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Introduction: Breast cancer (BC) is the leading cause of cancer-related deaths among women, with triple-negative breast cancer (TNBC) representing one of the most aggressive and treatment-resistant subtypes. In this study, we aimed to evaluate the antitumor potential of C14 and P8 molecules in both TNBC and radioresistant TNBC cells. These compounds were chosen for their ability to stabilize the complex formed by the overactivated form of K-Ras4BG13D and its membrane transporter (PDE6δ). Methods: The antitumor potential of C14 and P8 was assessed using TNBC cell lines, MDA-MB-231, and the radioresistant derivative MDA-MB-231RR, both carrying the K-Ras4B> G13D mutation. We investigated the compounds' effects on K-Ras signaling pathways, cell viability, and tumor growth in vivo. Results: Western blotting analysis determined the negative impact of C14 and P8 on the activation of mutant K-Ras signaling pathways in MDA-MB-231 and MDA-MB-231RR cells. Proliferation assays demonstrated their efficacy as cytotoxic agents against K-RasG13D mutant cancer cells and in inducing apoptosis. Clonogenic assays proven their ability to inhibit TNBC and radioresistant TNBC cell clonogenicity. In In vivo studies, C14 and P8 inhibited tumor growth and reduced proliferation, angiogenesis, and cell cycle progression markers. Discussion: These findings suggest that C14 and P8 could serve as promising adjuvant treatments for TNBC, particularly for non-responders to standard therapies. By targeting overactivated K-Ras and its membrane transporter, these compounds offer potential therapeutic benefits against TNBC, including its radioresistant form. Further research and clinical trials are warranted to validate their efficacy and safety as novel TNBC treatments.
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The radio-frequency spectrum shortage, which is primarily caused by the fixed allocation policy, is one of the main bottlenecks to the deployment of existing wireless communication networks, and to the development of new ones. The dynamic spectrum access policy is foreseen as the solution to this problem, since it allows shared spectrum usage by primary licensed and secondary unlicensed networks. In order to turn this policy into reality, the secondary network must be capable of acquiring reliable, real-time information on available bands within the service area, which can be achieved by means of spectrum sensing, spectrum occupancy databases, or a combination of them. This Review presents guidelines related to the design of a framework that can be adopted to foster dynamic spectrum access policies. The framework applies special-purpose Internet of Things (IoT) devices that perform spectrum sensing, subsequently feeding a spectrum occupancy database, which in turn will be used by the secondary network to gather information on location-dependent spectrum availability. The guidelines address technological enablers capable of making the framework feasible, reliable and secure.
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The aim of the study was providing rationale for using a new form of Ketorol Express for pain relief in outpatient dental practice. The study comprised 85 patients with an average age of 43.2 years, who were prescribed a three-day course of Ketorol Express therapy after a complex traumatic tooth extraction. Three different visual-analog scales were used to assess the severity of pain, the patient's General well-being, and the doctor's General well-being. After treatment with dispersed Ketorol Express tablets, the severity of the pain syndrome decreased from 4 to 1.8 points within three days. Anesthesia occurred on average in 10 minutes. This therapy was safe and well tolerated. There were no one serious adverse events, and no one patient stopped therapy due to side effects.
