RESUMEN
Topiramate is an antiepileptic drug indicated for the treatment of seizure disorders, migraine prophylaxis, and, more recently, weight loss. This new indication will likely increase the use of this agent significantly. As a carbonic anhydrase inhibitor, topiramate can affect the pH of bodily fluids and is known to increase the risk of nephrolithiasis. However, as discussed in the present report, these properties also result in an as yet unaddressed risk of the development of sialoliths, calcified stones formed in the salivary duct or glands. The physiologic mechanisms for stone development in the salivary gland are reviewed and the pharmacologic effects of topiramate on sialolith formation discussed. The present report describes a female patient treated with topiramate for migraine prophylaxis who subsequently presented with a sialolith in the left submandibular duct.
Asunto(s)
Inhibidores Enzimáticos/efectos adversos , Fructosa/análogos & derivados , Cálculos de las Glándulas Salivales/inducido químicamente , Enfermedades de la Glándula Submandibular/inducido químicamente , Adulto , Femenino , Fructosa/efectos adversos , Humanos , Cálculos de las Glándulas Salivales/diagnóstico , Enfermedades de la Glándula Submandibular/diagnóstico , TopiramatoRESUMEN
The antitumor activity of the tea tree oil (TTO) derived product, Melaleuca Alternifolia Concentrate (MAC) was characterized mechanistically at the molecular and cellular level. MAC was analyzed for its anticancer activity against human prostate (LNCaP) and breast (MCF-7) cancer cell lines growing in vitro. MAC (0.02-0.06% v/v) dose-dependently induced the intrinsic (mitochondrial) apoptotic pathway in both the LNCaP and MCF-7 cell lines, involving increased mitochondrial superoxide production, loss of mitochondrial membrane potential (MMP), caspase 3/7 activation, as well as the presence of TUNEL+ and cleaved-PARP+ cell populations. At concentrations of 0.01-0.04% v/v, MAC caused cell cycle arrest in the G0/1-phase, as well as autophagy. The in vivo anticancer actions of MAC were examined as a treatment in the FVB/N c-Neu murine model for spontaneously arising breast cancers. Intratumoral MAC injections (1-4% v/v) significantly suppressed tumor progression in a dose-dependent manner and was associated with greater levels of tumor infiltrating neutrophils exhibiting anticancer cytotoxic activity. Induction of breast cancer cell death by MAC via the mitochondrial apoptotic pathway was also replicated occurring in tumors treated in vivo. In conclusion, our data highlights the potential for the Melaleuca-derived MAC product inducing anticancer neutrophil influx, supporting its application as a novel therapeutic agent.
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Antineoplásicos/uso terapéutico , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Melaleuca , Aceite de Árbol de Té/uso terapéutico , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Chlorocebus aethiops , Femenino , Humanos , Neoplasias Mamarias Experimentales/inmunología , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones Transgénicos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Extractos Vegetales , Especies Reactivas de Oxígeno/metabolismo , Superóxidos/metabolismo , Aceite de Árbol de Té/farmacología , Células VeroRESUMEN
Molecular targeted therapy (MTT) represents the new generation of anti-cancer arsenals. In this study, we report an alternative approach using a hybrid toxin that utilises the high-affinity of receptor-binding fragment of Clostridium perfringens enterotoxin (CPE). CPE naturally binds to CLDN-4 through the C-terminal 30 amino acid. However, recent studies have shown that CLDN-4 is also overexpressed on a range of cancer cells. We thus constructed a cDNA comprising C-CPE and a well characterised toxic domain of Pseudomonas aeruginosa exotoxin A (C-CPE-ETA'). The recombinant C-CPE-ETA' fusion protein was shown to retain the specificity of binding to CLDN-4 and initiating rapid penetration into cytosol in five different CLDN-4 positive cancer cells (Breast-MCF7, Skin-A431, Colon-SW480, Prostate-PC3 and DU145) but not to CLDN-4 negative cells (Hela, HUVEC). C-CPE-ETA' was strongly cytotoxic towards CLDN-4 positive cancer cell, as opposed to cells lacking CLDN-4 expression. Furthermore, we demonstrated that the recombinant fusion protein had significant anti-cancer ability in CLDN-4 positive cancer models in vivo. Subcutaneously implanted MCF7 and SW480 xenograft tumours were significantly decreased or abolished after three repeated injection of the hybrid toxin. Taken together, our results convincingly show that the hybrid toxin targets CLDN-4 positive cancer through receptor-binding, and causes significant tumour cell apoptosis, suggesting its potential as an alternative molecular targeted therapy against a plethora of CLDN-4 positive cancers.
