Small molecules targeting histone H4 as potential therapeutics for chronic myelogenous leukemia

We recently identified a polyamide-chlorambucil conjugate, 1R-Chl, which alkylates and down-regulates transcription of the human histone H4c gene and inhibits the growth of several cancer cell lines in vitro and in a murine SW620 xenograft model, without apparent animal toxicity. In this study, we analyzed the effects of 1R-Chl in the chronic myelogenous leukemia cell line K562 and identified another polyamide conjugate, 6R-Chl, which targets H4 genes and elicits a similar cellular response. Other polyamide conjugates that do not target the H4 gene do not elicit this response. In a murine model, both 1R-Chl and 6R-Chl were found to be highly effective in blocking K562 xenograft growth with high-dose tolerance. Unlike conventional and distamycin-based alkylators, little or no cytotoxicities and animal toxicities were observed in mg/kg dosage ranges. These results suggest that these polyamide alkylators may be a viable treatment alternative for chronic myelogenous leukemia

Small molecules targeting histone H4 as potential therapeutics for chronic myelogenous leukemia

We recently identified a polyamide-chlorambucil conjugate, 1R-Chl, which alkylates and down-regulates transcription of the human histone H4c gene and inhibits the growth of several cancer cell lines in vitro and in a murine SW620 xenograft model, without apparent animal toxicity. In this study, we analyzed the effects of 1R-Chl in the chronic myelogenous leukemia cell line K562 and identified another polyamide conjugate, 6R-Chl, which targets H4 genes and elicits a similar cellular response. Other polyamide conjugates that do not target the H4 gene do not elicit this response. In a murine model, both 1R-Chl and 6R-Chl were found to be highly effective in blocking K562 xenograft growth with high-dose tolerance. Unlike conventional and distamycin-based alkylators, little or no cytotoxicities and animal toxicities were observed in mg/kg dosage ranges. These results suggest that these polyamide alkylators may be a viable treatment alternative for chronic myelogenous leukemia

Detección de genes de resistencia antimicrobiana en aislados de Escherichia coli de cerdos de producción con cuadros diarreicos

The aim of this study was to detect antibiotic resistance genes in Escherichia coli isolates obtained from pigs with diarrhoea in intensive pig farms in Metropolitan Lima from 2017 to 2020. In total, 119 E. coli isolates were evaluated. The isolates were reactivated to extract the DNA and detect the resistance genes to the main antibiotics and of greater importance in the pig industry, such as tetracyclines (tetA, tetB and tetC), sulfonamides (sul1, sul2 and sul3), streptomycin-spectinomycin (strA/strB, aadA) and apramycin (aac(3)IV) by conventional Polymerase Chain Reaction (PCR). Results showed that 98.3% (117/119) of the isolates were positive for at least one antimicrobial resistance gene, especially the tetracycline group (88.2%). Of the 10 antimicrobial resistance genes considered, the tetA gene had the highest frequency (68%; 81/119), followed by the sul3 gene (64.7%; 77/119). The high percentage of antimicrobial resistance genes indicates a reality of the problem of bacterial resistance against antimicrobials in the study area, hence the importance of antimicrobial resistance surveillance and the correct use of antibiotics.El estudio tuvo como objetivo la detección de los genes de resistencia a los antibióticos en aislados de Escherichia coli obtenidos de cerdos con cuadros diarreicos granjas tecnificadas de Lima Metropolitana desde 2017 hasta 2020. Se evaluaron 119 aislados de E. coli. Los aislados fueron reactivados para extraer el ADN y detectar los genes de resistencia a los principales antibióticos y de mayor importancia en la industria porcina, tales como las tetraciclinas (tetA, tetB y tetC), sulfonamidas (sul1, sul2 y sul3), estreptomicina-espectinomicina (strA/strB, aadA) y apramicina (aac(3)IV) mediante la Reacción en Cadena de Polimerasa (PCR) convencional. El 98.3% (117/119) de los aislados fueron positivos a por lo menos un gen de resistencia antimicrobiana, especialmente al grupo de las tetraciclinas (88.2%). De los 10 genes de resistencia antimicrobiana considerados, el gen tetA tuvo la frecuencia más alta (68%; 81/119), seguido del gen sul3 (64.7%; 77/119). El elevado porcentaje de genes de resistencia antimicrobiana indica una realidad a la problemática de la resistencia bacteriana contra los antimicrobianos en la zona del estudio, de allí la importancia de la vigilancia y el correcto uso de los antibióticos

