Effects of palbociclib on the cellular and immune response to trastuzumab and pertuzumab in HER2-positive breast cancer

El bloqueig dual anti-HER2, que combina anticossos monoclonals de trastuzumab i pertuzumab amb quimioteràpia, és l'estàndard d'atenció per a les dones amb càncer de mama HER2 positiu (HER2+) primerenc, així com a l'entorn metastàtic de primera línia. Aquest tractament aconsegueix la regressió del tumor mitjançant la supressió directa dels senyals intracel·lulars oncogènics de HER2 i l'activació de la citotoxicitat intervinguda per cèl·lules dependent d'anticossos (ADCC). Tot i això, un nombre significatiu de pacients desenvolupen resistència. En conseqüència, hi ha una necessitat urgent d'una comprensió més gran dels mecanismes de resistència. Entre ells, la desregulació del cicle cel·lular, provocada per l'augment de l'activitat de la ciclina D1 i les quinases dependents de ciclina 4 (CDK4), es va identificar com a mecanisme potencial de resistència als agents anti-HER2. Tot i això, l'addició de CDK4/6i a trastuzumab i pertuzumab ha mostrat una eficàcia limitada a l'entorn clínic.El bloqueo dual anti-HER2, que combina anticuerpos monoclonales de trastuzumab y pertuzumab con quimioterapia, es el esta¿ndar de atencio¿n para las mujeres con ca¿ncer de mama HER2 positivo (HER2+) temprano, asi¿ como en el entorno metasta¿sico de primera li¿nea. Este tratamiento logra la regresio¿n del tumor mediante la supresio¿n directa de las sen¿ales intracelulares oncoge¿nicas de HER2 y la activacio¿n de la citotoxicidad mediada por ce¿lulas dependiente de anticuerpos (ADCC). Sin embargo, un nu¿mero significativo de pacientes desarrollan resistencia. En consecuencia, existe una necesidad apremiante de una mayor comprensio¿n de los mecanismos de resistencia. Entre ellos, la desregulacio¿n del ciclo celular, provocada por el aumento de la actividad de la ciclina D1 y las quinasas dependientes de ciclina 4 (CDK4), se identifico¿ como un mecanismo potencial de resistencia a los agentes anti-HER2. Sin embargo, la adicio¿n de CDK4/6i a trastuzumab y pertuzumab ha mostrado una eficacia limitada en el entorno cli¿nico.Dual anti-HER2 blockade, combining trastuzumab and pertuzumab monoclonal antibodies with chemotherapy, is the standard of care for women with early HER2- positive (HER2+) breast cancer, as well as in the first-line metastatic setting. This treatment achieves tumor regression by directly suppressing HER2 oncogenic intracellular signals and activating antibody-dependent cell-mediated cytotoxicity (ADCC). However, a significant number of patients develop resistance. Consequently, there is a pressing need for further understanding of resistance mechanisms. Among them, dysregulation of the cell cycle, caused by increased activity of cyclin D1 and cyclin-dependent kinases 4 (CDK4), was identified as a potential mechanism of resistance to anti-HER2 agents. However, the addition of CDK4/6i to trastuzumab and pertuzumab has shown limited efficacy in the clinical setting.Universitat Autònoma de Barcelona. Programa de Doctorat en Medicin

Characterization of Polysaccharides with Antioxidant and Hepatoprotective Activities from the Edible Mushroom Oudemansiella radicata

The preliminary structure, in vitro antioxidant and in vivo hepatoprotective activities of water-soluble polysaccharides (ORWP) and alkali-soluble polysaccharides (ORAP), prepared from the mushroom Oudemansiella radicata, were investigated. Both ORWP and ORAP were heteropolysaccharides with mannose, glucose and galactose being the main monosaccharide components. Regarding the antioxidant activities, ORWP and ORAP showed effective 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, hydrogen peroxide scavenging activity and lipid peroxidation inhibitory effects, as well as moderate reducing power and Fe2+ chelating activity. For the hepatoprotective activity, administration of ORWP and ORAP prevented the increase in serum alanine aminotransferase and aspartate aminotransferase activities in a carbon tetrachloride-induced acute liver damage model, suppressed hepatic malondialdehyde formation and stimulated the activities of hepatic superoxide dismutase and glutathione peroxidase. Thus, we speculate that ORWP and ORAP may protect the liver from CCl4-induced hepatic damage via antioxidant mechanisms

Measurement and understanding of Cyberlocker URL-sharing sites: Focus on movie files

