Sodium valproate enhances urethane tumorigenicity in lungs of male but not female mice

In the study, the possible effect of sodium valproate (NaVP) on urethane-induced lung tumors in mice has been evaluated. BALB/c mice (n = 120; 4–6 weeks old, both sexes) were used in the following groups: 1) urethane-treated, 2) urethane–NaVP-treated, 3) only NaVP-treated, 4) control. In the same groups, castrated male mice (n = 48) were investigated. Urethane was given by intraperitoneal injections 10 mg/mouse, twice a week, the total dose 50 mg/mouse. In NaVP-treated mice, the 0.4 % NaVP aqueous solution was offered to mice ad libitum. The duration of the experiment was 6 months. The number of tumors per mouse in urethane–NaVP-treated males was significantly higher than in those treated with urethane only (13.82 ± 1.12 vs 6.77 ± 0.43, p < 0.0001). No significant difference in the number of tumors per mouse was revealed while comparing the female urethane- and urethane–NaVP-treated groups (6.50 ± 0.79 vs 8.15 ± 0.55, p = 0.105). No difference in the number of tumors per mouse was found in urethane–NaVP-treated castrated males as compared with urethane-treated castrated males. However, in the urethane–aVP-treated castrated males the number of tumors per mouse was significantly lower than in analogous non-castrated males (7.8 ± 1.67 vs 13.82 ± 1.12, p < 0.01). NaVP combined with urethane potentiates urethane tumorigenicity in BALB/c non-castrated but not in female and castrated male mice. These data indicate an important role of testosterone in the urethane-NaVP induced lung tumorigenesis

Trabajo social en la Argentina actual: ofensiva del capital, luchas sociales y poder contrahegemónico

El capitalismo a nivel mundial se encuentra en un período de crisis abierta en el año 2008 de la que no logra recuperarse. La caída del sistema financiero en EEUU a partir de la crisis de las hipotecas rápidamente generó sus efectos por todo el globo. Esto ha tenido diferentes impactos regionales. La imposibilidad de salir de la crisis a partir de un nuevo ciclo de crecimiento lleva a la aplicación de paquetes de ajuste o austeridad que buscan descargar los efectos de la crisis sobre la clase que vive del trabajo. Se profundiza entonces lo que David Harvey (2005) denomina el nuevo imperialismo caracterizado por la búsqueda de acumulación por desposesión. Entre otras estrategias dicha modalidad implica avanzar sobre los fondos públicos buscando generar mecanismos de valorización de capital en torno a los fondos de pensión, el espacio público, la vivienda social, el sistema de salud, la educación superior, las tierras no rentables, los bienes comunes, entre otros. En Argentina el ascenso en 2015 del gobierno de Cambiemos se orientó en esta dirección profundizando en algunos aspectos una matriz dependiente que el gobierno anterior no logró superar. El ciclo kirchnerista a lo largo de los doce años de gobierno cumplió una tarea central que de algún modo allanó el terreno para el avance de la derecha. Logró recomponer la hegemonía fuertemente cuestionada en el levantamiento popular del 2001 y logró recuperar la legitimidad de las instituciones del sistema representativo burgués. De este modo reencausó la conflictividad de clase en el marco de las disputas institucionales y relegitimó el sistema político. Sobre esta base, el ascenso del gobierno de corte neoconservador por la vía electoral, impulsó medidas que orientan la riqueza hacia los sectores más concentrados de la economía. Sin embargo a diferencia de otras coyunturas en nuestro país la correlación de fuerzas construida por parte del movimiento popular en lo que va desde fines de los años 90 hasta la actualidad, impide avanzar con el shock de ajuste y de transformaciones profundas en la matriz del gasto público. Nos proponemos desarrollar los argumentos que fundamenten que en esta heterogénea resistencia del movimiento popular argentino contra la ofensiva renovada del capital anida de modo latente, todavía no generalizado, elementos de un proyecto contrahegemónico de la clase trabajadora con la cual el trabajo social debe dialogar para contribuir desde su praxis a los procesos de ampliación de derechos en un horizonte emancipatorio.Eje temático 2: Territorialidad, sujetos colectivos, procesos de resistencia y organización.Grupo de trabajo 15: Movimientos sociales y sujetos colectivos: articulación con el Trabajo Social.Facultad de Trabajo Socia

Trabajo social en la Argentina actual: ofensiva del capital, luchas sociales y poder contrahegemónico

