Partial protection against collagen antibody-induced arthritis in PARP-1 deficient mice

Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear DNA-binding protein that participates in the regulation of DNA repair and maintenance of genomic integrity. In addition, PARP-1 has a role in several models of inflammation disease, where its absence or inactivation confers protection. The aim of this study was to analyze the impact of selective PARP-1 suppression in collagen antibody-induced arthritis. We show that PARP-1 deficiency partially reduces the severity of arthritis, although the incidence of disease was similar in control and deficient mice. Decreased clinical scores were accompanied by partial reduction of histopathological findings. Interestingly, quantitative real-time PCR and ELISA analysis revealed that the absence of PARP-1 down-regulated IL-1β and monocyte chemotactic protein 1 expression in arthritic joints whereas tumor necrosis factor-α transcription was not impaired. Our results provide evidence of the contribution of PARP-1 to the progression of arthritis and identify this protein as a potential therapeutic target for the treatment of rheumatoid arthritis

Matrix metalloproteinase-8 deficiency increases joint inflammation and bone erosion in the K/BxN serum-transfer arthritis model

Introduction Rheumatoid arthritis is an autoimmune disease in which joint inflammation leads to progressive cartilage and bone erosion. Matrix metalloproteinases (MMPs) implicated in homeostasis of the extracellular matrix play a central role in cartilage degradation. However, the role of specific MMPs in arthritis pathogenesis is largely unknown. The aim of the present study was to investigate the role of Mmp-8 (collagenase-2) in an arthritis model. Methods Arthritis was induced in Mmp8-deficient and wildtype mice by K/BxN serum transfer. Arthritis severity was measured by a clinical index and ankle sections were scored for synovial inflammation, cartilage damage and bone erosion. cDNA microarray analysis, real-time PCR and western blot were performed to identify differential changes in gene expression between mice lacking Mmp8 and controls. Results Mmp8 deficiency increased the severity of arthritis, although the incidence of disease was similar in control and deficient mice. Increased clinical score was associated with exacerbated synovial inflammation and bone erosion. We also found that the absence of Mmp8 led to increased expression of IL-1β, pentraxin-3 (PTX3) and prokineticin receptor 2 (PROKR2) in arthritic mice joints. Conclusions Lack of Mmp-8 is accompanied by exacerbated synovial inflammation and bone erosion in the K/BxN serum-transfer arthritis model, indicating that this Mmp has a protective role in arthritisThe present work was supported by grants PI04/0783, PI08/0038, RETICS Program, RD08/0075 (RIER), all from Fondo de Investigación Sanitaria, Instituto de Salud Carlos III within the VI PN de I+D+I 2008-2011 with participation of FEDER funds (European Union). SG is supported by Xunta de GaliciaS