Asunto(s)
ADP Ribosa Transferasas/uso terapéutico , Toxinas Bacterianas/uso terapéutico , Enterotoxinas/uso terapéutico , Exotoxinas/uso terapéutico , Proteínas de la Membrana/biosíntesis , Neoplasias/tratamiento farmacológico , Proteínas Recombinantes de Fusión/uso terapéutico , Factores de Virulencia/uso terapéutico , ADP Ribosa Transferasas/genética , ADP Ribosa Transferasas/metabolismo , Animales , Apoptosis , Toxinas Bacterianas/genética , Toxinas Bacterianas/metabolismo , Claudina-4 , Enterotoxinas/genética , Enterotoxinas/metabolismo , Exotoxinas/genética , Exotoxinas/metabolismo , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias/metabolismo , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Factores de Virulencia/genética , Factores de Virulencia/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Exotoxina A de Pseudomonas aeruginosaRESUMEN
Magnetic resonance imaging (MRI) provides a means to non-invasively investigate the neurological links with dyslexia, a learning disability that affects one's ability to read. Most previous brain MRI studies of dyslexia and reading skill have used structural or diffusion imaging to reveal regional brain abnormalities. However, volumetric and diffusion MRI lack specificity in their interpretation at the microstructural level. Myelin is a critical neural component for brain function and plasticity, and as such, deficits in myelin may impact reading ability. MRI can estimate myelin using myelin water fraction (MWF) imaging, which is based on evaluation of the proportion of short T2 myelin-associated water from multi-exponential T2 relaxation analysis, but has not yet been applied to the study of reading or dyslexia. In this study, MWF MRI, intelligence, and reading assessments were acquired in 20 participants aged 10-18 years with a wide range of reading ability to investigate the relationship between reading ability and myelination. Group comparisons showed markedly lower MWF by 16-69% in poor readers relative to good readers in the left and right thalamus, as well as the left posterior limb of the internal capsule, left/right anterior limb of the internal capsule, left/right centrum semiovale, and splenium of the corpus callosum. MWF over the entire group also correlated positively with three different reading scores in the bilateral thalamus as well as white matter, including the splenium of the corpus callosum, left posterior limb of the internal capsule, left anterior limb of the internal capsule, and left centrum semiovale. MWF imaging from T2 relaxation suggests that myelination, particularly in the bilateral thalamus, splenium, and left hemisphere white matter, plays a role in reading abilities. Myelin water imaging thus provides a potentially valuable in vivo imaging tool for the study of dyslexia and its remediation.
