Neuromuscular fatigue after resistance training.

This study examined the effects of heavy resistance training on dynamic exercise-induced fatigue task (5 x 10RM leg-press) after two loading protocols with the same relative intensity (%) (5 x 10RM(Rel)) and the same absolute load (kg) (5 x 10RM(Abs)) as in pretraining in men (n=12). Maximal strength and muscle power, surface EMG changes [amplitude and spectral indices of muscle fatigue], and metabolic responses (i.e.blood lactate and ammonia concentrations) were measured before and after exercise. After training, when the relative intensity of the fatiguing dynamic protocol was kept the same, the magnitude of exercise-induced loss in maximal strength was greater than that observed before training. The peak power lost after 5 x 10RM(Rel) (58-62%, pre-post training) was greater than the corresponding exercise-induced decline observed in isometric strength (12-17%). Similar neural adjustments, but higher accumulated fatigue and metabolic demand were observed after 5 x 10RM(Rel). This study therefore supports the notion that similar changes are observable in the EMG signal pre- and post-training at fatigue when exercising with the same relative load. However, after training the muscle is relatively able to work more and accumulate more metabolites before task failure. This result may indicate that rate of fatigue development (i.e. power and MVC) was faster and more profound after training despite using the same relative intensity.

[The immunotherapy potential of agonistic anti-CD137 (4-1BB) monoclonal antibodies for malignancies and chronic viral diseases]. / El potencial de la inmunomodulación con anticuerpos monoclonales anti-CD137 (4-1BB) para terapia de enfermedades malignas e infecciones virales crónicas.

Pharmacological intervention on the immune system to achieve more intense lymphocyte responses has potential application in tumour immunology and in the treatment of chronic viral diseases. Immunostimulating monoclonal antibodies are defined as a new family of drugs that augment cellular immune responses. They interact as artificial ligands with functional proteins of the immune system, either activating or inhibiting their functions. There are humanized monoclonal antibodies directed to the inhibitory receptor CD152 (CTLA-4) that are being tested in clinical trials with evidence of antitumoural activity. As a drawback, anti-CTLA-4 monoclonal antibodies induce severe autoimmunity reactions in a fraction of the patients. Anti-CD137 monoclonal antibodies have the ability to induce potent immune responses mainly mediated by cytotoxic lymphocytes with the result of frequent complete tumour eradications in mice. Comparative studies in experimental models indicate that the antitumour activity of anti-CD137 monoclonal antibodies is superior to that of anti-CD152. CD137 (4-1BB) is a leukocyte differentiation antigen selectively expressed on the surface of activated T and NK lymphocytes, as well as on dendritic cells. Monoclonal antibodies acting as artificial stimulatory ligands of this receptor (anti-CD137 agonist antibodies) enhance cellular antitumoural and antiviral immunity in a variety of mouse models. Paradoxically, anti-CD137 monoclonal antibodies are therapeutic or preventive in the course of model autoimmune diseases in mice. In light of these experimental results, a number of research groups have humanized antibodies against human CD137 and early clinical trials are about to start.

El potencial de la inmunomodulación con anticuerpos monoclonales anti-CD137 (4-1BB) para terapia de enfermedades malignas e infecciones virales crónicas / The immunotherapy potential of agonistic anti-CD137 (4-1BB) monoclonal antibodies for malignancies and chronic viral diseases

