The role and mechanism of supressor of cytokine signaling 1 in brain metastasis

Brain metastasis, which occurs in 40%-60% of patients with advanced melanoma, has led directly to death in the majority of cases. Unfortunately, little is known about the biological and molecular basis of melanoma brain metastases. In our previous study, we developed a model to study human melanoma brain metastasis and found that Stat3 activity was increased in human brain metastatic melanoma cells when compared with that in cutaneous melanoma cells. The increased activation of Stat3 is also responsible for affecting melanoma angiogenesis in vivo and melanoma cell invasion in vitro and significantly affecting the expression of bFGF, VEGF, and MMP-2 in vivo and in vitro. Interestingly, a member of a new family of cytokine-inducible inhibitors of signal transduction, termed suppressors of cytokine signaling 1 (SOCS1) was found to negatively regulate the Janus kinase signal transducer and activator of transcription (Jak/STAT) signaling cascade. Here we report that restoration of SOCS1 expression by transfecting of SOCS1-expressing vector effectively inhibited melanoma brain metastasis through inhibiting Stat3 activation and further affecting melanoma angiogenesis and melanoma cell invasion in vitro, and significantly affected the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 (MMP-2) in vitro and in vivo. In addition, we used cDNA array to compare mRNA expression in the SOCS1-transfected and vector-transfected cell lines and found some genes are tightly correlated to the restoration of SOCS1. One of them is Caveolin-1 (Cav-1). Cav-1 was reported to function as a tumor suppressor gene by several groups. Finally, the Cav-1 expression is up-regulated in SOCS1-overexpressing cell line. Further study found the regulation of Cav-1 by SOCS1 occurs through inhibiting Stat3 activation. Activated Stat3 binds directly to Cav-1 promoter and the Cav-1 promoter within -575bp is essential for active Stat3 binding. My studies reveal that Stat3 activation and SOCS1 expression play important roles in melanoma metastases. Moreover, the expression between SOCS1, Stat3 and Cav-1 forms a feedback regulation loop. ^

Vital function for PRELI and essential requirement for its LEA motif

Proteins containing the late embryogenesis abundant (LEA) motif comprise an evolutionarily conserved family, long postulated to protect plant embryos from stress and death. However, the significance of LEA-containing proteins and the mechanisms behind their function remain undetermined. Here we show that PRELI, a mammalian protein that possesses tandem repeats of the LEA motif, can protect cells against staurosporine, TNF-α or UV irradiation-induced apoptosis. We found that key to PRELI-dependent mechanisms that promote cell resistance to death are the stabilization of the respiratory chain, upholding of mitochondrial membrane potential and retention of apoptogenic molecules. By in vitro and in vivo studies, we also show that the expression of mutant PRELI/LEA- proteins lacking the LEA motif, results in the complete loss of PRELI's anti-apoptotic functions. Collectively, our data uncover a new molecular player in the control of apoptosis and support the hypothesis that LEA-containing proteins are evolutionarily conserved cell protectors against stress and death. ^

Analysis of prognostic factors for the development of metastases and survival in renal cell carcinoma patients

