HDAC inhibition is associated to valproic acid induction of early megakaryocytic markers

Valproic acid (VPA), a histone deacetylase inhibitor, causes differentiation in different cell lines and in a cell-specific manner; yet, its effect on megakaryocytic (MK) differentiation has not been studied. We evaluated whether VPA induces MK differentiation in a UT-7 cell line through histone acetylation in the GpIIIa gene region and activation of the ERK pathway. UT-7 cells, derived from megakaryoblastic leukemia, were treated with VPA at various concentrations, and the expression of differentiation markers as well as the gene expression profile was assessed. Flow cytometry, immunoblot analysis, and RT-PCR demonstrated that VPA induced the expression of the early MK markers GpIIIa (CD61) and GpIIb/IIIa (CD41) in a dose-dependent manner. The VPA-treated cells showed hyperacetylation of the histones H3 and H4; in particular, histone acetylation was found to have been associated with CD61 expression, in that the GpIIIa promoter showed H4 hyperacetylation, as demonstrated by the chromatin immunoprecipitation assay. Furthermore, activation of the ERK pathway was involved in VPA-mediated CD61/CD41 expression and in cell adhesion, as demonstrated by using the MEK/ERK inhibitor U0126. In conclusion, the capacity of VPA to commit UT-7 cells to MK differentiation is mediated by its inhibitory action on HDAC and the long-lived activation of ERK1/2

Efficacy of free glutathione and niosomal glutathione in the treatment of acetaminophen-induced hepatotoxicity in cats

Acetaminophen (APAP) administration results in hepatotoxicity and hematotoxicity in cats. The response to three different treatments against APAP poisoning was evaluated. Free glutathione (GSH) (200mg/kg), niosomal GSH (14 mg/kg) and free amino acids (180 mg/kg of N-acetylcysteine and 280 mg/kg of methionine) were administered to cats that were intoxicated with APAP (a single dose of 150 mg/kg, p.o.). Serum concentration of alanine aminotransferase (ALT) along with serum, liver and erythrocyte concentration of GSH and methemoglobin percentage were measured before and 4, 24 and 72 hours after APAP administration. Free GSH (200 mg/kg) and niosomal GSH (14 mg/kg) were effective in reducing hepatotoxicity and hematotoxicity in cats intoxicated with a dose of 150 mg/kg APAP. We conclude that both types of treatments can protect the liver and haemoglobin against oxidative stress in APAP intoxicated cats. Furthermore, our results showed that treatment with niosomal GSH represents an effective therapeutic approach for APAP poisoning.Fil: Denzoin Vulcano, L. A.. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatologia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; ArgentinaFil: Confalonieri, O.. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Clinicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; ArgentinaFil: Franci, R.. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Clinicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; ArgentinaFil: Tapia, Maria Ofelia. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatologia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; ArgentinaFil: Soraci, Alejandro Luis. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatologia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; Argentin

Cumulative Prognostic Score Predicting Mortality in Patients Older Than 80 Years Admitted to the ICU.

OBJECTIVES: To develop a scoring system model that predicts mortality within 30 days of admission of patients older than 80 years admitted to intensive care units (ICUs). DESIGN: Prospective cohort study. SETTING: A total of 306 ICUs from 24 European countries. PARTICIPANTS: Older adults admitted to European ICUs (N = 3730; median age = 84 years [interquartile range = 81-87 y]; 51.8% male). MEASUREMENTS: Overall, 24 variables available during ICU admission were included as potential predictive variables. Multivariable logistic regression was used to identify independent predictors of 30-day mortality. Model sensitivity, specificity, and accuracy were evaluated with receiver operating characteristic curves. RESULTS: The 30-day-mortality was 1562 (41.9%). In multivariable analysis, these variables were selected as independent predictors of mortality: age, sex, ICU admission diagnosis, Clinical Frailty Scale, Sequential Organ Failure Score, invasive mechanical ventilation, and renal replacement therapy. The discrimination, accuracy, and calibration of the model were good: the area under the curve for a score of 10 or higher was .80, and the Brier score was .18. At a cut point of 10 or higher (75% of all patients), the model predicts 30-day mortality in 91.1% of all patients who die. CONCLUSION: A predictive model of cumulative events predicts 30-day mortality in patients older than 80 years admitted to ICUs. Future studies should include other potential predictor variables including functional status, presence of advance care plans, and assessment of each patient's decision-making capacity

Duas novas espécies do gênero Scatonomus Er. 1835 (Col. scarabaeidae)

NO presente trabalho os autores descrevem duas novas espécies do gênero Scatonomus Er., uma do Uruguai e outra do Brasil, Mato Grosso; fornece também um gráfico e um quadro sinóptico para todas as espécies conhecidas do gênero

Insetos em presépios e as "formigas vestidas" de Jules Martin (1832-1906): uma curiosa manufatura paulistana do final do século XIX

