Tumorspheres were isolated from core biopsies collected from five patients with clinical diagnosis of invasive ductal carcinoma (IDC). Isolated tumorspheres were transplanted into the mammary fat pad of NUDE mice to establish tumorigenicity in vivo. At 3 months post-injection, micrometastases to the lung, liver, kidneys, brain and femur were detected by measuring content of human chromosome 17. Primary tumors variably expressed cytokeratins, Her2/neu, cytoplasmic E-cadherin, nuclear catenin and fibronectin but were negative for ER and vimentin. The injection of bone marrow isolated from mice previously injected with tumorspheres into the mammary fat pad, resulted in large tumor formation in the mammary fat pad 2 months post-injection. The tumors exhibited accelerated development of metastatic lesions within the lung, liver and kidney. The resultant tumors and the majority of metastatic lesions within the lung and liver exhibited a mesenchymal-like phenotype. Conclusions: Micrometastases in mouse organs demonstrated a dormancy period prior to outgrowth of macrometastases. Dormant disseminated tumor cells (DTCs) within the bone marrow were highly malignant upon injection into the mammary fat pad, with the accelerated development of metastatic lesions. These results indicate the acquisition of a more aggressive phenotype of DTCs during metastatic latency within the bone marrow microenvironment.

关键词：活检；骨髓；乳腺癌；转移

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Traumatic Brain Injury (TBI) is a well-established inducer of temporal lobe epilepsy (TLE), a frequently medically intractable and permanent epilepsy syndrome. Unlike many TLE models, which cause global brain injury that do not replicate the human condition, or other TBI models, which do not induce TLE reliably, the controlled cortical impact (CCI) model of posttraumatic epilepsy in mice results in localized cell loss, synaptic reorganization, and development of TLE. Abnormalities in inhibitory neurotransmission are important aspects of TLE in several animal models. Under this award, the CCI model was established in all three collaborating laboratories. Specific parameters of injury associated with epileptogenesis were determined. It was determined that upregulation of the JaK/STAT3 pathway in the injured hippocampus occurs after CCI, which could be blocked by post-injury administration of a JaK/STAT3 inhibitor. Blocking JaK/STAT3 activity did not prevent loss of GABA cells in the injured hippocampus. Inhibitory postsynaptic currents in the dentate gyrus ipsilateral to the injury were reduced in frequency weeks after the injury, recapitulating findings in other models in which aspects of epileptogenesis were attenuated by STAT3 inhibition. These results critically establish model parameters and control measurements, and provide the basis for remaining proposed experiments.

关键词：创伤性脑损伤；癫痫；海马

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Several in vitro studies have demonstrated the non-thermal (< 42 deg C) cell killing effect of pulsed HIFU, which resembles high linear energy transfer (LET) radiation cell damage that is not not affected by the local biochemical environment and shows less radiation resistance. However, there have been no in vivo animal studies performed on non-thermal HIFU using an animal model by comparing it with well-established treatment modalities such as radiation therapy. This project has two aims: (1) to determine if non-thermal HIFU can cause significant tumor growth delays in vivo as compared to radiotherapy using an animal model; and (2) to determine potential normal tissue toxicities, if any, associated with non-thermal HIFU treatment for breast cancer. Extensive phantom studies have been completed to determine suitable ultrasound parameters for the in vivo animal experiments demonstrated significant tumor growth delay by non-thermal HIFU that are comparable to radiotherapy without damage to overlapping tissues, which warrant future feasibility studies to determine optimal HIFU treatment parameters for human treatments and to quantify normal tissue toxicities associated with non-thermal HIFU treatments.

关键词：乳腺癌；辐射损伤；放射治疗；超声细胞

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Decision making in an unavoidable part of out daily lives. Many decisions are straightforward, but others require careful consideration of each alternative and many attributes characterizing each alternative. If these attributes are mutually dependent, the Choquet integral is a technique often used for modeling the decision making problem. With a large number of attributes to consider, decision making becomes an optimization problem that requires huge computational resources in order to be solved exactly. Instead of using a large amount of these resources, heuristic techniques have been used to speed the computations and find a suboptimal decision. Yet, these heuristic methods could be improved to find better approximation with minimal increase in required computational resources. Genetic algorithm has been used in many situations as a heuristic optimization technique. In this paper, we present some modifications to the genetic algorithm that allow more precise optimization.