Trastorno bipolar en embarazo y lactancia

El trastorno bipolar (TB) es una enfermedad psiquiátrica crónica, caracterizada por fluctuaciones del humor, desde la manía hasta la depresión bipolar. Dado que suele debutar en adultos jóvenes, afecta a mujeres en edad fértil y embarazadas. El TB se asocia con mayor riesgo de efectos adversos en el embarazo, incluyendo aquellos relacionados con la medicación y posibles recaídas de la enfermedad. El objetivo de esta revisión sistemática es analizar la bibliografía reciente y de calidad sobre el tratamiento farmacológico del TB. Para ello se realizó una búsqueda sistemática en PubMed de artículos publicados entre 2012 y 2017, seleccionando aquellos de mayor calidad siguiendo los criterios de la guía PRISMA. Los psicotrópicos empleados en el TB, que incluyen principalmente litio, algunos antiepilépticos, antipsicóticos, antidepresivos y benzodiacepinas, se han asociado con efectos adversos tales como malformaciones congénitas, anomalías cardiacas, afectación del neurodesarrollo, síndrome de adaptación neonatal, abortos espontáneos y parto pretérmino, entre otros. Las recomendaciones de las Guías de Práctica Clínica (GPC) deben interpretarse con cautela, ya que tienen grados variables de evidencia y gran parte de los datos disponibles necesitan mayor investigación en futuros estudios. En conclusión, para manejar el TB durante el embarazo y lactancia, se debe utilizar el fármaco con mejor perfil de seguridad, con la mínima dosis eficaz, y en monoterapia si es posible, y es obligado monitorizar estrechamente la evolución de la mujer y de su hijo. Las GPC proporcionan un apoyo apropiado y necesario, pero siempre se debe individualizar el tratamiento.Bipolar disorder (BD) is a psychiatric chronic disease, characterized by mood fluctuations, from mania to bipolar depression. Given that it usually debuts in young adults, it affects women in childbearing age and pregnant women. BD is associated with a higher risk of adverse outcomes during pregnancy, including those related to medication and possible relapses. The objective of this systematic review is to analyse recent and high-quality bibliography about the pharmacologic treatment of BD, by the means of a systematic research in PubMed, collecting articles published between 2012 and 2017, and selecting those with the highest quality according to the standards of the PRISMA guideline. Psychotropic medication used in BD, which is mainly lithium, some antiepileptic drugs, antipsychotics, antidepressants and benzodiazepines, has been associated with adverse outcomes such us congenital malformations, cardiac anomalies, neurodevelopmental problems, neonatal adaptation syndrome, spontaneous abortion and preterm delivery, among others. Recommendations provided by Clinical Practices Guidelines (CPG) must be interpreted with caution, given that they are based on variable levels of evidence, and most part of the available data needs to be further investigated in future studies. In conclusion, regarding the management of BD during pregnancy and breastfeeding, we must choose the drug with the best security profile, using the minimum effective dose, in monotherapy if possible, and it is mandatory to monitor closely the evolution of the woman and her child. CPG provide an adequate and necessary support, but treatment must be individualized

Prognostic significance of cyclins A2, B1, D1, and E1 and CCND1 numerical aberrations in oral squamous cell carcinomas

We analysed the expression of cyclins A2, B1, D1, and E1 by immunohistochemistry and numerical aberrations in CCND1 gene by fluorescence in situ hybridization technique in 67 primary oral squamous cell carcinomas (OSCC). Cyclin A2 expression was observed in 54 (83.1%) tumours, cyclin D1 in 58 (89.2%), cyclin B1 in 39 (60%), and cyclin E in 21 (32.8%). CCND1 region analysis revealed 26 (43.3%) tumours with the presence of numerical aberrations which were correlated with cyclin D1 high expression (Rho = 0.48; p < 0 001). Twenty-nine (45.3%) tumours were classified as high proliferative tumours assessed by Ki-67 protein expression and correlated with tumours with high expression of cyclin A2 (Rho = 0.30; p = 0 016) and cyclin B1 (Rho = 0.37; p = 0 003). In multivariate analysis for an overall five-year survival (OS), we found an adverse independent prognostic value for cyclin A2 high expression (p = 0 031) and for advanced tumour stage (p < 0 001). Our results confirm that several cyclins are commonly expressed in OSCC. CCND1 gene is abnormal in more than one-third of the cases and is frequently associated with cyclin D1 high expression. Moreover, cyclin A2 high expression is an independent indicator of worse OS suggesting that this protein may serve as a reliable biological marker to identify high-risk subgroups with poor prognosis.This study was supported by a grant from the Fundación de Investigación Médica Mutua Madrileña (Spain) and Instituto de Salud Carlos III (FIS PI 061902). The authors also thank the Biobanco del Complejo Hospitalario Universitario de Santiago and IINFACTS in CESPU (BubOral CESPU 2017; MacrOral CESPU 2017)S

Tumor microenvironment-targeted poly-L-glutamic acid-based combination conjugate for enhanced triple negative breast cancer treatment