Encontrados no Brasil desde os primórdios da colonização portuguesa, os presépios logo tiveram de adaptar-se à realidade local, circunstância muito propícia ao aparecimento de concepções heterodoxas e ao emprego de elementos exóticos da fauna e flora de cada região. Como registros envolvendo insetos são muito pouco comuns, chama a atenção que fêmeas de saúva, Atta sp. (Hymenoptera, Formicidae), tenham sido aproveitadas na composição de presépios no estado de São Paulo. Tendo subsistido pelo menos até a década 1960, os "presépios de formigas" existentes em cidades como Embu das Artes poderiam estar relacionados às "formigas vestidas" criadas por Jules Martin, curiosa manufatura paulistana do último quartel do século XIX.Present in Brazil since the beginning of Portuguese colonization, crèche nativity scenes were soon adapted to local reality, a propitious circumstance for the appearance of heterodox conceptions and the use of exotic elements of the fauna and flora peculiar to each region. As records about insects are very uncommon, it is noteworthy that females of leaf-cutting ants, Atta sp. (Hymenoptera, Formicidae), were used to compose crèche nativity scenes in São Paulo State. Having subsisted at least up to the decade of 1960, the "ant crèches" of cities such as Embu das Artes could be related to the then famous "dressed ants" created by Jules Martin, a curious manufacture of the city of São Paulo in the last quarter of the 19th century

Radioresistance in rhabdomyosarcomas: much more than a question of dose

Management of rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, frequently accounting the genitourinary tract is complex and requires a multimodal therapy. In particular, as a consequence of the advancement in dose conformity technology, radiation therapy (RT) has now become the standard therapeutic option for patients with RMS. In the clinical practice, dose and timing of RT are adjusted on the basis of patients' risk stratification to reduce late toxicity and side effects on normal tissues. However, despite the substantial improvement in cure rates, local failure and recurrence frequently occur. In this review, we summarize the general principles of the treatment of RMS, focusing on RT, and the main molecular pathways and specific proteins involved into radioresistance in RMS tumors. Specifically, we focused on DNA damage/repair, reactive oxygen species, cancer stem cells, and epigenetic modifications that have been reported in the context of RMS neoplasia in both in vitro and in vivo studies. The precise elucidation of the radioresistance-related molecular mechanisms is of pivotal importance to set up new more effective and tolerable combined therapeutic approaches that can radiosensitize cancer cells to finally ameliorate the overall survival of patients with RMS, especially for the most aggressive subtypes

Impact of COVID-19 Pandemic on Patients\u27 Perceptions of Safety and Need for Elective Foot and Ankle Surgery in the United States

Background: With the development of the COVID-19 pandemic, elective foot and ankle surgeries were delayed throughout the United States to divert health care resources and limit exposure. Little is known about the impact of COVID-19 on patient\u27s willingness to proceed with elective procedures once restrictions are lifted and factors contributing to such decision. Methods: Patients across 6 US orthopedic institutions who had their elective foot and ankle surgeries cancelled secondary to the pandemic were given a questionnaire. Specifically, patients were asked about their willingness to move forward with surgery once restrictions were lifted and if not why. Pain-level and pain medication use were also assessed. Univariate analysis was used to identify factors that contribute to patient\u27s decisions. Results: A total of 150 patients participated in this study. Twenty-one (14%) opted not to proceed with surgery once restrictions were lifted. Forty-three percent (n = 9) listed concern for COVID infection as the reason; however, 14% of them would proceed if procedures were performed in surgery center. Twenty-nine (19% of the total cohort) patients had increased pain and 11% of patients were taking more pain meds because of the delay to their procedure. Patients who decided not to proceed with surgery reported pain reduction (3% vs 14%) and lower increase in pain medication used (5% vs 12%). Conclusion: COVID-19 has made a significant impact on the health care system. Delay of elective foot and ankle procedures impact patient quality of life and outcomes. Access to surgery centers may provide a partial solution during the pandemic. Level of Evidence: Level III

The botanical drug PBI-05204, a supercritical CO2 extract of Nerium oleander, sensitizes alveolar and embryonal rhabdomyosarcoma to radiotherapy in vitro and in vivo

Treatment of rhabdomyosarcoma (RMS), the most common a soft tissue sarcoma in childhood, provides intensive multimodal therapy, with radiotherapy (RT) playing a critical role for local tumor control. However, since RMS efficiently activates mechanisms of resistance to therapies, despite improvements, the prognosis remains still largely unsatisfactory, mainly in RMS expressing chimeric oncoproteins PAX3/PAX7-FOXO1, and fusion-positive (FP)-RMS. Cardiac glycosides (CGs), plant-derived steroid-like compounds with a selective inhibitory activity of the Na+/K+-ATPase pump (NKA), have shown antitumor and radio-sensitizing properties. Herein, the therapeutic properties of PBI-05204, an extract from Nerium oleander containing the CG oleandrin already studied in phase I and II clinical trials for cancer patients, were investigated, in vitro and in vivo, against FN- and FP-RMS cancer models. PBI-05204 induced growth arrest in a concentration dependent manner, with FP-RMS being more sensitive than FN-RMS, by differently regulating cell cycle regulators and commonly upregulating cell cycle inhibitors p21Waf1/Cip1 and p27Cip1/Kip1. Furthermore, PBI-05204 concomitantly induced cell death on both RMS types and senescence in FN-RMS. Notably, PBI-05204 counteracted in vitro migration and invasion abilities and suppressed the formation of spheroids enriched in CD133+ cancer stem cells (CSCs). PBI-05204 sensitized both cell types to RT by improving the ability of RT to induce G2 growth arrest and counteracting the RT-induced activation of both Non‐Homologous End‐Joining and homologous recombination DSBs repair pathways. Finally, the antitumor and radio-sensitizing proprieties of PBI-05204 were confirmed in vivo. Notably, both in vitro and in vivo evidence confirmed the higher sensitivity to PBI-05204 of FP-RMS. Thus, PBI-05204 represents a valid radio-sensitizing agent for the treatment of RMS, including the intrinsically radio-resistant FP-RMS