Introduction and objective. A number of prognostic factors have been reported for predicting survival in patients with renal cell carcinoma. Yet few studies have analyzed the effects of those factors at different stages of the disease process. In this study, different stages of disease progression starting from nephrectomy to metastasis, from metastasis to death, and from evaluation to death were evaluated. ^ Methods. In this retrospective follow-up study, records of 97 deceased renal cell carcinoma (RCC) patients were reviewed between September 2006 to October 2006. Patients with TNM Stage IV disease before nephrectomy or with cancer diagnoses other than RCC were excluded leaving 64 records for analysis. Patient TNM staging, Furhman Grade, age, tumor size, tumor volume, histology and patient gender were analyzed in relation to time to metastases. Time from nephrectomy to metastasis, TNM staging, Furhman Grade, age, tumor size, tumor volume, histology and patient gender were tested for significance in relation to time from metastases to death. Finally, analysis of laboratory values at time of evaluation, Eastern Cooperative Oncology Group performance status (ECOG), UCLA Integrated Staging System (UISS), time from nephrectomy to metastasis, TNM staging, Furhman Grade, age, tumor size, tumor volume, histology and patient gender were tested for significance in relation to time from evaluation to death. Linear regression and Cox Proportional Hazard (univariate and multivariate) was used for testing significance. Kaplan-Meier Log-Rank test was used to detect any significance between groups at various endpoints. ^ Results. Compared to negative lymph nodes at time of nephrectomy, a single positive lymph node had significantly shorter time to metastasis (p<0.0001). Compared to other histological types, clear cell histology had significant metastasis free survival (p=0.003). Clear cell histology compared to other types (p=0.0002 univariate, p=0.038 multivariate) and time to metastasis with log conversion (p=0.028) significantly affected time from metastasis to death. A greater than one year and greater than two year metastasis free interval, compared to patients that had metastasis before one and two years, had statistically significant survival benefit (p=0.004 and p=0.0318). Time from evaluation to death was affected by greater than one year metastasis free interval (p=0.0459), alcohol consumption (p=0.044), LDH (p=0.006), ECOG performance status (p<0.001), and hemoglobin level (p=0.0092). The UISS risk stratified the patient population in a statistically significant manner for survival (p=0.001). No other factors were found to be significant. ^ Conclusion. Clear cell histology is predictive for both time to metastasis and metastasis to death. Nodal status at time of nephrectomy may predict risk of metastasis. The time interval to metastasis significantly predicts time from metastasis to death and time from evaluation to death. ECOG performance status, and hemoglobin levels predicts survival outcome at evaluation. Finally, UISS appropriately stratifies risk in our population. ^

Geographic variation in the utilization and survival associated with oxaliplatin chemotherapy in patients with stage III colon cancer

Background: Overall objectives of this dissertation are to examine the geographic variation and socio-demographic disparities (by age, race and gender) in the utilization and survival of newly FDA-approved chemotherapy agents (Oxaliplatin-containing regimens) as well as to determine the cost-effectiveness of Oxaliplatin in a large nationwide and population-based cohort of Medicare patients with resected stage-III colon cancer. Methods: A retrospective cohort of 7,654 Medicare patients was identified from the Surveillance, Epidemiology and End Results – Medicare linked database. Multiple logistic regression was performed to examine the relationship between receipt of Oxaliplatin-containing chemotherapy and geographic regions while adjusting for other patient characteristics. Cox proportional hazard model was used to estimate the effect of Oxaliplatin-containing chemotherapy on the survival variation across regions using 2004-2005 data. Propensity score adjustments were also made to control for potential bias related to non-random allocation of the treatment group. We used Kaplan-Meier sample average estimator to calculate the cost of disease after cancer-specific surgery to death, loss-to follow-up or censorship. Results: Only 51% of the stage-III patients received adjuvant chemotherapy within three to six months of colon-cancer specific surgery. Patients in the rural regions were approximately 30% less likely to receive Oxaliplatin chemotherapy than those residing in a big metro region (OR=0.69, p=0.033). The hazard ratio for patients residing in metro region was comparable to those residing in big metro region (HR: 1.05, 95% CI: 0.49-2.28). Patients who received Oxalipaltin chemotherapy were 33% less likely to die than those received 5-FU only chemotherapy (adjusted HR=0.67, 95% CI: 0.41-1.11). KMSA-adjusted mean payments were almost 2.5 times higher in the Oxaliplatin-containing group compared to 5-FU only group ($45,378 versus $17,856). When compared to no chemotherapy group, ICER of 5-FU based regimen was $12,767 per LYG, and ICER of Oxaliplatin-chemotherapy was $60,863 per LYG. Oxaliplatin was found economically dominated by 5-FU only chemotherapy in this study population. Conclusion: Chemotherapy use varies across geographic regions. We also observed considerable survival differences across geographic regions; the difference remained even after adjusting for socio-demographic characteristics. The cost-effectiveness of Oxaliplatin in Medicare patients may be over-estimated in the clinical trials. Our study found 5-FU only chemotherapy cost-effective in adjuvant settings in patients with stage-III colon cancer.^

End -of -life planning and decision -making: Implications for adults with mental retardation