RESUMEN
Overexpression of erbB2 is associated with resistance to apoptosis. We explored whether high level of erbB2 expression by cancer cells allows their targeting using an erbB2-binding peptide (LTVSPWY) attached to the proapoptotic alpha-tocopheryl succinate (alpha-TOS). Treating erbB2-low or erbB2-high cells with alpha-TOS induced similar levels of apoptosis, whereas alpha-TOS-LTVSPWY induced greater levels of apoptosis in erbB2-high cells. alpha-TOS rapidly accumulated in erbB2-high cells exposed to alpha-TOS-LTVSPWY. The extent of apoptosis induced in erbB2-high cells by alpha-TOS-LTVSPWY was suppressed by erbB2 RNA interference as well as by inhibition of either endocytotic or lysosomal function. alpha-TOS-LTVSPWY reduced erbB2-high breast carcinomas in FVB/N c-neu transgenic mice. We conclude that a conjugate of a peptide targeting alpha-TOS to erbB2-overexpressing cancer cells induces rapid apoptosis and efficiently suppresses erbB2-positive breast tumors.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Oligopéptidos/farmacocinética , Receptor ErbB-2/biosíntesis , Vitamina E/análogos & derivados , Neoplasias de la Mama/enzimología , Línea Celular Tumoral , Humanos , Oligopéptidos/administración & dosificación , Unión Proteica , Receptor ErbB-2/metabolismo , Tocoferoles , Vitamina E/administración & dosificación , Vitamina E/farmacocinéticaRESUMEN
Objective. To develop and evaluate the effectiveness of a structured model for reflective journal writing (RJW) and a grading rubric as part of a student portfolio designed to help Doctor of Pharmacy (PharmD) students create actionable goals. Methods. A structured, eight-domain format was developed to engage students in prioritization, identification, exploration, recollection, evaluation, and challenging/solidifying their own knowledge, while assembling an action plan for development (abbreviated using the acronym PIE-RECAP). After completing RJW using this model, students self-identified domains established by the Center for the Advancement of Pharmacy Education (CAPE) that corresponded to their entries. A grading rubric was designed and normalized to require minimal training for use. RJW and other elements of student portfolios were implemented simultaneously across three cohorts (N=296). Twenty-one faculty and staff graders each evaluated 10 to 15 student journal entries. Results. Of 771 journal entries, 648 (84%) met expectations, while 123 (16%) needed to be rewritten. Students identified experiences that were meaningful to them and shared in their RJW entry the knowledge and/or information that they did not know prior to the experience. Common themes identified in the students' RJWs included: curricular experiences (12.7%), cocurricular experiences (18.4%), and experiential training (68.6%). Conclusion. The PIE-RECAP method can be used to guide students in RJW and identify CAPE domains in their personal and professional experiences in pharmacy school. The associated grading rubric can be used to evaluate students' RJW entries and assess their growth in curricular, cocurricular and affective domains relative to their progression.
Asunto(s)
Educación en Farmacia/métodos , Curriculum , Evaluación Educacional/métodos , Docentes , Objetivos , Humanos , Aprendizaje , Evaluación de Programas y Proyectos de Salud , Estudiantes de Farmacia/psicología , EscrituraRESUMEN
Mitochondria have emerged recently as effective targets for novel anti-cancer drugs referred to as 'mitocans'. We propose that the molecular mechanism of induction of apoptosis by mitocans, as exemplified by the drug alpha-tocopheryl succinate, involves generation of reactive oxygen species (ROS). ROS then mediate the formation of disufide bridges between cytosolic Bax monomers, resulting in the formation of mitochondrial outer membrane channels. ROS also cause oxidation of cardiolipin, triggering the release of cytochrome c and its translocation via the activated Bax channels. This model may provide a general mechanism for the action of inducers of apoptosis and anticancer drugs, mitocans, targeting mitochondria via ROS production.
Asunto(s)
Antineoplásicos/metabolismo , Apoptosis/efectos de los fármacos , Membranas Mitocondriales/metabolismo , Neoplasias/metabolismo , Vitamina E/análogos & derivados , Proteína X Asociada a bcl-2/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Cardiolipinas/metabolismo , Citocromos c/metabolismo , Humanos , Mitocondrias/metabolismo , Neoplasias/tratamiento farmacológico , Oxidación-Reducción/efectos de los fármacos , Transporte de Proteínas/efectos de los fármacos , Especies Reactivas de Oxígeno , Tocoferoles , Vitamina E/metabolismo , Vitamina E/farmacología , Vitamina E/uso terapéuticoRESUMEN
Luciferase reporter constructs are widely used for analysis of gene regulation when characterizing promoter and enhancer elements. We report that the recently developed codon-modified Renilla luciferase construct included as an internal standard for cotransfection must be used with great caution with respect to the amount of DNA transfected. Also, the dual-luciferase reporter vectors encoding Photinus pyralis firefly or Renilla reniformis luciferase showed a linear increase in dose-response with increasing amounts of transfected DNA, but at higher levels of transfected DNA, a reduction in expressed levels of luciferase activity resulted. In addition, treatment with type I interferon (IFN) was found to significantly reduce levels of P. pyralis firefly and Renilla luciferase activity. In contrast, cells transfected with a green fluorescent protein (GFP) reporter construct showed no significant IFN-associated change. The reduction in luciferase activity resulting from IFN treatment was not due to IFN-mediated cytotoxicity, as no change in cellular propidium iodide (PI) staining was observed by flow cytometry. IFN treatment did not alter the levels of firefly luciferase activity in cell culture supernatants or the luciferase mRNA levels determined by quantitative real-time RT-PCR analysis. Based on these results, it is probable that the IFN-induced reduction in levels of luciferase activity detected in reporter assays occurs via a posttranscriptional mechanism. Thus, it is important to be aware of these complications when using luciferase reporter systems in general or for analyzing cytokine-mediated responsive regulation of target genes, particularly by the type I IFNs.
