Specific, Reversible Cytostatic Protection of Normal Cells Against Negative Effects of Chemotherapy

Chemotherapy is a common and effective method to treat many forms of cancer. However, treatment of cancer with chemotherapy has severe side effects which often limit the doses of therapy administered. Because some cancer chemotherapeutics target proliferating cells and tissues, all dividing cells, whether normal or tumor, are affected. Cell culture studies have demonstrated that UCN-01 is able to reversibly and selectively arrest normal dividing cells; tumor cells lines do not undergo this temporary arrest. Following UCN-01 treatment, normal cells displayed a 50-fold increase in IC50 for camptothecin; tumor cells showed no such increased tolerance. We have examined the response of the proliferating tissues of the mouse to UCN- 01 treatment, using the small bowel epithelium as a model system. Our results indicate that UCN-01 treatment can cause a cell cycle arrest in the gut epithelium, beginning 24 hours following UCN-01 administration, with cell proliferation remaining suppressed for one week. Two weeks post-UCN-01 treatment the rate of proliferation returns to normal levels. 5-FU administered during this period demonstrates that UCN-01 is able to provide protection to normal cells of the mouse within a narrow window of efficacy, from three to five days post-UCN-01. UCN-01 pretreated mice displayed improved survival, weight status and blood markers following 5-FU compared to control mice, indicating that UCN-01 can protect normal dividing tissues. The mechanism by which UCN-01 arrests normal cells in vivo was also examined. We have demonstrated that UCN-01 treatment in mice causes an increase in the G1 phase cell cycle proteins cdk4 and cyclin D, as well as the inhibitor p27. Phosphorylated Rb was also elevated in the arrested cells. These results are a departure from cell culture studies, in which inhibition of G1 phase cyclin dependent kinases led to hyposphosphorylation of Rb. Future investigation will be required to understand the mechanism of UCN-01 action. This is important information, especially for identification of alternate compounds which could provide the protection afforded by UCN-01.

Laser-induced transient grating analysis of dynamics of interaction between sensory rhodopsin II D75N and the HtrII transducer.

The interaction between sensory rhodopsin II (SRII) and its transducer HtrII was studied by the time-resolved laser-induced transient grating method using the D75N mutant of SRII, which exhibits minimal visible light absorption changes during its photocycle, but mediates normal phototaxis responses. Flash-induced transient absorption spectra of transducer-free D75N and D75N joined to 120 amino-acid residues of the N-terminal part of the SRII transducer protein HtrII (DeltaHtrII) showed only one spectrally distinct K-like intermediate in their photocycles, but the transient grating method resolved four intermediates (K(1)-K(4)) distinct in their volumes. D75N bound to HtrII exhibited one additional slower kinetic species, which persists after complete recovery of the initial state as assessed by absorption changes in the UV-visible region. The kinetics indicate a conformationally changed form of the transducer portion (designated Tr*), which persists after the photoreceptor returns to the unphotolyzed state. The largest conformational change in the DeltaHtrII portion was found to cause a DeltaHtrII-dependent increase in volume rising in 8 micros in the K(4) state and a drastic decrease in the diffusion coefficient (D) of K(4) relatively to those of the unphotolyzed state and Tr*. The magnitude of the decrease in D indicates a large structural change, presumably in the solvent-exposed HAMP domain of DeltaHtrII, where rearrangement of interacting molecules in the solvent would substantially change friction between the protein and the solvent.

