Reversal by RARα agonist Am580 of c-Myc-induced imbalance in RARα/RARγ expression during MMTV-Myc tumorigenesis

Introduction Retinoic acid signaling plays key roles in embryonic development and in maintaining the differentiated status of adult tissues. Recently, the nuclear retinoic acid receptor (RAR) isotypes α, β and γ were found to play specific functions in the expansion and differentiation of the stem compartments of various tissues. For instance, RARγ appears to be involved in stem cell compartment expansion, while RARα and RARβ are implicated in the subsequent cell differentiation. We found that over-expressing c-Myc in normal mouse mammary epithelium and in a c-Myc-driven transgenic model of mammary cancer, disrupts the balance between RARγ and RARα/β in favor of RARγ. Methods The effects of c-Myc on RAR isotype expression were evaluated in normal mouse mammary epithelium, mammary tumor cells obtained from the MMTV-Myc transgenic mouse model as well as human normal immortalized breast epithelial and breast cancer cell lines. The in vivo effect of the RARα-selective agonist 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carboxamido]benzoic acid (Am580) was examined in the MMTV-Myc mouse model of mammary tumorigenesis. Results Modulation of the RARα/β to RARγ expression in mammary glands of normal mice, oncomice, and human mammary cell lines through the alteration of RAR-target gene expression affected cell proliferation, survival and tumor growth. Treatment of MMTV-Myc mice with the RARα-selective agonist Am580 led to significant inhibition of mammary tumor growth (~90%, P\u3c0.001), lung metastasis (P\u3c0.01) and extended tumor latency in 63% of mice. Immunocytochemical analysis showed that in these mice, RARα responsive genes such as Cyp26A1, E-cadherin, cellular retinol-binding protein 1 (CRBP1) and p27, were up-regulated. In contrast, the mammary gland tumors of mice that responded poorly to Am580 treatment (37%) expressed significantly higher levels of RARγ. In vitro experiments indicated that the rise in RARγ was functionally linked to promotion of tumor growth and inhibition of differentiation. Thus, activation of the RARα pathway is linked to tumor growth inhibition, differentiation and cell death. Conclusions The functional consequence of the interplay between c-Myc oncogene expression and the RARγ to RARα/β balance suggests that prevalence of RARγ over-RARα/β expression levels in breast cancer accompanied by c-Myc amplification or over-expression in breast cancer should be predictive of response to treatment with RARα-isotype-specific agonists and warrant monitoring during clinical trials. See related editorial by Garattini et al http://breast-cancer-research.com/content/14/5/11

The Need for the Closer Monitoring of Novel Drugs in MS: A Siponimod Retrospective Cohort Study (Realhes Study)

Lymphopenia; Multiple sclerosis; PharmacovigilanceLinfopenia; Esclerosis múltiple; FarmacovigilanciaLimfopènia; Esclerosi múltiple; FarmacovigilànciaBackground: Severe cases of lymphopenia have been reported during siponimod clinical trials, which may negatively impact its benefit/risk profile. Objective: We aimed to evaluate the incidence of lymphopenia following the initiation of siponimod treatment in clinical practice. The secondary objectives included the analysis of factors predisposing to and the clinical relevance of lymphopenia events. Methods: In this multicenter retrospective cohort study, information collected from the medical records of 129 patients with MS from 15 tertiary hospitals in Spain who initiated treatment with Siponimod were followed-up for at least 3 months, including at least one lymphocyte count evaluation per patient. Results: Of the 129 patients, 121 (93.6%) reported lymphopenia events, including 110 (85.3%) with grade ≤ 3 and 11 (8.5%) with grade 4 lymphopenia, higher than those reported in the pivotal clinical trial (73.3% and 3.3% for grade ≤ 3 and grade 4 lymphopenia, respectively). The study included an unexpectedly high proportion of male subjects (72.9%), which might have led to an underestimation of the actual magnitude of the risk. Conclusions: In this study, the incidence and severity of lymphopenia after starting siponimod treatment were higher than those reported in previous clinical trials. Therefore, our results reinforce the need for the closer monitoring of novel MS drugs in clinical practice, as well as larger and longer follow-up studies to properly characterize this risk

Silibinin is a direct inhibitor of STAT3.