[EN] The intrinsic characteristics of the tumor microenvironment (TME), including acidic pH and overexpression of hydrolytic enzymes, offer an exciting opportunity for the rational design of TME-drug delivery systems (DDS). We developed and characterized a pH-responsive biodegradable poly-L-glutamic acid (PGA)-based combination conjugate family with the aim of optimizing anticancer effects. We obtained combination conjugates bearing Doxorubicin (Dox) and aminoglutethimide (AGM) with two Dox loadings and two different hydrazone pH sensitive linkers that promote the specific release of Dox from the polymeric backbone within the TME. Low Dox loading coupled with a short hydrazone linker yielded optimal effects on primary tumor growth, lung metastasis (-90% reduction), and toxicological profile in a preclinical metastatic triple-negative breast cancer (TNBC) murine model. The use of transcriptomic analysis helped us to identify the molecular mechanisms responsible for such results including a differential immunomodulation and cell death pathways among the conjugates. This data highlights the advantages of targeting the TME, the therapeutic value of polymer-based combination approaches, and the utility of -omits-based analysis to accelerate anticancer DDS.The authors would like to thank Dr. Stuart P. Atkinson for his collaboration in manuscript preparation and English revision, and Irene Borreda for essential immunohistological support. This work has been supported by the European Research Council (grant ERC-CoG-2014-648831 "MyNano") and the Spanish Ministry of Science and Innovation (CTQ2010-18195, SAF2013-44848-R, BES-2008-006801, IPT-2012-0712-010000, Programa I3, and BIO2015-71658-R). LBN is funded through a University of South Florida-Helmsley Foundation award. FHL is funded through NIH grant. Part of the equipment employed in this work has been funded by Generalitat Valenciana and co-financed with FEDER funds (PO FEDER of Comunitat Valenciana 2014-2020).Arroyo-Crespo, JJ.; Armiñán, A.; Charbonnier, D.; Balzano-Nogueira, L.; Huertas-López, F.; Martí, C.; Tarazona Campos, S.... (2018). Tumor microenvironment-targeted poly-L-glutamic acid-based combination conjugate for enhanced triple negative breast cancer treatment. Biomaterials. 186:8-21. https://doi.org/10.1016/j.biomaterials.2018.09.02382118

Characterization of triple‐negative breast cancer preclinical models provides functional evidence of metastatic progression

Triple‐negative breast cancer (TNBC), an aggressive, metastatic and recurrent breast cancer (BC) subtype, currently suffers from a lack of adequately described spontaneously metastatic preclinical models that faithfully reproduce the clinical scenario. We describe two preclinical spontaneously metastatic TNBC orthotopic murine models for the development of advanced therapeutics: an immunodeficient human MDA‐MB‐231‐Luc model and an immunocompetent mouse 4T1 model. Furthermore, we provide a broad range of multifactorial analysis for both models that could provide relevant information for the development of new therapies and diagnostic tools. Our comparisons uncovered differential growth rates, stromal arrangements and metabolic profiles in primary tumors, and the presence of cancer‐associated adipocyte infiltration in the MDA‐MB‐231‐Luc model. Histopathological studies highlighted the more rapid metastatic spread to the lungs in the 4T1 model following a lymphatic route, while we observed both homogeneous (MDA‐MB‐231‐Luc) and heterogeneous (4T1) metastatic spread to axillary lymph nodes. We encountered unique metabolomic signatures in each model, including crucial amino acids and cell membrane components. Hematological analysis demonstrated severe leukemoid and lymphoid reactions in the 4T1 model with the partial reestablishment of immune responses in the immunocompromised MDA‐MB‐231‐Luc model. Additionally, we discovered β‐immunoglobulinemia and increased basal levels of G‐CSF correlating with a metastatic switch, with G‐CSF also promoting extramedullary hematopoiesis (both models) and causing hepatosplenomegaly (4T1 model). Overall, we believe that the characterization of these preclinical models will foster the development of advanced therapeutic strategies for TNBC treatment, especially for the treatment of patients presenting both, primary tumors and metastatic spread

Molecular features in a biphenotypic small cell sarcoma with neuroectodermal and muscle differentiation

We report a case of a 13-year-old girl with soft tissue sarcoma of the hand, which showed muscle and neuroectodermal immunophenotypes. Molecular studies were performed on RNA collected from fine-needle aspiration (FNA) cytology and peripheral blood samples by nested reverse transcriptase-polymerase chain reaction (RT-PCR) and Southern blot analysis. This biphenotypic tumor showed simultaneous expression of EWS-FLI1 and PAX3-FKHR transcripts, specific of Ewing family tumors and alveolar rhabdomyosarcoma, respectively. Although childhood sarcomas with simultaneous muscle and neural differentiation have been described to have EWS-FLI1 transcripts, there are no reports of tumors with both transcripts. Cytological specimens are a good source of RNA for molecular studie