Improving the accuracy of radiation pneumonitis dose response models

The prognosis for lung cancer patients remains poor. Five year survival rates have been reported to be 15%. Studies have shown that dose escalation to the tumor can lead to better local control and subsequently better overall survival. However, dose to lung tumor is limited by normal tissue toxicity. The most prevalent thoracic toxicity is radiation pneumonitis. In order to determine a safe dose that can be delivered to the healthy lung, researchers have turned to mathematical models predicting the rate of radiation pneumonitis. However, these models rely on simple metrics based on the dose-volume histogram and are not yet accurate enough to be used for dose escalation trials. The purpose of this work was to improve the fit of predictive risk models for radiation pneumonitis and to show the dosimetric benefit of using the models to guide patient treatment planning. The study was divided into 3 specific aims. The first two specifics aims were focused on improving the fit of the predictive model. In Specific Aim 1 we incorporated information about the spatial location of the lung dose distribution into a predictive model. In Specific Aim 2 we incorporated ventilation-based functional information into a predictive pneumonitis model. In the third specific aim a proof of principle virtual simulation was performed where a model-determined limit was used to scale the prescription dose. The data showed that for our patient cohort, the fit of the model to the data was not improved by incorporating spatial information. Although we were not able to achieve a significant improvement in model fit using pre-treatment ventilation, we show some promising results indicating that ventilation imaging can provide useful information about lung function in lung cancer patients. The virtual simulation trial demonstrated that using a personalized lung dose limit derived from a predictive model will result in a different prescription than what was achieved with the clinically used plan; thus demonstrating the utility of a normal tissue toxicity model in personalizing the prescription dose.

ANALYSIS OF THE CORYNEBACTERIUM PARVUM-INDUCED DECLINE OF MURINE NATURAL KILLER CELL-MEDIATED CYTOTOXICITY

Treatment of mice with the immunomodulating agent, Corynebacterium parvum (C. parvum), was shown to result in a severe and long-lasting depression of splenic natural killer (NK) cell-mediated cytotoxicity 5-21 days post-inoculation. Because NK cells have been implicated in immunosurveillance against malignancy (due to their spontaneous occurrence and rapid reactivity to a variety of histological types of tumors), as well as in resistance to established tumors, this decreased activity was of particular concern, since this effect is contrary to that which would be considered therapeutically desirable in cancer treatment (i.e. a potentiation of antitumor effector functions, including NK cell activity, would be expected to lead to a more effective destruction of malignant cells). Therefore, an analysis of the mechanism of this decline of splenic NK cell activity in C.parvum treated mice was undertaken.^ From in vitro co-culturing experiments, it was found that low NK-responsive C. parvum splenocytes were capable of reducing the normally high-reactivity of cells from untreated syngeneic mice to YAC-1 lymphoma, suggesting the presence of NK-directed suppressor cells in C. parvum treated animals. This was further supported by the demonstration of normal levels of cytotoxicity in C. parvum splenocyte preparations following Ficoll-Hypaque separation, which coincided with removal of the NK-suppressive capabilities of these cells. The T cell nature of these regulatory cells was indicated by (1) the failure of C. parvum to cause a reduction of NK cell activity, or the generation of NK-directed suppressor cells in T cell-deficient athymic mice, (2) the removal of C. parvum-induced suppression by T cell-depleting fractionation procedures or treatments, and (3) demonstration of suppression of NK cell activity by T cell-enriched C. parvum splenocytes. These studies suggest, therefore, that the eventual reduction of suppression by T cell elimination and/or inhibition, may result in a promotion of the antitumor effectiveness of C. parvum due to the contribution of "freed" NK effector cell activity.^ However, the temporary suppression of NK cell activity induced by C. parvum (reactivity of treated mice returns to normal levels within 28 days after C. parvum injection), may in fact be favorable in some situations, e.g. in bone marrow transplantation cases, since NK cells have been suggested to play a role also in the process of bone marrow graft rejection.^ Therefore, the discriminate use of agents such as C. parvum may allow for the controlled regulation of NK cell activity suggested to be necessary for the optimalization of therapeutic regimens. ^

Towards the continuum limit in transport coefficient computations

The analytic continuation needed for the extraction of transport coefficients necessitates in principle a continuous function of the Euclidean time variable. We report on progress towards achieving the continuum limit for 2-point correlator measurements in thermal SU(3) gauge theory, with specific attention paid to scale setting. In particular, we improve upon the determination of the critical lattice coupling and the critical temperature of pure SU(3) gauge theory, estimating r0Tc ≃ 0.7470(7) after a continuum extrapolation. As an application the determination of the heavy quark momentum diffusion coefficient from a correlator of colour-electric fields attached to a Polyakov loop is discussed.