This research focused on the topic of end-of-life planning and decision-making for adults affected by mental retardation. Adults with mental retardation have unique challenges in this regard, including difficulty communicating their wishes without assistance and diminished decision-making skills. The primary research objective was to identify factors that can affect opportunities for adults with mental retardation in community-based services settings (and their advocates) to be involved in planning and deciding about their own end-of-life experience. ^ A descriptive qualitative inquiry was designed to explore issues related to death and dying, and the notion of end-of-life planning, from the perspective of adults with mental retardation who receive publicly-funded community services ("clients") and family members of individuals who receive such services. Study participants were recruited from a single mental retardation service provider in a large urban setting (the "Agency"). Sixteen clients and 14 families of Agency clients took part. Client data collection was accomplished through face-to-face interviews, focus group meetings, and record reviews; family members were involved in a face-to-face interview only. ^ An initial coding scheme was developed based upon literature and policy reviews, and themes related to the research questions. Analysis involved extracting data from transcripts and records and placing it into appropriate thematic categories, building support for each theme with the accumulated data. Coding themes were modified to accommodate new data when it challenged existing themes. ^ Findings suggest that adults with mental retardation do have the requisite knowledge, interest, and ability to participate in decisions about their end-of-life experience and handling of affairs. Siblings are overwhelmingly the chosen future surrogates and they (or their children) will likely be the end-of-life advocates for their brothers and sisters affected by mental retardation. Findings further point to a need for increased awareness, accurate information, and improved communication about end-of-life issues, both in general and particular to adults affected by mental retardation. Also suggested by the findings is a need to focus on creating accommodations and adaptations that can best uncover a person's authentic views on life and death and related end-of-life preferences. Practical implications and suggestions for further research are also discussed. ^

Inconfidencia (el Aleijadinho) de Abelardo Arias y correspondencia arte-religiosidad

En el año 1979, Abelardo Arias publica su segunda novela de base histórica titulada Inconfidencia (El Aleijadinho), la cual recrea el Brasil imperial de fines del siglo XVIII, ámbito que dio a luz a ese extraño genio de la plástica que fue el mestizo Antonio Francisco de Lisboa, "el Aleijadihno ". Arias elude la facilidad de la biografia novelada y logra acercarse al escultor leproso desde su propia tensión de artista. Comprende, por ello, su tortuosa vida de marginado y hombre desengañado del amor, que vuelca su existencia a la creación estética. La relación que el Aleijadihno tiene con su obra, oscilante entre la exaltación religiosa y la pasión amorosa, nos lleva a estudiar en profundidad las líneas de tensión en torno de la correspondencia entre arte mayor y religiosidad. Como señala Abel Posse al respecto: "El gran artista (el Aleijadihno) tiende a fundar su obra alrededor de un weltanschaung o cosmovisión total y esta ambición lo acerca al mundo religioso y a la especulación metafisica ". La obra, por lo tanto, desarrolla una silenciosa agonia existencial y religiosa, el combate callado de un "alejado ", de un condenado a muerte.

La literatura como medio para desarrollar las habilidades sociales en jóvenes sordos

El presente trabajo es producto de la tesis doctoral titulada La generación de mundos de ficción en jóvenes sordos. La literatura como herramienta para el desarrollo del pensamiento creativo y del Proyecto de investigación: Estrategias pedagógico-didácticas para el desarrollo y aprendizaje de las habilidades sociales en escuelas públicas de enseñanza común y especial del gran Mendoza, dirigido por el Dr. Benito Parés.2 En dicho trabajo se pone en evidencia cómo a través de espacios de literatura se desarrollan las habilidades sociales de autoafirmación, entre otras, tal como la autoestima y la confianza en uno mismo a partir de la utilización de técnicas de creatividad literaria. En esta investigación nos interesó indagar respecto de las posibilidades de los jóvenes sordos para generar textos de ficción que permitieran desarrollar el pensamiento divergente, y pudimos advertir también, las habilidades sociales que se ponen en juego ante las tareas solicitadas a dichos jóvenes. A partir de las propuestas de trabajo realizadas por las Personas Sordas que participaron del proyecto, observamos por un lado el cambio de actitud frente a la tarea y por otro las manifestaciones de placer al realizar las actividades propuestas. En relación con los resultados, pudimos apreciar la presencia de habilidades sociales de autoafirmación, resolución de problemas, comunicacionales, de expresión de emociones y sentimientos entre otras, como consecuencia del trabajo con textos literarios.

