正丰原药业前身创立于上世纪 60年代，1997年，由丰原集团联合五家地方大型医药企业发起成立丰原药业。如今，丰原药业已发展成为以大容量注射剂为主导，解热镇痛、心血管、妇儿及 原料药等系列产品为配套，集医药研发、生产、营销于一体的大型医药企业。2000年，公司在深交所上市(股票代码：000153)，从此，丰原药业进入了 快速发展时期，逐步迈入中国主流医药企业的行列：是国家高新技术企业、全国"百姓放心药品牌"，自2007年起连续进入中国医药工业百强。
Abstract 4281: Oncostatin M renders epithelial cell adhesion molecule-positive liver cancer stem cells sensitive to 5-fluorouracil by inducing hepatocytic differentiation
Recent evidence suggests that a certain type of () is hierarchically organized by a subset of cells with stem cell features (stem cells; ). Although normal stem cells and are considered to share similar self-renewal programs， it remains unclear whether differentiation programs are also maintained in and effectively used for eradication. In this study， we investigated the effect of oncostatin M ()， an -related cytokine known to induce the differentiation of hepatoblasts into hepatocytes， on liver . receptor expression was detected in the majority of epithelial molecule-positive (EpCAM(+)) with stem/progenitor cell features. treatment resulted in the induction of hepatocytic differentiation of EpCAM(+) cells by inducing signal transducer and activator of 3 activation， as determined by a decrease in stemness-related gene expression， a decrease in EpCAM， alpha-fetoprotein and protein expressions， and an increase in albumin protein expression. -treated EpCAM(+) cells showed enhanced with expansion of the EpCAM-negative non-population. Noticeably， combination of treatment with the chemotherapeutic agent (5-FU)， which eradicates EpCAM-negative non-， dramatically increased the number of apoptotic cells in vitro and suppressed in vivo compared with either saline control， ， or 5-FU treatment alone. Taken together， our data suggest that could be effectively used for the differentiation and active of dormant EpCAM(+) liver ， and the combination of and conventional chemotherapy with 5-FU efficiently eliminates by targeting both and non-.
Human aquaporin 4281-300 is the immunodominant linear determinant in the context of HLA-DRB1*03:01: relevance for diagnosing and monitoring patients with neuromyelitis optica.
Abstract OBJECTIVE To identify linear determinants of human aquaporin 4 (hAQP4) in the context of HLA-DRB1*03：01. DESIGN In this controlled study with humanized experimental animals， HLA-DRB1*03：01 transgenic mice were immunized with whole-protein hAQP4 emulsified in complete Freund adjuvant. To test T-cell responses， lymph node cells and splenocytes were cultured in vitro with synthetic peptides 20 amino acids long that overlap by 10 amino acids across the entirety of hAQP4. The frequency of interferon γ， interleukin (IL) 17， granulocyte-macrophage colony-stimulating factor， and IL-5-secreting CD4+ T cells was determined by the enzyme-linked immunosorbent sport assay. Quantitative immunofluorescence microscopy was performed to determine whether hAQP4281-300 inhibits the binding of anti-hAQP4 recombinant antibody to surface full-length hAQP4. SETTING Academic neuroimmunology laboratories. SUBJECTS Humanized HLA-DRB1*03：01+/+ H-2b-/- transgenic mice on a B10 background. RESULTS Peptide hAQP4281-300 generated a significantly (P <.01) greater TH1 and TH17 immune response than any of the other linear peptides screened. This 20mer peptide contains 2 dominant immunogenic 15mer peptides. hAQP4284-298 induced predominantly an IL-17 and granulocyte-macrophage colony-stimulating factor TH cell phenotype， whereas hAQP4285-299 resulted in a higher frequency of TH1 cells. hAQP4281-300 did not interfere with recombinant AQP4 autoantibody binding. CONCLUSIONS hAQP4281-330 is the dominant linear immunogenic determinant of hAQP4 in the context of HLA-DRB1*03：01. Within hAQP4281-330 are 2 dominant immunogenic determinants that induce differential TH phenotypes. hAQP4 determinants identified in this study can serve as diagnostic biomarkers in patients with neuromyelitis optica and may facilitate the monitoring of treatment responses to pharmacotherapies.
