Institute of Engineering in Medicine

San Diego, CA, United States

Institute of Engineering in Medicine

San Diego, CA, United States
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News Article | June 28, 2017
Site: www.sciencedaily.com

In a new study, published online in the July 26 issue of PNAS, researchers at University of California San Diego School of Medicine, with colleagues in Xijing Hospital and Sun Yat-sen Cancer Center in China, report that DNA methylation can provide effective markers for at least four major cancers, not only correctly differentiating malignant tissues from normal, but also providing information on prognosis and survival. "Choosing the proper cancer treatment with the best chance of recovery and survival depends greatly upon accurately diagnosing the specific type or subtype of cancer," said Kang Zhang, MD, PhD, founding director of the Institute for Genomic Medicine and co-director of biomaterials and tissue engineering at the Institute of Engineering in Medicine, both at UC San Diego School of Medicine. "If you can do that using a minimally invasive biopsy, it has significant implications for cancer science and medicine. Using DNA methylation markers may be a new and more effective a way forward." DNA methylation involves methyl groups -- one carbon atom bonded to three hydrogen atoms -- attaching to DNA molecules. It is a fundamental epigenetic process that regulates gene function without changing the DNA sequence of a gene, essential to normal development and associated with numerous key processes, including initiation and progression of cancer. Zhang and colleagues looked at DNA methylation for differentiating tumor tissue and normal tissue for the four most common cancers (lung, breast, colon and liver) in three different databases: a training cohort of 1,619 tumor samples and 173 matched adjacent normal tissue samples; a testing cohort of 791 tumor samples from The Cancer Genome Atlas and 93 matched adjacent normal tissue samples and another independent testing Chinese cohort of 394 tumor samples; and 324 matched adjacent normal tissue samples. They found that DNA methylation analysis could predict cancer versus normal tissue with more than 95 percent accuracy in the three cohorts, comparable to typical diagnostic methods, according to Zhang. In addition, the analysis correctly identified 97 percent colorectal cancer metastases to the liver and 94 percent colorectal cancer metastases to the lung. "Since 10 percent of cancers present as metastatic lesions or cancers of unknown primary origin, identification of tissue of origin is critical for choosing a correct therapy. This new simple method will be of great value to pinpoint the primary source of the tumor," said Michael Karin, co-senior author of the study and Distinguished Professor of Pharmacology, also at UC San Diego School of Medicine. Zhang suggested DNA methylation has the potential to improve outcomes by providing more accurate diagnoses, particularly of relatively indolent or aggressive tumors that may require more or less aggressive treatment. "Although we focused on just four common cancers here, we expect that DNA methylation analysis could be easily expanded to aid diagnoses of a much larger number of cancers," said Zhang. "A great benefit is that this approach requires only a small amount of tissue to obtain adequate DNA for analysis, potentially allowing the use of less invasive biopsies or biopsies of metastatic lesions where the tumor is of unknown primary cancer type." He said more studies have been planned to fully explore the clinical applications and potential of DNA methylation and its role in future personalized cancer care.