Selective targeting of collagen IV in the cancer cell microenvironment reduces tumor burden

Goodpasture antigen-binding protein (GPBP) is an exportable1 Ser/Thr kinase that induces collagen IV expansion and has been associated with chemoresistance following epithelial-to-mesenchymal transition (EMT). Here we demonstrate that cancer EMT phenotypes secrete GPBP (mesenchymal GPBP) which displays a predominant multimeric oligomerization and directs the formation of previously unrecognized mesh collagen IV networks (mesenchymal collagen IV). Yeast twohybrid (YTH) system was used to identify a 260SHCIE264 motif critical for multimeric GPBP assembly which then facilitated design of a series of potential peptidomimetics. The compound 3-[4''-methoxy-3,2'-dimethyl-(1,1';4',1'')terphenyl-2''-yl]propionic acid, or T12, specifically targets mesenchymal GPBP and disturbs its multimerization without affecting kinase catalytic site. Importantly, T12 reduces growth and metastases of tumors populated by EMT phenotypes. Moreover, low-dose doxorubicin sensitizes epithelial cancer precursor cells to T12, thereby further reducing tumor load. Given that T12 targets the pathogenic mesenchymal GPBP, it does not bind significantly to normal tissues and therapeutic dosing was not associated with toxicity. T12 is a first-in-class drug candidate to treat cancer by selectively targeting the collagen IV of the tumor cell microenvironment.This work was supported by grants: PET 2006_0721, TRA2009_0026, IPT-010000-2010-45, IPT-2011-1527- 010000, RTC-2014-2415-1, PCB-010000-2010-031, PCB- 010000-2010-032, EQU-2014-1-0301 of the Plan Nacional de Investigación, Desarrollo e Innovación of the Spanish Government and IMGESA/06/78, IMGESA/06/79 of Conselleria d’Empresa, Universitat i Ciencia of Generalitat Valenciana to Fibrostatin, S.L. and J.S.; SAF 2001/0453, SAF 2003-09772-C03-01, SAF 2006-12520-C02-01, SAF 2009-10703 of the Plan Nacional de Investigación, Desarrollo e Innovación of the Spanish Government and PROMETEO/2009/065, PROMETEOII/2014/048 of Conselleria de Educaciò of Generalitat Valenciana to J.S. Additional funding came from ERESA, BioStratum Inc. and NephroGenex Inc. R&D programs, and personal funding from Vicente Saus and Carmen Cano to J.S.. Torres Quevedo program of the Spanish Government granted F.R., F-R-R., R.B., E.L-P and A.P-S.Medicin

Family History and Breast Cancer Hormone Receptor Status in a Spanish Cohort

Breast cancer is a heterogenous disease that impacts racial/ethnic groups differently. Differences in genetic composition, lifestyles, reproductive factors, or environmental exposures may contribute to the differential presentation of breast cancer among Hispanic women.A population-based study was conducted in the city of Santiago de Compostela, Spain. A total of 645 women diagnosed with operable invasive breast cancer between 1992 and 2005 participated in the study. Data on demographics, breast cancer risk factors, and clinico-pathological characteristics of the tumors were collected. Hormone receptor negative tumors were compared with hormone receptor postive tumors on their clinico-pathological characteristics as well as risk factor profiles.Among the 645 breast cancer patients, 78% were estrogen receptor-positive (ER+) or progesterone receptor-positive (PR+), and 22% were ER−&PR−. Women with a family history of breast cancer were more likely to have ER−&PR− tumors than women without a family history (Odds ratio, 1.43; 95% confidence interval, 0.91–2.26). This association was limited to cancers diagnosed before age 50 (Odds ratio, 2.79; 95% confidence interval, 1.34–5.81).An increased proportion of ER−&PR− breast cancer was observed among younger Spanish women with a family history of the disease