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Manejo del Dolor , Dolor Postoperatorio , Adulto , Método Doble Ciego , Humanos , Dimensión del Dolor , Extracción DentalRESUMEN
Repressible knockdown approaches were investigated to manipulate for transgenic sterilization in channel catfish, Ictalurus punctatus. Two primordial germ cell (PGC) marker genes, nanos and dead end, were targeted for knockdown and an off-target gene, vasa, was monitored. Two potentially copper-sensitive repressible promoters, yeast ctr3 (M) and ctr3-reduced (Mctr), were coupled with four knockdown strategies separately including: ds-sh RNA targeting the 5' end (N1) or 3' end (N2) of channel catfish nanos, full-length cDNA sequence of channel catfish nanos for overexpression (cDNA), and ds-sh RNA-targeting channel catfish dead end (DND). Each construct had an untreated group and treated group with copper sulfate as the repressor compound. Spawning rates of full-sibling P1 fish exposed or not exposed to the constructs as treated and untreated embryos were 85 and 54%, respectively, indicating potential sterilization of fish and repression of the constructs. In F1 fish, mRNA expressions of PGC marker genes for most constructs were downregulated in the untreated group and the knockdown was repressed in the treated group. Gonad development in transgenic, untreated F1 channel catfish was reduced compared to non-transgenic fish for MctrN2, MN1, MN2, and MDND. For 3-year-old adults, gonad size in the transgenic untreated group was 93.4% smaller than the non-transgenic group for females and 92.3% for males. However, mean body weight of transgenic females (781.8 g) and males (883.8 g) was smaller than of non-transgenic counterparts (984.2 and 1254.3 g) at 3 years of age, a 25.8 and 41.9% difference for females and males, respectively. The results indicate that repressible transgenic sterilization is feasible for reproductive control of fish, but negative pleiotropic effects can result.
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Animales Modificados Genéticamente/metabolismo , Embrión no Mamífero/metabolismo , Células Germinativas/metabolismo , Ictaluridae/metabolismo , Animales , Animales Modificados Genéticamente/genética , Cobre/metabolismo , Ictaluridae/genética , Reacción en Cadena de la Polimerasa , Interferencia de ARN , Reproducción/genética , Reproducción/fisiología , Esterilización Reproductiva/métodosRESUMEN
Our aim was to transplant blue catfish germ line stem cells into blastulae of triploid channel catfish embryos to produce interspecific xenogenic catfish. The morphological structure of the gonads of blue catfish (Ictalurus furcatus) in ~ 90- to 100-day-old juveniles, two-year-old juveniles, and mature adults was studied histologically. Both oogonia (12-15 µm, diameter with distinct nucleus 7-8 µm diameter) and spermatogonia (12-15 µm, with distinct nucleus 6-7.5 µm diameter) were found in all ages of fish. The percentage of germ line stem cells was higher in younger blue catfish of both sexes. After the testicular tissue was trypsinized, a discontinuous density gradient centrifugation was performed using 70, 45, and 35% Percoll to enrich the percentage of spermatogonial stem cells (SSCs). Four distinct cell bands were generated after the centrifugation. It was estimated that 50% of the total cells in the top band were type A spermatogonia (diameter 12-15 µm) and type B spermatogonia (diameter 10-11 µm). Germ cells were confirmed with expression of vasa. Blastula-stage embryos of channel catfish (I. punctatus) were injected with freshly dissociated blue catfish testicular germ cells as donor cells for transplantation. Seventeen days after the transplantation, 33.3% of the triploid channel catfish fry were determined to be xenogenic catfish. This transplantation technique was efficient, and these xenogenic channel catfish need to be grown to maturity to verify their reproductive capacity and to verify that for the first time SSCs injected into blastulae were able to migrate to the genital ridge and colonize. These results open the possibility of artificially producing xenogenic channel catfish males that can produce blue catfish sperm and mate with normal channel catfish females naturally. The progeny would be all C × B hybrid catfish, and the efficiency of hybrid catfish production could be improved tremendously in the catfish industry.
