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The prognosis of high-grade gliomas, such as glioblastoma multiforme (GBM), is extremely poor due to the highly invasive nature of these aggressive cancers. Previous work has demonstrated that TNF-weak like factor (TWEAK) induction of the noncanonical NF-κB pathway promotes the invasiveness of GBM cells in an NF-κB-inducing kinase (NIK)-dependent manner. While NIK activity is predominantly regulated at the posttranslational level, we show here that NIK (MAP3K14) is upregulated at the transcriptional level in invading cell populations, with the highest NIK expression observed in the most invasive cells. GBM cells with high induction of NIK gene expression demonstrate characteristics of collective invasion, facilitating invasion of neighboring cells. Furthermore, we demonstrate that the E2F transcription factors E2F4 and E2F5 directly regulate NIK transcription and are required to promote GBM cell invasion in response to TWEAK. Overall, our findings demonstrate that transcriptional induction of NIK facilitates collective cell migration and invasion, thereby promoting GBM pathogenesis.

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The prognosis of high-grade gliomas, such as glioblastoma multiforme (GBM), is extremely poor due to the highly invasive nature of these aggressive cancers. Previous work has demonstrated that TNF-weak like factor (TWEAK) induction of the noncanonical NF-κB pathway increases the invasiveness of glioma cells in an NF-κB-inducing kinase (NIK)-dependent manner. While NIK activity is predominantly regulated at the posttranslational level, we show here that NIK ( MAP3K14 ) is upregulated at the transcriptional level in invading cell populations, with the highest expression observed in the most invasive cells. Glioma cells with high induction of NIK gene expression demonstrate characteristics of collective invasion, facilitating invasion of neighboring cells. Furthermore, we demonstrate that the E2F transcription factors E2F4 and E2F5 directly regulate NIK transcription and are required to promote glioma cell invasion in response to TWEAK. Overall, our findings demonstrate that transcriptional induction of NIK facilitates collective cell migration and invasion, thereby promoting glioma pathogenesis.

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BACKGROUND: Trypanosoma cruzi causes Chagas disease, an endemic and debilitating illness in Latin America. Lately, owing to extensive population movements, this neglected tropical disease has become a global health concern. The two clinically available drugs for the chemotherapy of Chagas disease have rather high toxicity and limited efficacy in the chronic phase of the disease, and may induce parasite resistance. The development of new anti-T. cruzi agents is therefore imperative. The enzyme N-myristoyltransferase (NMT) has recently been biochemically characterized, shown to be essential in Leishmania major, Trypanosoma brucei, and T. cruzi¸ and proposed as promising chemotherapeutic target in these trypanosomatids. METHODOLOGY/PRINCIPAL FINDINGS: Here, using high-content imaging we assayed eight known trypanosomatid NMT inhibitors, against mammal-dwelling intracellular amastigote and trypomastigote stages and demonstrated that three of them (compounds 1, 5, and 8) have potent anti-proliferative effect at submicromolar concentrations against T. cruzi, with very low toxicity against human epithelial cells. Moreover, metabolic labeling using myristic acid, azide showed a considerable decrease in the myristoylation of proteins in parasites treated with NMT inhibitors, providing evidence of the on-target activity of the inhibitors. CONCLUSIONS/SIGNIFICANCE: Taken together, our data point out to the potential use of NMT inhibitors as anti-T. cruzi chemotherapy.

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In this study, we assessed the antileishmanial activity of 126 α,ß-unsaturated ketones. The compounds NC901, NC884, and NC2459 showed high leishmanicidal activity for both the extracellular (50% effective concentration [EC50], 456 nM, 1,122 nM, and 20 nM, respectively) and intracellular (EC50, 1,870 nM, 937 nM, and 625 nM, respectively) forms of Leishmania major propagated in macrophages, with little or no toxicity to mammalian cells. Bioluminescent imaging of parasite replication showed that all three compounds reduced the parasite burden in the murine model, with no apparent toxicity.