La manipulación farmacológica del sistema inmunitario para conseguir respuestas linfocitarias de mayor intensidad tiene aplicación potencial en inmunoterapia tumoral y en el tratamiento de enfermedades virales crónicas. Los anticuerpos monoclonales inmunoestimuladores se definen como una familia de fármacos que aumentan la respuesta inmunitaria al interaccionar como ligandos artificiales con proteínas funcionales del sistema inmunitario, activando o inhibiendo su función. Hay anticuerpos monoclonales humanizados dirigidos frente al receptor inhibidor linfocitario CD152 (CTLA-4) que se están probando en ensayos clínicos con evidencia de actividad antitumoral, aunque con la contrapartida de producir reacciones autoinmunitarias severas. Los anticuerpos anti-CD137 tienen la capacidad de inducir potentes respuestas inmunitarias, mediadas principalmente por linfocitos T citotóxicos, con el resultado de erradicar tumores transplantables de ratón de forma comparativamente superior a los anticuerpos frente a CD152. CD137 (4-1BB) es un antígeno de diferenciación expresado selectivamente en la superficie de linfocitos T y NK activados y sobre células dendríticas. Los anticuerpos monoclonales que actúan como ligandos artificiales estimuladores de este receptor (anticuerpos monoclonales agonistas anti-CD137) potencian la inmunidad celular antitumoral y antiviral en modelos experimentales murinos. Paradójicamente, estos mismos anticuerpos previenen o mejoran el curso de enfermedades autoinmunitarias establecidas en ratones como modelo. A la luz de estos datos experimentales, varios grupos de investigación han procedido a la humanización de anticuerpos dirigidos frente a CD137 humano y se plantea la inminente realización de los primeros ensayos clínicos

Pharmacological intervention on the immune system to achieve more intense lymphocyte responses has potential application in tumour immunology and in the treatment of chronic viral diseases. Immunostimulating monoclonal antibodies are defined as a new family of drugs that augment cellular immune responses. They interact as artificial ligands with functional proteins of the immune system, either activating or inhibiting their functions. There are humanized monoclonal antibodies directed to the inhibitory receptor CD152 (CTLA-4) that are being tested in clinical trials with evidence of antitumoural activity. As a drawback, anti-CTLA-4 monoclonal antibodies induce severe autoimmunity reactions in a fraction of the patients. Anti-CD137 monoclonal antibodies have the ability to induce potent immune responses mainly mediated by cytotoxic lymphocytes with the result of frequent complete tumour eradications in mice. Comparative studies in experimental models indicate that the antitumour activity of anti-CD137 monoclonal antibodies is superior to that of anti-CD152. CD137 (4-1BB) is a leukocyte differentiation antigen selectively expressed on the surface of activated T and NK lymphocytes, as well as on dendritic cells. Monoclonal antibodies acting as artificial stimulatory ligands of this receptor (anti-CD137 agonist antibodies) enhance cellular antitumoural and antiviral immunity in a variety of mouse models. Paradoxically, anti-CD137 monoclonal antibodies are therapeutic or preventive in the course of model autoimmune diseases in mice. In light of these experimental results, a number of research groups have humanized antibodies against human CD137 and early clinical trials are about to start

Critical appraisal of the current status of dendritic cell based therapy

Una serie de circunstancias históricas han otorgado a las células dendríticas un lugar importante en la inmunoterapia antitumoral. El descubrimiento de su papel fundamental en la presentación antigénica ha propiciado su uso como adyuvantes en protocolos de vacunación en modelos tumorales de ratón. En estos modelos se llegaron a obtener remisiones tumorales. A finales de los años 90 la coincidencia de (i) estos prometedores resultados preclínicos, (ii) la disponibilidad en hospitales de áreas de terapiacelular (desarrolladas sobre todo para transplantes de médula ósea y (iii) protocolos de cultivo sencillos para diferenciar células dendríticas a partir de monocitos o precursores mieloides han impulsado la realización de múltiples ensayos clínicos. Los primeros datos clínicos no cumplieron las expectativas, pero se están extrayendo conclusiones sobre la actividad biológica e incluso se han obtenido algunos casos de respuestas clínicas en pacientes con cánceres avanzados. En cualquier caso, algunos de los ensayos que mejores resultados estaban obteniendo se encuentran bajo sospecha de fraude científico y otros buenos resultados obtenidos en los grupos piloto no se han reproducido cuando se han utilizado los mismos protocolos en grupos más amplios de pacientes.La situación actual del campo puede ser vista como una botella medio llena o medio vacía. En cualquier caso, se necesita mejorarla potencia terapéutica a nivel preclínico incluso con el riesgo de efectos adversos (AU)