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Biomarcadores/metabolismo , Bagres/crecimiento & desarrollo , Trasplante de Células/veterinaria , Embrión no Mamífero/citología , Espermatozoides/trasplante , Testículo/citología , Animales , Bagres/clasificación , Bagres/embriología , Bagres/metabolismo , Separación Celular/veterinaria , Células Cultivadas , Embrión no Mamífero/fisiología , Xenoinjertos , Masculino , Espermatogénesis , Espermatozoides/citología , Espermatozoides/fisiología , Testículo/fisiologíaRESUMEN
Repressible knockdown approaches were investigated for transgenic sterilization in channel catfish, Ictalurus punctatus. Two primordial germ cell (PGC) marker genes, nanos and dead end, were targeted for knockdown, and an off-target gene, vasa, was monitored. Two potentially salt sensitive repressible promoters, zebrafish adenylosuccinate synthase 2 (ADSS) and zebrafish racemase (Rm), were each coupled with four knockdown strategies: ds-sh RNA targeting the 5' end (N1) or 3' end (N2) of channel catfish nanos, full-length cDNA sequence of channel catfish nanos for overexpression (cDNA) and ds-sh RNA targeting channel catfish dead end (DND). Each construct had an untreated group and treated group with sodium chloride as the repressor compound. Spawning rates of full-sibling P1 fish exposed or not exposed to the constructs as treated and untreated embryos were 93% and 59%, respectively, indicating potential sterilization of fish and repression of the constructs. Although the mRNA expression data of PGC marker genes were inconsistent in P1 fish, most F1 individuals were able to downregulate the target genes in untreated groups and repress the knockdown process in treated groups. The results indicate that repressible transgenic sterilization is feasible for reproductive control of fish, but more data from F2 or F3 are needed for evaluation.
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Animales Modificados Genéticamente/genética , Bagres/genética , Células Germinativas/metabolismo , Ictaluridae/genética , Reproducción/genética , Cloruro de Sodio/metabolismo , Animales , Animales Modificados Genéticamente/metabolismo , Secuencia de Bases , Bagres/metabolismo , ADN Complementario/genética , Embrión no Mamífero/metabolismo , Femenino , Técnicas de Silenciamiento del Gen , Masculino , Regiones Promotoras Genéticas/genética , Esterilización/métodos , Pez Cebra/genética , Pez Cebra/metabolismoRESUMEN
The D727E germline polymorphism in the thyroid-stimulating hormone receptor gene (TSHR) may cause genetic susceptibility to the development of goiter. Therefore, in this study we investigated allele frequencies and genotype distributions of the TSHR D727E polymorphism, their association with clinical parameters, and the development of goiter in the Turkish population. We investigated the TSHR D727E polymorphism in 123 patients and 97 healthy subjects using the polymerase chain reaction-restriction fragment length polymorphism technique. Peripheral blood was used for DNA extraction. Although no significant difference was found in TSHR D727E polymorphism frequencies between the patients with nodular goiters (26/123 patients, 21.1%) and the controls (12/97 patients, 12.4%) (P = 0.107), the frequency of the TSHR D727E polymorphism in the hyperthyroid+subclinical hyperthyroid patient groups (23%) was significantly higher than in the control subjects (12.4%) (P = 0.024). In this study, nodular goiter presented significantly earlier in GC genotype patients (mean age 35 years) than in CC genotype patients (mean age 42 years) in the hyperthyroid group (P = 0.009). More importantly, TSH levels in the GC variant controls were closely significant lower (1.26 ± 0.49) than in the CC variant controls (1.74 ± 0.84) (P = 0.053). The TSHR D727E polymorphism might be involved in the pathogenesis of toxic multinodular goiter (TMNG). Moreover, this polymorphism might be an indication of early-onset TMNG. However, development of MNG is multifactorial. Therefore, further case-control studies with larger populations are required to verify these observations.
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Alelos , Predisposición Genética a la Enfermedad , Bocio Nodular/genética , Polimorfismo Genético , Receptores de Tirotropina/genética , Estudios de Casos y Controles , Frecuencia de los Genes , Genotipo , Humanos , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , TurquíaRESUMEN
Channel catfish (Ictalurus punctatus) is the most important freshwater aquaculture species in the USA. Genetically enhanced fish that are sterile could both profit the catfish industry and reduce potential environmental and ecological risks. As the first step to generate sterile channel catfish, three sets of zinc finger nuclease (ZFN) plasmids targeting the luteinizing hormone (LH) gene were designed and electroporated into one-cell embryos, different concentrations were introduced, and the Cel-I assay was conducted to detect mutations. Channel catfish carrying the mutated LH gene were sterile, as confirmed by DNA sequencing and mating experiments. The overall mutation rate was 19.7 % for 66 channel catfish, and the best treatment was ZFN set 1 at the concentration 25 µg/ml. To our knowledge, this is the first instance of gene editing of fish via plasmid introduction instead of mRNA microinjection. The introduction of the ZFN plasmids may have reduced mosaicism, as mutated individuals were gene edited in every tissue evaluated. Apparently, the plasmids were eventually degraded without integration, as they were not detectable in mutated individuals using PCR. Carp pituitary extract failed to induce spawning and restoration of fertility, indicating the need for developing other hormone therapies to achieve reversal of sterility upon demand. This is the first sterilization achieved using ZFN technology in an aquaculture species and the first successful gene editing of channel catfish. Our results will help understand the roles of the LH gene, purposeful sterilization of teleost fishes, and is a step towards control of domestic, hybrid, exotic, invasive, and transgenic fishes.