关键词：决策；医药；遗传算法

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Vascular disruption agents (VDAs) have been shown to selectively destroy established tumor vasculature, which results in the ischemic death of up to 99% of tumor cells. The weakness of VDA monotherapy is that it often leaves a rim of surviving tumor cells which can then regrow and spread. The overall goal of this study (addressed in Task 2) was to enhance VDA therapy by inducing hyperthermia, targeted to the neovascular endothelium, through the use of superparamagnetic iron oxide nanoparticles (SPIONs), in order to halt, or significantly slow down tumor growth. Therefore, the first aim of this study (Task 1) was to maximize the delivery of SPIONs to the tumor rim, through a combination of neovascular targeting and increased vascular permeability induced by the VDA. Covalent coupling of primary amines on VEGFR-2 antibodies to carboxyl groups on the SPIONs activated by EDC/Sulfo-NHS resulted in stable particles that showed specific binding to endothelial cells in vitro. Current in vivo results suggest a modest enhancement of SPION delivery to the tumor rim when VEGFR-2 targeting of PEG-coated particles and 15 min pre-administration of DMXAA (a VDA) are employed. The results suggest that the combination of targeting the neovasculature and increasing vascular permeability through the action of the VDA is an effective SPION delivery strategy; however, statistically-significant nanoparticle quantitation (by mass spectrometry) was not realized, due to high endogenous iron levels in tumor tissue. In vitro testing of SPION heating in the presence of an alternating magnetic field demonstrated that heating is optimized using 20 nm SPIONs. Reformulation of the poorly soluble DMXAA (using bicarbonate buffer to replace DMSO) was shown to improve long-term survival of the mice after DMXAA administration, which will enable in vivo longitudinal measurements of therapeutic efficacy to be carried out in a future study.

关键词：乳腺癌；转移；肿瘤细胞（生物学）

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Apoptin-containing nanocapsules have been shown to be efficiently internalized by mammalian cells and induce tumor-specific apoptosis in vitro and in vivo. Identification of targeting moieties can further improve the efficacy of these nanoparticles. Targeting nanoparticles by conjugating various specific ligands has shown potential therapeutic efficacy in nanomedicine. However, poor penetration of antitumor drugs into solid tumors remains a major obstacle. We demonstrated a targeting strategy by conjugating nanoparticles with a tumor-penetrating peptide, iRGD. The results showed that iRGD could facilate the binding and cellular uptake of nanoparticles. Colocalization data revealed that iRGD-conjugated nanoparticles entered cells via the clathrin- mediated pathway, followed by endosome-lysosome transport. In addition, we were able to demonstrate that the biofunctional chelator AmBaSar could be used in the 64Cu labeling of nanoparticles and the positron emission tomography-based images of particle distribution could be obtained at several time points after intravenous administration of nanoparticles. Our data support the further experiment to use iRGD for targeting nanocapsules and to use PET imaging for investigating bioditribution of nanocapsule in vivo.

关键词：乳腺癌；凋亡细胞（生物学）；肿瘤

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Most cancer-related deaths arise from metastasis produced by circulating tumor cells (CTCs). A new concept of this research is that circulating cancer stem cell (CSC)-platelet aggregates (CSCPA) represent the most aggressive subset of CTCs responsible for breast cancer metastasis. The goal of this proposal is to identify and count CSCPAs in vivo in preclinical models of metastatic breast cancer, and to define the correlation of CSCPA amount with metastasis development. We developed a novel, in vivo multicolor photoacoustic (PA) flow cytometry (PAFC) platform for the detection of CSCPAs using the principle of flow cytometry, negative and positive PA contrasts, multispectral high-pulse-repetition-rate lasers, bioconjugated nanoparticles and a mouse model of human breast cancer. Using this approach, we provided a proof-of-concept for highly sensitive detection of CSCPAs and individual CSCs in real biological environments in a whole body in vivo. For the first time, we demonstrated the ability of CSCs to form aggregates with platelets (CSCPAs) in blood circulation of tumorbearing mice. Furthermore we showed that the number of CSCPAs increased during development of metastatic disease. Obtained preclinical results can advance general understanding of cancer stem cell biology and metastasis progression as well as will be used as the basis for initiating highly innovative clinical research in cancer patients.