News Article | June 27, 2017
Site: www.eurekalert.org

In a new study, published online in the July 26 issue of PNAS, researchers at University of California San Diego School of Medicine, with colleagues in Xijing Hospital and Sun Yat-sen Cancer Center in China, report that DNA methylation can provide effective markers for at least four major cancers, not only correctly differentiating malignant tissues from normal, but also providing information on prognosis and survival. "Choosing the proper cancer treatment with the best chance of recovery and survival depends greatly upon accurately diagnosing the specific type or subtype of cancer," said Kang Zhang, MD, PhD, founding director of the Institute for Genomic Medicine and co-director of biomaterials and tissue engineering at the Institute of Engineering in Medicine, both at UC San Diego School of Medicine. "If you can do that using a minimally invasive biopsy, it has significant implications for cancer science and medicine. Using DNA methylation markers may be a new and more effective a way forward." DNA methylation involves methyl groups -- one carbon atom bonded to three hydrogen atoms -- attaching to DNA molecules. It is a fundamental epigenetic process that regulates gene function without changing the DNA sequence of a gene, essential to normal development and associated with numerous key processes, including initiation and progression of cancer. Zhang and colleagues looked at DNA methylation for differentiating tumor tissue and normal tissue for the four most common cancers (lung, breast, colon and liver) in three different databases: a training cohort of 1,619 tumor samples and 173 matched adjacent normal tissue samples; a testing cohort of 791 tumor samples from The Cancer Genome Atlas and 93 matched adjacent normal tissue samples and another independent testing Chinese cohort of 394 tumor samples; and 324 matched adjacent normal tissue samples. They found that DNA methylation analysis could predict cancer versus normal tissue with more than 95 percent accuracy in the three cohorts, comparable to typical diagnostic methods, according to Zhang. In addition, the analysis correctly identified 97 percent colorectal cancer metastases to the liver and 94 percent colorectal cancer metastases to the lung. "Since 10 percent of cancers present as metastatic lesions or cancers of unknown primary origin, identification of tissue of origin is critical for choosing a correct therapy. This new simple method will be of great value to pinpoint the primary source of the tumor," said Michael Karin, co-senior author of the study and Distinguished Professor of Pharmacology, also at UC San Diego School of Medicine. Zhang suggested DNA methylation has the potential to improve outcomes by providing more accurate diagnoses, particularly of relatively indolent or aggressive tumors that may require more or less aggressive treatment. "Although we focused on just four common cancers here, we expect that DNA methylation analysis could be easily expanded to aid diagnoses of a much larger number of cancers," said Zhang. "A great benefit is that this approach requires only a small amount of tissue to obtain adequate DNA for analysis, potentially allowing the use of less invasive biopsies or biopsies of metastatic lesions where the tumor is of unknown primary cancer type." He said more studies have been planned to fully explore the clinical applications and potential of DNA methylation and its role in future personalized cancer care. Co-authors include: Xiaoke Hao, Fourth Military Medical University, Xi'an, China; Huiyan Luo and Rui-hua Xu, Sun Yat-sen University Cancer Center, Guangzhou, China; Michal Krawczyk, Wei Wei, Ken Flagg, Jiayi Hou, Shaohua Yi, Maryam Jafari, Danni Lin, Christopher Chung, Bennett A. Caughey, William Shi, Jie Zhu, Xin Fu, Edward Zhang, Charlotte Zhang, and Debanjan Dhar, UC San Diego; Heng Zhang, Lianghong Zheng, and Rui Hou, Chinese Academy of Sciences, Shanghai, China; and Gen Li and Liang Zhao, Guangzhou Youze Biological Pharmaceutical Technology Company, Guangzhou, China.


Mo A.H.,Materials Science and Engineering Program | Landon P.B.,Institute of Engineering in Medicine | Gomez K.S.,Institute of Engineering in Medicine | Gomez K.S.,University of Sonora | And 12 more authors.
Nanoscale | Year: 2016

Composite colloidal structures with multi-functional properties have wide applications in targeted delivery of therapeutics and imaging contrast molecules and high-throughput molecular bio-sensing. We have constructed a multifunctional composite magnetic nanobowl using the bottom-up approach on an asymmetric silica/polystyrene Janus template consisting of a silica shell around a partially exposed polystyrene core. The nanobowl consists of a silica bowl and a gold exterior shell with iron oxide magnetic nanoparticles sandwiched between the silica and gold shells. The nanobowls were characterized by electron microscopy, atomic force microscopy, magnetometry, vis-NIR and FTIR spectroscopy. Magnetically vectored transport of these nanobowls was ascertained by time-lapsed imaging of their flow in fluid through a porous hydrogel under a defined magnetic field. These magnetically-responsive nanobowls show distinct surface enhanced Raman spectroscopy (SERS) imaging capability. The PEGylated magnetically-responsive nanobowls show size-dependent cellular uptake in vitro. © 2016 The Royal Society of Chemistry.