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Desoxirribonucleasas/genética , Proteínas de Peces/genética , Silenciador del Gen , Ictaluridae/genética , Hormona Luteinizante/genética , Reproducción , Esterilización Reproductiva/métodos , Animales , Animales Modificados Genéticamente , Secuencia de Bases , Carpas/metabolismo , Mezclas Complejas/farmacología , Desoxirribonucleasas/metabolismo , Electroporación , Embrión no Mamífero , Femenino , Proteínas de Peces/antagonistas & inhibidores , Proteínas de Peces/metabolismo , Ictaluridae/metabolismo , Hormona Luteinizante/antagonistas & inhibidores , Hormona Luteinizante/metabolismo , Masculino , Hipófisis/química , Plásmidos/química , Plásmidos/metabolismo , Reproducción/efectos de los fármacos , Dedos de ZincRESUMEN
Methoxyflurane is a volatile, halogenated analgesic, self-administered in a controlled low dose from the Penthrox(®) inhaler for short-term pain relief. It was formerly used in significantly higher doses to produce anaesthesia, when it caused a specific type of dose-related renal tubular damage. The pathogenesis of the renal damage and clinical use of methoxyflurane are discussed here with evidence that a low but effective analgesic dose is not associated with the risk of renal adverse effects. The maximum dose employed to produce analgesia is limited to methoxyflurane 6 mL/day and 15 mL/week, producing a minimum alveolar concentration (MAC) of 0.59 MAC-hours. Renal damage is due to the metabolism of methoxyflurane and release of fluoride ions. Exposure of humans to methoxyflurane ≤2.0 MAC-hours, resulting in serum fluoride ≤40 µmol/L, has not been associated with renal tubular toxicity. The safety margin of analgesic use of methoxyflurane in the Penthrox ((®)) inhaler is at least 2.7- to 8-fold, based on methoxyflurane MAC-hours or serum fluoride level, with clinical experience suggesting it is higher. It is concluded from clinical experience in emergency medicine, surgical procedures and various experimental and laboratory investigations that the analgesic use of methoxyflurane in subanaesthetic doses in the Penthrox inhaler does not carry a risk of nephrotoxicity.
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Anestésicos por Inhalación/efectos adversos , Anestésicos por Inhalación/farmacología , Enfermedades Renales/inducido químicamente , Metoxiflurano/efectos adversos , Metoxiflurano/farmacología , Anestésicos por Inhalación/química , Animales , Humanos , Metoxiflurano/químicaRESUMEN
Complementary DNA overexpression and short hairpin RNA interference approaches were evaluated for decreasing expression of primordial germ cell (PGC) marker genes and thereby sterilizing channel catfish, Ictalurus punctatus, by delivering knockdown constructs driven by a constitutive promoter from yeast and a copper transport protein gene into fish embryos by electroporation. Two PGC marker genes, nanos and dead end, were the target knockdown genes, and their expressions, along with that of an off-target gene, vasa, were evaluated temporally using real-time polymerase chain reaction. Copper sulfate was evaluated as a repressor compound. Some of the constructs knocked down PGC marker gene expression, and some of the constructs were partially repressed by application of 0.1-ppm copper sulfate. When the rate of sexual maturity was compared for three-year-old broodfish that had been exposed to the sterilizing constructs during embryologic development and controls that had not been exposed, several treatments had reduced sexual maturity for the exposed fish. Of two promoter systems evaluated, the one which had been designed to be less sensitive to copper generally was more effective at achieving sterilization and more responsive to repression. Knockdown constructs based on 3' nanos short hairpin RNA interference appeared to result in the best repression and restoration of normal sexual maturity. We conclude that these copper-based systems exhibited good potential for repressible transgenic sterilization. Optimization of this system could allow environmentally safe application of transgenic technology and might be applicable to other applications for aquatic organisms.