Uma história da grave das tecelâs/ôes de Salvador-Bahia en setembro de 1919

This article aims to analyze the movement of weavers' strike (according to an specific context), its origins, actions and consequences, prompting the internal system of factories (their regulations), the hierarchical relationships of power, and struggles to guarantee the right of association, which resulted in the stoppage of all activities of the textile sector. The attitude to go on a strike, mobilizations and the stroll show that the direction of the movement and the working class were aware of their actions and those likely consequences, what signalize, beforehand, the ideological, classist and political character of women´s actions: radicalized by the practices of confronting the authoritarianism employers and threats (police repression, harassment of the press). They endured through the collective support and a network of solidarity

Que ningún desgraciado muera de hambre: agricultura, reciprocidad y reelaboración de identidades entre los ranqueles en la década de 1840

La imagen de las sociedades indígenas que habitaron las pampas rioplatenses con posterioridad al siglo XVI - y especialmente la visión acerca de su economía - ha sido objeto de una profunda revisión historiográfica y antropológica en las últimas décadas. La perspectiva que sólo se limitaba a consignar diversas formas predatorias fue reemplazada por un enfoque más amplio que reconoce la variedad y complejidad de la organización productiva. El propósito de este artículo - inscripto en ese enfoque - consiste en analizar las condiciones históricas que rodearon la incorporación y actualización de prácticas agrícolas por parte de los ranqueles durante la década de 1840, utilizando como fuente principal un texto descriptivo de las profundas transformaciones experimentadas por aquellos, redactado por el joven cautivo Santiago Avendaño y omitido en las versiones editadas de sus memorias. Luego de las gravosas derrotas sufridas en los años 30, los ranqueles lograron reconstruir su deteriorada base demográfica y económica, entre otros medios, incorporando contingentes boroganos, y con ellos ciertos manejos agrícolas de origen trasandino. La combinación de estos últimos con los tradicionales dio como resultado un conjunto flexible y diversificado que, unido a una nueva política de comensalidad consistente en la extensión fuera de sus límites normales de la reciprocidad generalizada, fue capaz de sustentar la recuperación social del grupo.

Uma história da grave das tecelâs/ôes de Salvador-Bahia en setembro de 1919

This article aims to analyze the movement of weavers' strike (according to an specific context), its origins, actions and consequences, prompting the internal system of factories (their regulations), the hierarchical relationships of power, and struggles to guarantee the right of association, which resulted in the stoppage of all activities of the textile sector. The attitude to go on a strike, mobilizations and the stroll show that the direction of the movement and the working class were aware of their actions and those likely consequences, what signalize, beforehand, the ideological, classist and political character of women´s actions: radicalized by the practices of confronting the authoritarianism employers and threats (police repression, harassment of the press). They endured through the collective support and a network of solidarity

Que ningún desgraciado muera de hambre: agricultura, reciprocidad y reelaboración de identidades entre los ranqueles en la década de 1840

La imagen de las sociedades indígenas que habitaron las pampas rioplatenses con posterioridad al siglo XVI - y especialmente la visión acerca de su economía - ha sido objeto de una profunda revisión historiográfica y antropológica en las últimas décadas. La perspectiva que sólo se limitaba a consignar diversas formas predatorias fue reemplazada por un enfoque más amplio que reconoce la variedad y complejidad de la organización productiva. El propósito de este artículo - inscripto en ese enfoque - consiste en analizar las condiciones históricas que rodearon la incorporación y actualización de prácticas agrícolas por parte de los ranqueles durante la década de 1840, utilizando como fuente principal un texto descriptivo de las profundas transformaciones experimentadas por aquellos, redactado por el joven cautivo Santiago Avendaño y omitido en las versiones editadas de sus memorias. Luego de las gravosas derrotas sufridas en los años 30, los ranqueles lograron reconstruir su deteriorada base demográfica y económica, entre otros medios, incorporando contingentes boroganos, y con ellos ciertos manejos agrícolas de origen trasandino. La combinación de estos últimos con los tradicionales dio como resultado un conjunto flexible y diversificado que, unido a una nueva política de comensalidad consistente en la extensión fuera de sus límites normales de la reciprocidad generalizada, fue capaz de sustentar la recuperación social del grupo.