News Article | November 16, 2016
Site: www.eurekalert.org

LA JOLLA--(November 16, 2016) Salk Institute researchers have discovered a holy grail of gene editing--the ability to, for the first time, insert DNA at a target location into the non-dividing cells that make up the majority of adult organs and tissues. The technique, which the team showed was able to partially restore visual responses in blind rodents, will open new avenues for basic research and a variety of treatments, such as for retinal, heart and neurological diseases. "We are very excited by the technology we discovered because it's something that could not be done before," says Juan Carlos Izpisua Belmonte, a professor in Salk's Gene Expression Laboratory and senior author of the paper published on November 16, 2016 in Nature. "For the first time, we can enter into cells that do not divide and modify the DNA at will. The possible applications of this discovery are vast." Until now, techniques that modify DNA--such as the CRISPR-Cas9 system--have been most effective in dividing cells, such as those in skin or the gut, using the cells' normal copying mechanisms. The new Salk technology is ten times more efficient than other methods at incorporating new DNA into cultures of dividing cells, making it a promising tool for both research and medicine. But, more importantly, the Salk technique represents the first time scientists have managed to insert a new gene into a precise DNA location in adult cells that no longer divide, such as those of the eye, brain, pancreas or heart, offering new possibilities for therapeutic applications in these cells. To achieve this, the Salk researchers targeted a DNA-repair cellular pathway called NHEJ (for "non-homologous end-joining"), which repairs routine DNA breaks by rejoining the original strand ends. They paired this process with existing gene-editing technology to successfully place new DNA into a precise location in non-dividing cells. "Using this NHEJ pathway to insert entirely new DNA is revolutionary for editing the genome in live adult organisms," says Keiichiro Suzuki, a senior research associate in the Izpisua Belmonte lab and one of the paper's lead authors. "No one has done this before." First, the Salk team worked on optimizing the NHEJ machinery for use with the CRISPR-Cas9 system, which allows DNA to be inserted at very precise locations within the genome. The team created a custom insertion package made up of a nucleic acid cocktail, which they call HITI, or homology-independent targeted integration. Then they used an inert virus to deliver HITI's package of genetic instructions to neurons derived from human embryonic stem cells. "That was the first indication that HITI might work in non-dividing cells," says Jun Wu, staff scientist and co-lead author. With that feat under their belts, the team then successfully delivered the construct to the brains of adult mice. Finally, to explore the possibility of using HITI for gene-replacement therapy, the team tested the technique on a rat model for retinitis pigmentosa, an inherited retinal degeneration condition that causes blindness in humans. This time, the team used HITI to deliver to the eyes of 3-week-old rats a functional copy of Mertk, one of the genes that is damaged in retinitis pigmentosa. Analysis performed when the rats were 8 weeks old showed that the animals were able to respond to light, and passed several tests indicating healing in their retinal cells. "We were able to improve the vision of these blind rats," says co-lead author Reyna Hernandez-Benitez, a Salk research associate. "This early success suggests that this technology is very promising." The team's next steps will be to improve the delivery efficiency of the HITI construct. As with all genome editing technologies, getting enough cells to incorporate the new DNA is a challenge. The beauty of HITI technology is that it is adaptable to any targeted genome engineering system, not just CRISPR-Cas9. Thus, as the safety and efficiency of these systems improve, so too will the usefulness of HITI. "We now have a technology that allows us to modify the DNA of non-dividing cells, to fix broken genes in the brain, heart and liver," says Izpisua Belmonte. "It allows us for the first time to be able to dream of curing diseases that we couldn't before, which is exciting." Other researchers on the study were Euiseok J. Kim, Fumiyuki Hatanaka, Mako Yamamoto, Toshikazu Araoka, Masakazu Kurita, Tomoaki Hishida, Mo Li, Emi Aizawa, April Goebl, Rupa Devi Soligalla, Concepcion Rodriguez Esteban, Travis Berggren and Edward M. Callaway of the Salk Institute; Yuji Tsunekawa and Fumio Matsuzaki of RIKEN Center for Developmental Biology; Pierre Magistretti of King Abdullah University of Science and Technology; Jie Zhu, Tingshuai Jiang, Xin Fu, Maryam Jafari and Kang Zhang of Shiley Eye Institute and Institute for Genomic Medicine, University of California San Diego; Zhe Li, Shicheng Guo, Song Chen and Kun Zhang of Institute of Engineering in Medicine, University of California San Diego; Jing Qu and Guang-Hui Liu of Chinese Academy of Sciences; Jeronimo Lajara, Estrella Nuñez and Pedro Guillen of Universidad Catolica San Antonio de Murcia; and Josep M. Campistol of the University of Barcelona. The work and the researchers involved were supported in part by the National Institutes of Health, The Leona M. and Harry B. Helmsley Charitable Trust, the G. Harold and Leila Y. Mathers Charitable Foundation, The McKnight Foundation, The Moxie Foundation, the Dr. Pedro Guillen Foundation and Universidad Catolica San Antonio de Murcia, Spain. Every cure has a starting point. The Salk Institute embodies Jonas Salk's mission to dare to make dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new understandings in neuroscience, genetics, immunology and more. The Institute is an independent nonprofit organization and architectural landmark: small by choice, intimate by nature and fearless in the face of any challenge. Be it cancer or Alzheimer's, aging or diabetes, Salk is where cures begin. Learn more at: salk.edu.


