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News Article | May 11, 2017
Site: www.eurekalert.org

Tumors, inflammation and circulatory disorders locally disturb the body's acid-base balance. These changes in pH value could be used for example to verify the success of cancer treatments. Up to now, however, there has been no imaging method to render such changes visible in patients. Now a team from the Technical University of Munich (TUM) has developed a pH sensor that renders pH values visible through magnetic resonance imaging (MRI) - in a non-invasive, radiation-free manner. Four years ago, during a magnetic resonance experiment with tumor cells, TUM physicist Dr. Franz Schilling found signals from a molecule that was highly sensitive towards pH changes. The molecule, which was identified as zymonic acid in subsequent investigations, could play an important role in the future of medical imaging. As a biosensor for pH values, it could provide insights into the body which had been impossible in the past. "An appropriate pH imaging method would make it possible to visualize abnormal changes in tissue and specifically metabolic processes of tumors," explains Franz Schilling. Areas surrounding tumors and inflammations are usually slightly more acidic than areas surrounding healthy tissue, a phenomenon possibly linked to the aggressiveness of tumors. Schilling sees further potential uses in treatment prognoses: "pH values are also interesting when it comes to evaluating the efficacy of tumor treatments. Even before a successfully treated tumor starts to shrink, its metabolism and thus the pH value of the surrounding area could change. An appropriate pH imaging method would indicate at a much earlier stage whether or not the right approach has been selected." Schilling is now Director of the working group for Preclinical Imaging and Medical Physics at the Clinic and Polyclinic for Nuclear Medicine in the TUM Klinikum rechts der Isar. In past years, he has joined together with colleagues from the departments of Physics, Chemistry and Medicine to research zymonic acid as a biosensor. In the journal Nature Communications the team describes how it can be used to reliably represent pH values in the bodies of small animals. In order to make pH values visible using zymonic acid, the molecule is injected into the body and then a magnetic resonance imaging (MRI) investigation is made of the object tissue. In greatly simplified terms: In a strong magnetic field, radiowaves excite the nuclear spins of the zymonic acid to oscillation. The reactions of the nuclei are then recorded. This data is used to calculate frequency spectra that in turn provide information about the chemical properties of the molecular surroundings of the nuclei. Ultimately, the pH value at any examined location in the tissue can be represented based on pH-dependent molecular changes in the zymonic acid. Zymonic acid has to be marked with carbon 13 in order to be visible in MRI images. This means that the molecules contain carbon 13 atoms (13C) instead of "normal" carbon 12 atoms. But zymonic acid marked in this manner is still not measurable: its MRI signal is too weak. "We therefore use a relatively new method, hyperpolarization," explains Stephan Düwel, physicist and first author of the study. "We use a special device to transfer the polarization of electrons to the 13C atomic nuclei using microwaves at very low temperatures, which results in an MRI signal up to 100,000 times stronger." A hot liquid is then used to quickly return the zymonic acid to room temperature. After this, the scientists need to act quickly. The biosensor is injected intravenously into the organism, then the MRI scan has to be made immediately: It only takes 60 seconds for the signal-amplifying effect of the hyperpolarization to wear off again. "We're currently working on expanding this time window," says Düwel. "On the one hand, we're trying to improve the MRI properties of zymonic acid with appropriate modifications to the molecule; On the other hand, we're looking for other pH-sensitive molecules," explains biochemist Christian Hundshammer, second author of the study. Franz Schilling and his team have succeeded in showing that their method is sensitive enough to represent medically relevant pH value changes in the organism. Using zymonic acid it is furthermore possible to specifically investigate the pH value outside of the cell membrane: With other biosensors it is often not clear whether measured changes take place inside or outside of the cell (intracellular or extracellular). This is important because the intracellular value is usually stable, while changes in metabolism have a much greater impact on the extracellular value. In contrast to optical methods, which are limited to superficial penetration into the body