Detección molecular de Staphylococcus pseudintermedius en piodermas caninas

Pyoderma is one of the most diagnosed skin diseases in canines. Among the agents most involved were Staphylococcus intermedius; however, in 2005 it was reclassified into three phenotypically similar species: S. intermedius, S. pseudintermedius and S. delphini, which cannot be identified by conventional biochemistry. Various studies report S. pseudintermedius as the most frequently isolated bacterial agent in pyoderma. Therefore, this study evaluated the presence of S. pseudintermedius using PCR-RFLP in 141 Staphylococcus sp isolates in the Laboratory of Bacteriology of the Faculty of Veterinary Medicine, Universidad Nacional Mayor de San Marcos, Lima, Perú from cases of canine pyoderma in the period 2016-2018, finding that 87.9% of Staphylococcus sp isolates have been identified as S. pseudintermedius and 12.1% as Staphylococcus sp.La pioderma es una de las enfermedades de la piel más diagnosticada en caninostaphylococcus intermedius; sin embargo, en 2005 fue reclasificado en tres especies fenotípicamente similares: S. intermedius, S. pseudintermedius y S. delphini, por lo cual no pueden ser identificadas por bioquímica convencional. Diversos estudios reportan S. pseudintermedius como el agente bacteriano más frecuentemente aislado en piodermas. Por ello, este estudio evaluó la presencia S. pseudintermedius mediante PCR-RFLP en 141 aislados de Staphylococcus sp en el Laboratorio de Bacteriología de la Facultad de Medicina Veterinaria de la Universidad Nacional Mayor de San Marcos, Lima, Perú, provenientes de casos de pioderma canina en el periodo 2016-2018, encontrando que 87.9% de los aislados de Staphylococcus sp han sido identificados como S. pseudintermedius y 12.1% como Staphylococcus sp

Identifying candidate drivers of alcohol dependence-induced excessive drinking by assembly and interrogation of brain-specific regulatory networks

Background: A systems biology approach based on the assembly and interrogation of gene regulatory networks, or interactomes, was used to study neuroadaptation processes associated with the transition to alcohol dependence at the molecular level. Results: Using a rat model of dependent and non-dependent alcohol self-administration, we reverse engineered a global transcriptional regulatory network during protracted abstinence, a period when relapse rates are highest. We then interrogated the network to identify master regulator genes that mechanistically regulate brain region-specific signatures associated with dependent and non-dependent alcohol self-administration. Among these, the gene coding for the glucocorticoid receptor was independently identified as a master regulator in multiple brain regions, including the medial prefrontal cortex, nucleus accumbens, central nucleus of the amygdala, and ventral tegmental area, consistent with the view that brain reward and stress systems are dysregulated during protracted abstinence. Administration of the glucocorticoid antagonist mifepristone in either the nucleus accumbens or ventral tegmental area selectively decreased dependent, excessive, alcohol self-administration in rats but had no effect on non-dependent, moderate, alcohol self-administration. Conclusions: Our study suggests that assembly and analysis of regulatory networks is an effective strategy for the identification of key regulators of long-term neuroplastic changes within specific brain regions that play a functional role in alcohol dependence. More specifically, our results support a key role for regulatory networks downstream of the glucocorticoid receptor in excessive alcohol drinking during protracted alcohol abstinence