We herein combined experimental and computational efforts to delineate the mechanism of action through which the flavonolignan silibinin targets STAT3. Silibinin reduced IL-6 inducible, constitutive, and acquired feedback activation of STAT3 at tyrosine 705 (Y705). Silibinin attenuated the inducible phospho-activation of Y705 in GFP-STAT3 genetic fusions without drastically altering the kinase activity of the STAT3 upstream kinases JAK1 and JAK2. A comparative computational study based on docking and molecular dynamics simulation over 14 different STAT3 inhibitors (STAT3i) predicted that silibinin could directly bind with high affinity to both the Src homology-2 (SH2) domain and the DNA-binding domain (DBD) of STAT3. Silibinin partially overlapped with the cavity occupied by other STAT3i in the SH2 domain to indirectly prevent Y705 phosphorylation, yet showing a unique binding mode. Moreover, silibinin was the only STAT3i predicted to establish direct interactions with DNA in its targeting to the STAT3 DBD. The prevention of STAT3 nuclear translocation, the blockade of the binding of activated STAT3 to its consensus DNA sequence, and the suppression of STAT3-directed transcriptional activity confirmed silibinin as a direct STAT3i. The unique characteristics of silibinin as a bimodal SH2- and DBD-targeting STAT3i make silibinin a promising lead for designing new, more effective STAT3i.This work was supported by grants from the Ministerio de Ciencia e Innovacion (Grant SAF2016-80639-P to J. A. Menendez), Plan Nacional de I + D + I, Spain, and the Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR) (Grant 2014 SGR229 to J. A. Menendez). This study was supported also by unrestricted research grants from Roche Pharma (Spain) and Astellas Pharma (Spain) to the Program Against Cancer Therapeutic Resistance (ProCURE, Catalan Institute of Oncology). Joaquim Bosch-Barrera is supported by SEOM, Pfizer (Grant WI190764), Boehringer Ingelheim, Meda Pharma, and Pla strategic de recerca i innovacio en salut 2016-2020 de la Generalitat de Catalunya (SLT006/17/114). Elisabet Cuyas is supported by a Sara Borrell postdoctoral contract (CD15/00033) from the Ministerio de Sanidad y Consumo, Fondo de Investigacion Sanitaria (FIS), Spain. The authors would like to thank Dr. Kenneth McCreath for editorial support.S

Clinical characteristics and outcome of Spanish patients with ANCA-associated vasculitides Impact of the vasculitis type, ANCA specificity, and treatment on mortality and morbidity

The aim of this study was to describe the clinical characteristics of ANCA-associated vasculitides (AAV) at presentation, in a wide cohort of Spanish patients, and to analyze the impact of the vasculitis type, ANCA specificity, prognostic factors, and treatments administered at diagnosis, in the outcome. A total of 450 patients diagnosed between January 1990 and January 2014 in 20 Hospitals from Spain were included. Altogether, 40.9% had granulomatosis with polyangiitis (GPA), 37.1% microscopic polyangiitis (MPA), and 22% eosinophilic granulomatosis with polyangiitis (EGPA). The mean age at diagnosis was 55.6±17.3 years, patients with MPA being significantly older (P<0.001). Fever, arthralgia, weight loss, respiratory, and ear-nose-throat (ENT) symptoms, were the most common at disease onset. ANCAs tested positive in 86.4% of cases: 36.2% C-ANCA-PR3 and 50.2% P-ANCA-MPO. P-ANCA-MPO was significantly associated with an increased risk for renal disease (OR 2.6, P<0.001) and alveolar hemorrhage (OR 2, P=0.010), while C-ANCA-PR3 was significantly associated with an increased risk for ENT (OR 3.4, P<0.001) and ocular involvement (OR 2.3, P=0.002). All patients received corticosteroids (CS) and 74.9% cyclophosphamide (CYC). The median follow-up was 82 months (IQR 100.4). Over this period 39.9% of patients suffered bacterial infections and 14.6% opportunistic infections, both being most prevalent in patients with highcumulated doses of CYC and CS (P<0.001). Relapses were recorded in 36.4% of cases with a mean rate of 2.5±2.3, and were more frequent in patients with C-ANCA-PR3 (P=0.012). The initial disease severity was significantly associated with mortality but not with the occurrence of relapses. One hundred twenty-nine (28.7%) patients (74 MPA, 41 GPA, 14 EGPA) died. The mean survival was 58 months (IQR 105) and was significantly lower for patients with MPA (P<0.001). Factors independently related to death were renal involvement (P=0.010), cardiac failure (P=0.029) and age over 65 years old (P<0.001) at disease onset, and bacterial infections (P<0.001). An improved outcome with significant decrease in mortality and treatment-related morbidity was observed in patients diagnosed after 2000, and was related to the implementation of less toxic regimens adapted to the disease activity and stage, and a drastic reduction in the cumulated CYC and CS dose