because of the low transparency of tissue, there are no limitations to the depth of penetration for MRI. It has furthermore been demonstrated that zymonic acid is not toxic in the concentrations used with small animals and is also created in low concentrations as a by-product of the metabolite pyruvic acid which is present in the body. "We believe zymonic acid is a highly promising biosensor for patient applications," says Franz Schilling. For the time being, however, additional pre-clinical studies are planned in order to ascertain the advantages of this new imaging biomarker compared to conventional methods and to further improve the spatial resolution of pH imaging. The research project was funded by the Collaborative Research Centre 824 (SFB824) "Imaging for Selection, Monitoring and Individualization of Cancer Therapies" led by Prof. Markus Schwaiger. S. Düwel, C. Hundshammer, M. Gersch, B. Feuerecker, K. Steiger, A. Buck, A. Walch, A. Haase, S. J. Glaser, M. Schwaiger, F. Schilling, "Imaging of pH in vivo using hyperpolarized 13C-labeled zymonic acid". Nature Communications (2017). Doi: 10.1038/NCOMMS15126 F. Schilling, S. Düwel, U. Köllisch, M. Durst, R.F. Schulte, S.J. Glaser, A. Haase, A.M. Otto, M.I. menzel. "Diffusion of hyperpolarized 13C-metabolites in tumor cell spheroids using real-time NMR spectroscopy". NMR Biomed., 26:5 (2013) 557-568. doi:10.1002/nbm.2892


News Article | May 11, 2017
Site: phys.org

Four years ago, during a magnetic resonance experiment with tumor cells, TUM physicist Dr. Franz Schilling found signals from a molecule that was highly sensitive towards pH changes. The molecule, which was identified as zymonic acid in subsequent investigations, could play an important role in the future of medical imaging. As a biosensor for pH values, it could provide insights into the body which had been impossible in the past. "An appropriate pH imaging method would make it possible to visualize abnormal changes in tissue and specifically metabolic processes of tumors," explains Franz Schilling. Areas surrounding tumors and inflammations are usually slightly more acidic than areas surrounding healthy tissue, a phenomenon possibly linked to the aggressiveness of tumors. Schilling sees further potential uses in treatment prognoses: "pH values are also interesting when it comes to evaluating the efficacy of tumor treatments. Even before a successfully treated tumor starts to shrink, its metabolism and thus the pH value of the surrounding area could change. An appropriate pH imaging method would indicate at a much earlier stage whether or not the right approach has been selected." Schilling is now Director of the working group for Preclinical Imaging and Medical Physics at the Clinic and Polyclinic for Nuclear Medicine in the TUM Klinikum rechts der Isar. In past years, he has joined together with colleagues from the departments of Physics, Chemistry and Medicine to research zymonic acid as a biosensor. In the journal Nature Communications the team describes how it can be used to reliably represent pH values in the bodies of small animals. In order to make pH values visible using zymonic acid, the molecule is injected into the body and then a magnetic resonance imaging (MRI) investigation is made of the object tissue. In greatly simplified terms: In a strong magnetic field, radiowaves excite the nuclear spins of the zymonic acid to oscillation. The reactions of the nuclei are then recorded. This data is used to calculate frequency spectra that in turn provide information about the chemical properties of the molecular surroundings of the nuclei. Ultimately, the pH value at any examined location in the tissue can be represented based on pH-dependent molecular changes in the zymonic acid. Zymonic acid has to be marked with carbon 13 in order to be visible in MRI images. This means that the molecules contain carbon 13 atoms (13C) instead of "normal" carbon 12 atoms. But zymonic acid marked in this manner is still not measurable: its MRI signal is too weak. "We therefore use a relatively new method, hyperpolarization," explains Stephan Düwel, physicist and first author of the study. "We use a special device to transfer the polarization of electrons to the 13C atomic nuclei using microwaves at very low temperatures, which results in an MRI signal up to 100,000 times stronger." A hot liquid is then used to quickly return the zymonic acid to room temperature. After this, the scientists need to act quickly. The biosensor is injected intravenously into the organism, then the MRI scan has to be made immediately: It only takes 60 seconds for the signal-amplifying effect of the hyperpolarization to wear off again. "We're currently working on expanding this time window," says Düwel. "On the one hand, we're trying to improve the MRI properties of zymonic acid with