Abstract 4281: Determination of the Relative Potency of a Selective Agonist of the Intermediate-Affinity IL-2 Receptor on Lymphocytes from Human, Cynomolgus Monkey and Mouse
RDB 1450 is an engineered fusion protein designed to selectively activate the intermediate-affinity IL-2 receptor versus the high-affinity IL-2 receptor. The potencies of RDB 1450 and IL-2 for activation of distinct subsets of effector and regulatory lymphocytes from murine， non-human primate and human donors were determined. Splenocytes isolated from mice or leukocytes isolated from human or cyno blood were stimulated with either RDB 1450 or IL-2. Multicolor flow cytometry was used to identify distinct subpopulations and the extent of phosphorylation of STAT5 was measured. Whereas IL-2 is 2-3 orders of magnitude more potent on immunosuppressive T regs relative to NK cells and memory CD8 T cells， RDB 1450 induces activation of NK cells， memory CD8 T cells and T regs at comparable concentrations within each species. The non-differentiated potency of RDB 1450 on the lymphocyte subpopulations examined suggests that its effects are mediated through the intermediate affinity receptors even on CD25-expressing T regs . The preferential activation of T regs by IL-2 may lead to immunosuppression and limit its antitumor efficacy. In contrast， RDB 1450 does not exhibit the same preference for T reg activation and is expected to be more effective in driving antitumor immune responses. These results highlight the differentiated immunological profile of RDB 1450 and support its potential as a novel human immunotherapy.Citation Format： Emily E. Rosentrater， Heather Flick， Jared E. Lopes， Heather C. Losey， Chunhua Wang， Juan C. Alvarez. Determination of the Relative Potency of a Selective Agonist of the Intermediate-Affinity IL-2 Receptor on Lymphocytes from Human， Cynomolgus Monkey and Mouse. [abstract]. In： Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia， PA. Philadelphia (PA)： AACR; Cancer Res 2015;75(15 Suppl)：Abstract nr 4281. doi：10.1158/1538-7445.AM2015-4281
Background： To provide a systematic analysis of formalin fixation artifacts on Illumina sequencing libraries and results， we generated two complementary sequencing libraries (target enrichment sequencing and whole exome sequencing) from 11 pairs of matched formalin-fixed paraffin-embedded (FFPE) and fresh-frozen (FF) tumor samples and two pairs of matched FFPE and FF germline samples. We also generated whole genome sequencing data from a single pair of FF/FFPE tumor samples. Results： The results indicate minimal variations in library fragment size， coverage， and PCR duplicates within FF/FFPE paired samples that are less than 1 year old; whereas， a large variation in these parameters were observed in FF/FFPE pairs in samples that are approximately 2 years old. No significant increase in global mismatch rates and C•G>T•A substitutions were observed in FFPE samples from the former group; whereas， a discernible increase in mismatch rates and C•G>T•A substitutions were observed in FFPE samples from the latter group. However， over 99.7% and 99.5% of concordant calls were observed between matched FF and FFPE pairs at reference and non-reference positions within the targeted regions， respectively. Although an increased rate of global mismatches and C•G>T•A substitutions were observed in some FFPE samples， discordant rates were low (T•A substitutions are comparable in non-reference positions in paired FF and FFPE samples. Conclusions： We developed upfront quality assessment and library preparation method that use low input DNA from FFPE samples to perform next-generation sequencing. The results from our studies indicate the suitability of FFPE samples in sequencing studies. Citation Format： Sarah Munchel， Yen Hoang， Yue Zhao， Joseph Cottrell， Brandy Klotzle， Andrew Godwin， Janelle Noel， Brooke Fridley， Peter Beyerlein， Jian-Bing Fan， Marina Bibikova， Jeremy R. Chien. Targeted or whole genome sequencing of formalin-fixed tissue samples. [abstract]. In： Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego， CA. Philadelphia (PA)： AACR; Cancer Res 2014;74(19 Suppl)：Abstract nr 4281. doi：10.1158/1538-7445.AM2014-4281