A set of historical circumstances has centred the field of cancer immunotherapy on dendritic cells (DC). The discovery of their central role in antigen presentation for immunization gave rise to their use as adjuvants for cancer vaccination in transplantable tumour models in mice. Tumour rejections of experimental transplantable tumour models were achieved. During the late 90s concurrence of (i) this encouraging preclinical data, (ii) the availability of hospital cell therapy facilities that have been mainly set up for bone marrow transplantation and (iii) simple culture means to differentiate DC from monocytes or myeloid precursors spurred many clinical trials worldwide. Early clinical experience has not met the great expectations raised, but many lessons are being learned in terms of biological activity and cases of clinical response in advanced cases are routinely reported. However, some of the trials that reported the most encouraging clinical responses have confronted controversy due to scientific misconduct orto accumulation of successful cases in the pilot groups of patients that were not so reproducible when more patients were studied under the same protocols. The current status of the field could be seen as a half empty or a half full bottle. In either case, improvements are needed from the lab bench to increase therapeutic potency, even at the risk of side effects (AU)

Critical appraisal of the current status of dendritic cell based therapy

Una serie de circunstancias históricas han otorgado a las célulasdendríticas un lugar importante en la inmunoterapia antitumoral.El descubrimiento de su papel fundamental en la presentaciónantigénica ha propiciado su uso como adyuvantes en protocolosde vacunación en modelos tumorales de ratón. En estosmodelos se llegaron a obtener remisiones tumorales. A finales delos años 90 la coincidencia de (i) estos prometedores resultadospreclínicos, (ii) la disponibilidad en hospitales de áreas de terapiacelular (desarrolladas sobre todo para transplantes de médulaósea y (iii) protocolos de cultivo sencillos para diferenciar célulasdendríticas a partir de monocitos o precursores mieloides hanimpulsado la realización de múltiples ensayos clínicos. Los primerosdatos clínicos no cumplieron las expectativas, pero se estánextrayendo conclusiones sobre la actividad biológica e incluso sehan obtenido algunos casos de respuestas clínicas en pacientescon cánceres avanzados. En cualquier caso, algunos de los ensayosque mejores resultados estaban obteniendo se encuentran bajosospecha de fraude científico y otros buenos resultados obtenidosen los grupos piloto no se han reproducido cuando se hanutilizado los mismos protocolos en grupos más amplios de pacientes.La situación actual del campo puede ser vista como una botellamedio llena o medio vacía. En cualquier caso, se necesita mejorarla potencia terapéutica a nivel preclínico incluso con el riesgode efectos adversos

A set of historical circumstances has centred the field of cancerimmunotherapy on dendritic cells (DC). The discovery of theircentral role in antigen presentation for immunization gave rise totheir use as adjuvants for cancer vaccination in transplantabletumour models in mice. Tumour rejections of experimental transplantabletumour models were achieved. During the late 90s concurrenceof (i) this encouraging preclinical data, (ii) the availabilityof hospital cell therapy facilities that have been mainly set upfor bone marrow transplantation and (iii) simple culture meansto differentiate DC from monocytes or myeloid precursors spurredmany clinical trials worldwide. Early clinical experience hasnot met the great expectations raised, but many lessons are beinglearned in terms of biological activity and cases of clinical responsein advanced cases are routinely reported. However, someof the trials that reported the most encouraging clinical responseshave confronted controversy due to scientific misconduct orto accumulation of successful cases in the pilot groups of patientsthat were not so reproducible when more patients were studiedunder the same protocols. The current status of the field could beseen as a half empty or a half full bottle. In either case, improvementsare needed from the lab bench to increase therapeuticpotency, even at the risk of side effects

Cytokine gene transfer into dendritic cells for cancer treatment.

