RESUMEN
We previously reported that eribulin mesylate (eribulin), a tubulin-binding drug (TBD), could remodel tumor vasculature (i.e. increase tumor vessels and perfusion) in human breast cancer xenograft models. However, the role of this vascular remodeling in antitumor effects is not fully understood. Here, we investigated the effects of eribulin-induced vascular remodeling on antitumor activities in multiple human cancer xenograft models. Microvessel densities (MVD) were evaluated by immunohistochemistry (CD31 staining), and antitumor effects were examined in 10 human cancer xenograft models. Eribulin significantly increased MVD compared to the controls in six out of 10 models with a correlation between enhanced MVD levels and antitumor effects (R2 = 0.54). Because of increased MVD, we next used radiolabeled liposomes to examine whether eribulin treatment would result in increased tumoral accumulation levels of these macromolecules and, indeed, we found that eribulin, unlike vinorelbine (another TBD) enhanced them. As eribulin increased accumulation of radiolabeled liposomes, we postulated that this treatment might enhance the antitumor effect of Doxil (a liposomal anticancer agent) and facilitate recruitment of immune cells into the tumor. As expected, eribulin enhanced antitumor activity of Doxil in a post-erlotinib treatment H1650 (PE-H1650) xenograft model. Furthermore, infiltrating CD11b-positive immune cells were significantly increased in multiple eribulin-treated xenografted tumors, and natural killer (NK) cell depletion reduced the antitumor effects of eribulin. These findings suggest a contribution of the immune cells for antitumor activities of eribulin. Taken together, our results suggest that vascular remodeling induced by eribulin acts as a microenvironment modulator and, consequently, this alteration enhanced the antitumor effects of eribulin.
Asunto(s)
Furanos/administración & dosificación , Cetonas/administración & dosificación , Neoplasias/tratamiento farmacológico , Microambiente Tumoral/efectos de los fármacos , Remodelación Vascular/efectos de los fármacos , Animales , Doxorrubicina/administración & dosificación , Doxorrubicina/análogos & derivados , Femenino , Células HCT116 , Humanos , Ratones , Neoplasias/patología , Polietilenglicoles/administración & dosificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Liposomal anticancer agents can effectively deliver drugs to tumor lesions, but their therapeutic effects are enhanced in only limited number of patients. Appropriate biomarkers to identify responder patients to these liposomal agents will improve their treatment efficacies. We carried out pharmacological and histopathological analyses of mouse xenograft models bearing human ovarian cancers (Caov-3, SK-OV-3, KURAMOCHI, and TOV-112D) to correlate the therapeutic effects of doxorubicin-encapsulated liposome (Doxil(®) ) and histological characteristics linked to the enhanced permeability and retention effect. We next generated (111) In-encapsulated liposomes to examine their capacities to determine indications for Doxil(®) treatment by single-photon emission computed tomography (SPECT)/CT imaging. Antitumor activities of Doxil(®) were drastically enhanced in Caov-3, moderately in SK-OV-3, and minimally in KURAMOCHI and TOV-112D when compared to doxorubicin. Microvessel density and vascular perfusion were high in Caov-3 and SK-OV-3, indicating a close relation with the enhanced antitumor effects. Next, (111) In-encapsulated liposomes were given i.v. to the animals. Their tumor accumulation and area under the curve values over 72 h were high in Caov-3, relatively high in SK-OV-3, and low in two other tumors. Importantly, as both Doxil(®) effects and liposomal accumulation varied in the SK-OV-3 group, we individually obtained SPECT/CT images of SK-OV-3-bearing mouse (n = 11) before Doxil(®) treatment. Clear correlation between liposomal tumor accumulation and effects of Doxil(®) was confirmed (R(2) = 0.73). Taken together, our experiments definitely verified that enhanced therapeutic effects through liposomal formulations of anticancer agents depend on tumor accumulation of liposomes. Tumor accumulation of the radiolabeled liposomes evaluated by SPECT/CT imaging is applicable to appropriately determine indications for liposomal antitumor agents.