Asunto(s)
Genes Reporteros , Vectores Genéticos , Luciferasas de Luciérnaga , Luciferasas de Renilla , Luciferasas/genética , Animales , Línea Celular Tumoral , Luciérnagas/enzimología , Luciérnagas/genética , Citometría de Flujo , Colorantes Fluorescentes , Fluorometría , Proteínas Fluorescentes Verdes/genética , Células HeLa , Humanos , Interferón-alfa/farmacología , Interferón beta/farmacología , Interferón gamma/farmacología , Luciferasas/efectos de los fármacos , Melanoma , Plásmidos , Propidio/metabolismo , ARN Mensajero/metabolismo , Renilla/enzimología , Renilla/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , TransfecciónRESUMEN
Melaleuca alternifolia concentrate (MAC) is a mixture predominantly composed of monoterpenoids and sesquiterpenes, refined from the essential oil of the tea tree by removing up to 99% of the more toxic, hydrophobic monoterpenes. MAC was examined here for its immunomodulatory effects on the human THP1 and murine RAW264.7 myeloid leukemic cell lines as models for macrophage-like cells. Firstly, MAC levels were determined that did not affect either the survival or proliferation of these cell lines in vitro. Next, the levels of lipopolysaccharide (LPS)-induced production of cytokines (IL-6, TNFα, IL-10, GM-CSF, IFNγ and IL-3) were examined from the myeloid cell lines using multiplex assays. Many of the LPS-inducible cytokines produced by either cell lines could be significantly inhibited by MAC. Closer examination of the mechanism of action of MAC showed that it inhibited the LPS-induced activation of IκB phosphorylation and nuclear factor (NF)-κB signalling and translocation, inhibiting iNOS protein expression and NO production. These results demonstrate that MAC exerts its immunomodulatory effects by inhibiting NF-κB signalling activation and levels of cytokine production by macrophage-like cell lines.
Asunto(s)
Citocinas/biosíntesis , Factores Inmunológicos/farmacología , Melaleuca/química , Células Mieloides/efectos de los fármacos , FN-kappa B/antagonistas & inhibidores , Aceite de Árbol de Té/química , Animales , Western Blotting , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Citocinas/genética , Expresión Génica/efectos de los fármacos , Humanos , Factores Inmunológicos/aislamiento & purificación , Factores Inmunológicos/toxicidad , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Células Mieloides/inmunología , FN-kappa B/genéticaRESUMEN
This study was conducted to verify, prospectively, the ability of an anatomical risk index (ARI) constructed from seven anatomical measures of cerebral volume and perisylvian asymmetry to predict reading ability in 43 children aged 9 to 18. We found that negative ARIs (low cerebral volume and symmetry) were associated with poor reading ability only in children with low processing speed. Regression analysis showed that anatomy, speed, and an interaction term predicted 53% of the variance in real word reading (p < .0001). Leftward perisylvian asymmetry and larger cerebral volumes may support cognitive flexibility in children with low processing speed.