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Eight new ruthenium complexes of clotrimazole (CTZ) with high antiparasitic activity have been synthesized, cis,fac-[Ru(II)Cl(2)(DMSO)(3)(CTZ)] (1), cis,cis,trans-[Ru(II)Cl(2)(DMSO)(2)(CTZ)(2)] (2), Na[Ru(III)Cl(4)(DMSO)(CTZ)] (3), Na[trans-Ru(III)Cl(4)(CTZ)(2)] (4), [Ru(II)(η(6)-p-cymene)Cl(2)(CTZ)] (5), [Ru(II)(η(6)-p-cymene)(bipy)(CTZ)][BF(4)](2) (6), [Ru(II)(η(6)-p-cymene)(en)(CTZ)][BF(4)](2) (7), and [Ru(II)(η(6)-p-cymene)(acac)(CTZ)][BF(4)] (8) (bipy = bipyridine; en = ethlylenediamine; acac = acetylacetonate). The crystal structures of compounds 4-8 are described. Complexes 1-8 are active against promastigotes of Leishmania major and epimastigotes of Trypanosoma cruzi. Most notably, complex 5 increases the activity of CTZ by factors of 110 and 58 against L. major and T. cruzi, with no appreciable toxicity to human osteoblasts, resulting in nanomolar and low micromolar lethal doses and therapeutic indexes of 500 and 75, respectively. In a high-content imaging assay on L. major-infected intraperitoneal mice macrophages, complex 5 showed significant inhibition on the proliferation of intracellular amastigotes (IC(70) = 29 nM), while complex 8 displayed some effect at a higher concentration (IC(40) = 1 µM).

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Baseado na idéia anti-manicomial, surge, dentre outras modalidades, o Acompanhamento Terapêutico (AT). O AT vem a ser uma modalidade prática que visa à integração ou reintegração do indivíduo na sociedade. O AT trabalha sempre integrado a outros profissionais da saúde, sendo um instrumento de apoio à terapia. Não há um setting específico para a prática do AT – como existe na terapia tradicional – o que há é uma tentativa de melhor compreender o paciente no seu dia-a-dia; logo o AT pode acontecer onde se faça mais necessário. É uma prática que pode ser utilizada para diversas patologias, considerando as neuroses e psicoses(AU)

Based on the anti-manicomial idea, appears, among other modalities, the Therapeutic Attendance (TA). The TA comes to be a pratice that has is view the integration or reintegration of the person in the society. The TA always works integrated to other professionals of health, being this tool of support to the therapy. There is not a specific setting to the TA pratice, just like in the tradicional therapy, what exists is a tentative of better understanding the patient in his day by day. Therefore, the TA may happen where it is more necessary. It is a pratice that may be utilized for several pathologies, regarding the neurosis and the psychosis(AU)

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OBJECTIVE: The objective of this study was to measure the agreement in classification of patients' race/ethnicity in the medical charts and the automated practice management systems (PMSs) of seven community health centers. SETTING: Community health centers are on the frontlines of providing primary care to the under-served and racial/ethnic minorities. Public and private investments in information technology and the increasing use of automated disease registries hold promise to improve care and reduce ethnic and racial disparities. However, data quality may limit the accuracy of race/ethnicity classification and the ability to measure the effect of population-based clinical quality improvements. DESIGN/PARTICIPANTS: In a cross-sectional study, a probability sample of 947 patients with encounters in 2002 was selected from 79,119 patients. Each PMS used a single data field with a pick list that combined ethnicity and race. Race/ethnicity on registration forms completed by patients was abstracted from medical charts. Race/ethnicity classifications were aggregated into seven major categories: Asian/Pacific Islander, Black/African-American, Native American, White, Hispanic/Latino, Other, Missing/Unknown. OUTCOME MEASURES: The sensitivity, positive predictive value, and proportion of agreement were outcome measures of agreement between information in the medical chart and PMS. RESULTS: The overall proportion of agreement (PA) between the medical chart (reference) and PMS was 87%. The PA varied significantly by health center (95%-74%). Hispanic/Latino had the highest sensitivity (91%) and positive predictive value (95%) and White the lowest (84% and 80%, respectively). CONCLUSIONS: In broad categories, correspondence of race/ethnicity classifications in medical charts and PMS was good, although health centers varied. A careful appraisal of data quality of race/ethnicity is warranted before administrative databases are used in clinical quality improvement programs or research to assess health disparities.

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Community health centers serve ethnically diverse populations that may pose challenges for record linkage based on name and date of birth. The objective was to identify an optimal deterministic algorithm to link patient encounters and laboratory results for hemoglobin A1c testing and examine its variability by health center site, patient ethnicity, and other variables. Based on data elements of last name, first name, date of birth, gender, and health center site, matches with >/=50% to < 100% of a maximum score were manually reviewed for true matches. Match keys based on combinations of name substrings, date of birth, gender, and health center were used to link encounter and laboratory files. The optimal match key was the first two letters of the last name and date of birth, which had a sensitivity of 92.7% and a positive predictive value of 99.5%. Sensitivity marginally varied by health center, age, gender, but not by ethnicity. An algorithm that was inexpensive, accurate, and easy to implement was found to be well suited for population-based measurement of clinical quality.

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