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Proteínas de Transporte de Catión/metabolismo , Cobre/metabolismo , Ictaluridae/metabolismo , Esterilización/métodos , Secuencia de Aminoácidos , Animales , Animales Modificados Genéticamente , Secuencia de Bases , Proteínas de Transporte de Catión/genética , Embrión no Mamífero , Femenino , Regulación del Desarrollo de la Expresión Génica/fisiología , Técnicas de Silenciamiento del Gen , Ictaluridae/genética , Masculino , Datos de Secuencia MolecularRESUMEN
Testicular germ cells of channel catfish, Ictalurus punctatus, and blue catfish, I. furcatus were separated into four layers with Percoll density gradient centrifugation, containing different cell types (40% in the first layer were spermatogonial stem cells, SSCs). Expression of seventeen genes was analyzed for cells from different layers by real-time quantitative PCR. Pfkfb4, Urod, Plzf, Integrin6, IntegrinV, Thy1 and Cdh1 genes showed the same expression change pattern in both channel and blue catfish as these genes were down-regulated in the spermatocytes and even more so in spermatids. Plzf and Integrin6 had especially high expression in SSCs and can be used as SSCs specific markers. Sox2 gene was up-regulated in spermatocytes and even more highly up-regulated in spermatids, which indicated it could be a spermatid marker. In contrast to channel catfish, Id4, Smad5 and Prdm14 gene expressions were strongly down-regulated in spermatocyte cells, but up-regulated in spermatid cells in blue catfish. Smad5 gene was down-regulated in spermatocytes, but up-regulated in both spermatogonia and spermatids, allowing identification as a marker for spermatocytes in blue catfish. Oct4, Id4, Gfrα2, Pum2 and Prdm14 genes showed different expression patterns in the testicular germ cells of channel and blue catfish. This may be a partial explanation to the differing responses of channel catfish and blue catfish to induced spawning technologies. The SSCs specific markers can be used for further SSCs labeling, which can increase the SSCs sorting efficiency and be applied in various studies involving SSCs and other germ cells.
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Células Madre Adultas/metabolismo , Biomarcadores/metabolismo , Ictaluridae , Espermatogonias/citología , Células Madre Adultas/citología , Animales , Expresión Génica , Masculino , Espermátides/metabolismo , Espermatocitos/metabolismo , Espermatogonias/metabolismo , Testículo/citologíaRESUMEN
The aim of the present study was to evaluate the effect of bovine somatotropin (bST; 500mg) administration on lactating buffalo donors submitted to two different ovum pick-up (OPU) and in vitro embryo production schemes with a 7 or 14d intersession OPU interval. A total of 16 lactating buffalo cows were randomly assigned into one of four experimental groups according to the bST treatment (bST or No-bST) and the OPU intersession interval (7 or 14d) in a 2×2 factorial design (16 weeks of OPU sessions). The females submitted to OPU every 14d had a larger (P<0.001) number of ovarian follicles suitable for puncture (15.6±0.7 vs. 12.8±0.4) and an increased (P=0.004) number of cumulus-oocyte complexes (COCs) recovered (10.0±0.5 vs. 8.5±0.3) compared to the 7d interval group. However, a 7 or 14d interval between OPU sessions had no effect (P=0.34) on the number of blastocysts produced per OPU (1.0±0.1 vs. 1.3±0.2, respectively). In addition, bST treatment increased (P<0.001) the number of ovarian follicles suitable for puncture (15.3±0.5 vs. 12.1±0.4) but reduced the percentage (18.9% vs. 10.9%; P=0.009) and the number (1.4±0.2 vs. 0.8±0.1; P=0.003) of blastocysts produced per OPU session compared with the non-bST-treated buffaloes. In conclusion, the 14d interval between OPU sessions and bST treatment efficiently increased the number of ovarian follicles suitable for puncture. However, the OPU session interval had no effect on embryo production, and bST treatment reduced the in vitro blastocyst outcomes in lactating buffalo donors.