Asunto(s)
Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/análogos & derivados , Neoplasias Ováricas/diagnóstico por imagen , Animales , Línea Celular Tumoral , Doxorrubicina/farmacocinética , Femenino , Humanos , Radioisótopos de Indio/farmacocinética , Liposomas , Ratones , Ratones Desnudos , Polietilenglicoles/farmacocinética , Tomografía Computarizada de Emisión de Fotón Único , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Eribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B and an inhibitor of microtubule dynamics. Some tubulin-binding drugs are known to have antivascular (antiangiogenesis or vascular-disrupting) activities that can target abnormal tumor vessels. Using dynamic contrast-enhanced MRI analyses, here we show that eribulin induces remodeling of tumor vasculature through a novel antivascular activity in MX-1 and MDA-MB-231 human breast cancer xenograft models. Vascular remodeling associated with improved perfusion was shown by Hoechst 33342 staining and by increased microvessel density together with decreased mean vascular areas and fewer branched vessels in tumor tissues, as determined by immunohistochemical staining for endothelial marker CD31. Quantitative RT-PCR analysis of normal host cells in the stroma of xenograft tumors showed that eribulin altered the expression of mouse (host) genes in angiogenesis signaling pathways controlling endothelial cell-pericyte interactions, and in the epithelial-mesenchymal transition pathway in the context of the tumor microenvironment. Eribulin also decreased hypoxia-associated protein expression of mouse (host) vascular endothelial growth factor by ELISA and human CA9 by immunohistochemical analysis. Prior treatment with eribulin enhanced the anti-tumor activity of capecitabine in the MDA-MB-231 xenograft model. These findings suggest that eribulin-induced remodeling of abnormal tumor vasculature leads to a more functional microenvironment that may reduce the aggressiveness of tumors due to elimination of inner tumor hypoxia. Because abnormal tumor microenvironments enhance both drug resistance and metastasis, the apparent ability of eribulin to reverse these aggressive characteristics may contribute to its clinical benefits.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Furanos/farmacología , Cetonas/farmacología , Moduladores de Tubulina/farmacología , Microambiente Tumoral/efectos de los fármacos , Remodelación Vascular/efectos de los fármacos , Animales , Neoplasias de la Mama/patología , Capecitabina , Línea Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Femenino , Fluorouracilo/análogos & derivados , Fluorouracilo/farmacología , Humanos , Ratones Endogámicos BALB C , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Liposomes are drug delivery systems that can alter the pharmacokinetic properties of compounds. The adverse effects of anticancer agents are a limiting factor for cancer chemotherapy, therefore, liposomal formulations have the potential to improve the therapeutic efficacy of anticancer agents by enhancing their accumulation in tumors and reducing non-selective distribution to normal tissues, which is known as the enhanced permeability and retention effect. To develop a liposomal anticancer agent as a drug product, its formulation must be designed to ensure its quality until it is administered to patients and to exert maximum potency in clinical use rather than in animal experiments. The chemical stability and physicochemical stability of the ingredients are key factors in the design of liposomal formulations. Drug release rates are critical factors in the therapeutic efficacy of liposomal drug products because the encapsulated drug has no pharmacological activity, and only released drug can exert antitumor/toxic activities. Liposomes should maintain the drug in a stable state in the circulation and then promptly release it after accumulation in the target tissue in order to achieve a sufficient drug concentration. To understand the profile of the formulation and to guarantee the quality of drug product, a reliable analytical method that can determine the released and encapsulated drugs in biological fluids is required. Simple online solid phase extractions of the released and encapsulated drugs using a column-switching HPLC system meet the requirements and this system enables accurate in vitro release testing and in vivo pharmacokinetic evaluation. This review introduces the process of liposomal drug product development from various viewpoints.
Asunto(s)
Antineoplásicos/administración & dosificación , Animales , Antineoplásicos/química , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Liposomas , Neoplasias/tratamiento farmacológico , Control de CalidadRESUMEN
Classical swine fever is a disease that infects wild boars and pigs and had a significant negative economic impact on the swine industry. Oral vaccination is an effective method for controlling classical swine fever. However, information on oral vaccination program has been limited, and its efficiency has not been clarified in Japan. The purpose of this study was to determine the seasonal variation in factors affecting the ingestion of oral vaccines by wild boars. The Gifu Prefecture oral vaccination program was initiated in March 2019, and by February 2021, six seasonal programs had been conducted. We investigated the relationship between the ingestion of oral vaccines by wild boar and pre-baiting, vaccination event, environmental and topographical factors in six vaccination events in three seasonal programs (summer 2019, winter 2019-2020, and spring 2020). This study showed that pre-baiting and the repeated vaccination events were more important factors for the ingestion of oral vaccines by wild boars than topographical and land use factors. Thus, it is a possibility that habitat selection of wild boars is irrelevant in increasing the feeding rate of wild boars on oral vaccines. Consequently, wildlife managers should not only conduct pre-baiting and repeated vaccination events, but also identify areas where wild boars are more abundant immediately prior to oral vaccination programs. To increase the effectiveness of vaccination, it is important for wildlife managers to first implement estimating wild boar density in their habitat areas, followed by efficient oral vaccination programs depending on their densities. Thereafter, they should specifically consider the influence of ingestion by other species and differences in feeding rates by age class.
