

Cancer is a highly heterogeneous disease in terms of the genetic profile and the response to therapeutics. An early identification of a genomic marker in drug discovery may help select patients that would respond to treatment in clinical trials. Here we suggest coupling compound screening with comparative genomic hybridization analysis of the model systems for early discovery of genomic biomarkers. A Bcl-2 antagonist, ABT-737, has recently been discovered and shown to induce regression of solid tumors, but its activity is limited to a fraction of small-cell lung carcinoma (SCLC) models tested. We used comparative genomic hybridization on high-density single-nucleotide polymorphism genotyping arrays to carry out a genome-wide analysis of 23 SCLC cell lines sensitive and resistant to ABT-737. The screen revealed a number of novel recurrent gene copy number abnormalities, which were also found in an independent data set of 19 SCLC tumors and confirmed by real-time quantitative PCR. A previously unknown amplification was identified on 18q and associated with the sensitivity of SCLC cell lines to ABT-737 and another Bcl-2 antagonist. The region of gain contains Bcl-2 and NOXA, two apoptosis-related genes. Expression microarray profiling showed that the genes residing in the amplified region of 18q are also overexpressed in the sensitive lines relative to the resistant lines. Fluorescence in situ hybridization analysis of tumors revealed that Bcl-2 gain is a frequent event in SCLC. Our findings suggest that 18q21-23 copy number will be a clinically relevant predictor for sensitivity of SCLC to Bcl-2 family inhibitors. The 18q21-23 genomic marker may have a broader application in cancer because Bcl-2 is associated with apoptosis evasion and chemoresistance.


Asunto(s)
Carcinoma de Células Pequeñas/genética , Aberraciones Cromosómicas , Dosificación de Gen , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Hibridación de Ácido Nucleico/métodos , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Línea Celular Tumoral , Cromosomas Humanos Par 18 , Análisis por Conglomerados , Genes Relacionados con las Neoplasias , Marcadores Genéticos , Genoma , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Proto-Oncogénicas c-bcl-2/genética
14.
Mol Cancer Ther ; 6(1): 253-61, 2007 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17237284

RESUMEN

Patients with prostate cancer develop osteoblastic metastases when tumor cells arrive in the bone and stimulate osteoblasts by secreting growth-promoting factors. Endothelin 1 (ET-1) is believed to be a key factor in promoting osteoblastic metastasis. Selective blockade of the ET(A) receptor is an established strategy in the development of cancer therapeutics. However, the molecular mechanisms whereby prostate cancer promotes abnormal bone growth are not fully understood. In this study, we have applied genomic approaches to elucidate the molecular mechanism of stimulation of osteoblasts by ET-1. To examine the ET-1 axis, we generated genomic signatures for osteoblasts treated with ET-1, in the presence and absence of a selective ET(A) antagonist (ABT-627). The ET-1 signature was comprised of several motifs, such as osteoblastic differentiation, invasion, and suppression of apoptosis. The signature also pointed at possible activation of the calcineurin/NFAT pathway. We showed that ET-1 activates calcineurin and causes nuclear translocation of NFATc1, implicating the pathway in the ET-1-mediated stimulation of osteoblasts. We also showed that ET-1 inhibits apoptosis in osteoblasts, implying that the suppression of apoptosis may be an important factor in the promotion of osteoblastic growth by ET-1.


Asunto(s)
Calcineurina/metabolismo , Endotelinas/farmacología , Genoma , Factores de Transcripción NFATC/metabolismo , Osteoblastos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Anexina A5/metabolismo , Diferenciación Celular/efectos de los fármacos , Núcleo Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Endotelinas/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Genoma/efectos de los fármacos , Humanos , Células Madre Mesenquimatosas/citología , Ratones , Osteoblastos/citología , Transporte de Proteínas/efectos de los fármacos
15.
Mol Cancer Ther ; 6(1): 269-76, 2007 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17237286

RESUMEN

To identify cancer-specific targets, we have conducted a synthetic lethal screen using a small interfering RNA (siRNA) library targeting approximately 4,000 individual genes for enhanced killing in the DLD-1 colon carcinoma cell line that expresses an activated copy of the K-Ras oncogene. We found that siRNAs targeting baculoviral inhibitor of apoptosis repeat-containing 5 (survivin) significantly reduced the survival of activated K-Ras-transformed cells compared with its normal isogenic counterpart in which the mutant K-Ras gene had been disrupted (DKS-8). In addition, survivin siRNA induced a transient G(2)-M arrest and marked polyploidy that was associated with increased caspase-3 activation in the activated K-Ras cells. These results indicate that tumors expressing the activated K-Ras oncogene may be particularly sensitive to inhibitors of the survivin protein.