Bone marrow-derived dendritic cells have been used to treat established experimental tumors by unleashing a cellular immune response against tumor antigens. Such antigens are artificially loaded onto dendritic cells' antigen-presenting molecules by different techniques including incubation with synthetic antigenic determinants, tumor lysates or nucleic acids encoding for those relevant antigens. Ex vivo gene transfer with viral and non-viral vectors is frequently used to obtain expression of the tumor antigens and thereby to formulate the therapeutic vaccines. Efficacy of the approaches is greatly enhanced if dendritic cells are transfected with a number of genes which encode immunostimulating factors. In some cases, such as with IL-12, IL-7 and CD40L genes, injection inside experimental malignancies of thus transfected dendritic cells induces complete tumor regression in several models. In this case tumor antigens are captured by dendritic cells by still unclear mechanisms and transported to lymphoid organs where productive antigen presentation to T-cells takes place. Many clinical trials testing dendritic cell-based vaccines against cancer are in progress and partial clinical efficacy has been already proved. Transfection of genes further strengthening the immunogenicity of such strategies will join the clinical club soon.

Alpha(v)beta(3) integrin-mediated adenoviral transfer of interleukin-12 at the periphery of hepatic colon cancer metastases induces VCAM-1 expression and T-cell recruitment.

We previously reported that systemic injection of recombinant adenovirus resulted in a rim of gene transduction around experimental liver tumor nodules. This zone of higher infection is dependent on the alpha(v)beta(3) integrin, acting as an adenovirus internalization receptor, which is overexpressed in tissues surrounding liver metastases. When a recombinant adenovirus encoding interleukin-12 (AdCMVIL-12) is given into a subcutaneous tumor nodule in mice also bearing concomitant liver tumors, a fraction of AdCMVIL-12 reaches the systemic circulation and infects liver tissue, especially at the malignant/healthy tissue interface. As a result of the expression at this location of the interleukin-12 transgenes, VCAM-1 is induced on vessel cells and mediates the recruitment of adoptively transferred anti-tumor cytolytic T-lymphocytes. These studies provide mechanistic explanations for the potent therapeutic synergy observed between interleukin-12 gene transfer and adoptive T-cell therapy.

Antimycobacterial activity of new quinoxaline-2-carbonitrile and quinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives.

The compounds being reported in this paper have all been evaluated within the TAACF Antituberculosis Screen Program, and some of them have been shown to possess high growth inhibition activity against Mycobacterium tuberculosis and Mycobacterium avium in the run of the first and second level in vitro screenings. The three compounds which have shown a good SI (Selectivity Index) are 2b, 4b and 4d; in addition, 6,7-dimethyl-3-[4-(4'-nitrophenyl)piperazinl-yl]quinoxaline-2-carbonitrilo 1,4-di-N-oxide (4b) is currently being tested within the in vivo antituberculosis screening in view of its very good in vitro activity.

Ignorancia inmunológica de antígenos tumorales e inyección intratumoral de células del sistema inmunitario / Immunological ignorance of tumor antigens and intratumor injection of immune system cells

La última década ha sido testigo de un debate sobre el status de la respuesta inmunitaria específica frente a antígenos asociados a células malignas en pacientes portadores de tumores. Algunos sostienen que existe una situación de tolerancia producto de la anergia o deleción de los clones linfocitarios relevantes, mientras que los modelos experimentales demuestran a menudo que existe un estado de ignorancia en el Sistema Inmunitario, en el que coexisten elementos re s p o n d e d o res y antígenos sin que ocurra tolerización ni respuesta efectora medible. Varios factores pueden explicar este estado, pero el que pare c e tener más importancia es la falta de acceso en condiciones apropiadas de las células del Sistema Inmunitario a las células malignas. En algunos casos la ignorancia inmunológica no puede ser distinguida de cierto grado de tolerancia periférica parcial. Proponemos que la inyección intratumoral de linfocitos T o NK y/o de células dendríticas con fines inmunoterapéuticos puede romper estos mecanismos de ignorancia o tolerancia parcial (AU)