Ibero-American Consensus on Low- and No-Calorie Sweeteners: Safety, Nutritional Aspects and Benefits in Food and Beverages

International scientific experts in food, nutrition, dietetics, endocrinology, physical activity, paediatrics, nursing, toxicology and public health met in Lisbon on 2-4 July 2017 to develop a Consensus on the use of low- and no-calorie sweeteners (LNCS) as substitutes for sugars and other caloric sweeteners. LNCS are food additives that are broadly used as sugar substitutes to sweeten foods and beverages with the addition of fewer or no calories. They are also used in medicines, health-care products, such as toothpaste, and food supplements. The goal of this Consensus was to provide a useful, evidence-based, point of reference to assist in efforts to reduce free sugars consumption in line with current international public health recommendations. Participating experts in the Lisbon Consensus analysed and evaluated the evidence in relation to the role of LNCS in food safety, their regulation and the nutritional and dietary aspects of their use in foods and beverages. The conclusions of this Consensus were: (1) LNCS are some of the most extensively evaluated dietary constituents, and their safety has been reviewed and confirmed by regulatory bodies globally including the World Health Organisation, the US Food and Drug Administration and the European Food Safety Authority; (2) Consumer education, which is based on the most robust scientific evidence and regulatory processes, on the use of products containing LNCS should be strengthened in a comprehensive and objective way; (3) The use of LNCS in weight reduction programmes that involve replacing caloric sweeteners with LNCS in the context of structured diet plans may favour sustainable weight reduction. Furthermore, their use in diabetes management programmes may contribute to a better glycaemic control in patients, albeit with modest results. LNCS also provide dental health benefits when used in place of free sugars; (4) It is proposed that foods and beverages with LNCS could be included in dietary guidelines as alternative options to products sweetened with free sugars; (5) Continued education of health professionals is required, since they are a key source of information on issues related to food and health for both the general population and patients. With this in mind, the publication of position statements and consensus documents in the academic literature are extremely desirable

Genotype-phenotype features of germline variants of the TMEM127 pheochromocytoma susceptibility gene: A 10-year update