appropriate modifications to the molecule; On the other hand, we're looking for other pH-sensitive molecules," explains biochemist Christian Hundshammer, second author of the study. Franz Schilling and his team have succeeded in showing that their method is sensitive enough to represent medically relevant pH value changes in the organism. Using zymonic acid it is furthermore possible to specifically investigate the pH value outside of the cell membrane: With other biosensors it is often not clear whether measured changes take place inside or outside of the cell (intracellular or extracellular). This is important because the intracellular value is usually stable, while changes in metabolism have a much greater impact on the extracellular value. In contrast to optical methods, which are limited to superficial penetration into the body because of the low transparency of tissue, there are no limitations to the depth of penetration for MRI. It has furthermore been demonstrated that zymonic acid is not toxic in the concentrations used with small animals and is also created in low concentrations as a by-product of the metabolite pyruvic acid which is present in the body. "We believe zymonic acid is a highly promising biosensor for patient applications," says Franz Schilling. For the time being, however, additional pre-clinical studies are planned in order to ascertain the advantages of this new imaging biomarker compared to conventional methods and to further improve the spatial resolution of pH imaging. More information: S. Düwel, C. Hundshammer, M. Gersch, B. Feuerecker, K. Steiger, A. Buck, A. Walch, A. Haase, S. J. Glaser, M. Schwaiger, F. Schilling, "Imaging of pH in vivo using hyperpolarized 13C-labeled zymonic acid". Nature Communications (2017). DOI: 10.1038/NCOMMS15126 F. Schilling, S. Düwel, U. Köllisch, M. Durst, R.F. Schulte, S.J. Glaser, A. Haase, A.M. Otto, M.I. menzel. "Diffusion of hyperpolarized 13C-metabolites in tumor cell spheroids using real-time NMR spectroscopy". NMR Biomed., 26:5 (2013) 557–568. DOI: 10.1002/nbm.2892


News Article | May 4, 2017
Site: www.eurekalert.org

Researchers from Charité - Universitätsmedizin Berlin have challenged traditional teaching and learning concepts employed in medical training. A comparison with conventional learning methods led them to conclude that tablet-based, multimedia-enhanced training improves medical examination results. Their study, which has been published in the journal PLOS ONE*, clearly shows that an integrated program of tablet-based theoretical training and clinical practice enhances medical training. The use of digital media forms an integral part of both clinical practice and biomedical research, with resources ranging from multidimensional imaging data of the human body to video animations of human physiological processes. However, traditional teaching and learning concepts fail to utilize the full potential of information technologies. "Ideally, medical training should be taking place at the patient's bedside rather than in lecture halls," explains Prof. Dr. Daniel C. Baumgart, from Charité's Hepatology and Gastroenterology unit on Campus Virchow-Klinikum. "Communication devices, such as tablet computers, digital assistants and smartphones, make medical data and learning materials available anywhere and anytime. Therefore, our aim was to study the impact of a systematic integration of such devices into medical teaching and training." The multimedia package trialled included the Mobile Medical EducatorSM software package (developed in-house) as well as other multimedia learning materials, such as eBooks, eJournals, slide kits, podcasts, videos, animations, image data, and the American College of Physicians' validated self-assessment software. The participants, who were made up of medical students on their final year rotation and residents, had to complete exams at the beginning and the end of their training rotations. While the control group had access to all conventional learning resources available at Charité, the multimedia group also had access to a tablet computer throughout the duration of their participation. Results showed that the multimedia-enhanced training package had a significant impact on results in US-style medical examinations, which were based on official American Board of Internal Medicine exams. "We were able to show improvements in internal medicine exam results, which were independent of socio-demographic factors. Participant feedback was particularly positive in relation to an integrated, fully-digitized workflow for clinical practice and training," reports Prof. Baumgart. According to this study, medical journals (accessed via the US National Library of Medicine (NLM), PubMed and others) were the most frequently-used resource for clinical practice-based problem-solving.