North African Influences and Potential Bias in Case-Control Association Studies in the Spanish Population

BACKGROUND: Despite the limited genetic heterogeneity of Spanish populations, substantial evidences support that historical African influences have not affected them uniformly. Accounting for such population differences might be essential to reduce spurious results in association studies of genetic factors with disease. Using ancestry informative markers (AIMs), we aimed to measure the African influences in Spanish populations and to explore whether these might introduce statistical bias in population-based association studies. METHODOLOGY/PRINCIPAL FINDINGS: We genotyped 93 AIMs in Spanish (from the Canary Islands and the Iberian Peninsula) and Northwest Africans, and conducted population and individual-based clustering analyses along with reference data from the HapMap, HGDP-CEPH, and other sources. We found significant differences for the Northwest African influence among Spanish populations from as low as ≈ 5% in Spanish from the Iberian Peninsula to as much as ≈ 17% in Canary Islanders, whereas the sub-Saharan African influence was negligible. Strikingly, the Northwest African ancestry showed a wide inter-individual variation in Canary Islanders ranging from 0% to 96%, reflecting the violent way the Islands were conquered and colonized by the Spanish in the XV century. As a consequence, a comparison of allele frequencies between Spanish samples from the Iberian Peninsula and the Canary Islands evidenced an excess of markers with significant differences. However, the inflation of p-values for the differences was adequately controlled by correcting for genetic ancestry estimates derived from a reduced number of AIMs. CONCLUSIONS/SIGNIFICANCE: Although the African influences estimated might be biased due to marker ascertainment, these results confirm that Northwest African genetic footprints are recognizable nowadays in the Spanish populations, particularly in Canary Islanders, and that the uneven African influences existing in these populations might increase the risk for false positives in association studies. Adjusting for population stratification assessed with a few dozen AIMs would be sufficient to control this effect

The imperative for quality control programs in Monkeypox virus DNA testing by PCR: CIBERINFEC quality control

© 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.To evaluate molecular assays for Mpox diagnosis available in various clinical microbiology services in Spain through a quality control (QC) approach. A total of 14 centers from across Spain participated in the study. The Reference Laboratory dispatched eight serum samples and eight nucleic acid extracts to each participating center. Some samples were spiked with Mpox or Vaccinia virus to mimic positive samples for Mpox or other orthopox viruses. Participating centers provided information on the results obtained, as well as the laboratory methods used. Among the 14 participating centers seven different commercial assays were employed, with the most commonly used kit being LightMix Modular Orthopox/Monkeypox (Mpox) Virus (Roche®). Of the 12 centers conducting Mpox determinations, concordance ranged from 62.5% (n = 1) to 100% (n = 11) for eluates and from 75.0% (n = 1) to 100% (n = 10) for serum. Among the 10 centers performing Orthopoxvirus determinations, a 100% concordance was observed for eluates, while for serum, concordance ranged from 87.5% (n = 6) to 100% (n = 4). Repeatedly, 6 different centers reported a false negative in serum samples for Orthopoxvirus diagnosis, particularly in a sample with borderline Ct = 39. Conversely, one center, using the TaqMan™ Mpox Virus Microbe Detection Assay (Thermo Fisher), reported false positives in Mpox diagnosis for samples spiked with vaccinia virus due to cross-reactions. We observed a positive correlation of various diagnostic assays for Mpox used by the participating centers with the reference values. Our results highlight the significance of standardization, validation, and ongoing QC in the microbiological diagnosis of infectious diseases, which might be particularly relevant for emerging viruses.This research was supported by CIBER (Strategic Action for Monkeypox)—Consorcio Centro de Investigación Biomédica en Red—(CB 2021), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea—NextGenerationEU. A. d. S. is supported by ‘Instituto de Salud Carlos III’ (grant number JR22/00055).Peer reviewe

Role of Ring1B in ephitelial to mesenchimal transition, invasion and migration of mammary epithelial cells