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Mapeo Encefálico , Encéfalo/patología , Dislexia/patología , Lectura , Adolescente , Factores de Edad , Encéfalo/crecimiento & desarrollo , Niño , Femenino , Lateralidad Funcional/fisiología , Humanos , Modelos Logísticos , Imagen por Resonancia Magnética , Masculino , Pruebas Neuropsicológicas , Factores de RiesgoRESUMEN
OBJECTIVE: This study compared the effects of different doses (J/cm(2)) of laser phototherapy at wavelengths of either 780, 830, or 904 nm on human breast carcinoma, melanoma, and immortalized human mammary epithelial cell lines in vitro. In addition, we examined whether laser irradiation would malignantly transform the murine fibroblast NIH3T3 cell line. BACKGROUND: Laser phototherapy is used in the clinical treatment of breast cancer-related lymphoedema, despite limited safety information. This study contributes to systematically developing guidelines for the safe use of laser in breast cancer-related lymphoedema. METHODS: Human breast adenocarcinoma (MCF-7), human breast ductal carcinoma with melanomic genotypic traits (MDA-MB-435S), and immortalized human mammary epithelial (SVCT and Bre80hTERT) cell lines were irradiated with a single exposure of laser. MCF-7 cells were further irradiated with two and three exposures of each laser wavelength. Cell proliferation was assessed 24 h after irradiation. RESULTS: Although certain doses of laser increased MCF-7 cell proliferation, multiple exposures had either no effect or showed negative dose response relationships. No sign of malignant transformation of cells by laser phototherapy was detected under the conditions applied here. CONCLUSION: Before a definitive conclusion can be made regarding the safety of laser for breast cancer-related lymphoedema, further in vivo research is required.
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Adenocarcinoma/radioterapia , Neoplasias de la Mama/radioterapia , Carcinoma Ductal de Mama/radioterapia , Proliferación Celular/efectos de la radiación , Células Epiteliales/efectos de la radiación , Láseres de Semiconductores , Terapia por Luz de Baja Intensidad/métodos , Melanoma/radioterapia , Análisis de Varianza , Línea Celular , Línea Celular Tumoral , Transformación Celular Neoplásica , Relación Dosis-Respuesta en la Radiación , Humanos , Modelos Lineales , TransfecciónRESUMEN
High level galectin-1 expression results in cancer cell evasion of the immune response, increased tumour survival and aggressive metastases. Using a galectin-1 polyclonal antibody, high levels of galectin-1 protein were shown to be expressed by breast cancer cells established from FVB/N MMTV-c-neu mice as well as by the B16F10 melanoma cell line. In mixed lymphocyte cultures using tumour cells as antigenic stimulators, addition of recombinant galectin-1 dose-dependently inhibited lymphocyte production. Disaccharides were identified that inhibited galectin-1 function and increased growth and activation of CD8(+) CTL's killing cancer cells. X-ray crystallographic structures of human galectin-1 in complex with inhibitory disaccharides revealed their mode of binding. Combining galectin-blocking carbohydrates as adjuvants with vaccine immunotherapy in vivo to promote immune responses significantly decreased tumour progression and improved the outcomes for tumour challenged mice. This is the first report showing that suitably selected galectin-1 blocking disaccharides will act as adjuvants promoting vaccine stimulated immune responses against tumours in vivo.