Purpose: This work aimed to evaluate genotype-phenotype associations in individuals carrying germline variants of transmembrane protein 127 gene (TMEM127), a poorly known gene that confers susceptibility to pheochromocytoma (PHEO) and paraganglioma (PGL). Design: Data were collected from a registry of probands with TMEM127 variants, published reports, and public databases. Main Outcome Analysis: Clinical, genetic, and functional associations were determined. Results: The cohort comprised 110 index patients (111 variants) with a mean age of 45 years (range, 21-84 years). Females were predominant (76 vs 34, P <. 001). Most patients had PHEO (n = 94; 85.5%), although PGL (n = 10; 9%) and renal cell carcinoma (RCC, n = 6; 5.4%) were also detected, either alone or in combination with PHEO. One-third of the cases had multiple tumors, and known family history was reported in 15.4%. Metastatic PHEO/PGL was rare (2.8%). Epinephrine alone, or combined with norepinephrine, accounted for 82% of the catecholamine profiles of PHEO/PGLs. Most variants (n = 63) occurred only once and 13 were recurrent (2-12 times). Although nontruncating variants were less frequent than truncating changes overall, they were predominant in non-PHEO clinical presentations (36% PHEO-only vs 69% other, P <. 001) and clustered disproportionately within transmembrane regions (P <. 01), underscoring the relevance of these domains for TMEM127 function. Integration of clinical and previous experimental data supported classification of variants into 4 groups based on mutation type, localization, and predicted disruption. Conclusions: Patients with TMEM127 variants often resemble sporadic nonmetastatic PHEOs. PGL and RCC may also co-occur, although their causal link requires further evaluation. We propose a new classification to predict variant pathogenicity and assist with carrier surveillance.Fil: Armaiz Pena, Gustavo. University Of Texas Health Science Center At San Antonio;; Estados UnidosFil: Flores, Shahida K.. No especifíca;Fil: Cheng, Zi Ming. No especifíca;Fil: Zhang, Xhingyu. No especifíca;Fil: Esquivel, Emmanuel. No especifíca;Fil: Poullard, Natalie. No especifíca;Fil: Vaidyanathan, Anusha. No especifíca;Fil: Liu, Qianqian. No especifíca;Fil: Michalek, Joel. No especifíca;Fil: Santillan Gomez, Alfredo A.. No especifíca;Fil: Liss, Michael. No especifíca;Fil: Ahmadi, Sara. No especifíca;Fil: Katselnik, Daniel. No especifíca;Fil: Maldonado, Enrique. No especifíca;Fil: Salgado, Sarimar Agosto. No especifíca;Fil: Jimenez, Camilo. No especifíca;Fil: Fishbein, Lauren. No especifíca;Fil: Hamidi, Oksana. No especifíca;Fil: Else, Tobias. No especifíca;Fil: Lechan, Ron. Tufts Medical Center; Estados UnidosFil: Tischler, Art S.. Tufts Medical Center; Estados UnidosFil: Benn, Diana E.. No especifíca;Fil: Dwight, Trisha. University of Technology Sydney; AustraliaFil: Clifton Bligh, Rory. University of Technology Sydney; AustraliaFil: Sanso, Elsa Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Barontini, Marta Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Vincent, Deepa. Massachusetts Institute of Technology; Estados UnidosFil: Aronin, Neil. Massachusetts Institute of Technology; Estados UnidosFil: Biondi, Bernadette. University of Naples Federico II; ItaliaFil: Koops, Maureen. University of Texas Health San Antonio; Estados UnidosFil: Bowhay Carnes, Elizabeth. No especifíca;Fil: Gimenez Roqueplo, Anne Paule. No especifíca;Fil: Alvarez Eslava, Andrea. No especifíca;Fil: Bruder, Jan M.. No especifíca;Fil: Kitano, Mio. No especifíca;Fil: Burnichon, Nelly. No especifíca;Fil: Ding, Yanli. No especifíca;Fil: Dahia, Patricia L. M.. No especifíca

A comprehensive fracture prevention strategy in older adults : The European union geriatric medicine society (EUGMS) statement

Published also in Aging Clinical and Experimental Research, Vol.28, No.4, WOS: 000379034800030Prevention of fragility fractures in older people has become a public health priority, although the most appropriate and cost-effective strategy remains unclear. In the present statement, the Interest group on falls and fracture prevention of the European union geriatric medicine society (EUGMS), in collaboration with the International association of gerontology and geriatrics for the European region (IAGG-ER), the European union of medical specialists (EUMS), the Fragility fracture network (FFN), the International osteoporosis foundation (IOF) - European society for clinical and economic aspects of osteoporosis and osteoarthritis (ECCEO), outlines its views on the main points in the current debate in relation to the primary and secondary prevention of falls, the diagnosis and treatment of bone fragility, and the place of combined falls and fracture liaison services for fracture prevention in older people. (C) 2016 Published by Elsevier Masson SAS.Peer reviewe

A comprehensive fracture prevention strategy in older adults: The European union geriatric medicine society (EUGMS) statement

Prevention of fragility fractures in older people has become a public health priority, although the most appropriate and cost-effective strategy remains unclear. In the present statement, the Interest group on falls and fracture prevention of the European union geriatric medicine society (EUGMS), in collaboration with the International association of gerontology and geriatrics for the European region (IAGG-ER), the European union of medical specialists (EUMS), the Fragility fracture network (FFN), the International osteoporosis foundation (IOF) – European society for clinical and economic aspects of osteoporosis and osteoarthritis (ECCEO), outlines its views on the main points in the current debate in relation to the primary and secondary prevention of falls, the diagnosis and treatment of bone fragility, and the place of combined falls and fracture liaison services for fracture prevention in older people