Que ningún desgraciado muera de hambre: agricultura, reciprocidad y reelaboración de identidades entre los ranqueles en la década de 1840

La imagen de las sociedades indígenas que habitaron las pampas rioplatenses con posterioridad al siglo XVI - y especialmente la visión acerca de su economía - ha sido objeto de una profunda revisión historiográfica y antropológica en las últimas décadas. La perspectiva que sólo se limitaba a consignar diversas formas predatorias fue reemplazada por un enfoque más amplio que reconoce la variedad y complejidad de la organización productiva. El propósito de este artículo - inscripto en ese enfoque - consiste en analizar las condiciones históricas que rodearon la incorporación y actualización de prácticas agrícolas por parte de los ranqueles durante la década de 1840, utilizando como fuente principal un texto descriptivo de las profundas transformaciones experimentadas por aquellos, redactado por el joven cautivo Santiago Avendaño y omitido en las versiones editadas de sus memorias. Luego de las gravosas derrotas sufridas en los años 30, los ranqueles lograron reconstruir su deteriorada base demográfica y económica, entre otros medios, incorporando contingentes boroganos, y con ellos ciertos manejos agrícolas de origen trasandino. La combinación de estos últimos con los tradicionales dio como resultado un conjunto flexible y diversificado que, unido a una nueva política de comensalidad consistente en la extensión fuera de sus límites normales de la reciprocidad generalizada, fue capaz de sustentar la recuperación social del grupo.

Uma história da grave das tecelâs/ôes de Salvador-Bahia en setembro de 1919

This article aims to analyze the movement of weavers' strike (according to an specific context), its origins, actions and consequences, prompting the internal system of factories (their regulations), the hierarchical relationships of power, and struggles to guarantee the right of association, which resulted in the stoppage of all activities of the textile sector. The attitude to go on a strike, mobilizations and the stroll show that the direction of the movement and the working class were aware of their actions and those likely consequences, what signalize, beforehand, the ideological, classist and political character of women´s actions: radicalized by the practices of confronting the authoritarianism employers and threats (police repression, harassment of the press). They endured through the collective support and a network of solidarity

(Table 1) Uncompacted and compacted sedimentation rate values corrected for bedding attitudes at DSDP Leg 66 Holes

Sediment accumulation rates, computed using agesediment thickness curves obtained from DSDP cores, are rarely corrected for compaction or bedding attitude to better approximate true sediment accumulation rates (c.f. van Andel et al., 1975; Davies et al., 1977; and Whitman and Davies, 1979). Variations with depth in either of these factors can hinder interpreting relative rates of sedimentary processes associated with a particular depositional environment. This problem becomes particularly relevant for convergent margin sediments, which often display variable bedding attitudes and pronounced changes in porosity, bulk density, and other parameters related to the compaction process at shallow depth. These rapid shallow changes render correlation of sedimentation rates within a single transect of holes very difficult. Two techniques have been applied to data collected from a transect of holes along the southwestern Mexico continental margin, DSDP Leg 66 (Fig. 1), to correct sediment accumulation rates for variations in compaction and bedding attitude. These corrections should help resolve true fluctuations in accumulation rates and their implications regarding convergent margin processes.

Body mass, flipper length, oxidative balance indices and telomere length of king penguin chicks (A. patagonicus) on Possession Island

One of the reasons for animals not to grow as fast as they potentially could is that fast growth has been shown to be associated with reduced lifespan. However, we are still lacking a clear description of the reality of growth-dependent modulation of ageing mechanisms in wild animals. Using the particular growth trajectory of small king penguin chicks naturally exhibiting higher-than-normal growth rate to compensate for the winter break, we tested whether oxidative stress and telomere shortening are related to growth trajectories. Plasma antioxidant defences, oxidative damage levels and telomere length were measured at the beginning and at the end of the post-winter growth period in three groups of chicks (small chicks, which either passed away or survived the growth period, and large chicks). Small chicks that died early during the growth period had the highest level of oxidative damage and the shortest telomere lengths prior to death. Here, we show that small chicks that grew faster did it at the detriment of body maintenance mechanisms as shown by (i) higher oxidative damage and (ii) accelerated telomere loss. Our study provides the first evidence for a mechanistic link between growth and ageing rates under natural conditions.