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Weisberg E.,Dana-Farber Cancer Institute | Halilovic E.,Novartis | Cooke V.G.,Novartis | Nonami A.,Dana-Farber Cancer Institute | And 22 more authors.
Molecular Cancer Therapeutics | Year: 2015

The tumor suppressor p53 is a key regulator of apoptosis and functions upstream in the apoptotic cascade by both indirectly and directly regulating Bcl-2 family proteins. In cells expressing wild-type (WT) p53, the HDM2 protein binds to p53 and blocks its activity. Inhibition of HDM2:p53 interaction activates p53 and causes apoptosis or cell-cycle arrest. Here, we investigated the ability of the novel HDM2 inhibitor CGM097 to potently and selectively kill WT p53-expressing AML cells. The antileukemic effects of CGM097 were studied using cellbased proliferation assays (human AML cell lines, primary AML patient cells, and normal bone marrow samples), apoptosis, and cell-cycle assays, ELISA, immunoblotting, and an AML patient-derived in vivo mouse model. CGM097 potently and selectively inhibited the proliferation of human AML cell lines and the majority of primary AML cells expressing WT p53, but not mutant p53, in a target-specific manner. Several patient samples that harbored mutant p53 were comparatively unresponsive to CGM097. Synergy was observed when CGM097 was combined with FLT3 inhibition against oncogenic FLT3-expressing cells cultured both in the absence as well as the presence of cytoprotective stromal-secreted cytokines, as well as when combined with MEK inhibition in cells with activated MAPK signaling. Finally, CGM097 was effective in reducing leukemia burden in vivo. These data suggest that CGM097 is a promising treatment for AML characterized as harboring WT p53 as a single agent, as well as in combination with other therapies targeting oncogene-activated pathways that drive AML. © 2015 AACR. Source

Stany M.P.,U.S. National Institutes of Health | Stone P.J.B.,SCL Physicians | Felix J.C.,University of Southern California | Amezcua C.A.,University of Southern California | And 8 more authors.
International Journal of Gynecological Pathology | Year: 2015

Although patients with early-stage cervical cancer have in general a favorable prognosis, 10% to 40% patients still recur depending on pathologic risk factors. The objective of this study was to evaluate if the presence of lymph node micrometastasis (LNmM) had an impact on patient's survival. We performed a multi-institutional retrospective review on patients with early-stage cervical cancer, with histologically negative lymph nodes, treated with radical hysterectomy and pelvic lymphadenectomy for the study period 1994 to 2004. Tissue blocks of lymph nodes from the patient's original surgery were recut and then evaluated for the presence of micrometastases. One hundred twenty-nine patients were identified who met inclusion criteria. LNmM were found in 26 patients (20%). In an average follow-up time of 70 mo, there were 11 recurrences (8.5%). Of the 11 recurrences, 2 (18%) patients had LNmM. Patients with LNmM were more likely to have received adjuvant radiation and chemotherapy. In stratified log-rank analysis, LNmM were not associated with any other high-risk clinical or pathologic variables. Survival data analysis did not demonstrate an association between the presence of LNmM and recurrence or overall survival. The presence of LNmM was not associated with an unfavorable prognosis nor was it associated with other high-risk clinical or pathologic variables predicting recurrence. Further study is warranted to understand the role of micrometastases in cervical cancer. © 2015 International Society of Gynecological Pathologists. Source