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Búfalos/fisiología , Fertilización In Vitro/veterinaria , Hormona del Crecimiento/farmacología , Recuperación del Oocito/veterinaria , Folículo Ovárico/fisiología , Óvulo/fisiología , Animales , Bovinos , Células del Cúmulo , Técnicas de Cultivo de Embriones/veterinaria , Femenino , Lactancia , Recuperación del Oocito/métodos , Folículo Ovárico/citología , Folículo Ovárico/efectos de los fármacosRESUMEN
Channel catfish (Ictalurus punctatus) embryos were electroporated with sterilization constructs targeting primordial germ cell proteins or with buffer. Some embryos then were treated with repressor compounds, cadmium chloride, copper sulfate, sodium chloride or doxycycline, to prevent expression of the transgene constructs. Promoters included channel catfish nanos and vasa, salmon transferrin (TF), modified yeast Saccharomyces cerevisiae copper transport protein (MCTR) and zebrafish racemase (RM). Knock-down systems were the Tet-off (nanos and vasa constructs), MCTR, RM and TF systems. Knock-down genes included shRNAi targeting 5' nanos (N1), 3' nanos (N2) or dead end (DND), or double-stranded nanos RNA (dsRNA) for overexpression of nanos mRNA. These constructs previously were demonstrated to knock down nanos, vasa and dead end, with the repressors having variable success. Exogenous DNA affected percentage hatch (% hatch), as all 14 constructs, except for the TF dsRNA, TF N1 (T), RM DND (C), vasa DND (C), vasa N1 (C) and vasa N2 (C), had lower % hatch than the control electroporated with buffer. The MCTR and RM DND (T) constructs resulted in delayed hatch, and the vasa and nanos constructs had minimal effects on time of hatch (P < 0.05). Cadmium chloride appeared to counteract the slow development caused by the TF constructs in two TF treatments (P < 0.05). The 4 ppt sodium chloride treatment for the RM system decreased % hatch (P < 0.05) and slowed development. In the case of nanos constructs, doxycycline greatly delayed hatch (P < 0.05). Adverse effects of the transgenes and repressors continued for several treatments for the first 6 days after hatch, but only in a few treatments during the next 10 days. Repressors and gene expression impacted the yield of putative transgenic channel catfish fry, and need to be considered and accounted for in the hatchery phase of producing transgenically sterilized catfish fry and their fertile counterparts. This fry output should be considered to ensure that sufficient numbers of transgenic fish are produced for future applications and for defining repressor systems that are the most successful.
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Bagres/genética , Células Germinativas/crecimiento & desarrollo , Reproducción/genética , Transgenes , Animales , Animales Modificados Genéticamente , Bagres/crecimiento & desarrollo , Embrión no Mamífero , Regulación del Desarrollo de la Expresión Génica , Células Germinativas/efectos de los fármacos , ARN Mensajero/biosíntesis , Racemasas y Epimerasas/administración & dosificación , Pez Cebra/genética , Pez Cebra/metabolismoRESUMEN
We propose a simple algorithm for improving the MDL (minimum description length) estimator of the number of sources of signals impinging on multiple sensors. The algorithm is based on the norms of vectors whose elements are the normalized and nonlinearly scaled eigenvalues of the received signal covariance matrix and the corresponding normalized indexes. Such norms are used to discriminate the largest eigenvalues from the remaining ones, thus allowing for the estimation of the number of sources. The MDL estimate is used as the input data of the algorithm. Numerical results unveil that the so-called norm-based improved MDL (iMDL) algorithm can achieve performances that are better than those achieved by the MDL estimator alone. Comparisons are also made with the well-known AIC (Akaike information criterion) estimator and with a recently-proposed estimator based on the random matrix theory (RMT). It is shown that our algorithm can also outperform the AIC and the RMT-based estimator in some situations.