Asunto(s)
Transformación Celular Neoplásica/patología , Genes ras , Proteínas Asociadas a Microtúbulos/deficiencia , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas de Neoplasias/deficiencia , Proteínas de Neoplasias/metabolismo , Alelos , Apoptosis , Muerte Celular , Supervivencia Celular , Células Clonales , Fase G2 , Genes Relacionados con las Neoplasias , Humanos , Proteínas Inhibidoras de la Apoptosis , Mitosis , Proteínas Mutantes/metabolismo , Poliploidía , ARN Interferente Pequeño/metabolismo , Survivin
16.
PLoS One ; 13(6): e0198439, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29924829

RESUMEN

Describing the physical habitat diversity of stream types is important for understanding stream ecosystem complexity, but also prioritizing management of stream ecosystems, especially those that are rare. We developed a stream classification system of six physical habitat layers (size, gradient, hydrology, temperature, valley confinement, and substrate) for approximately 1 million stream reaches within the Eastern United States in order to conduct an inventory of different types of streams and examine stream diversity. Additionally, we compare stream diversity to patterns of anthropogenic disturbances to evaluate associations between stream types and human disturbances, but also to prioritize rare stream types that may lack natural representation in the landscape. Based on combinations of different layers, we estimate there are anywhere from 1,521 to 5,577 different physical types of stream reaches within the Eastern US. By accounting for uncertainty in class membership, these estimates could range from 1,434 to 6,856 stream types. However, 95% of total stream distance is represented by only 30% of the total stream habitat types, which suggests that most stream types are rare. Unfortunately, as much as one third of stream physical diversity within the region has been compromised by anthropogenic disturbances. To provide an example of the stream classification's utility in management of these ecosystems, we isolated 5% of stream length in the entire region that represented 87% of the total physical diversity of streams to prioritize streams for conservation protection, restoration, and biological monitoring. We suggest that our stream classification framework could be important for exploring the diversity of stream ecosystems and is flexible in that it can be combined with other stream classification frameworks developed at higher resolutions (meso- and micro-habitat scales). Additionally, the exploration of physical diversity helps to estimate the rarity and patchiness of riverscapes over large region and assist in conservation and management.


Asunto(s)
Biodiversidad , Movimientos del Agua , Conservación de los Recursos Naturales , Ríos , Temperatura , Estados Unidos
17.
Nucleic Acids Res ; 33(14): 4527-35, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-16091630

RESUMEN

A growing body of evidence suggests that siRNA could generate off-target effects through different mechanisms. However, the full impact of off-target gene regulation on phenotypic induction and accordingly on data interpretation in the context of large-scale siRNA library screen has not been reported. Here we report on off-target gene silencing effects observed in a large-scale knockdown experiment designed to identify novel regulators of the HIF-1 pathway. All of the three 'top hits' from our screen have been demonstrated to result from off-target gene silencing. Two of the three 'siRNA hits' were found to directly trigger down-regulation of hif-1alpha mRNA through a 7 nt motif, AGGCAGT, that is present in both the hif-1alpha mRNA and the siRNAs. Further analysis revealed that the generation of off-target gene silencing via this 7 nt motif depends on the characteristics of the target mRNA, including the sequence context surrounding the complementary region, the position of the complementary region in the mRNA and the copy number of the complementary region. Interestingly, the off-target siRNA against hif-1alpha was also shown to trigger mRNA degradation with high probability of other genes that possess multiple copies of the AGGCAGT motif in the 3'-untranslated region. Lessons learned from this study will be a valuable asset to aid in designing siRNAs with more stringent target selectivity and improving 'hits-follow-up' strategies for future large-scale knockdown experiments.


Asunto(s)
Interferencia de ARN , ARN Interferente Pequeño/química , Factores de Transcripción/genética , Agammaglobulinemia Tirosina Quinasa , Secuencia de Bases , Línea Celular , Regulación hacia Abajo , Quinasa 4 del Receptor Acoplado a Proteína-G , Biblioteca de Genes , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , ARN Mensajero/química , ARN Mensajero/metabolismo , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo
18.
Clin Cancer Res ; 23(4): 992-1000, 2017 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-27573171