Kerckhoffs R.C.P.,Institute of Engineering in Medicine | Kerckhoffs R.C.P.,University of California at San Diego | Omens J.H.,Institute of Engineering in Medicine | McCulloch A.D.,Institute of Engineering in Medicine | Mulligan L.J.,Medtronic Inc.
Circulation: Heart Failure | Year: 2010

Background-Heart failure (HF) in combination with mechanical dyssynchrony is associated with a high mortality rate. To quantify contractile dysfunction in patients with HF, investigators have proposed several indices of mechanical dyssynchrony, including percentile range of time to peak shortening (WTpeak), circumferential uniformity ratio estimate (CURE), and internal stretch fraction (ISF). The goal of this study was to compare the sensitivity of these indices to 4 major abnormalities responsible for cardiac dysfunction in dyssynchronous HF: dilation, negative inotropy, negative lusitropy, and dyssynchronous activation. Methods and Results-All combinations of these 4 major abnormalities were included in 3D computational models of ventricular electromechanics. Compared with a nonfailing heart model, ventricles were dilated, inotropy was reduced, twitch duration was prolonged, and activation sequence was changed from normal to left bundle branch block. In the nonfailing heart, CURE, ISF, and WTpeak were 0.97±0.004, 0.010±0.002, and 78±1 milliseconds, respectively. With dilation alone, CURE decreased 2.0±0.07%, ISF increased 58±47%, and WTpeak increased 31±3%. With dyssynchronous activation alone, CURE decreased 15±0.6%, ISF increased 14-fold (±3), and WTpeak increased 121±4%. With the combination of dilation and dyssynchronous activation, CURE decreased 23±0.8%, ISF increased 20-fold (±5), and WTpeak increased 147±5%. Conclusions-Dilation and left bundle branch block combined synergistically decreased regional cardiac function. CURE and ISF were sensitive to this combination, but WTpeak was not. CURE and ISF also reflected the relative nonuniform distribution of regional work better than WTpeak. These findings might explain why CURE and ISF are better predictors of reverse remodeling in cardiac resynchronization therapy. © 2010 American Heart Association, Inc.