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Virus de la Fiebre Porcina Clásica , Peste Porcina Clásica , Enfermedades de los Porcinos , Vacunas Virales , Administración Oral , Animales , Animales Salvajes , Peste Porcina Clásica/epidemiología , Peste Porcina Clásica/prevención & control , Sus scrofa , Porcinos , Vacunación/métodos , Vacunación/veterinariaRESUMEN
The number of endangered avian-related species increase in Japan recently. The application of new technologies, such as induced pluripotent stem cells (iPSCs), may contribute to the recovery of the decreasing numbers of endangered animals and conservation of genetic resources. We established novel iPSCs from three endangered avian species (Okinawa rail, Japanese ptarmigan, and Blakiston's fish owl) with seven reprogramming factors (M3O, Sox2, Klf4, c-Myc, Nanog, Lin28, and Klf2). The iPSCs are pluripotency markers and express pluripotency-related genes and differentiated into three germ layers in vivo and in vitro. These three endangered avian iPSCs displayed different cellular characteristics even though the same reprogramming factors use. Japanese ptarmigan-derived iPSCs have different biological characteristics from those observed in other avian-derived iPSCs. Japanese ptarmigan iPSCs contributed to chimeras part in chicken embryos. To the best of our knowledge, our findings provide the first evidence of the potential value of iPSCs as a resource for endangered avian species conservation.
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Células Madre Pluripotentes Inducidas , Embrión de Pollo , Animales , Reprogramación Celular , Especies en Peligro de Extinción , Diferenciación Celular/genética , Factores de Transcripción/genéticaRESUMEN
We evaluated the stored body fat of Japanese black bears (Ursus thibetanus japonicus) killed as nuisances in Gifu and Fukushima prefectures, Japan, during 2005-2007. We employed femur marrow fat (FMF), modified kidney fat index (mKFI), and abdominal subcutaneous fat (ASF) as indices for quantitative evaluation. We examined the basic characteristics of these indices, such as seasonality, age and sex dependency, and the quantitative relationship among them. mKFI and ASF increased towards the beginning of the denning period (December), while FMF was relatively stable throughout the sampling period (July-December). In cubs, all indices showed significantly lower values than in the older age classes. There seemed to be a catabolizing order between FMF and mKFI, but not between mKFI and ASF. We also evaluated the yearly change in the indices, and discussed its relevance to the incidence of bear intrusion into human residential areas. Bears nuisance-killed in summer (July-September) 2006 had a significantly larger amount of stored body fat than those killed in summer 2007, although the number of nuisance kills was larger in 2006 than in 2007. This suggests that poor nutritional condition is not a direct cause of bear intrusion.
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Tejido Adiposo/fisiología , Composición Corporal/fisiología , Ursidae/fisiología , Distribución por Edad , Animales , Metabolismo Energético , Femenino , Japón , Masculino , Estaciones del AñoRESUMEN
There is a possibility that classical swine fever (CSF) virus outbreak has negative impacts on wild boar. To adequately manage native wild boar populations, wildlife managers need to gather the field data on wild boar and implement population management practices. We aimed to report the relative abundance index of wild boar before and after this outbreak. Our results showed that relative abundance index declined from 2017 (8.88 wild boars/100 trap days) to 2019 (2.03 wild boars/100 trap days), because of the negative impact of this virus and continuous culling programs. Although the eradication risk from the synergistic effect is low, wildlife managers need to consider the relationship between the trade-off between the risk of CSF and the conservation ecology risk of native species eradication.