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Abstract: By studying an unusual group of magnetic microorganisms, scientists at UC Berkeley have uncovered a new and unexpected function for a ubiquitous protein family. Proteases are workhorse enzymes found in all living organisms that act in general cellular maintenance and communication by chewing up proteins. In a paper publishing in the Open Access journal PLOS Biology on March 16th 2016, the Komeili lab, along with collaborators in the Hurley and Chang groups, have now shown that a bacterial protein called MamO has been transformed from a common protease to an inactive enzyme that helps to build magnetic nanoparticles using a novel metal-binding motif. Many organisms, ranging from mammals to small single-celled algae, add functionality to their cells through the construction of elaborate three-dimensional minerals. The products of these "biomineralization" processes are of great interest in both basic and industrial settings. "We would like to know how minerals are built in nature since they constitute a fundamental survival strategy for many organisms," said Dr. Komeili. In addition, scientists are interested in mimicking natural biomineralization systems to design customized nanoparticles for use in a number of applications. In order to study the biological control of mineral production, Komeili and his team have been studying how a group of microorganisms, called magnetotactic bacteria, makes chains of magnetic crystals that allow the cells to swim along the earth's geomagnetic field. Their study focuses on Magnetospirillum magneticum AMB-1, a bacterium that builds small compartments called magnetosomes, which house the machinery for crystallizing iron atoms to make magnetite. Komeili's group knew that two proteins, MamE and MamO, are required at the earliest stages of mineral formation in AMB-1. Based on predicted similarities to known enzymes in the DNA sequences for each gene, both proteins had been designated as proteases. In an effort to understand details about how the protein works, David Hershey, a graduate student in the Komeili lab, wanted to understand the precise architecture and activity of MamO. They used X-ray crystallography to define the atomic structure of MamO. At first glance, MamO adopts a shape that is quite similar to that of other proteases. But by examining the structure more closely, Hershey and his colleagues found that MamO is riddled with changes that show it has lost the ability to perform its protease function. Instead, they discovered that MamO has an unexpected metal-binding activity that is required for AMB-1 to make magnetic crystals. Their results show that this ancient protease scaffold has been transformed into a novel metal-binding feature. Surprisingly, they found that a process similar to the one discovered in AMB-1 has occurred in all major groups of magnetotactic bacteria. Using the motifs they identified in MamO, they show that the genomes of these very diverse species also have inactive proteases. By tracing their evolutionary trajectory they found that the inactive proteases have arisen numerous times throughout the evolution of magnetosomes by convergent evolution. "We really thought that something this unusual would have evolved only once. That just isn't the case. It really just cements how unusual this process is," says David Hershey. Komeili and his team think that dramatic changes to the environment in the distant past provided the selective pressure that necessitated the presence of inactive proteases for formation of magnetic nanoparticles. The unexpected findings on the structure, activity and evolution of MamO has set the stage for a whole host of future explorations of biomineralization. Komeili's group wants to continue to investigate the precise role of metal-binding by MamO in biomineralization. Does MamO directly sequester iron to build the nucleus of the magnetic crystals? Or, does it act as a monitoring system for the local magnetosome environment, initiating biomineralization at the appropriate time? More broadly, Dr. Komeili hopes that the metal-binding activity of MamO can be exploited to produce magnetic particles synthetically using a simplified chemical system. Funding: DMH and AK are supported by grants from the National Institutes of Health R01GM084122 and the Office of Naval Research N000141310421. Beamline 8.3.1 at the Advanced Light Source, LBNL, is supported by the UC Office of the President, Multicampus Research Programs and Initiatives grant MR?15?328599 and the Program for Breakthrough Biomedical Research, which is partially funded by the Sandler Foundation. The Advanced Light Source is supported by the Director, Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. For more information, please click If you have a comment, please us. Issuers of news releases, not 7th Wave, Inc. or Nanotechnology Now, are solely responsible for the accuracy of the content.