Time-Resolved Ultra–High Resolution Optical Coherence Tomography for Real-Time Monitoring of Selective Retina Therapy

Purpose: Selective retina therapy (SRT) is a novel treatment for retinal pathologies, solely targeting the retinal pigment epithelium (RPE). During SRT, the detection of an immediate tissue reaction is challenging as tissue effects remain limited to intracellular RPE photodisruption. Time-resolved ultra-high axial resolution optical coherence tomography (OCT) is thus evaluated for the monitoring of dynamic optical changes at and around the RPE during SRT. Methods: An experimental OCT system with an ultra-high axial resolution of 1.78 µm was combined with an SRT system and time-resolved OCT M-scans of the target area were recorded from four patients undergoing SRT. OCT scans were analyzed and OCT morphology was correlated with findings in fluorescein angiography, fundus photography and cross-sectional OCT. Results: In cases where the irradiation caused RPE damage proven by fluorescein angiography, the lesions were well discernible in time-resolved OCT images but remained invisible in fundus photography and cross-sectional OCT acquired after treatment. If RPE damage was introduced, all applied SRT pulses led to detectable signal changes in the time-resolved OCT images. The extent of optical signal variation seen in the OCT data appeared to scale with the applied SRT pulse energy. Conclusion: The first clinical results proved that successful SRT irradiation induces detectable changes in the OCT M-scan signal while it remains invisible in conventional ophthalmoscopic imaging. Thus, real-time high-resolution OCT is a promising modality to monitor and analyze tissue effects introduced by selective retina therapy and may be used to guide SRT in an automatic feedback mode.

Mobility and Bandwidth Prediction as a Service in Virtualized LTE Systems

Recently telecommunication industry benefits from infrastructure sharing, one of the most fundamental enablers of cloud computing, leading to emergence of the Mobile Virtual Network Operator (MVNO) concept. The most momentous intents by this approach are the support of on-demand provisioning and elasticity of virtualized mobile network components, based on data traffic load. To realize it, during operation and management procedures, the virtualized services need be triggered in order to scale-up/down or scale-out/in an instance. In this paper we propose an architecture called MOBaaS (Mobility and Bandwidth Availability Prediction as a Service), comprising two algorithms in order to predict user(s) mobility and network link bandwidth availability, that can be implemented in cloud based mobile network structure and can be used as a support service by any other virtualized mobile network services. MOBaaS can provide prediction information in order to generate required triggers for on-demand deploying, provisioning, disposing of virtualized network components. This information can be used for self-adaptation procedures and optimal network function configuration during run-time operation, as well. Through the preliminary experiments with the prototype implementation on the OpenStack platform, we evaluated and confirmed the feasibility and the effectiveness of the prediction algorithms and the proposed architecture.

Do Proctored Exams Matter In Online Classes?

Does the format of assessment (proctored or un-proctored exams) affect test scores in online principles of economics classes? This study uses data from two courses of principles of economics taught by the same instructor to gain some insight into this issue. When final exam scores are regressed against human capital factors, the R-squared statistic is 61.6% for the proctored format exams while it is only 12.2% for the un-proctored format. Three other exams in the class that had the proctored final were also un-proctored and also produced lower R-squared values, averaging 30.5%. These two findings suggest that some cheating may have taken place in the un-proctored exams. Although it appears some cheating took place, the results suggest that cheating did not pay for these students since the proctored exam grades were 4.9 points higher than the un-proctored exam grades although this difference was significantly different at only the 10% level. One possible explanation for this is that there was slightly higher human capital in the class that had the proctored exam although this must have occurred by chance since the students did not know if the exams were going to be proctored in advance so there is no issue of selection bias. A Oaxaca decomposition of this difference in grades was conducted to see how much was due to human capital and how much was due to the differences in the rates of return to human capital. This analysis reveals that 17% of the difference was due to the higher human capital with the remaining 83% due to differences in the returns to human capital. It is possible that the un-proctored exam format does not encourage as much studying as the proctored format reducing both the returns to human capital and the exam scores.