News Article | December 15, 2016
Site: www.eurekalert.org

New cancer therapies harness the immune system to fight tumors. One of the main principles behind these therapies is to find out precisely which molecules on cancer cells trigger an immune response. A team at the Technical University of Munich (TUM) and the Max Planck Institute of Biochemistry has for the first time identified suitable protein structures directly from patients' tumor cells. Unlike former approaches, their method does not rely on prediction algorithms but makes use of mass spectrometry. The procedure therefore opens up new possibilities for individualized targeted cancer treatments. Through evolution, the immune system has developed sophisticated mechanisms for fighting illnesses associated with viruses and tumors. T cells play an important role in this setting. They can identify small protein structures, known as peptides, on cells. The body's own cells "present" the peptides on their surface and thus offer information about molecules on the inside. Individual peptides may, for example, indicate a viral infection or a mutation - the latter being a characteristic of tumor cells. Peptides identified by immune cells are known as antigens. T cells that recognize antigens can trigger a reaction that destroys the targeted cells. In recent years research teams, including TUM researchers, have successfully utilized this characteristic for cancer treatments. Different approaches have emerged. Vaccinating a patient with an antigen can stimulate the body to enhance the production of specific T cells. Another possibility is to enrich T cells that are "trained" for certain antigens and transfer them to the patient. In both cases, it is important to know which antigens derived from viruses or tumors may be recognized by the T cells. Many different peptides can be found on the body's own cells and cancer cells. Consequently, the pool of potential candidates when searching for suitable antigens is very large. The authors of the new study identified approximately 100,000 different peptides from tumor tissue samples derived from only 25 melanoma patients. The T cells are particularly good at identifying peptides on tumor cells with mutations, i.e. structural changes. The peptides that mutate and the type of mutations they undergo generally varies from one patient to another. In the past, the search for mutated peptides actually presented on the tumor was a time-consuming and error-prone process. Scientists had to start by sequencing the DNA from tumor cells. That process alone takes one to two weeks. The sequencing data is then fed into prediction algorithms to determine which mutated peptides might be found on the surface of the cell. Subsequently, time-consuming laboratory experiments had to be performed in order to find out whether these molecules actually existed and were presented on the cell surface. An alternative to this process has now been developed by a team led by Angela M. Krackhardt, professor of translational immunotherapy at the Third Medical Clinic at TUM's Klinikum rechts der Isar, and Professor Matthias Mann of the Department of Proteomics and Signal Transduction at the Max Planck Institute of Biochemistry. Krackhardt and Mann have described their approach in an article published in the journal Nature Communications. Unlike other methods, it is not based on predictive models. Instead, the scientists use a mass spectrometer to identify the peptides actually present on the tumor surface. The genomic sequence, or blueprint, of the tumor cells is also required for the new method. At the same time, surface structures of the malignant cell - in this case presented peptides - are removed directly from tumor tissue and investigated by mass spectrometry. Combining both analyses by bioinformatics results in the identification of mutated antigens actually presented on the cells with considerable accuracy. The team headed by Krackhardt and Mann was also able to demonstrate the clinical relevance of the new method: In the blood of melanoma patients they found T cells that recognized tumor cells by means of antigens identified with mass spectrometry. The new approach offers numerous advantages. By avoiding time-consuming simulations and laboratory experiments, information on mutated peptides on the tumor cells is much faster available. "For the first time, we have used the mass spectrometer to investigate not just expanded, cells, but rather heterogeneous tumor tissues of real patients," adds Matthias Mann. "That gives us much more detailed information about the molecular characteristics of the tumor." Moreover, the method is highly sensitive. The results of the study are already serving as the starting point for promising research initiatives, for example on the role of phosphorylated peptides. Angela Krackhardt sees no major obstacles for clinical application of the method. "Our approach opens up new possibilities for the personalized treatment of cancer," says Krackhardt. "Identification of suitable antigens by this method will allow us to provide individualized vaccines or adoptive T-cell therapies for our patients within weeks to a few months." M. Bassani-Sternberg, E. Bräunlein, R. Klar, T. Engleitner, P. Sinitcyn, S. Audehm, M. Straub, J. Weber, J. Slotta-Huspenina, K. Specht, M.E. Martignoni, A. Werner, R. Hein, D. Busch, C. Peschel ,R. Rad, J. Cox, M. Mann, A.M. Krackhardt. "Direct identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry". Nat Commun. 2016 Nov 21;7:13404.