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Virus de la Fiebre Porcina Clásica , Peste Porcina Clásica , Enfermedades de los Porcinos , Animales , Animales Salvajes , Peste Porcina Clásica/epidemiología , Japón/epidemiología , Sus scrofa , PorcinosRESUMEN
Monitoring the mortality of wildlife provides basic demographic information to support management plan preparation. The utility of mortality records for conservation measures was investigated in the Japanese serow, focusing on temporal trends and spatial distribution. Using the mortality records of Japanese serow from 2006 to 2018 in Gifu prefecture, cause-specific mortality was categorized into five groups (disease, accident, vehicle collision, parapoxvirus infection, and unknown), and the sex ratios were examined. A state space model was used to analyze the time series for the monthly mortalities, and kernel estimation was used for the spatial distribution of the parapoxvirus infection. Land cover type around the detection point was also reported. Disease, accident, and vehicle collision mortality were similar, and 30% of mortality was of anthropogenic origin. The number of mortality records for males was higher, and the larger home range of males could account for this. The state space model showed moderate increases in monthly mortalities over time and a seasonal variation with the highest level in spring and lowest in winter. Land cover analysis demonstrated a temporal increase in the proportion of human settlement areas, suggesting the change of the Japanese serow habitat. The proximity of Japanese serow to human settlements contributed to increase in mortality records. The point pattern analysis indicated spatial clustering for parapoxvirus infection in the area where an epidemic had occurred in the past. Several measures are recommended; however, mortality records can help develop improved conservation plan.
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Parapoxvirus , Rumiantes , Animales , Animales Salvajes , Ecosistema , Japón/epidemiologíaRESUMEN
The emergence and dissemination of resistance to clinically important antimicrobials in wild animals is of great concern. The aim of our study was to reveal the prevalence and intraspecies dissemination of quinolone-resistant Escherichia coli (QREC) in sika deer (Cervus nippon) in Nara Park, a famous tourist spot in Japan. Fecal samples were collected from 59 wild deer in Nara Park between July and October 2018. We isolated QREC using deoxycholate-hydrogen sulfide-lactose agar containing nalidixic acid and subjected it to antimicrobial susceptibility testing. The mutations in the quinolone resistance-determining region (QRDR) of the gyrA and parC genes of the isolates were analyzed and fragment patterns of genomic DNA were compared by pulsed-field gel electrophoresis (PFGE). A total of 105 QREC isolates were obtained from 41 deer (70%). All isolates had mutations within the QRDR. Other than quinolone resistance, QREC isolates also showed resistance to various other antimicrobial agents. The QREC isolates were classified into 15 PFGE clusters, of which seven were observed in multiple deer. Our results suggest clonal transmission of QREC in a high-density deer population. Spread of QREC in deer inhabiting a tourist location could have potential impact on public health.
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Antibacterianos/farmacología , Ciervos/microbiología , Farmacorresistencia Bacteriana , Infecciones por Escherichia coli/veterinaria , Escherichia coli/efectos de los fármacos , Quinolonas/farmacología , Animales , Ciudades , Infecciones por Escherichia coli/epidemiología , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/transmisión , Heces/microbiología , Japón/epidemiología , Parques RecreativosRESUMEN
In Arabidopsis thaliana, the Ethylene-dependent Gravitropism-deficient and Yellow-green 1 (EGY1) gene encodes a thylakoid membrane-localized protease involved in chloroplast development in leaf mesophyll cells. Recently, EGY1 was also found to be crucial for the maintenance of grana in mesophyll chloroplasts. To further explore the function of EGY1 in leaf tissues, we examined the phenotype of chloroplasts in the leaf epidermal guard cells and pavement cells of two 40Ar17+ irradiation-derived mutants, Ar50-33-pg1 and egy1-4. Fluorescence microscopy revealed that fully expanded leaves of both egy1 mutants showed severe chlorophyll deficiency in both epidermal cell types. Guard cells in the egy1 mutant exhibited permanent defects in chloroplast formation during leaf expansion. Labeling of plastids with CaMV35S or Protodermal Factor1 (PDF1) promoter-driven stroma-targeted fluorescent proteins revealed that egy1 guard cells contained the normal number of plastids, but with moderately reduced size, compared with wild-type guard cells. Transmission electron microscopy further revealed that the development of thylakoids was impaired in the plastids of egy1 mutant guard mother cells, guard cells, and pavement cells. Collectively, these observations demonstrate that EGY1 is involved in chloroplast formation in the leaf epidermis and is particularly critical for chloroplast differentiation in guard cells.
