475 research outputs found
The Role of RASSF5 on Cell Growth and Hippo Signaling in Rhabdomyosarcoma
Introduction: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. Dysregulation of the Hippo pathway, a signaling cascade that regulates many biological processes, is associated with many human cancers. The goal of my project was to delete RASSF5, a regulator of the Hippo pathway, in RMS cells utilizing CRISPR/Cas9 and then to evaluate how the absence of RASSF5 affects RMS cell growth and Hippo signaling, with and without DNMTi Tx.
Methods: A lipofectamine transfection was performed in two different RMS cell lines, Rh30 & RD, in which two different CRIPSR/Cas9 vectors with RASSF5 guide RNA were introduced. Then IncuCyte growth assays, western blot and qPCR were performed
Results: The IncuCyte growth curve for one of the RASSF5 CRISPR Rh30 cell lines, Sg1, revealed a faster rate of cell growth compared to the control Rh30s. Also, when treated with SGI110 Tx, there is reduction of drug induced growth inhibition of Sg1 Rh30 cells compared to controls. When looking at the protein level, although Cas9 expression was observed, there was no baseline reduction in RASSF5.
Discussion: While some of this data suggests that we have less activation of the Hippo pathway, which would result from a reduction in RASSF5, other data implies that RASSF5 was not deleted entirely. Further research is needed to elucidate RASSF5’s role in both RMS and the altered Hippo pathway in RMS
Low Dose Histone Deacetylase Inhibitor, Depsipeptide (FR901228), Promotes Adenoviral Transduction in Human Rhabdomyosarcoma Cell Lines
Purpose. Transduction of rhabdomyosarcoma (RMS) cells with adenoviral vectors for in vivo and in vitro applications has
been limited by the low to absent levels of coxackie and adenovirus receptor (CAR). This study investigates the potential use
of low doses of a histone deacetylase inhibitor, depsipeptide (FR901228), currently in Phase II human trials, to enhance
adenoviral uptake in six rhabdomyosarcoma cell lines
Disruption of the MyoD/p21 Pathway in Rhabdomyosarcoma
Purpose. Rhabdomyosarcoma (RMS) is an embryonal tumor thought to arise from skeletal muscle cells that fail to
differentiate terminally. The majority of RMSs express MyoD, a protein essential to the differentiation of skeletal muscle.
It was recently shown that during myogenesis, MyoD activates the expression of the cyclin-dependent kinase inhibitor
(CDKi), p21, which itself plays a critical role in normal muscle development. To investigate the integrity of the MyoD/p21
pathway in RMS, we analyzed p21 and its relationship to MyoD expression in RMS
Molecular Alterations in Pediatric Sarcomas: Potential Targets for Immunotherapy
Purpose/results/discussion. Recurrent chromosomal translocations are common features of many human malignancies. While such translocations often serve as diagnostic markers, molecular analysis of these breakpoint regions and the characterization of the affected genes is leading to a greater understanding of the causal role such translocations play in
malignant transformation. A common theme that is emerging from the study of tumor-associated translocations is the generation of chimeric genes that, when expressed, frequently retain many of the functional properties of the wild-type genes from which they originated. Sarcomas, in particular, harbor chimeric genes that are often derived from transcription factors, suggesting that the resulting chimeric transcription factors contribute to tumorigenesis. The tumor-specific expression of the fusion proteins make them likely candidates for tumor-associated antigens (TAA) and are thus of interest in the development of new therapies. The focus of this review will be on the translocation events associated with Ewing's sarcomas/PNETs (ES), alveolar rhabdomyosarcoma (ARMS), malignant melanoma of soft parts (MMSP) (clear cell sarcoma), desmoplastic small round cell tumor (DSRCT), synovial sarcoma (SS), and liposarcoma (LS), and the potential for targeting the resulting chimeric proteins in novel immunotherapies
Autocrine Transforming Growth Factor-β Growth Pathway in Murine Osteosarcoma Cell Lines Associated with Inability to Affect Phosphorylation of Retinoblastoma Protein
Purpose. Production of active transforming growth factor-β (TGF-β )
by human osteosarcoma may contribute to malignant progression through mechanisms
that include induction of angiogenesis, immune suppression and autocrine growth
stimulation of tumor cell growth.To study events associated with induction of cell proliferation
by TGF-β , we have evaluated the TGF-β pathway in two murine osteosarcoma cell lines, K7
and K12
Hole spin polarization in GaAlAs:Mn structures
A self-consistent calculation of the electronic properties of GaAlAs:Mn
magnetic semiconductor quantum well structures is performed including the
Hartree term and the sp-d exchange interaction with the Mn magnetic moments.
The spin polarization density is obtained for several structure configurations.