News Article | November 16, 2016
Site: www.sciencedaily.com

A new bioinformatic framework developed by researchers at University of California San Diego School of Medicine has identified key proteins significantly altered at the gene-expression level in biopsied tissue from patients with diabetic kidney disease, a result that may reveal new therapeutic targets. In a recently published paper in JCI Insights, researchers, led by Kumar Sharma, MD, professor of medicine at UC San Diego School of Medicine, revealed that the protein MDM2 was consistently down-regulated and played a key role in diabetic kidney disease progression. The researchers used the new "MetBridge Generator" bioinformatics framework to identify the relevant enzymes and bridge proteins that link human metabolomics data to the pathophysiology of diabetic kidney disease at a molecular level. "MetBridge Generator allows for efficient, focused analysis of urine metabolomics data from patients with diabetic kidney disease, providing researchers an opportunity to develop new hypotheses based on the possible cellular or physiological role of key proteins," said Sharma, senior author and director of the Institute for Metabolomic Medicine and the Center for Renal Translational Medicine at UC San Diego School of Medicine. "The framework may also be used in the interpretation of other metabolomic signatures from a variety of diseases. For example, MDM2 is also involved in regulating tumor protein p53, which is a target for cancer treatments." In a previous study, the authors identified 13 metabolites that were found to be altered in patients with diabetic kidney disease. Combining this information and publicly available data on metabolic pathways, the researchers tested an hypothesis that some proteins act as bridges creating less well-defined pathways. The framework then created a map of metabolic and protein-protein interaction (PPI) networks. This allowed the team to look deeper into relevant bridges with the greatest number of interactions with enzymes that regulate the 13-metabolite signature of diabetic kidney disease. The authors already identified protein-RNA interactions as possible sources for additional key pathways underlying disease progression that could be added to the MetBridge Generator network. This growth will continue to add to possible therapeutic targets for disease treatment. Study co-authors include: Rintaro Saito, Young-Hyun You, Manjula Darshi, Benjamin Van Espen, Satoshi Miyamoto, Jessica Pham, Minya Pu, Loki Natarajan, Keiichiro Ono, Trey Ideker, UC San Diego; Anaïs Rocanin-Arjo, Simone Romoli, Dana Thomasova, Shrikant R. Mulay, Hans Joachim Anders, Klinikum der Universität München, LMU Munich; Wenjun Ju, Matthias Kretzler, University of Michigan; Robert Nelson, National Institute of Diabetes and Digestive and Kidney Diseases; Vivette D'Agati, Columbia University; Ergin Beyret, and Juan Carlos Izpisua Belmonte, Salk Institute for Biological Studies. This research was funded, in part, by the National Institutes of Health (DP3 DK094352), National Resource for Network Biology (P41 GM103504), San Diego Center for Systems Biology (P50 GM085764), University of Michigan O'Brien Kidney Translational Core Center (P30DK081943), Juvenile Diabetes Research Foundation and a VA Merit Award (5101BX000277), Deutsche Forschungsgemeinschaft (TH 1836/1-2, AN372/11-2), Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. Disclosure: Sharma is the co-founder of ClinMet, Inc. He was on the board of directors, a scientific adviser and held an equity interest. Sharma's spouse is co-founder and was the president and chief operating officer and also held an equity interest.


