Down-regulation of myeloid cell leukemia-1 through inhibiting Erk/Pin 1 pathway by sorafenib facilitates chemosensitization in breast cancer

[[abstract]]Myeloid cell leukemia-1 (Mcl-1), a Bel-2-like antiapoptotic protein, plays a role in cell immortalization and chemoresistance in a number of human malignancies. A peptidylprolyl cis/trans isomerase, Pinl is involved in many cellular events, such as cell cycle progression, cell proliferation, and differentiation through isomerizing prophosphorylated substrates. It has been reported that down-regulation of Pint induces apoptosis, and that Erk phosphorylates and upregulates Mcl-1; however, the underlying mechanisms for the two phenomena are not clear yet. Here, we showed that Pin I stabilizes Mcl-1, which is required for Mcl-I posphorylation by Erk. First, we found expression of Mcl-1 and Not were positively correlated and associated with poor survival in human breast cancer. We then showed that Erk could phosphorylate Mcl-1 at two consensus residues, Thr 92 and 163, which is required for the association of Mcl-1 and Pin 1, resulting in stabilization of Mcl-I. Moreover, Not is also required for the up-regulation of Mcl-I by Erk activation. Based on this newly identified mechanism of Mcl-1 stabilization, two strategies were used to overcome Mcl-1-mediated chemoresistance: inhibiting Erk by Sorafenib, an approved clinical anticancer drug, or knocking down Pinl by using a SiRNA technique. In conclusion, the current report not only unravels a novel mechanism to link Erk/Pinl pathway and Mcl-1-mediated chemoresistance but also provides a plausible combination therapy, Taxol (Paclitaxel) plus Sorafenib, which was shown to be effective in killing breast cancer cells

Observation of CR Anisotropy with ARGO-YBJ

The measurement of the anisotropies of cosmic ray arrival direction provides important informations on the propagation mechanisms and on the identification of their sources. In this paper we report the observation of anisotropy regions at different angular scales. In particular, the observation of a possible anisotropy on scales between $\sim$ 10 $^{\circ}$ and $\sim$ 30 $^{\circ}$ suggests the presence of unknown features of the magnetic fields the charged cosmic rays propagate through, as well as potential contributions of nearby sources to the total flux of cosmic rays. Evidence of new weaker few-degree excesses throughout the sky region $195^{\circ}\leq$ R.A. $\leq 315^{\circ}$ is reported for the first time.Comment: Talk given at 12th TAUP Conference 2011, 5-9 September 2011, Munich, German

Observation of the cosmic ray moon shadowing effect with the ARGO-YBJ experiment

Cosmic rays are hampered by the Moon and a deficit in its direction is expected (the so-called Moon shadow). The Moon shadow is an important tool to determine the performance of an air shower array. Indeed, the westward displacement of the shadow center, due to the bending effect of the geomagnetic field on the propagation of cosmic rays, allows the setting of the absolute rigidity scale of the primary particles inducing the showers recorded by the detector. In addition, the shape of the shadow permits to determine the detector point spread function, while the position of the deficit at high energies allows the evaluation of its absolute pointing accuracy. In this paper we present the observation of the cosmic ray Moon shadowing effect carried out by the ARGO-YBJ experiment in the multi-TeV energy region with high statistical significance (55 standard deviations). By means of an accurate Monte Carlo simulation of the cosmic rays propagation in the Earth-Moon system, we have studied separately the effect of the geomagnetic field and of the detector point spread function on the observed shadow. The angular resolution as a function of the particle multiplicity and the pointing accuracy have been obtained. The primary energy of detected showers has been estimated by measuring the westward displacement as a function of the particle multiplicity, thus calibrating the relation between shower size and cosmic ray energy. The stability of the detector on a monthly basis has been checked by monitoring the position and the deficit of the Moon shadow. Finally, we have studied with high statistical accuracy the shadowing effect in the ''day/night’’ time looking for possible effect induced by the solar wind

Highlights from the ARGO-YBJ experiment

The ARGO-YBJ experiment at YangBaJing in Tibet (4300 m a.s.l.) has been taking data with its full layout since October 2007. Here we present a few significant results obtained in gamma-ray astronomy and cosmic-ray physics. Emphasis is placed on the analysis of gamma-ray emission from point-like sources (Crab Nebula, MRK 421), on the preliminary limit on the antiproton/proton flux ratio, on the large-scale cosmic-ray anisotropy and on the proton–air cross-section. The performance of the detector is also discussed, and the perspectives of the experiment are outlined

Long-term outcomes of early childhood science education: insight from a cross-national comparative case study on conceptual understanding of science

The purpose of this research was to explore the long term outcomes of either participating or not participating in early childhood science education on Grade 6 students’ conceptual understanding of science. The research is situated in a conceptual framework that evokes Piagetian developmental levels as both potential curriculum constraints and potential models of efficacy. The research design was a multiple case study of Grade 6 children from three schools in China (n=140) who started formal science education in the third grade, and Grade 6 children from three matched schools in Australia (n=105) who started learning science in kindergarten. The students’ understanding was assessed by a science quiz and in-depth interview. The data showed that participating children from the high socio-economic schools in China and Australia had similar understandings of science. Divergence between the medium and low socio-economic schools, however, indicated that the grounding in early childhood science education in Australia may have placed these children at an advantage. Alternative explanations for the divergence including the nature of classroom instruction in the two countries are discussed