El espacio de lo provincial en el siglo XIX : memoria descriptiva sobre el Tucumán, de Juan Bautista Alberdi

Hacia el año 1834, Juan Bautista Alberdi regresa a su Tucumán natal, luego de una larga ausencia. En ese momento, instigado por el entonces gobernador, general Alejandro Heredia, redactó su Memoria descriptiva sobre el Tucumán, considerada el primer exponente de la literatura provincial en la Argentina. En este breve texto, de menos de treinta páginas, el escritor aúna a su perspectiva de extra-ambientado, de viajero, la del romántico y la del patriota, las cuales determinan las isotopías que lo estructuran. Este trabajo intenta rescatar del olvido tan valioso texto. Para ello se analizan la estructura, procedimientos y recursos que, estando al servicio de una intención precisamente manifestada por el autor, configuran una visión idealizada del terruño natal. El procedimiento descriptivo es el principal canal de textualización. A través de él, el autor ofrece una visión subjetiva, idealizadora y humanizada del paisaje para detenerse luego en la presentación del hombre tucumano, cuyo temperamento aparece determinado por la geografía de su entorno. Finalmente, Alberdi centra su mirada en los monumentos históricos; en este caso, su discurso materializa la confrontación entre lo que ve y lo que recuerda e identifica la vida de la patria con su propia vida.

La espacialidad en Eero Tarasti : aportes a un modelo de análisis semiótico

El trabajo retoma el análisis semiótico de Eero Tarasti y en particular el concepto de espacialidad desarrollado en su Sémiotique musicale (1996), y basado en los estudios del estructuralista A. J. Greimas. A partir de un nuevo estudio de caso, se proponen modificaciones que permitirán complementar el análisis armónico tradicional, y suplir algunas falencias que toda traducción a un nuevo código implica. El aparato metodológico es concebido como herramienta para el conocimiento profundo de las estructuras narrativas y como apoyo para la interpretación.

El desierto y su semilla : política e ironía

El presente artículo estudia la relación entre el arte y lo político en la novela El desierto y su semilla, de Jorge Baron Biza (2013), caracterizada por una intencionalidad irónica, porque hace uso de técnicas propias de esta figura del discurso que le permiten decir lo político difiriendo del enunciado literal. Se dejan de lado las lecturas biográficas y acudimos a los aportes de Jacques Rancière acerca de la estética elusiva, que hace al arte político y sus advertencias sobre las diversas formas en que el arte es repolitizado. Por otra parte, se tendrá en cuenta el estudio propuesto por Ana María Amar Sánchez sobre el discurso de los perdedores, para así poder complementar el estudio sobre la novela y la reflexión en torno a lo político. Por último, la intencionalidad irónica del autor se expresa en el uso de la alusión que le permite hablar de lo político, alterando así, en términos de Rancière, el dispositivo estético que vuelve a la obra subversiva.

Lucha obrera, conflicto sindical y organización armada : El caso de la Juventud Trabajadora Peronista de Propulsora Siderúrgica [1973-1976]

El presente trabajo aborda el caso de la Juventud Trabajadora Peronista en la empresa Propulsora Siderúrgica de la localidad de Ensenada en el período 1973-1976, constituyendo éste un período clave en la historia política argentina en tanto significó el retorno del peronismo al poder luego de dieciocho años de proscripción legal. Enmarcada en la extensa constelación de experiencias de la ?nueva izquierda? que irrumpe con fuerza en Argentina a partir de fines de los años sesenta, y específicamente en la amplia experiencia de las fuerzas peronistas revolucionarias dentro de ella, la Juventud Trabajadora Peronista aparece como un espacio político-sindical especialmente rico para el estudio y análisis en el campo de la historia reciente argentina y dentro de ella de las prácticas sindicales radicalizadas. Fundada en 1973, la JTP nace como frente de masas sindical de la organización armada Montoneros. Fundada en el contexto histórico, político y social de retorno de Perón al país y de crisis del gobierno peronista, ésta seráparte de la emergencia de particulares formas de vínculo social en el que se entrecruzan elementos ligados a la práctica de los militantes obreros, sus agrupaciones sindicales, el proceso de radicalización general del período y la singular participación de las organizaciones armadas peronistas. Contemplado el entrecruzamiento entre organizaciones armadas revolucionarias, organizaciones sindicales combativas y la radicalización de sectores de la clase trabajadora, nuestro trabajo enfatiza la capacidad política obrera para imponer condiciones al capital, al gobierno y a sectores burocráticos del sindicalismo. Es en estos tres frentes de combate en los que se verán inmersos los sectores radicalizados de la clase obrera argentina que buscamos poner en un primer plano a lo largo de esta investigación

"En el monumento Resuçitest, fust alos ynfiernos" : ¿Error del poeta o influencia de una fuente en el Cantar de Mio Cid?