RESUMEN
Although the first cases of classical swine fever were reported in 2018, no studies have explored this impact on wild boar populations in Japan. Comparing the relative abundance indices and age ratios in the wild boar population before and after the outbreak, we investigated the impact of classical swine fever virus on wild boar population dynamics in August 2017-December 2019. Relative abundance indices declined from 2017 to 2019 drastically, while there were no significant differences in age ratios throughout the study period. Consequently, wildlife managers should consider that wild boars continue to contract classical swine fever virus, and they should intensively implement countermeasures in agricultural lands and in pig farms, in addition to wild boar population management.
Asunto(s)
Peste Porcina Clásica , Brotes de Enfermedades/veterinaria , Sus scrofa , Distribución por Edad , Animales , Virus de la Fiebre Porcina Clásica/aislamiento & purificación , Japón , Dinámica Poblacional , PorcinosRESUMEN
BACKGROUND/AIM: There is no established standard chemotherapy after administration of the combination endocrine plus CDK4/6 inhibitor therapy for luminal-type breast cancer. We used patient-derived xenograft (PDX) models to determine the antitumor activity of eribulin and capecitabine after endocrine therapy plus CDK4/6 inhibitor. MATERIALS AND METHODS: We examined the antitumor activity of fulvestrant, palbociclib, eribulin, and capecitabine in 4 luminal-type breast cancer PDX models (OD-BRE-0188, -0438, -0450, -0745). In OD-BRE-0438, we determined the antitumor activity of chemotherapy after fulvestrant-palbociclib treatment. We also performed immunohistochemical analysis to explore the effects of treatment on E-cadherin in tumor tissues. RESULTS: Fulvestrant, fulvestrant-palbociclib and chemotherapy had antitumor activity in the 4 PDX models. In OD-BRE-0438 (the most resistant to fulvestrant-palbociclib), eribulin had superior antitumor activity to capecitabine after fulvestrant plus palbociclib. Only eribulin tended to increase E-cadherin expression. CONCLUSION: Eribulin had superior antitumor activity to capecitabine after fulvestrant-palbociclib in the OD-BRE-0438 model.
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Neoplasias de la Mama/tratamiento farmacológico , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Fulvestrant/uso terapéutico , Furanos/uso terapéutico , Cetonas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/metabolismo , Femenino , Fulvestrant/farmacología , Furanos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Cetonas/farmacología , Ratones Endogámicos BALB C , Ratones Desnudos , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
Although to date there have been no conclusive pathophysiological findings in support of the degenerative theory of the etiology of schizophrenia, the results of neuroimaging studies have suggested that progressive changes in the brain do occur during the clinical course of schizophrenia. However, there has been no report on alterations in regional cerebral blood flow (rCBF) under resting condition, which was compared between the first-episode and the chronic patients of schizophrenia and healthy controls. Therefore, in this study, we applied three-dimensional stereotactic surface projection analysis of resting SPECT (3D-SSP SPECT) in patients with first-episode (n=18) and chronic schizophrenia (n=23) and age-/sex-matched healthy controls (n=40). The rCBFs in the middle/inferior/medial frontal gyrus and the anterior cingulate gyrus were significantly decreased in both patient groups, relative to the respective controls (Z>3.0, P<0.001, uncorrected). The chronic group showed significant hypoperfused region in the left inferior parietal lobule and middle/inferior temporal gyrus. Furthermore, within-cases comparison between the first-episode and chronic schizophrenia, revealed that the significant hypoperfused regions in the chronic group, compared to the first-episode group, were not only the lateral and medial prefrontal cortex, but also the inferior parietal cortex, posterior part of the temporal lobe, and the cuneus. The present study suggested that the reduction in rCBF occurs in the posterior brain area in addition to the frontal lobe across all clinical stages of schizophrenia.