The Polycomb group (PcG) family of proteins form chromatin-modifying complexes essential for embryonic development, and stem cell renewal and are commonly deregulated in cancer. There are several reports that address the possible implication of PcG proteins in tumor progression and metastasis, but very little is known about the specific role of these proteins in tumor progression and invasion. On the other hand, the molecular processes of the worst cancer prognosis, metastasis, which leads to an incurable disease, are yet incompletely elucidated. Here we show a role for Ring1B, a PcG protein, in three processes related to metastasis: in the Epithelial-mesenchymal transition (EMT), a critical morphogenic event that occurs during embryonic development and during the progression of various epithelial tumors, an in the migration and the invasion of mammary epithelial cells.Las proteínas del grupo Polycomb (PcG) forman complejos modificadores de la cromatina esenciales en el desarrollo embrionario y en la renovación de las células madre, y su desregulación ha sido asociada al cáncer. Varios estudios muestran la posible implicación de las proteínas de PcG en la progresión tumoral y en la metástasis, pero a pesar de ello se sabe muy poco de los procesos moleculares en los que estas proteínas están participando. Por otro lado, los procesos moleculares responsables del peor pronóstico en cáncer, la metástasis, que continua siendo una enfermedad incurable, siguen sin estar completamente elucidados. En esta disertación mostramos el papel de Ring1B, una proteína del PcG, en tres procesos implicados en la metástasis: en la transición epitelio-mesénquima (EMT), un proceso morfogénico crítico en el desarrollo embrionario y durante la progresión de varios cánceres epiteliales, y en la migración y la invasión de las células epiteliales mamarias

Monoparentalidades y políticas públicas: prestaciones públicas y permisos parentales

En las puertas del siglo XXI, las familias monoparentales se han convertido en un fenómeno creciente en nuestras sociedades. Sin embargo, en el Estado español, el régimen de bienestar y las políticas familiares desarrolladas no tienen suficientemente en cuenta las necesidades de las distintas modalidades monoparentales, especialmente monomarentales, y muchas de estas familias están en situaciones de precariedad laboral, dificulta des de conciliación y exclusión social. El artículo se basa en algunos de los resultados de una investigación-acción sobre familias monoparentales, y de una de sus herramientas, la encuesta sobre monoparentalidad y diversidad familiar -EMODIF- que contó con la participación de 300 familias monoparentales residentes en Catalunya. A partir de sus datos analizaremos las transferencias y prestaciones a las que tienen acceso o reciben las familias monoparentales, así como lo relativo a sus permisos parentales para poder evaluar las polí- ticas familiares hacia estas familias

Monoparentalidades y políticas públicas: prestaciones económicas y permisos parentales

En las puertas del siglo XXI, las familias monoparentales se han convertido en un fenómeno creciente en nuestras sociedades. Sin embargo, en el Estado español, el régimen de bienestar y las políticas familiares desarrolladas no tienen suficientemente en cuenta las necesidades de las distintas modalidades monoparentales, especialmente monomarentales, y muchas de estas familias están en situaciones de precariedad laboral, dificulta des de conciliación y exclusión social. El artículo se basa en algunos de los resultados de una investigación-acción sobre familias monoparentales, y de una de sus herramientas, la encuesta sobre monoparentalidad y diversidad familiar –EMODIF– que contó con la participación de 300 familias monoparentales residentes en Catalunya. A partir de sus datos analizaremos las transferencias y prestaciones a las que tienen acceso o reciben las familias monoparentales, así como lo relativo a sus permisos parentales para poder evaluar las polí- ticas familiares hacia estas familias.In the XXI century, one parent families have become a growing phenomenon in our societies. However, in the Spanish State, the welfare regime and family policies do not sufficiently take into account the needs of different types of one parent families, especially the ones headed by women. Many of these families suffer from precarious employment, as well as work-life balance difficulties and social exclusion. This article is based on the results of an action research on one parent families, specifically on the EMODIF survey, survey on one-parent families and family diversity, that was answered by 300 one parent families living in Catalonia. From the data we analyse the use of social transfers and benefits they receive or have access to, as well as regarding parental leave among those families, in order to evaluate family policies towards one parent familie

Monoparentalidades y políticas públicas: prestaciones públicas y permisos parentales

En las puertas del siglo XXI, las familias monoparentales se han convertido en un fenómeno creciente en nuestras sociedades. Sin embargo, en el Estado español, el régimen de bienestar y las políticas familiares desarrolladas no tienen suficientemente en cuenta las necesidades de las distintas modalidades monoparentales, especialmente monomarentales, y muchas de estas familias están en situaciones de precariedad laboral, dificulta des de conciliación y exclusión social. El artículo se basa en algunos de los resultados de una investigación-acción sobre familias monoparentales, y de una de sus herramientas, la encuesta sobre monoparentalidad y diversidad familiar -EMODIF- que contó con la participación de 300 familias monoparentales residentes en Catalunya. A partir de sus datos analizaremos las transferencias y prestaciones a las que tienen acceso o reciben las familias monoparentales, así como lo relativo a sus permisos parentales para poder evaluar las polí- ticas familiares hacia estas familias