关键词：血液中的血小板；乳腺癌；临床医学

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Persistent pain is a common reason for reduced quality of life after a spinal cord injury (SCI). Biomarkers of neuropathic pain may facilitate translational research and the understanding of underlying mechanisms. Research suggests that pain and affective distress are anatomically and functionally integrated in the anterior cingulate cortex and can modulate sensory and affective aspects of pain. We hypothesized that severe neuropathic pain with a significant psychosocial impact would be associated with metabolite concentrations (obtained by magnetic resonance spectroscopy) in the anterior cingulate cortex, indicating neuronal and/or glial dysfunction. Participants with SCI and severe, high-impact neuropathic pain (SCI-HPI; n = 16), SCI and moderate, low-impact neuropathic pain (SCI-LPI; n = 24), SCI without neuropathic pain (SCInoNP; n = 14), and able-bodied, pain-free control subjects (A-B; n = 22) underwent a 3-T magnetic resonance imaging brain scan. Analyses revealed that the SCI-HPI group had significantly higher levels of myoinositol (Ins).

关键词：代谢产物；疼痛；脊髓；浓度（构图）

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Nanotechnology is a relatively recent field of scientific research. Richard Feynman first propounded the concept in 1959. An official definition of nanotechnology is still a controversial issue and there are many scientific committees hard at work to harmonize the term and obtain universal regulation. There are enormous expectations with regard to the potential for nanotechnology in many different scientific fields. Over the last ten years, a large number of potential applications for nanotechnology have been described, most especially in the fields of biology, biotechnology and medicine. The term nanomedicine is used to describe the medical application of nanotechnology in the diagnosis, prevention and treatment of several diseases. Such applications have led to significant advances in clinical areas such as oncology (nanoncology), neuroscience, cardiovascular disease and many others. Nanomedicine has the potential to improve the efficiency of existing drugs while reducing their side effects, to create new therapeutic systems, to enhance diagnosis to achieve higher levels of detection, to create new scaffolds for tissue regeneration and to create internal surveillance systems in order to avoid the development of disease. With the great potential of nanotechnology it is expected to have significant impact, both on an economic and technological level. However, concerns about possible toxicity and certain ethical issues are delaying the launch of this promising new technology. The purpose of the present review is to highlight new findings in the field of nanomedicine, most especially in the area of oncology, and to describe its major benefits, possible risks and current regulations, as well as to enumerate some of the nanomaterials developed up to now. Additionally we discuss future prospects for the development of certain emerging nanotechnologies and their potential contributions to medicine and market impact will be discussed.

关键词：纳米医学；医药；治疗学

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The Six1 homeoprotein encodes a transcription factor that is critical during embryonic development. Six1 expression is normally limited to embryogenesis, however is found to be overexpressed in human breast cancers. Using cell culture and mouse models, we have previously shown that Six1 not only promotes proliferation and survival, contributing to tumorigenesis, but also upregulates the TGF pathway, brings about an EMT-like transformation, increases the cancer stem cell population, aand promotesmetastasis. To further investigate the mechanism by which Six1 mediates the switch in TGF signaling, we performed a miRNA microarray screen and identified a cluster of miRNAs, the miR106b-25 cluster, that is upregulated in response to Six1 overexpression. The miR106b-25 cluster consists of three miRNAs, miR-106b, miR-93, and miR-25, which reside together in the intron of the MCM7 gene. Importantly, overexpression and knockdown experiments demonstrate that Six1 regulates all three miRNAs within the cluster. Interestingly, these miRNA have previously been implicated in the impairment of TGF -mediated growth suppression through repression of the cell cycle inhibitor, p21, and pro-apoptotic factor, Bim. These data suggest that Six1-induced upregulation of these miRNA may mediate the switch in TGF signaling from tumor suppressive to tumor promotional. Surprinsingly, bioinformatic analysis revealed that the miR106b-25 cluster may also contribute to the activation of TGF signaling through repression of the TGF signaling inhibitor, Smad7, which mediates the degradation of T RI. Indeed, we now report that overexpression of the miR106b-25 cluster results in repression of the Smad7 3 UTR, with concominant upregulation of T RI.

关键词：乳腺癌；核糖核酸；体内分析

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