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Encéfalo/patología , Circulación Cerebrovascular/fisiología , Esquizofrenia/patología , Esquizofrenia/fisiopatología , Adulto , Encéfalo/diagnóstico por imagen , Mapeo Encefálico , Estudios Transversales , Progresión de la Enfermedad , Femenino , Humanos , Imagenología Tridimensional/métodos , Masculino , Persona de Mediana Edad , Esquizofrenia/diagnóstico por imagen , Tomografía Computarizada de Emisión de Fotón Único/métodos , Adulto JovenRESUMEN
In order to examine reproductive characteristics of feral raccoons in Kamakura, 335 raccoons were collected from March 2005 to March 2007. Raccoons were classified into five age classes: Class I, less than 5 months old; Class II, 5-11 months; Class III, 12-17 months; Class IV, 18-23 months; and Class V, over 23 months old. Females were examined for their age specific pregnancy rate and litter size. To determine when raccoon births occur in the region, birth months of fetuses were estimated by the fetal growth rate, and birth months of Class I individuals were examined by tooth eruption. From fetuses of 18 pregnant females and 47 Class I individuals, it was found that the raccoon births occur from February to October. Of 163 females examined, all of Class I-II females were nulliparous. Pregnancy rate was 47.6% in Class III females, which was significantly lower than 75.0% in Class IV and 78.1% in Class V. The litter size of fetuses ranged from 2 to 5, and 3.9 on average; and that of placental scars ranged from 1 to 7, 3.8 on average. Our findings suggest that parturition of raccoons is a bimodal distribution and age at first parturition may occur between 12 and 17 months old. In order to reduce the raccoon population successfully, females of all ages should be captured throughout the year.
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Control de Plagas , Mapaches/fisiología , Reproducción/fisiología , Animales , Femenino , Japón , Tamaño de la Camada , Masculino , EmbarazoRESUMEN
The small Indian mongoose (Herpestes auropunctatus) was introduced to Japanese islands and has impacted on the island's biodiversity. Population control has been attempted through capturing but its efficiency has rapidly declined. Therefore, new additional control methods are required. Our focus has been on the immunocontraceptive vaccines, which act in an especially species-specific manner. The amino-acid sequence of the mongoose ovum zona pellucida protein 3 (ZP3) was decoded and two types of synthetic peptides (A and B) were produced. In this study, these peptides were administered to mongooses (each n=3) and the sera were collected to verify immunogenicity using ELISA and IHC. Treated mongoose sera showed an increasing of antibody titer according to immunizations and the antigen-antibody reactions against the endogenous mongoose ZP. In addition, IHC revealed that immune sera absorbed with each peptide showed a marked reduction in reactivity, which indicated the specificity of induced antibodies. These reactions were marked in peptide A treated mongoose sera, and the antibody titer of one of them lasted for at least 21 weeks. These results indicated that peptide A was a potential antigen, inducing autoantibody generation. Moreover, immunized rabbit antibodies recognized mongoose ZP species-specifically. However, the induction of robust immune memory was not observed. Also, the actual sterility effects of peptides remain unknown, it should be verified as a next step. In any case, this study verified synthetic peptides we developed are useful as the antigen candidates for immunocontraception of mongooses.
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Anticoncepción Inmunológica/veterinaria , Herpestidae , Especies Introducidas , Vacunas/inmunología , Zona Pelúcida/inmunología , Animales , Anticuerpos/inmunología , Antígenos/inmunología , Ensayo de Inmunoadsorción Enzimática/veterinaria , Femenino , Herpestidae/sangre , Herpestidae/inmunología , Zona Pelúcida/ultraestructuraRESUMEN
BACKGROUND: Two transmission patterns of Sarcoptes scabiei in host mammal communities have been reported based on microsatellite-level genetic studies in the last two decades. While one involves restrictions among different host taxa, the other is associated with predator-prey interactions between different host taxa. In contrast to these observations, the present study reports a possible irregular case of transmission of S. scabiei between herbivorous Japanese serow and omnivorous Caniformia mammals in Japan, though under very weak predator-prey relationships. METHODS: DNA from 93 Sarcoptes mites isolated from omnivorous Caniformia (such as the domestic dog, raccoon dog, raccoon and Japanese marten), omnivorous Cetartiodactyla (wild boar) and herbivorous Cetartiodactyla (Japanese serow) in Japan were analyzed by amplifying nine microsatellite markers. Principal components analyses (PCA), Bayesian clustering analyses using STRUCTURE software, and phylogenetic analyses by constructing a NeighborNet network were applied to determine the genetic relationships among mites associated with host populations. RESULTS: In all the analyses, the genetic differentiation of Sarcoptes mites from wild boars and Japanese serows was observed. Conversely, considerably close genetic relationships were detected between Caniformia-derived and Japanese serow-derived mites. Because the predator-prey interactions between the omnivorous Caniformia and herbivorous Japanese serow are quite limited and epidemiological history shows at least a 10-year lag between the emergence of sarcoptic mange in Japanese serow and that in Caniformia, the transmission of S. scabiei from Caniformia to Japanese serow is highly suspected. CONCLUSIONS: The close genetic relationships among mites beyond Host-taxon relationships and without obvious predator-prey interactions in Caniformia and Japanese serow deviate from previously reported S. scabiei transmission patterns. This type of cryptic relationship of S. scabiei populations may exist in local mammalian communities worldwide and become a risk factor for the conservation of the remnant and fragmented populations of wild mammals.