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Head and neck squamous cell carcinoma (HNSCC), the eighth most common cancer worldwide, accounts for approximately 600,000 new cases per year. The mobile tongue is the most common site for oral cancer and is associated with a poorer survival than other HNSCC sites. Standard therapeutic strategies have failed to significantly improve survival rates that have remained around 50% over the past four decades. In the last decade intense investigations on oral cancer highlighted the mandatory role of the tumor microenvironment (TME), in addition to the genetic aberrations and molecular biology changes within the cancer cells. Furthermore, the molecular crosstalk between cancer cells and TME components (i.e., cancer-associated fibroblasts, inflammatory pro-tumorigenic cells, etc.) has a crucial role in growth, invasion, spread and metastases of the cancer cells and consequently leads to poor prognosis. Recent studies suggest that plant-derived dietary agents nutraceuticals, especially curcumin and green tea, have the advantage to combat both malignant cells and TME components, unlike standard anti-cancer protocols that target only cancer cells. However, due to a very low bioavailability, nutraceuticals do not currently constitute an integral part of these protocols. Ongoing developments in nanotechnology for improved delivery are expected to overcome their challenging pharmacokinetics.
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Carcinoma de Células Escamosas/tratamiento farmacológico , Suplementos Dietéticos , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de la Boca/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/patología , Curcumina/uso terapéutico , Neoplasias de Cabeza y Cuello/patología , Humanos , Neoplasias de la Boca/patología , Nanotecnología/métodos , Pronóstico , Carcinoma de Células Escamosas de Cabeza y Cuello , Tasa de Supervivencia , Té/química , Microambiente TumoralRESUMEN
The masou salmon Δ5-desaturase-like gene (D5D) driven by the common carp ß-actin promoter was transferred into common carp (Cyprinus carpio) that were fed two diets. For P1 transgenic fish fed a commercial diet, Δ6-desaturase-like gene (D6D) and stearoyl-CoA desaturase (SCD) mRNA levels in muscle were up-regulated (P < 0.05) 12.7- and 17.9-fold, respectively, and the D6D mRNA level in the gonad of transgenic fish was up-regulated 6.9-fold (P < 0.05) compared to that of non-transgenic fish. In contrast, D6D and SCD mRNA levels in transgenic fish were dramatically down-regulated (P < 0.05), 50.2- and 16.7-fold in brain, and 5.4- and 2.4-fold in liver, respectively, in comparison with those of non-transgenic fish. When fed a specially formulated diet, D6D and SCD mRNA levels in muscle of transgenic fish were up-regulated (P < 0.05) 41.5- and 8.9-fold, respectively, and in liver 6.0- and 3.3-fold, respectively, compared to those of non-transgenic fish. In contrast, D6D and SCD mRNA levels in the gonad of transgenic fish were down-regulated (P < 0.05) 5.5- and 12.4-fold, respectively, and D6D and SCD mRNA levels in the brain were down-regulated 14.9- and 1.4-fold (P < 0.05), respectively, compared to those of non-transgenic fish. The transgenic common carp fed the commercial diet had 1.07-fold EPA, 1.12-fold DPA, 1.07-fold DHA, and 1.07-fold higher observed total omega-3 fatty acid levels than non-transgenic common carp. Although these differences were not statistically different (P > 0.05), there were significantly (P < 0.10) higher omega-3 fatty acid levels when considering the differences for all of the individual omega-3 fatty acids. The genotype × diet interactions observed indicated that the potential of desaturase transgenesis cannot be realized without using a well-designed diet with the needed amount of substrates.
