Deletion of chromosomal region 8p21 confers resistance to Bortezomib and is associated with upregulated Decoy trail receptor expression in patients with multiple myeloma

Loss of the chromosomal region 8p21 negatively effects survival in patients with multiple myeloma (MM) that undergo autologous stem cell transplantation (ASCT). In this study, we aimed to identify the immunological and molecular consequences of del(8)(p21) with regards to treatment response and bortezomib resistance. In patients receiving bortezomib as a single first line agent without any high-dose therapy, we have observed that patients with del(8)(p21) responded poorly to bortezomib with 50% showing no response while patients without the deletion had a response rate of 90%. In vitro analysis revealed a higher resistance to bortezomib possibly due to an altered gene expression profile caused by del(8)(p21) including genes such as TRAIL-R4, CCDC25, RHOBTB2, PTK2B, SCARA3, MYC, BCL2 and TP53. Furthermore, while bortezomib sensitized MM cells without del(8)(p21) to TRAIL/APO2L mediated apoptosis, in cells with del(8)(p21) bortezomib failed to upregulate the pro-apoptotic death receptors TRAIL-R1 and TRAIL-R2 which are located on the 8p21 region. Also expressing higher levels of the decoy death receptor TRAIL-R4, these cells were largely resistant to TRAIL/APO2L mediated apoptosis. Corroborating the clinical outcome of the patients, our data provides a potential explanation regarding the poor response of MM patients with del(8)(p21) to bortezomib treatment. Furthermore, our clinical analysis suggests that including immunomodulatory agents such as Lenalidomide in the treatment regimen may help to overcome this negative effect, providing an alternative consideration in treatment planning of MM patients with del(8)(p21)

Molecular signatures for CCN1, p21 and p27 in progressive mantle cell lymphoma

Mantle cell lymphoma (MCL) is a comparatively rare non-Hodgkin’s lymphoma characterised by overexpression of cyclin D1.Many patients present with or progress to advanced stage disease within 3 years. MCL is considered an incurable disease withmedian survival between 3 and 4 years. We have investigated the role(s) of CCN1 (CYR61) and cell cycle regulators inprogressive MCL. We have used the human MCL cell lines REC1 G519 > JVM2 cells by RQ-PCR, depicting a decrease in CCN1expression with disease progression. Investigation of CCN1 isoform expression by western blotting showed that whilst expres-sion of full-length CCN1 was barely altered in the cell lines, expression of truncated forms (18–20 and 28–30 kDa) decreasedwith disease progression. We have then demonstrated that cyclin D1 and cyclin dependent kinase inhibitors (p21CIP1and p27KIP1)are also involved in disease progression. Cyclin D1 was highly expressed in REC1 cells (OD: 1.0), reduced to one fifth in G519cells (OD: 0.2) and not detected by western blotting in JVM2 cells. p27KIP1followed a similar profile of expression as cyclin D1.Conversely, p21CIP1was absent in the REC1 cells and showed increasing expression in G519 and JVM2 cells. Subcellularlocalization detected p21CIP1/p27KIP1primarily within the cytoplasm and absent from the nucleus, consistent with altered roles in treatment resistance. Dysregulation of the CCN1 truncated forms are associated with MCL progression. In conjunction withreduced expression of cyclin D1 and increased expression of p21, this molecular signature may depict aggressive disease andtreatment resistance

Comparación del impacto de los valores de género en el trabajo no remunerado en dos tipos de Estado del Bienestar: Reino Unido y España = The impact of gender values on unpaid work in two countries with different welfare traditions: UK and Spain

Este trabajo tiene como objetivo comparar la brecha entre los valores de género y la práctica doméstica en el Reino Unido y España. Los datos se obtuvieron de una muestra de encuestados británicos y españoles, hombres y mu­jeres, en el módulo “Familia y cambio de roles de género” del Programa Internacional de Encuestas Sociales (ISSP 2002; 2012) y se utilizaron para crear modelos multivari­antes utilizando técnicas de regresión de mínimos cuadra­dos ordinarios. Los hallazgos sugieren que los valores de género afectan a las prácticas domésticas. Sin embargo, este efecto no se observó para el cuidado. Se encontró que el impacto de los valores de género en la división por sexo de las tareas domésticas era similar en el Reino Unido y España. También se observó un movimiento gradual ha­cia ideales más igualitarios en ambos países durante el período de 10 años estudiado. / This study aimed to compare the gap between gender role values and domestic practice in the UK and Spain. The data were drawn from a sample of British and Spanish male and female respondents to the International Social Survey Programme’s (ISSP) ‘Family and Changing Gender Roles’ module (2002, 2012) and used to create multivariate models using ordinary least-squares regression techniques. The findings suggest that gender role values impacts domestic practice: more time is devoted to housework by egalitarian than non-egalitarian men and less by egalitarian than non-egalitarian women. That effect was not observed for care-giving, however. The impact of gender values on the division by sex of household chores was found to be similar in the UK and Spain. A gradual move to more egalitarian ideals was also observed in both countries over the 10 year period studied