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Caniformia/parasitología , Sarcoptes scabiei/genética , Escabiosis/veterinaria , Sus scrofa/parasitología , Animales , Herbivoria , Japón , Filogenia , Rumiantes/parasitología , Escabiosis/transmisión , Piel/parasitologíaRESUMEN
Despite their outstanding antitumour activity in mice, the limited supply from the natural sources has prevented drug discovery/development based on intact halichondrins. We achieved a total synthesis of C52-halichondrin-B amine (E7130) on a >10 g scale with >99.8% purity under GMP conditions. Interestingly, E7130 not only is a novel microtubule dynamics inhibitor but can also increase intratumoural CD31-positive endothelial cells and reduce α-SMA-positive cancer-associated fibroblasts at pharmacologically relevant compound concentrations. According to these unique effects, E7130 significantly augment the effect of antitumour treatments in mouse models and is currently in a clinical trial. Overall, our work demonstrates that a total synthesis can address the issue of limited material supply in drug discovery/development even for the cases of complex natural products.
Asunto(s)
Antineoplásicos Fitogénicos/síntesis química , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma de Células Escamosas/tratamiento farmacológico , Éteres Cíclicos/síntesis química , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Macrólidos/síntesis química , Moduladores de Tubulina/síntesis química , Actinas/genética , Actinas/metabolismo , Animales , Antineoplásicos Fitogénicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica , Productos Biológicos/síntesis química , Productos Biológicos/farmacología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Fibroblastos Asociados al Cáncer/efectos de los fármacos , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Cetuximab/farmacología , Descubrimiento de Drogas , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Éteres Cíclicos/farmacología , Femenino , Expresión Génica/efectos de los fármacos , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/patología , Humanos , Macrólidos/farmacología , Ratones , Ratones Endogámicos BALB C , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/genética , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Análisis de Supervivencia , Moduladores de Tubulina/farmacología , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: The effects of fentanyl with ketamine for postoperative pain are unknown. We investigated the adjuvant effects of ketamine for fentanyl patient-controlled analgesia. METHODS: Cervical and lumbar spine surgery patients were divided into three groups: ketamine 1 mg/kg followed by 42 and 83 microg x kg(-1) x h(-1) in ketamine-1 and ketamine-2 group, respectively, and a control group. Postoperative patient-controlled analgesia fentanyl was administered with a background infusion. RESULTS: Pain scores and analgesia requirement in the ketamine-2 group were significantly lower than those of the control group after cervical surgery. Ketamine partially improved the analgesic effects of fentanyl after lumbar surgery. CONCLUSION: Small-dose ketamine improved the analgesic effects of fentanyl after cervical surgery.
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Analgesia Controlada por el Paciente/métodos , Fentanilo/administración & dosificación , Cirugía General/métodos , Ketamina/administración & dosificación , Dolor Postoperatorio/tratamiento farmacológico , Columna Vertebral/cirugía , Anciano , Analgésicos/administración & dosificación , Analgésicos Opioides/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
In the present study, assay of the serum leptin concentration of the Japanese black bear (Ursus thibetanus japonicus) was attempted using a canine-leptin-specific sandwich enzyme-linked immunosorbent assay (ELISA). The dose-response curve of the bear serum was linear and parallel to the canine leptin standard curve. In mated and unmated bears, the serum leptin concentration was stable at low levels from May to August or September, gradually increased from September or October, and then remarkably increased in late November. We conclude that this method may be useful for measuring bear serum leptin concentration and that the serum leptin concentration changes annually with a peak in late November.