OMER, Israel, Dec. 13, 2016 (GLOBE NEWSWIRE) -- Medigus Ltd. (Nasdaq:MDGS) (TASE:MDGS), a medical device company developing minimally invasive endosurgical tools and a leader in direct visualization technology, today announced the completion of a live transoral fundoplication (TF) procedure using the Medigus Ultrasonic Surgical Endostapler (MUSE™) system. The procedure was performed at the Endo-Update, one of the largest and most well-attended live endoscopy conferences in Europe, by renowned gastroenterologists from Germany, Professors Helmut Messmann, Klinikdirektor and Internist, Gastroenterologe at Klinikum Augsberg and Horst Neuhaus, MD, Head of the Department of Gastroenterology of the Evangelisches Krankenhaus in Düsseldorf, Germany. The procedure was performed on a 34 year old male patient, who had been presenting with symptoms of GERD for five years, with no prior surgery for this condition. “MUSE addresses an unmet need in long-term GERD care by providing a true solution between drug therapy and invasive surgical procedures,” said professor Messmann. “By addressing the anatomical cause of GERD, patients can find long-term relief from troublesome symptoms following a patient-friendly procedure, and be able to return to their daily activities within a couple of weeks.” The MUSE system integrates the latest innovations in microvisualization, ultrasound and surgical stapling capabilities into one platform, enabling a single physician to perform transoral fundoplication for the treatment of GERD. MUSE has the potential to improve GERD-related quality of life for many patients by addressing the root cause of the disease, not just offer symptom relief, which is often in contrast to many drug therapies. “I am pleased to demonstrate to the European gastroenterology and endoscopy communities the clinical and patient benefits of MUSE over more invasive techniques,” said professor Neuhaus. “This procedure is generally well-tolerated by most patients and the technique can be repeated if needed, which may be beneficial for patients with severe GERD.” GERD is a common and costly disorder in Germany1, one that can increase with a person’s age. In a study of over 7,000 patients, 14% of subjects suffered moderate symptoms and 4% suffered severe symptoms.2 Because of their high prevalence, reflux symptoms are of major public health importance.2 In Germany, the impact of GERD on the ability to work as well as on overall work-related productivity has been studied and found that 61% of patients experienced reduced productivity as a consequence of their disease.3 “GERD can have widespread impact on a patient’s health-related quality of life. Medigus’ MUSE system has the potential to offer a meaningful solution to thousands of people who suffer with this disease in Germany and around the world,” said Chris Rowland, CEO of Medigus. “We are honored to work with leaders such as professors Messman and Neuhaus, and we thank them for their support raising awareness of this important technology amongst their peers.” About GERD Gastroesophageal reflux disease (GERD) occurs when the lower esophageal sphincter spontaneously opens or does not properly close after use, allowing stomach acids to rise (or reflux) into the esophagus, which causes heartburn, irritation and potentially other discomforts. GERD affects approximately 81 million Americans each year, 8.6 million of whom experience severe symptoms.i While some patients can attain symptom relief through the use of proton pump inhibitors, or PPIs, (acid reducing medications), there is growing concern around the prolonged use of PPIs, including increased risk of renal failureii, dementiaiii, bone fracture and interference with the adsorption of essential vitamins and minerals.iv A persistent state of untreated GERD may lead to Barrett’s esophagus, a precancerous condition which can progress to esophageal cancer. Patients who suffer from persistent GERD are seven times more likely to develop esophageal cancer.ii About The MUSE™ System The MUSE™ system is a flexible transoral stapler that enables a minimally-invasive procedure for the long-term treatment of GERD. The device is fully integrated with latest technological advancements in microvisualization, ultrasound and surgical stapling, which allows a single physician or surgeon to perform anterior partial fundoplication more easily than with leading laparoscopic methods. Its intuitive endosurgical platform consists of a single use flexible surgical endostapler, equipped with a proprietary miniature camera, an ultrasonic sight and