Asunto(s)
Disacáridos/farmacología , Galectinas/metabolismo , Inmunidad/efectos de los fármacos , Neoplasias Mamarias Experimentales/inmunología , Animales , Western Blotting , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/inmunología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Citotoxicidad Inmunológica/efectos de los fármacos , Disacáridos/química , Disacáridos/metabolismo , Femenino , Galectina 1/química , Galectina 1/genética , Galectina 1/metabolismo , Galectina 3/química , Galectina 3/genética , Galectina 3/metabolismo , Galectinas/química , Galectinas/genética , Humanos , Inmunoterapia/métodos , Neoplasias Mamarias Experimentales/patología , Neoplasias Mamarias Experimentales/terapia , Ratones , Ratones Endogámicos , Modelos Moleculares , Unión Proteica , Tiogalactósidos/química , Tiogalactósidos/metabolismo , Tiogalactósidos/farmacología , Carga Tumoral/efectos de los fármacosRESUMEN
The search for a selective and efficient anticancer agent for treating all neoplastic disease has yet to deliver a universally suitable compound(s). The majority of established anticancer drugs either are nonselective or lose their efficacy because of the constant mutational changes of malignant cells. Until recently, a largely neglected target for potential anticancer agents was the mitochondrion, showing a considerable promise for future clinical applications. Vitamin E (VE) analogs, epitomized by alpha-tocopheryl succinate, belong to the group of "mitocans" (mitochondrially targeted anticancer drugs). They are selective for malignant cells, cause destabilization of their mitochondria, and suppress cancer in preclinical models. This review focuses on our current understanding of VE analogs in the context of their proapoptotic/anticancer efficacy and suggests that their effect on mitochondria may be amplified by modulation of alternative pathways operating in parallel. We show here that the analogs of VE that cause apoptosis (which translates into their anticancer efficacy) generally do not possess antioxidant (redox) activity and are prototypical of the mitocan group of anticancer compounds. Therefore, by analogy to Oscar Wilde's play The Importance of Being Earnest, we use the motto in the title "the importance of being redox-silent" to emphasize an essentially novel paradigm for cancer therapy, in which redox-silence is a prerequisite property for most of the anticancer activities described in this communication.
Asunto(s)
Antineoplásicos/farmacología , Mitocondrias/efectos de los fármacos , Vitamina E/análogos & derivados , Vitamina E/farmacología , Animales , Apoptosis/efectos de los fármacos , Humanos , Oxidación-Reducción/efectos de los fármacos , Relación Estructura-Actividad , Vitamina E/químicaRESUMEN
"Mitocans" from the vitamin E group of selective anticancer drugs, alpha-tocopheryl succinate (alpha-TOS) and its ether analogue alpha-TEA, triggered apoptosis in proliferating but not arrested endothelial cells. Angiogenic endothelial cells exposed to the vitamin E analogues, unlike their arrested counterparts, readily accumulated reactive oxygen species (ROS) by interfering with the mitochondrial redox chain and activating the intrinsic apoptotic pathway. The vitamin E analogues inhibited angiogenesis in vitro as assessed using the "wound-healing" and "tube-forming" models. Endothelial cells deficient in mitochondrial DNA (mtDNA) were resistant to the vitamin E analogues, both in ROS accumulation and apoptosis induction, maintaining their angiogenic potential. alpha-TOS inhibited angiogenesis in a mouse cancer model, as documented by ultrasound imaging. We conclude that vitamin E analogues selectively kill angiogenic endothelial cells, suppressing tumor growth, which has intriguing clinical implications.
Asunto(s)
Antineoplásicos/uso terapéutico , Mitocondrias/fisiología , Neovascularización Patológica/prevención & control , Estrés Oxidativo/fisiología , Vitamina E/análogos & derivados , Vitamina E/uso terapéutico , Inhibidores de la Angiogénesis/uso terapéutico , Apoptosis/efectos de los fármacos , ADN Mitocondrial/genética , Resistencia a Medicamentos , Endotelio Vascular , Humanos , Mitocondrias/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacosRESUMEN
Mitochondria are proving to be worthy targets for activating specific killing of cancer cells in tumors and a diverse range of mitochondrial targeted drugs are currently in clinical trial to determine their effectiveness as anti-cancer therapies. The mechanism of action of mitochondrial targeted anti-cancer drugs relies on their ability to disrupt the energy producing systems of cancer cell mitochondria, leading to increased reactive oxygen species and activation of the mitochondrial dependent cell death signaling pathways inside cancer cells. We propose that this emerging class of drugs be called "mitocans", a term that reflects their mitochondrial targeting and anti-cancer roles. They are discussed in this review in the context of their mode of action whereby they target the functional differences and altered properties of the mitochondria inside cancerous but not normal cells. Hence, mitocans include drugs affecting the following mitochondrial associated activities: hexokinase inhibitors; electron transport/respiratory chain blockers; activators of the mitochondrial membrane permeability transition pore targeting constituent protein subunits, either the voltage dependent anion-selective channel (VDAC) or adenine nucleotide transporter (ANT); inhibitors of Bcl-2 anti-apoptotic family proteins and Bax/Bid pro-apoptotic mimetics. In particular, a recent surge has occurred in the number of patent documents describing small molecule inhibitors and BH3 mimetic blockers of Bcl-2/Bcl-x(L) function as obvious and important targets for promoting mitochondrial induced cancer cell death and for enhancing the actions of other chemotherapeutic agents. One of the other highly significant results to emerge from clinical applications of mitochondrial targeted drugs as cancer therapies to date is that they have shown limited side-effects on the normal "healthy" cell populations in vivo. It is still too early to judge the clinical impact that mitocans will make in treating cancer. Further clinical studies will be required before these novel drugs become established as single modality anti-cancer therapies or are used in conjunction with existing chemotherapies. However, it is clear from the present studies that mitocans offer great potential as effective and exciting new developments in cancer therapy, providing direct activation of cancer cell death by mitochondrial mediated apoptosis and that this complements the other pathways by which existing treatments kill cancer cells. Undoubtedly, mitocans will become an integral part of modern weaponry in the fight to eliminate cancer.
Asunto(s)
Antineoplásicos/farmacología , Mitocondrias/efectos de los fármacos , Mitógenos/farmacología , Neoplasias/tratamiento farmacológico , Animales , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Arsénico/farmacología , Calcio/fisiología , Permeabilidad de la Membrana Celular , Supervivencia Celular/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Genes bcl-2/efectos de los fármacos , Glucólisis/efectos de los fármacos , Hexoquinasa/antagonistas & inhibidores , Hexoquinasa/metabolismo , Humanos , Cinética , Mitocondrias/fisiología , Mitógenos/síntesis química , Neoplasias/diagnóstico , Neoplasias/metabolismo , Neoplasias/patología , Patentes como Asunto , Fotoquimioterapia , Vitamina E/análogos & derivados , Vitamina E/farmacologíaRESUMEN
Dichotic pitch perception reflects the auditory system's use of binaural cues to perceptually separate different sound sources and to determine the spatial location of sounds. Several studies were conducted to identify factors that influence children's dichotic pitch perception thresholds. An initial study of school children revealed an age-related improvement in thresholds for lateralizing dichotic pitch tones. In subsequent studies potential sensory and nonsensory limitations on young children's performance of dichotic pitch lateralization tasks were examined. A training study showed that with sufficient practice, young children lateralize dichotic pitch stimuli as well as adults, indicating an age difference in perceptual learning of the lateralization task. Changing the task requirements so that young children made a judgment about the pitch of dichotic pitch tones, rather than the spatial location of the tones, also resulted in significantly better thresholds. These findings indicate that nonsensory factors limit young children's performance of dichotic pitch tasks.
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Pruebas de Audición Dicótica , Percepción de la Altura Tonal/fisiología , Sensación/fisiología , Adolescente , Umbral Auditivo/fisiología , Niño , Preescolar , Señales (Psicología) , Femenino , Humanos , Juicio , MasculinoRESUMEN
Antigen-specific suppression of a previously primed immune response is a major challenge for immunotherapy of autoimmune disease. RelB activation is required for myeloid DC differentiation. Here, we show that antigen-exposed DCs in which RelB function is inhibited lack cell surface CD40, prevent priming of immunity, and suppress previously primed immune responses. DCs generated from CD40-deficient mice similarly confer suppression. Regulatory CD4+ T cells induced by the DCs transfer antigen-specific "infectious" tolerance to primed recipients in an interleukin-10-dependent fashion. Thus CD40, regulated by RelB activity, determines the consequences of antigen presentation by myeloid DCs. These observations have significance for autoimmune immunotherapy and suggest a mechanism by which peripheral tolerance might be constitutively maintained by RelB(-) CD40(-) DCs.