El capitalismo a nivel mundial se encuentra en un período de crisis abierta en el año 2008 de la que no logra recuperarse. La caída del sistema financiero en EEUU a partir de la crisis de las hipotecas rápidamente generó sus efectos por todo el globo. Esto ha tenido diferentes impactos regionales. La imposibilidad de salir de la crisis a partir de un nuevo ciclo de crecimiento lleva a la aplicación de paquetes de ajuste o austeridad que buscan descargar los efectos de la crisis sobre la clase que vive del trabajo. Se profundiza entonces lo que David Harvey (2005) denomina el nuevo imperialismo caracterizado por la búsqueda de acumulación por desposesión. Entre otras estrategias dicha modalidad implica avanzar sobre los fondos públicos buscando generar mecanismos de valorización de capital en torno a los fondos de pensión, el espacio público, la vivienda social, el sistema de salud, la educación superior, las tierras no rentables, los bienes comunes, entre otros. En Argentina el ascenso en 2015 del gobierno de Cambiemos se orientó en esta dirección profundizando en algunos aspectos una matriz dependiente que el gobierno anterior no logró superar. El ciclo kirchnerista a lo largo de los doce años de gobierno cumplió una tarea central que de algún modo allanó el terreno para el avance de la derecha. Logró recomponer la hegemonía fuertemente cuestionada en el levantamiento popular del 2001 y logró recuperar la legitimidad de las instituciones del sistema representativo burgués. De este modo reencausó la conflictividad de clase en el marco de las disputas institucionales y relegitimó el sistema político. Sobre esta base, el ascenso del gobierno de corte neoconservador por la vía electoral, impulsó medidas que orientan la riqueza hacia los sectores más concentrados de la economía. Sin embargo a diferencia de otras coyunturas en nuestro país la correlación de fuerzas construida por parte del movimiento popular en lo que va desde fines de los años 90 hasta la actualidad, impide avanzar con el shock de ajuste y de transformaciones profundas en la matriz del gasto público. Nos proponemos desarrollar los argumentos que fundamenten que en esta heterogénea resistencia del movimiento popular argentino contra la ofensiva renovada del capital anida de modo latente, todavía no generalizado, elementos de un proyecto contrahegemónico de la clase trabajadora con la cual el trabajo social debe dialogar para contribuir desde su praxis a los procesos de ampliación de derechos en un horizonte emancipatorio.Eje temático 2: Territorialidad, sujetos colectivos, procesos de resistencia y organización.Grupo de trabajo 15: Movimientos sociales y sujetos colectivos: articulación con el Trabajo Social.Facultad de Trabajo Socia

A RT-qPCR system using a degenerate probe for specific identification and differentiation of SARS-CoV-2 Omicron (B.1.1.529) variants of concern

Fast surveillance strategies are needed to control the spread of new emerging SARS-CoV-2 variants and gain time for evaluation of their pathogenic potential. This was essential for the Omicron variant (B.1.1.529) that replaced the Delta variant (B.1.617.2) and is currently the dominant SARS-CoV-2 variant circulating worldwide. RT-qPCR strategies complement whole genome sequencing, especially in resource lean countries, but mutations in the targeting primer and probe sequences of new emerging variants can lead to a failure of the existing RT-qPCRs. Here, we introduced an RT-qPCR platform for detecting the Delta- and the Omicron variant simultaneously using a degenerate probe targeting the key ΔH69/V70 mutation in the spike protein. By inclusion of the L452R mutation into the RT-qPCR platform, we could detect not only the Delta and the Omicron variants, but also the Omicron sub-lineages BA.1, BA.2 and BA.4/BA.5. The RT-qPCR platform was validated in small- and large-scale. It can easily be incorporated for continued monitoring of Omicron sub-lineages, and offers a fast adaption strategy of existing RT-qPCRs to detect new emerging SARS-CoV-2 variants using degenerate probes.</p

Structure-Guided Computational Approaches to Unravel Druggable Proteomic Landscape of Mycobacterium leprae.

Leprosy, caused by Mycobacterium leprae (M. leprae), is treated with a multidrug regimen comprising Dapsone, Rifampicin, and Clofazimine. These drugs exhibit bacteriostatic, bactericidal and anti-inflammatory properties, respectively, and control the dissemination of infection in the host. However, the current treatment is not cost-effective, does not favor patient compliance due to its long duration (12 months) and does not protect against the incumbent nerve damage, which is a severe leprosy complication. The chronic infectious peripheral neuropathy associated with the disease is primarily due to the bacterial components infiltrating the Schwann cells that protect neuronal axons, thereby inducing a demyelinating phenotype. There is a need to discover novel/repurposed drugs that can act as short duration and effective alternatives to the existing treatment regimens, preventing nerve damage and consequent disability associated with the disease. Mycobacterium leprae is an obligate pathogen resulting in experimental intractability to cultivate the bacillus in vitro and limiting drug discovery efforts to repositioning screens in mouse footpad models. The dearth of knowledge related to structural proteomics of M. leprae, coupled with emerging antimicrobial resistance to all the three drugs in the multidrug therapy, poses a need for concerted novel drug discovery efforts. A comprehensive understanding of the proteomic landscape of M. leprae is indispensable to unravel druggable targets that are essential for bacterial survival and predilection of human neuronal Schwann cells. Of the 1,614 protein-coding genes in the genome of M. leprae, only 17 protein structures are available in the Protein Data Bank. In this review, we discussed efforts made to model the proteome of M. leprae using a suite of software for protein modeling that has been developed in the Blundell laboratory. Precise template selection by employing sequence-structure homology recognition software, multi-template modeling of the monomeric models and accurate quality assessment are the hallmarks of the modeling process. Tools that map interfaces and enable building of homo-oligomers are discussed in the context of interface stability. Other software is described to determine the druggable proteome by using information related to the chokepoint analysis of the metabolic pathways, gene essentiality, homology to human proteins, functional sites, druggable pockets and fragment hotspot maps