El presente trabajo vuelve a los vv. 358-361 del Cantar de Mio Cid sobre un tema que ha perturbado a la crítica: el texto conservado en el Códice de Vivar refiere que Jesús resucitó primero, y luego descendió a los Infiernos, lo cual implica una inversión del orden tradicional de los acontecimientos. En consecuencia, se revisan aquí las distintas opiniones sobre el particular, que en general pueden dividirse básicamente en dos grupos -aquellas que sostienen que el poeta cometió un error, y otras que afirman que el autor del poema adhirió a un determinado modelo, proveniente ya de la épica francesa, ya de la liturgia-, y se intenta arribar a una solución que considere más satisfactoriamente la especificidad del texto manuscrito.

Fuerzas productivas y lógica económica del modo de producción feudal

Este artículo regresa al debate acerca de la importancia relativa de las fuerzas productivas y de las relaciones de producción en el modo de producción feudal. Sostiene, utilizando evidencia del occidente medieval, que esta relación es empírica y que varía según los modos, quizás incluso dentro de cada uno de ellos. Propone, además, que en el caso específico del feudalismo, no solo las relaciones de producción fueron la fuerza motriz, sino que de hecho los desarrollos en las fuerzas productivas dependieron de ellas

Paleomagnetic analysis of ODP Site 133-820

Paleomagnetic analysis of sediment samples from Ocean Drilling Program (ODP) Leg 133, Site 820, 10 km from the outer edge of the Great Barrier Reef, is undertaken to investigate the mineral magnetic response to environmental (sea level) changes. Viscous remanent magnetization (VRM) of both multidomain and near-superparamagnetic origin is prevalent and largely obscures the primary remanence, except in isolated high-magnetization zones. The Brunhes/Matuyama boundary cannot be identified, but is expected to be below 120 mbsf. The only evidence that exists for a geomagnetic excursion occurs at about 33 mbsf (-135 k.y.). Only one-half the cores were oriented, and many suffered from internal rotation about the core axis, caused by coring and/or slicing. The decay of magnetic remanence below the surface layer (0-2 mbsf) is attributed to sulfate reduction processes. The magnetic susceptibility (K) record is central for describing and understanding the magnetic properties of the sediments, and their relationship to glacio-eustatic fluctuations in sea level. Three prominent magnetic susceptibility peaks, at about 7, 32, and 64 mbsf, are superimposed on a background of smaller susceptibility oscillations. Fluctuations in susceptibility and remanence in the ôbackgroundö zone are controlled predominantly by variations in the concentration, rather than the composition of ferrimagnetics, with carbonate dilution playing an important role (type-A properties). The sharp susceptibility maxima occur at the start of the marine transgressions following low stands in sea level (high d18O, glacial maxima), and are characterized by a stable single-domain remanence, with a significant contribution from ultra-fine, superparamagnetic grains (type-C properties). During the later marine transgression, the susceptibility gradually returns to low values and the remanence is carried by stable single-domain magnetite (type-B properties). The A, B, and C types of sediment have distinctive ARM/K ratios. Throughout most of the sequence a strong inverse correlation exists between magnetic susceptibility and both CaCO3 and d18O variations. However, in the sharp susceptibility peaks (early transgression), more complex phase relationships are apparent among these parameters. In particular, the K-d18O correlation switches to positive, then reverts to negative during the course of the late transgression, indicating that two distinct mechanisms are responsible for the K-d18O correlation. Lower in the sequence, where sea-level-controlled cycles of upward-coarsening sediments, we find that the initial, mud phase of each cycle has been enriched in high-coercivity magnetic material, which is indicative of more oxic conditions. The main magnetic characteristics of the sediments are thought to reflect sea-level-controlled variations in the sediment source regions and related run-off conditions. Some preliminary evidence is seen that biogenic magnetite may play a significant role in the magnetization of these sediments.