Available experimental results are compared with theory.Comment: 4 page
Elevated plasma and urinary concentration of green tea catechins associated with improved plasma lipid profile in healthy Japanese women
This study investigated green tea catechins in plasma and urine and chronic disease biomarkers. We hypothesized that plasma and urinary concentration of green tea catechins are associated with cardiovascular disease and diabetes biomarkers. First void urine and fasting plasma samples were collected from 57 generally healthy females aged 38 to 73 years (mean, 52 ± 8 years) recruited in Himeji, Japan. The concentrations of plasma and urinary green tea catechins were determined by liquid chromatography coupled with mass tandem spectrometer. Low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, glucose, insulin, glycated hemoglobin, and C-reactive protein in plasma/serum samples were analyzed by a commercial diagnostic laboratory. Statistical associations were assessed using Spearman correlation coefficients. The results showed weak associations between plasma total catechin and triglyceride (r = -0.30) and LDL cholesterol (r = -0.28), whereas plasma (-)-epigallocatechin-3-gallate, (-)-epigallocatechin, (-)-epicatechin-3-gallate, and (-)-epicatechin exhibited weak to moderate associations with triglyceride or LDL cholesterol, but little associations with HDL cholesterol, body fat, and body mass index were evident. Urinary total catechin was weakly associated with triglyceride (r = -0.19) and LDL cholesterol (r = -0.15), whereas urinary (-)-epigallocatechin-3-gallate (r = -0.33), (-)-epigallocatechin (r = -0.23), and (-)-epicatechin-3-gallate (r = -0.33) had weak to moderate correlations with triglyceride and similarly with body fat and body mass index. Both plasma (r = -0.24) and urinary (r = -0.24) total catechin, as well as individual catechins, were weakly associated with glycated hemoglobin. Plasma total and individual catechins were weakly to moderately associated with C-reactive protein, but not the case for urinary catechins. In conclusion, we found weak to moderate associations between plasma and urinary green tea catechin concentrations and plasma biomarkers of cardiovascular disease and diabetes
Post-Transcriptional Dysregulation by miRNAs Is Implicated in the Pathogenesis of Gastrointestinal Stromal Tumor [GIST]
peer-reviewedIn contrast to adult mutant gastrointestinal stromal tumors [GISTs], pediatric/wild-type GISTs remain poorly understood
overall, given their lack of oncogenic activating tyrosine kinase mutations. These GISTs, with a predilection for gastric origin
in female patients, show limited response to therapy with tyrosine kinase inhibitors and generally pursue a more indolent
course, but still may prove fatal. Defective cellular respiration appears to underpin tumor development in these wild-type
cases, which as a group lack expression of succinate dehydrogenase [SDH] B, a surrogate marker for respiratory chain
metabolism. Yet, only a small subset of the wild-type tumors show mutations in the genes coding for the SDH subunits
[SDHx]. To explore additional pathogenetic mechanisms in these wild-type GISTs, we elected to investigate posttranscriptional
regulation of these tumors by conducting microRNA (miRNA) profiling of a mixed cohort of 73 cases
including 18 gastric pediatric wild-type, 25 (20 gastric, 4 small bowel and 1 retroperitoneal) adult wild-type GISTs and 30
gastric adult mutant GISTs. By this approach we have identified distinct signatures for GIST subtypes which correlate tightly
with clinico-pathological parameters. A cluster of miRNAs on 14q32 show strikingly different expression patterns amongst
GISTs, a finding which appears to be explained at least in part by differential allelic methylation of this imprinted region.
Small bowel and retroperitoneal wild-type GISTs segregate with adult mutant GISTs and express SDHB, while adult wildtype
gastric GISTs are dispersed amongst adult mutant and pediatric wild-type cases, clustering in this situation on the basis
of SDHB expression. Interestingly, global methylation analysis has recently similarly demonstrated that these wild-type,
SDHB-immunonegative tumors show a distinct pattern compared with KIT and PDGFRA mutant tumors, which as a rule do
express SDHB. All cases with Carney triad within our cohort cluster together tightly.Funding was obtained from the Medical Research Charities Group (http://www.mrcg.ie/) and Health Research Board of Ireland (http://www.hrb.ie)
(MO’S), The Children’s Medical and Research Foundation (http://www.cmrf.org) (MO’S), the GIST Cancer Awareness Foundation [GCAF] (http://www.