RESUMEN

Purpose: Despite the importance of the MET oncogene in many malignancies, clinical strategies targeting c-Met have benefitted only small subsets of patients with tumors driven by signaling through the c-Met pathway, thereby necessitating selection of patients with MET amplification and/or c-Met activation most likely to respond. An ADC targeting c-Met could overcome these limitations with potential as a broad-acting therapeutic.Experimental Design: ADC ABBV-399 was generated with the c-Met-targeting antibody, ABT-700. Antitumor activity was evaluated in cancer cells with overexpressed c-Met or amplified MET and in xenografts including patient-derived xenograft (PDX) models and those refractory to other c-Met inhibitors. The correlation between c-Met expression and sensitivity to ABBV-399 in tumor and normal cell lines was assessed to evaluate the risk of on-target toxicity.Results: A threshold level of c-Met expressed by sensitive tumor but not normal cells is required for significant ABBV-399-mediated killing of tumor cells. Activity extends to c-Met or amplified MET cell line and PDX models where significant tumor growth inhibition and regressions are observed. ABBV-399 inhibits growth of xenograft tumors refractory to other c-Met inhibitors and provides significant therapeutic benefit in combination with standard-of-care chemotherapy.Conclusions: ABBV-399 represents a novel therapeutic strategy to deliver a potent cytotoxin to c-Met-overexpressing tumor cells enabling cell killing regardless of reliance on MET signaling. ABBV-399 has progressed to a phase I study where it has been well tolerated and has produced objective responses in c-Met-expressing non-small cell lung cancer (NSCLC) patients. Clin Cancer Res; 23(4); 992-1000. ©2016 AACR.


Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Proteínas Proto-Oncogénicas c-met/genética , Animales , Anticuerpos Monoclonales/efectos adversos , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células MCF-7 , Ratones , Neoplasias/inmunología , Neoplasias/patología , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
19.
Cancer Chemother Pharmacol ; 57(2): 234-40, 2006 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-16180015

RESUMEN

1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and its analogues have been shown to inhibit proliferation of human cancer cells mediated by vitamin D receptor (VDR). The over-expression of 25-hydroxyvitamin D-24-hydroxylase (CYP24A1), an enzyme involved in the metabolism of 1,25(OH)2D3 and its analogues, is associated with poor prognosis of some human cancers. In this study, we employed real-time reverse transcription PCR to examine the expression of VDR and CYP24A1 mRNA in a cohort of human breast, lung, colon and ovary tumor samples. We found that CYP24A1 mRNA was significantly up-regulated in colon, ovary and lung tumors, but down-regulated in breast tumor relative to the analogous normal tissues. As a comparison, VDR mRNA was modestly down-regulated in colon, breast and lung tumors, but highly up-regulated in ovarian tumors. Treatment of two breast cancer cell lines, SW-620 and MCF-7, and one colon cancer cell line, HT-29, by 1,25(OH)2D3 for 48 h profoundly stimulated CYP24A1 mRNA expression (EC50=0.6, 0.8 and 29.5 nM in SW-620, HT-29 and MCF-7, respectively), but did not significantly affect VDR mRNA expression. Growth as assessed by DNA synthesis was modestly arrested by 1,25(OH)2D3 after 72 h of incubation, but was not altered after a 5-day incubation period. These data suggest that the VDR signaling pathway may be compromised via the modulation of CYP24A1 and VDR in human tumors.


Asunto(s)
Neoplasias de la Mama/patología , Neoplasias del Colon/patología , Neoplasias Pulmonares/patología , Neoplasias Ováricas/patología , Receptores de Calcitriol/biosíntesis , Esteroide Hidroxilasas/biosíntesis , Neoplasias de la Mama/genética , Calcitriol/metabolismo , Neoplasias del Colon/genética , ADN/biosíntesis , Regulación hacia Abajo , Femenino , Perfilación de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Ováricas/genética , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Esteroide Hidroxilasas/metabolismo , Células Tumorales Cultivadas , Vitamina D3 24-Hidroxilasa
20.
Curr Opin Drug Discov Devel ; 8(1): 59-65, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15679173

RESUMEN

Drug-induced toxicity is a major barrier to the development of new therapeutic agents. The majority of drug candidates that cause toxicity are screened out at the discovery or development stage. Some, however, are not detected until the drug is in late-stage clinical trials or has become available to the public. Often, this is caused by what is known as an 'idiosyncratic drug response', and several theories have been proposed regarding the underlying mechanisms for idiosyncratic toxicity. These include the formation of reactive metabolites in certain individuals due to the presence of polymorphisms in drug-metabolizing enzymes, immune-mediated responses to the drug (or one of its metabolites), the combination of drugs with low-level inflammatory reactions, and drug-induced mitochondrial toxicity. This review will focus on recent evidence supporting these theories, as well as some of the preclinical models that can be used to test and study idiosyncratic drug responses.


Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Toxicología/métodos , Animales , Diseño de Fármacos , Humanos , Polimorfismo Genético/genética
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