Increment of Skeletal Muscle Mass Predicts Survival Benefit for Hepatocellular Carcinoma Treated with Transarterial Chemoembolization Combining Molecular Targeted Agents and Immune Checkpoint Inhibitors

Wen Chen,1,&ast; Hai-Tao Yan,1,&ast; Jin-Xing Zhang,1 Xiao Shen,1 Jin Liu,2 Sheng Liu,1 Hai-Bin Shi,1 Ye Ding,3 Qing-Quan Zu1 1Department of Interventional Radiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, People’s Republic of China; 2Department of Clinical Medicine Research Institution, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, People’s Republic of China; 3Department of Maternal, Child and Adolescent Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ye Ding, Department of Maternal, Child and Adolescent Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, People’s Republic of China, Tel +86-025-8686-8459, Email [email protected] Qing-Quan Zu, Department of Interventional Radiology, The First Affiliated Hospital with Nanjing Medical University, No. 300, Guangzhou Road, Nanjing, 210029, People’s Republic of China, Tel +86-13913807470, Email [email protected]: To assess the relationship between clinical prognosis and changes of skeletal muscle mass for unresectable hepatocellular carcinoma (uHCC) patients who received transarterial chemoembolization (TACE) with molecular-targeted agents and immune checkpoint inhibitors (TACE-MTAs-ICIs).Methods: From June 2019 to June 2023, a total of 92 uHCC patients who received TACE-MTAs-ICIs therapy were included. Skeletal muscle mass was assessed before and 6 months after treatment. Skeletal muscle index (SMI) is calculated as skeletal muscle area at the L3 vertebra divided by the square of height, then the change rate of SMI (ΔSMI) is calculated. Patients were stratified based on ΔSMI as muscle gain and non-muscle gain groups. Overall survival (OS) was compared between groups and prognostic factors for OS were analyzed. Progression-free survival (PFS) was also recorded.Results: The median OS in the muscle gain group was significantly longer than that in the non-muscle gain group (Not reach vs 25.2 months, P < 0.001). The median PFS did not reach significant between two groups (16.2 vs 9.1 months, P = 0.101). Multivariate analyses revealed that skeletal muscle gain (HR = 0.20; 95% CI, 0.06– 0.68; P = 0.010) and Barcelona Clinic Liver Cancer stage (HR = 1.94; 95% CI, 1.02– 3.69; P = 0.044) were independent prognostic factors for OS.Conclusion: SMI increment appeared as a favorable predictor for these uHCC patients who received TACE-MTAs-ICIs therapy.Keywords: hepatocellular carcinoma, immune checkpoint inhibitors, molecular targeted therapy, sarcopenia, transarterial chemoembolizatio

Bioactive gelatin-siloxane hybrids as tissue engineering scaffold

Ca2+-containing porous gelatin-siloxane hybrids were prepared using sol-gel process, post-gelation soaking, and freeze-drying. The porosity and pore size of the hybrids could be well controlled by the freezing temperature and the pH value of the soaking solution. The pore characteristics were related to the structure change during the soaking treatment. A bone-like apatite layer was able to form in the Ca2+-containing porous gelatin-siloxane hybrids upon soaking in a stimulated body fluid. The porous gelatin-siloxane hybrids could release gentamicin sulfate which is an antibiotic drug in bone chemotherapy. Thus, those hybrid materials are proposed to find application as novel bioactive and biodegradable scaffolds in bone tissue engineering

Multiple Roles for the Non-Coding RNA SRA in Regulation of Adipogenesis and Insulin Sensitivity

Peroxisome proliferator-activated receptor-γ (PPARγ) is a master transcriptional regulator of adipogenesis. Hence, the identification of PPARγ coactivators should help reveal mechanisms controlling gene expression in adipose tissue development and physiology. We show that the non-coding RNA, Steroid receptor RNA Activator (SRA), associates with PPARγ and coactivates PPARγ-dependent reporter gene expression. Overexpression of SRA in ST2 mesenchymal precursor cells promotes their differentiation into adipocytes. Conversely, knockdown of endogenous SRA inhibits 3T3-L1 preadipocyte differentiation. Microarray analysis reveals hundreds of SRA-responsive genes in adipocytes, including genes involved in the cell cycle, and insulin and TNFα signaling pathways. Some functions of SRA may involve mechanisms other than coactivation of PPARγ. SRA in adipocytes increases both glucose uptake and phosphorylation of Akt and FOXO1 in response to insulin. SRA promotes S-phase entry during mitotic clonal expansion, decreases expression of the cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1, and increases phosphorylation of Cdk1/Cdc2. SRA also inhibits the expression of adipocyte-related inflammatory genes and TNFα-induced phosphorylation of c-Jun NH2-terminal kinase. In conclusion, SRA enhances adipogenesis and adipocyte function through multiple pathways

Measurement of the antiproton/proton ratio in the few-TeV energy range with ARGO-YBJ

Cosmic ray antiprotons provide an important probe for the study of cosmic ray propagation in the interstellar space and to investigate the existence of Galactic dark matter. The ARGO-YBJ experiment is observing the Moon shadow with high statistical significance at an energy threshold of a few hundred GeV. Using all the data collected until November 2009, we set two upper limits on the antip/p flux ratio: 5% at an energy of 1.4 TeV and 6% at 5 TeV with a confidence level of 90%. In the few-TeV range the ARGO-YBJ results are the lowest available, useful to constrain models for antiproton production in antimatter domains.Comment: Talk given at the CRIS 2010 Conference, September 2010, Catania - Italy, 6 page