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Carpas/metabolismo , Dieta , Ácido Graso Desaturasas/genética , Ácidos Grasos Omega-3/biosíntesis , Regulación Enzimológica de la Expresión Génica/fisiología , Linoleoil-CoA Desaturasa/metabolismo , Estearoil-CoA Desaturasa/metabolismo , Actinas/genética , Animales , Animales Modificados Genéticamente , Cromatografía de Gases , Cartilla de ADN/genética , delta-5 Desaturasa de Ácido Graso , Electroporación , Ácidos Grasos Omega-3/metabolismo , Regulación Enzimológica de la Expresión Génica/genética , Técnicas de Transferencia de Gen , Gónadas/metabolismo , Linoleoil-CoA Desaturasa/genética , Oncorhynchus/genética , Plásmidos/genética , Regiones Promotoras Genéticas/genética , Estearoil-CoA Desaturasa/genética , Transgenes/genéticaRESUMEN
For gene therapy to improve lung function in cystic fibrosis (CF) subjects, repeated administration of the gene transfer agent over the lifetime of patients is likely to be necessary. This requirement limits the utility of adenoviral and adeno-associated viral vectors (both previously evaluated in CF gene therapy trials) because of induced adaptive immune responses that render repeated dosing ineffective. For CF gene therapy trials, non-viral vectors are currently the only viable option. We previously showed that the cationic lipid formulation GL67A is the most efficient of several non-viral vectors analysed for airway gene transfer. Here, we assessed the efficacy and safety of administering 12 inhaled doses of GL67A complexed with pGM169, a CpG-free plasmid encoding human CFTR complementary DNA, into mice. We show that repeated administration of pGM169/GL67A to murine lungs is feasible, safe and achieves reproducible, dose-related and persistent gene expression (>140 days after each dose) using an aerosol generated by a clinically relevant nebuliser. This study supports progression into the first non-viral multidose lung trial in CF patients.
Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Terapia Genética , Vectores Genéticos , Lípidos/administración & dosificación , Lípidos/toxicidad , Pulmón/efectos de los fármacos , Plásmidos , Administración por Inhalación , Animales , Terapia Combinada , Fibrosis Quística/patología , Fibrosis Quística/terapia , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: A relapsing systemic inflammatory process is a well-known feature of Behcet's disease. Because systemic inflammation and dyslipidemia are involved in the pathogenesis of atherosclerosis, Behcet's disease may play a part in the development of atherosclerosis. Lipid profile in Behcet's disease and the development of atherosclerosis remain to be controversial. In order to learn more about this relationship, our study compared blood lipid levels in healthy controls to those in patients with Behcet's disease during both their active and inactive stages. PATIENTS AND METHODS: Between December 2010 and March 2012, this prospective, observational study was designed to evaluate three groups The study included 91 Behcet's patients (36 in active and 55 in inactive period) and 61 healthy control subjects matched for age, gender, and body mass index. Data from lipid profiles included total cholesterol, triglyceride, low-density lipoprotein, and high-density lipoprotein. Acute phase reactants were also recorded, including high sensitive C-reactive protein and erythrocyte sedimentation rate levels. RESULTS: Total cholesterol, low density lipoprotein, and high density lipoprotein cholesterol levels of patients in active stage were significantly lower than those in inactive stage, while total cholesterol and low density lipoprotein levels were lower in the control group (p < 0.05). CONCLUSIONS: Patients with Behcet's disease in the active period may be less susceptible to atherogenic events as compared with the controls and those in the inactive period of the disease.
Asunto(s)
Aterosclerosis/etiología , Síndrome de Behçet/complicaciones , Lípidos/sangre , Adolescente , Adulto , Síndrome de Behçet/fisiopatología , Sedimentación Sanguínea , Proteína C-Reactiva/metabolismo , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto JovenRESUMEN
La discinesia apical transitoria, Síndrome de Tako-tsubo (y otras sinonimias), es una situación clínica descrita inicialmente en Japón, y luego en otras latitudes, que simula el infarto agudo de miocardio. Los trastornos de la contractilidad segmentaria del ventrículo izquierdo se recuperan en pocas semanas. La letalidad es muy baja comparada con el infarto, pero debe conocerse por los profesionales que atienden en los servicios de urgencias a pacientes con síndrome coronario agudo. Se presenta una paciente egresada de nuestro servicio con este diagnóstico, y se muestran las imágenes electrocardiográficas, ecocardiográficas y angiográficas(AU)