gistawareness.org/)(MO’S), and research grants from the Life Raft Group (http://www.liferaftgroup.org/)(MD-R) and from the Fonds voor Wetenschappelijk
Onderzoek Vlaanderen (http://www.fwo.be/)(grant # G.0286.05 MD-R)
Phase II Study of Sequential Gemcitabine Followed by Docetaxel for Recurrent Ewing Sarcoma, Osteosarcoma, or Unresectable or Locally Recurrent Chondrosarcoma: Results of Sarcoma Alliance for Research Through Collaboration Study 003
Background.Gemcitabine and docetaxel have a broad spectrum of clinical activity in patients with carcinoma. The Sarcoma Alliance for Research Through Collaboration conducted a phase II trial of gemcitabine in combination with docetaxel in children and adults with recurrent Ewing sarcoma (EWS), osteosarcoma (OS), or unresectable or recurrent chondrosarcoma. The primary objective was to determine the objective response rate using Response Evaluation Criteria in Solid Tumors (RECIST).Methods.Gemcitabine (675 mg/m2 i.v. over 90 minutes on days 1 and 8) was administered in combination with docetaxel (75 mg/m2 i.v. over 1 hour on day 8) every 21 days. All patients received filgrastim or pegfilgrastim. A Bayesian formulation was used to determine the probability of achieving the target response rate for each subtype—0.35 for EWS and OS or 0.20 for chondrosarcoma. If the probability of achieving the target response rate was <0.05, the combination was considered inactive. Toxicity was graded according to Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.Results.Fifty‐three eligible patients were enrolled in the three subtype groups—OS (n = 14), EWS (n = 14), and chondrosarcoma (n = 25). Toxicities included neutropenia, thrombocytopenia, fatigue, dyspnea, bronchospasm, edema, neuropathy, and liver function abnormalities. Dose modification for toxicity was required for eight patients during cycle 1 and 16 patients in subsequent cycles. Seven patients withdrew from therapy as a result of toxicity. No complete responses were observed. Partial responses were observed in OS (n = 1), EWS (n = 2), and chondrosarcoma (n = 2) patients.Conclusion.Gemcitabine in combination with docetaxel was associated with a probability of reaching the target 35% response rate of <5% in OS patients and 5.6% in EWS patients; the probability of reaching a 20% response rate in chondrosarcoma patients was 14%.摘要背景. 吉西他滨与多西他赛对癌症患者有广谱的临床疗效。 肉瘤研究联盟协作组在复发的尤文肉瘤 (EWS)、 骨肉瘤 (OS)、 不可切除或复发的软骨肉瘤成人和儿童患者中开展了吉西他滨联合多西他赛的 II 期试验。 主要目的为通过实体瘤疗效评估标准 (RECIST) 确定客观缓解率。方法. 吉西他滨 (675 mg/m2, 静脉滴注 90 分钟以上, 第 1 和 8 天) 联合多西他赛 (75 mg/m2, 静脉滴注 1 小时以上, 第 8 天) 每 21 天给药 1 次。 全部患者均同时接受非格司亭或乙二醇化非格司亭。 利用贝叶斯公式来确定各个亚型达到目标缓解率的概率——EWS 和 OS 为 0.35, 软骨肉瘤为 0.20。 如果达到目标缓解率的概率 < 0.05, 则认为联合方案无效。 毒性反应根据不良事件通用术语标准 (CTCAE) 3.0 版来分级。结果. 53 例合格患者入组 3 个亚型组 : OS (n=14)、 EWS (n=14)、 软骨肉瘤 (n=25)。 毒性反应包括中性粒细胞减少、 血小板减少、 乏力、 呼吸困难、 支气管痉挛、 水肿、 神经病变以及肝功能异常。 第 1 个周期有 8 例患者、 其后周期有 16 例患者因毒性反应而需要剂量调整。 7 例患者因毒性反应而撤出治疗。 未观察到完全缓解。 OS (n=1)、 EWS (n=2) 和软骨肉瘤 (n=2) 组均有患者达到部分缓解。结论. 吉西他滨联合多西他赛在 < 5% 的 OS 患者、 5.6% 的 EWS 患者中达到目标缓解率的概率为 35%; 14% 软骨肉瘤患者中达到目标缓解率的概率为 20%。讨论. 贝叶斯公式能够评估各个亚型在分别进行缓解率评估后预测达到目标缓解率的概率。 通过多角度来看这些数据, 在考量达到目标缓解率的概率以及入组率之后即能发现本研究设计方案阻碍了研究的继续开展。 因为这一设计方案并未设定判断治疗为 “有效” 的规则, 所以并不适合与标准的分 2 阶段进行的 II 期试验设计直接比较。 关闭 EWS 和软骨肉瘤亚组的决定, 某种程度上是基于入组缓慢, 另外达到目标缓解率的概率较低也支持这一决定。 入组率而不是统计设计, 对试验周期有显著影响。The Oncologist 2012;17:321‐e329Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139909/1/onco0321-sup-0002.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139909/2/onco0321-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139909/3/onco0321.pd
Indirect exchange in GaMnAs bilayers via spin-polarized inhomogeneous hole gas: Monte Carlo simulation
The magnetic order resulting from an indirect exchange between magnetic
moments provided by spin-polarized hole gas in the metallic phase of a GaMnAs
double layer structure is studied via Monte Carlo simulation. The coupling
mechanism involves a perturbative calculation in second order of the
interaction between the magnetic moments and carriers (holes). We take into
account a possible polarization of the hole gas due to the existence of an
average magnetization in the magnetic layers, establishing, in this way, a
self-consistency between the magnetic order and the electronic structure. That
interaction leads to an internal ferromagnetic order inside each layer, and a
parallel arrangement between their magnetizations, even in the case of thin
layers. This fact is analyzed in terms of the inter- and intra-layer
interactions.Comment: 17 pages and 14 figure
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