Recently, Cyberlocker services have gained great popularity in the file-sharing market. Driven by tremendous benefits a large number of files such as popular movies are uploaded to Cyberlockers. We explore the profit chain of filesharing networks based on Cyberlockers and find that an important issue is how to collect the download URLs of popular files stored at different Cyberlockers and share them with public users. In this paper, we focus on these sites collecting and sharing the Cyberlocker URLs of movies, called Cyberlocker URL-sharing sites. First, we extract 1,587 URL-sharing sites based on 31,525 valid pages returned by Google search and demonstrate that the quality distribution of these sites follows a power-law. Second, we analyze the link citations among URLsharing sites and build the directed link citation graph. By characterizing basic metrics of the graph, such as cited strength and in/out-degree, we understand the structure of URL-sharing sites in depth. Furthermore, we discover that Cyberlocker URLs can be disseminated dynamically through crawler mechanisms among different sites, and highlight the implications of such metrics in this context. Additionally, we study the security risks of 1,587 URL-sharing sites. The results show that security risks do exist when surfing 155 suspicious URL-sharing sites such as myrls.me and rapid4me.com although the majority sites (90.23%) are safe. Finally, some preliminary suggestions are discussed from the industry point of view for how to improve the effectiveness of searching, collecting and disseminating Cyberlocker URLs. To the best of our knowledge, this is the first work on the measurement and understanding of Cyberlocker URL-sharing sites. Copyright 2013 ACM

Adiponectin and adiponectin receptors in common carp (Cyprinus carpio): Tissue distribution and their expressions in response to high-carbohydrate and high-lipid diets

In order to investigate the roles of adiponectin in glucose and lipid metabolism in common carp, the tissue distribution of adiponectin and its receptor genes in common carp were firstly detected in this study, and then the effects of high-carbohydrate (45%) and high-lipid (11%) diets on their expressions were studied in the feeding trial. The results showed that adipoqa and adipoqb mRNA levels were highest in the red muscle, followed by the heart and white muscle. Adiponectin receptor genes were widely expressed in all tested tissues. Two subtypes of adiponectin receptor 1 genes (adipor1a and adipor1b) were expressed at the highest level in the brain, while adipor2 mRNA was highly expressed in the heart and red muscle. The high-carbohydrate diet significantly up-regulated adipoqa and adipoqb mRNA level in the heart of common carp, while the high-lipid diet significantly promoted adipoqa mRNA expression in the red muscle and heart, compared to the control diet. For adiponectin receptor gene expression, a high-carbohydrate diet up-regulated adipor2 mRNA level in the hepatopancreas, while a high-lipid diet significantly promoted adipor1a, adipor1b and adipor2 mRNA expression in the red muscle and hepatopancreas. The results showed that both high-carbohydrate and high-lipid diets could induce adiponectin genes expression in common carp, and AdipoRs expression was more likely to be increased by the high-lipid diet than the high-carbohydrate diet. This study suggested that adiponectin and its receptors were involved in the metabolic regulation of fish under high dietary carbohydrate and lipid levels

mTOR inhibition and T-DM1 in HER2-positive breast cancer

In patients with trastuzumab-resistant HER2-positive breast cancer, the combination of everolimus (mTORC1 inhibitor) with trastuzumab failed to show a clinically significant benefit. However, the combination of mTOR inhibition and the antibody-drug conjugate (ADC) trastuzumab-emtansine (T-DM1) remains unexplored. We tested T-DM1 plus everolimus in a broad panel of HER2-positive breast cancer cell lines. The combination was superior to T-DM1 alone in four cell lines (HCC1954, SKBR3, EFM192A, and MDA-MB-36) and in two cultures from primary tumor cells derived from HER2-positive patient-derived xenografts (PDX), but not in BT474 cells. In the trastuzumab-resistant HCC1954 cell line, we characterized the effects of the combination using TAK-228 (mTORC1 and -2 inhibitor) and knockdown of the different mTOR complex components. T-DM1 did not affect mTOR downstream signaling nor induct autophagy. Importantly, mTOR inhibition increased intracellular T-DM1 levels, leading to increased lysosomal accumulation of the compound. The increased efficacy of mTOR inhibition plus T-DM1 was abrogated by lysosome inhibitors (chloroquine and bafilomycin A1). Our experiments suggest that BT474 are less sensitive to T-DM1 due to lack of optimal lysosomal processing and intrinsic resistance to the DM1 moiety. Finally, we performed several in vivo experiments that corroborated the superior activity of T-DM1 and everolimus in HCC1954 and PDX-derived mouse models. In summary, everolimus in combination with T-DM1 showed strong antitumor effects in HER2-positive breast cancer, both in vitro and in vivo. This effect might be related, at least partially, to mTOR-dependent lysosomal processing of T-DM1, a finding that might apply to other ADCs that require lysosomal processing.This work was supported by ISCIII (CIBERONC CB16/12/00481, CB16/12/00241, PI18/00382, PI18/00006, PI18/01219), Generalitat de Catalunya (2017 SGR 507). MINECO through gBFU2015-71371-R grant and the CRIS Cancer Foundation supported work in AP lab. D. Casadevall was supported by ISCIII (Rio Hortega Research Contract CM16/00023 and Juan Rodés Research Contract JR18/00003). F.J. Sánchez-Martín and S. Menéndez were supported by Department de Salut Generalitat de Catalunya (PERIS SLT002/16/00008 and PERIS SLT006/17/00040). M. Qin received financial support from the China Scholarship Council (CSC) for her doctoral fellowship. Work carried out in our laboratories receives support from the European Community through the Regional Development Funding Program (FEDER)