The ubiquitin ligase Nedd4 is an ubuiquitin ligase (E3) which belongs to the HECT family. Like other member of this family members， such as Itch and Smurf， Nedd4 has been proposed to regulate a number of signaling pathways， as well as the traffic of several cell surface molecules， however， its physiological role in mammals has not been well characterized. Former reports identified reduction in the mitogenic activity and increase of the adaptor protein Grb10， aberrant IGF-1， VEGF and FGF receptor localization and / or signaling. In the present study， we performed an analysis of Nedd4-null murine embryonal fibroblastoid cells (MEFs) to show that loss of Nedd4 may affect any additional growth factor signaling. Surface expression of PDGF receptor was significantly increased in homozygous mutant mouse embryonic fibroblasts. Accordingly， PDGF-BB stimulation induced enhanced signaling as judged by MAP kinase p42/44 and Akt phosphorylation. Knockdown of Nedd4 in cell lines also induced similar phenotype. Nedd4， when transiently expressed， ubiquitinated PDGF receptor， which lead to degradation. Under the presence of lysosome inhibitors， PDGF receptor down regulation was at least partially blocked， suggesting its lysosome-dependent degradation. Subcellular localization of the PDGF receptor was also analyzed， but apparent difference was not observed. In the scratch assay， Nedd4 knockout cells showed enhanced migration activity， suggesting their active movement. Thus， Nedd4 appears to negatively control PDGF signaling partly through the regulation of its lysosome dependent degradation.Citation Format： Nobuyuki Tanaka， Kyoko Oyama， Keiichi Tamai. Nedd4 controls cell migration by regulating PDGF receptor signaling. [abstract]. In： Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington， DC. Philadelphia (PA)： AACR; Cancer Res 2013;73(8 Suppl)：Abstract nr 4281. doi：10.1158/1538-7445.AM2013-4281
Ryu H, Lee J, Olofsson BA, Mwidau A, Dedeoglu A, Escudero M et al.. Histone deacetylase inhibitors prevent oxidative neuronal death independent of expanded polyglutamine repeats via an Sp1-dependent pathway. Proc Natl Acad Sci USA 100: 4281-4286
ABSTRACT Oxidative stress is believed to be an important mediator of neurodegeneration. However， the transcriptional pathways induced in neurons by oxidative stress that activate protective gene responses have yet to be fully delineated. We report that the transcription factor Sp1 is acetylated in response to oxidative stress in neurons. Histone deacetylase (HDAC) inhibitors augment Sp1 acetylation， Sp1 DNA binding， and Sp1-dependent gene expression and confer resistance to oxidative stress-induced death in vitro and in vivo. Sp1 activation is necessary for the protective effects of HDAC inhibitors. Together， these results demonstrate that HDAC inhibitors inhibit oxidative death independent of polyglutamine expansions by activating an Sp1-dependent adaptive response.
IJMS, Vol. 16, Pages 4281-4305: Personalization of the Immunosuppressive Treatment in Renal Transplant Recipients: The Great Challenge in “Omics” Medicine
Renal transplantation represents the most favorable treatment for patients with advanced renal failure and it is followed， in most cases， by a significant enhancement in patients’ quality of life. Significant improvements in one-year renal allograft and patients’ survival rates have been achieved over the last 10 years primarily as a result of newer immunosuppressive regimens. Despite these notable achievements in the short-term outcome， long-term graft function and survival rates remain less than optimal. Death with a functioning graft and chronic allograft dysfunction result in an annual rate of 3%–5%. In this context， drug toxicity and long-term chronic adverse effects of immunosuppressive medications have a pivotal role. Unfortunately， at the moment， except for the evaluation of trough drug levels， no clinically useful tools are available to correctly manage immunosuppressive therapy. The proper use of these drugs could potentiate therapeutic effects minimizing adverse drug reactions. For this purpose， in the future， “omics” techniques could represent powerful tools that may be employed in clinical practice to routinely aid the personalization of drug treatment according to each patient’s genetic makeup. However， it is unquestionable that additional studies and technological advances are needed to standardize and simplify these methodologies.
Selection of glycopeptide-resistant mutants of VanB-type Enterococcus faecalis BM4281 in vitro and in experimental endocarditis.
Enterococcus faecalis BM4281 is resistant to vancomycin， susceptible to teicoplanin (VanB phenotype)， and intrinsically resistant to low levels of gentamicin. The efficacy of glycopeptides against BM4281 was investigated in a rabbit model of experimental endocarditis for reduction of bacterial counts in cardiac vegetations and selection of mutants with increased resistance to glycopeptides. Teicoplanin led to a 100-fold reduction of bacteria in the vegetations， whereas vancomycin had no effect. Monotherapy with either antibiotic selected mutants with homogeneous or heterogeneous resistance to high levels of both glycopeptides. Vancomycin also selected mutants that required the antibiotic for growth. The combination of gentamicin plus teicoplanin was bactericidal， prevented the emergence of mutants， and allowed sterilization of the vegetations in 25% of the rabbits， indicating that the combination may be an alternative if penicillin cannot be used against VanB-type enterococci.