Abstract: Kaho Maeda, Dr. Hideto Ito, Professor Kenichiro Itami of the JST-ERATO Itami Molecular Nanocarbon Project and the Institute of Transformative Bio-Molecules (ITbM) of Nagoya University, and their colleagues have reported in the Journal of the American Chemical Society, on the development of a new and simple strategy, "helix-to-tube" to synthesize covalent organic nanotubes. Organic nanotubes (ONTs) are organic molecules with tubular nanostructures. Nanostructures are structures that range between 1 nm and 100 nm, and ONTs have a nanometer-sized cavity. Various applications of ONTs have been reported, including molecular recognition materials, transmembrane ion channel/sensors, electro-conductive materials, and organic photovoltaics. Most ONTs are constructed by a self-assembly process based on weak non-covalent interactions such as hydrogen bonding, hydrophobic interactions and π-π interactions between aromatic rings. Due to these relatively weak interactions, most non-covalent ONTs possess a relatively fragile structure. Covalent ONTs, whose tubular skeletons are cross-linked by covalent bonding (a bond made by sharing of electrons between atoms) could be synthesized from non-covalent ONTs. While covalent ONTs show higher stability and mechanical strength than non-covalent ONTs, the general synthetic strategy for covalent ONTs was yet to be established. A team led by Hideto Ito and Kenichiro Itami has succeeded in developing a simple and effective method for the synthesis of robust covalent ONTs (tube) by an operationally simple light irradiation of a readily accessible helical polymer (helix). This so-called "helix-to-tube" strategy is based on the following steps: 1) polymerization of a small molecule (monomer) to make a helical polymer followed by, 2) light-induced cross-linking at longitudinally repeating pitches across the whole helix to form covalent nanotubes. With their strategy, the team designed and synthesized diacetylene-based helical polymers (acetylenes are molecules that contain carbon-carbon triple bonds), poly(m-phenylene diethynylene)s (poly-PDEs), which has chiral amide side chains that are able to induce a helical folding through hydrogen-bonding interactions. The researchers revealed that light-induced cross-linking at longitudinally aligned 1,3-butadiyne moieties (a group of molecules that contain four carbons with triple bonds at the first and third carbons) could generate the desired covalent ONT. "This is the first time in the world to show that the photochemical polymerization reaction of diynes is applicable to the cross-linking reaction of a helical polymer," says Maeda, a graduate student who mainly conducted the experiments. The "helix-to-tube" method is expected to be able to generate a range of ONT-based materials by simply changing the arene (aromatic ring) unit in the monomer. "One of the most difficult parts of this research was how to obtain scientific evidence on the structures of poly-PDEs and covalent ONTs," says Ito, one of the leaders of this study. "We had little experience with the analysis of polymers and macromolecules such as ONTs. Fortunately, thanks to the support of our collaborators in Nagoya University, who are specialists in these particular research fields, we finally succeeded in characterizing these macromolecules by various techniques including spectroscopy, X-ray diffraction, and microscopy." "Although it took us about a year to synthesize the covalent ONT, it took another one and a half year to determine the structure of the nanotube," says Maeda. "I was extremely excited when I first saw the transmission electron microscopy (TEM) images, which indicated that we had actually made the covalent ONT that we were expecting," she continues. "The best part of the research for me was finding that the photochemical cross-linking had taken place on the helix for the first time," says Maeda. "In addition, photochemical cross-linking is known to usually occur in the solid phase, but we were able to show that the reaction takes place in the solution phase as well. As the reactions have never been carried out before, I was dubious at first, but it was a wonderful feeling to succeed in making the reaction work for the first time in the world. I can say for sure that this was a moment where I really found research interesting." "We were really excited to develop this simple yet powerful method to achieve the synthesis of covalent ONTs," says Itami, the director of the JST-ERATO project and the center director of ITbM. "The "helix-to-tube" method enables molecular level design and will lead to the synthesis of various covalent ONTs with fixed diameters and tube lengths with desirable functionalities." "We envisage that ongoing advances in the "helix-to-tube" method may lead to the development of various ONT-based materials including electro-conductive materials and luminescent materials," says Ito. "We are currently carrying out work on the "helix-to-tube" methodology and we hope to synthesize covalent ONTs with interesting properties for various applications." About Nagoya University JST-ERATO Itami Molecular Nanocarbon Project The JST-ERATO Itami Molecular Nanocarbon Project was launched at Nagoya University in April 2014. This is a 5-year project that seeks to open the new field of nanocarbon science. This project entails the design and synthesis of as-yet largely unexplored nanocarbons as structurally well-defined molecules, and the development of novel, highly functional materials based on these nanocarbons. Researchers combine chemical and physical methods to achieve the controlled synthesis of well-defined uniquely structured nanocarbon materials, and conduct interdisciplinary research encompassing the control of molecular arrangement and orientation, structural and functional analysis, and applications in devices and biology. The goal of this project is to design, synthesize, utilize, and understand nanocarbons as molecules. About WPI-ITbM The Institute of Transformative Bio-Molecules (ITbM) at Nagoya University in Japan is committed to advance the integration of synthetic chemistry, plant/animal biology and theoretical science, all of which are traditionally strong fields in the university. ITbM is one of the research centers of the Japanese MEXT (Ministry of Education, Culture, Sports, Science and Technology) program, the World Premier International Research Center Initiative (WPI). The aim of ITbM is to develop transformative bio-molecules, innovative functional molecules capable of bringing about fundamental change to biological science and technology. Research at ITbM is carried out in a "Mix-Lab" style, where international young researchers from various fields work together side-by-side in the same lab, enabling interdisciplinary interaction. Through these endeavors, ITbM will create "transformative bio-molecules" that will dramatically change the way of research in chemistry, biology and other related fields to solve urgent problems, such as environmental issues, food production and medical technology that have a significant impact on the society. About JST-ERATO ERATO (The Exploratory Research for Advanced Technology), one of the Strategic Basic Research Programs, aims to form a headstream of science and technology, and ultimately contribute to science, technology, and innovation that will change society and the economy in the future. In ERATO, a Research Director, a principal investigator of ERATO research project, establishes a new research base in Japan and recruits young researchers to implement his or her challenging research project within a limited time frame. For more information, please click If you have a comment, please us. Issuers of news releases, not 7th Wave, Inc. or Nanotechnology Now, are solely responsible for the accuracy of the content.

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Centinel Spine, West Chester, Pa., has developed Ti-Active titanium plasma spray coatings on polyetheretherketone implants. The coating enhances the PEEK implants by providing an integrated microporous titanium surface designed to increase the coefficient of friction for enhanced insertion stability. The coating also enables cellular attachment and proliferation to maximize opportunities for fusion. Retrospective studies show clinically favorable outcomes for hip stems with plasma spray titanium coatings that result in excellent bony on-growth and long-term stability. Recent literature shows that 100% titanium interbody cages have more cellular attachment and proliferation properties than traditional PEEK cages. However, all-titanium cages have a higher modulus of elasticity and an increased risk of subsidence. Built on over 15 years of science and experience, Centinel Spine engineered the Ti-Active technology to merge the translucent and biomechanical advantages of PEEK with the hydrophilic and cell-friendly properties of titanium. Ti-Active devices are 20 times rougher than uncoated PEEK devices, and the 3D topography increases the surface area in contact with the bony endplates, maximizing the potential for fusion. "When titanium is added to the PEEK implant it makes the implant easier for cells to adhere and proliferate," says Celeste Abjornson, Ph.D., project coordinator with the Integrated Spine Research Programs at Hospital for Special Surgery in New York City. These scientists recently published a paper examining the different roughness profiles of titanium coatings. They reported that when the titanium coating achieves the right roughness, the cells are able to express different growth factors and proteins.

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