Mazor R.,Institute of Engineering in Medicine | Alsaigh T.,Institute of Engineering in Medicine | Shaked H.,University of California at San Diego | Altshuler A.E.,Institute of Engineering in Medicine | And 6 more authors.
Journal of Biological Chemistry | Year: 2013

Matrix metalloproteinase-1 (MMP-1) is a collagenase that is highly active in extracellular matrix and vascular remodeling, angiogenesis, and tumor progression. Vascular endothelial growth factor receptor-2 (VEGFR2), the main receptor for VEGF-A, is expressed on endothelial cells and promotes cell survival, proliferation, and other functions. Although MMP-1 and VEGFR2 co-exist in many normal and pathophysiological conditions, the effect of MMP-1 on cellular VEGFR2 that can promote the above processes is unknown. In this study we test the hypothesis that stimulation of endothelial cells with MMP-1 increases their levels of VEGFR2. The increased VEGFR2 is then available to bind VEGF-A, resulting in increased response. Indeed we found that endothelial cells incubated with active MMP-1 had higher mRNA and protein levels of VEGFR2. Furthermore, VEGF-A-dependent phosphorylation of intracellular signaling molecules and endothelial proliferation were elevated after MMP-1 treatment. MMP-1 caused activation of the nuclear factor-κB (NF-κB) pathway (p65/RelA) in endothelial cells, and this response was dependent upon activation of protease activated receptor-1 (PAR-1). Chromatin immunoprecipitation was used to confirm NF-κB-mediated active transcription of the VEGFR2 (KDR) gene. Elevation in VEGFR2 after MMP-1 stimulation was inhibited by PAR-1 knockdown and NF-κB specific inhibition. We conclude that MMP-1 promotes VEGFR2 expression and proliferation of endothelial cells through stimulation of PAR-1 and activation of NF-κB. These results suggest a mechanism by which MMP-1 may prime or sensitize endothelial cell functions. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.


Wei C.-S.,Institute for Neural Computation | Wei C.-S.,Institute of Engineering in Medicine | Wei C.-S.,University of California at San Diego | Lin Y.-P.,Institute for Neural Computation | And 3 more authors.
Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) | Year: 2016

Recent developments of brain-computer interfaces (BCIs) for driving lapse detection based on electroencephalogram (EEG) have made much progress. This study aims to leverage these new developments and explore the use of robust principal component analysis (RPCA) to extract informative EEG features associated with neurocognitive lapses. Study results showed that the RPCA decomposition could separate lapse-related EEG dynamics from the task-irrelevant spontaneous background activity, leading to more robust neural correlates of neurocognitive lapse as compared to the original EEG signals. This study will shed light on the development of a robust lapse-detection BCI system in real-world environments. © Springer International Publishing Switzerland 2016.


Hwang M.T.,University of California at San Diego | Landon P.B.,University of California at San Diego | Lee J.,University of California at San Diego | Mo A.,University of California at San Diego | And 3 more authors.
Nanoscale | Year: 2015

DNA can be manipulated to design nano-machines through specific sequence recognition. We report a switchable DNA carrier for repeatable capture and release of a single stranded DNA. The activity of the carrier was regulated by the interactions among a double-stranded actuator, single stranded target, fuel, and anti-fuel DNA strands. Inosine was used to maintain a stable triple-stranded complex when the actuator's conformation was switched between open (capture) and closed (release) configurations. Time lapse fluorescence measurements show repeatable capture and release of target strands. TEM images also show visible capture of target DNA strands when gold nanoparticles were attached to the DNA carrier and the target DNA strand. The carrier activity was controlled by length of toeholds, number of mismatches, and inosine substitutions. Significantly, unlike in previously published work that reported the devices functioned only when there is a perfect match between the interacting DNA strands, the present device works only when there are mismatches in the fuel strand and the best performance is achieved for 1-3 mismatches. The device was used to successfully capture and release gold nanoparticles when linked to the target single-stranded DNA. In general, this type of devices can be used for transport and delivery of theranostic molecules. © The Royal Society of Chemistry 2015.

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