Safe Implementation of Treatments in Stroke: A study on intravenous thrombolysis in patients over 80 years of age with acute ischaemic stroke

\ua9 Author(s) (or their employer(s)) 2025. Objectives: To investigate the safety and efficacy outcomes of intravenous thrombolysis (IVT) in patients aged &gt;80 years with acute ischaemic stroke (AIS) after IVT was approved in this patient population in several European and non-European countries during 2018-2019. Design: This is an observational registry study using prospectively collected data from the Safe Implementation of Treatment in Stroke (SITS) registry. Comparisons will be performed between patients treated post-approval (July 2018 to December 2021) period with those treated pre-approval (June 2015 to June 2018) period using propensity score matching (PSM). Setting This is a multicentre international study in hospitals treating AIS with IVT. Participants Patients aged &gt;80 years who otherwise followed the IVT Summary of Product Characteristics of European countries as part of the mutual recognition procedure. Primary and secondary outcomes: The main outcomes were symptomatic intracerebral haemorrhage per SITS monitoring study definition, death and functional independency as defined by a modified Rankin Scale score of 0-2 at 90 days. Results: After PSM, 614 patients remained in each group (mean age 87 years, 39% males). All baseline data were well balanced after PSM. There were no statistically significant differences in outcomes between pre- and post-approval patients for SICH (2.5% vs 2.3%, risk ratio (RR) 1.064, 95% CI 0.345-1.784), death (25.3% vs 28.4%, RR 0.889, 0.699-1.08) and functional independency at 90 days (40.3% vs 37%, RR 1.089, 0.942-1.237). Conclusions: In this observational study of IVT treatment in patients &gt;80 years of age with AIS before and after formal approval for this treatment, we did not find any difference in outcomes between the pre- and post-approval periods

Sodium Valproate Enhances the Urethane-Induced Lung Adenomas and Suppresses Malignization of Adenomas in Ovariectomized Female Mice

In the present study, the possible effect of sodium valproate (NaVP) on urethane-induced lung tumors in female mice has been evaluated. BALB/c mice (n=60; 4–6 weeks old, females) were used in the following groups: (1) urethane-treated; (2) urethane-NaVP-treated; (3) only NaVP-treated; (4) control. In the same groups, ovariectomized female mice (n=60) were investigated. Urethane was given intraperitoneally, with a total dose of 50 mg/mouse. In NaVP-treated mice groups, 0.4% aqueous solution of NaVP was offered to mice ad libitum. The duration of the experiment was 6 months. The number of tumors per mouse in ovariectomized mice and in those treated with urethane and NaVP was significantly higher than in mice treated with urethane only (8.29±0.58 versus 6.0±0.63, p<0.02). No significant difference in the number of tumors per mouse was revealed while comparing the nonovariectomized urethane- and urethane-NaVP-treated groups (p=0.13). A significant decrease of adenocarcinoma number in ovariectomized mice treated with a urethane-NaVP as compared with ovariectomized mice treated with urethane only was found (p=0.031). NaVP together with low estrogen may have a protective effect on the malignization of adenomas in ovariectomized mice

Defining Satisfactory Methods of Treatment in Rare Diseases When Evaluating Significant Benefit-The EU Regulator's Perspective

Since the implementation of the EU Orphan Regulation in 2000, the Committee for Orphan Medicinal Products at the European Medicines Agency has been evaluating the benefits of proposed orphan medicines vs. satisfactory treatment methods. This type of evaluation is foreseen in the Orphan Regulation as the orphan designation criterion called the "significant benefit." In this article, based on 20 years of experience, we provide a commentary explaining what is considered a satisfactory method of treatment in the context of the EU Orphan Regulation and for the purpose of the assessment of significant benefit. We discuss the challenges posed by continuously changing clinical practise, which is associated with the increasing number of treatment options, evolving nature of medicinal therapeutic indications and our understanding of them