a range finder, and includes a handle with controls, an 80 cm flexible shaft, a 5 cm rigid section holding a cartridge with 5 standard 4.8mm titanium surgical staples, a ratchet controlled one-way articulating section, and a new, rounded distal tip for easier insertion. The MUSE system is FDA cleared and CE marked for the treatment of GERD and is reimbursable in the U.S. under Current Procedural Terminology (CPT®) code 43210 for Esophagogastric Fundoplasty Trans-Orifice Approach. CPT codes are descriptive terms physicians use for reporting all medical, surgical, and diagnostic services and procedures; Category I codes are most frequently used by healthcare providers when reporting a significant portion of their services. MUSE also has obtained the necessary licenses to market the product in Canada and Israel. For more information, visit www.RefluxHelp.com. This press release may contain statements that are “Forward-Looking Statements,” which are based upon the current estimates, assumptions and expectations of the company’s management and its knowledge of the relevant market. The company has tried, where possible, to identify such information and statements by using words such as “anticipate,” “believe,” “envision,” “estimate,” “expect,” “intend,” “may,” “plan,” “predict,” “project,” “target,” “potential,” “will,” “would,” “could,” “should,” “continue,” “contemplate” and other similar expressions and derivations thereof in connection with any discussion of future events, trends or prospects or future operating or financial performance, although not all forward-looking statements contain these identifying words.  These forward-looking statements represent Medigus’ expectations or beliefs concerning future events, and it is possible that the results described in this news release will not be achieved. By their nature, Forward-Looking Statements involve known and unknown risks, uncertainties and other factors which may cause future results of the company’s activity to differ significantly from the content and implications of such statements. Among the factors which may cause the actual results to differ from the Forward-Looking Statements are changes in the target market and the introduction of competitive products, our ability to secure favorable reimbursement rates, regulatory, legislative and policy changes, and clinical results. Other risk factors affecting the company are discussed in detail in the Company's filings with the Securities and Exchange Commission. Forward-Looking Statements are pertinent only as of the date on which they are made, and the company undertakes no obligation to update or revise any Forward-Looking Statements, whether as a result of new information, future developments or otherwise. Neither the company nor its shareholders, officers and employees, shall be liable for any action and the results of any action taken by any person based on the information contained herein, including without limitation the purchase or sale of company securities. Nothing in this press release should be deemed to be medical or other advice of any kind. 1 Gross M, Beckenbauer U, Burkowitz J, Walther H, Brueggenjuergen B. Impact of gastro-esophageal reflux disease on work productivity despite therapy with proton pump inhibitors in Germany. Eur J Med Res. 2010;15:124-130. 2 Nocon M, Keil T, Willich SN. Prevalence and sociodemographics of reflux symptoms in Germany - results from a national survey. Aliment Pharmacol Ther. 2006;23:1601-1605 3 Gross M, Beckenbauer U, Burkowitz J, Walther H, Brueggenjuergen B. Impact of gastro-oesophageal reflux disease on work productivity despite therapy with proton pump inhibitors in Germany. Eur J Med Res. 2010;15:124-130. i Rubenstein JH & Taylor JB. (2010). Meta-analysis: the association of oesophageal adenocarcinoma with symptoms of gastro-oesophageal reflux. Alimentary Pharmacology & Therapeutics,32(10):1222-7. doi: 10.1111/j.1365-2036.2010.04471.x. Epub 2010 Sep 23. ii Lazarus, B., Chen, Y., Wilson, F. P., Sang, Y., Chang, A. R., Coresh, J., & Grams, M. E. (2016). Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease.JAMA Internal Medicine JAMA Intern Med, 176(2). doi:10.1001/jamainternmed.2015.7193 iii Gomm, W., Holt, K. V., Thomé, F., Broich, K., Maier, W., Fink, A., . . . Haenisch, B. (2016). Association of Proton Pump Inhibitors With Risk of Dementia. JAMA Neurology JAMA Neurol, 73(4), 410. doi:10.1001/jamaneurol.2015.4791 iv Tetsuhide Ito, MD, PhD & Robert T. Jensen, MD (2010). Association of Long-term Proton Pump Inhibitor Therapy with Bone Fractures and effects on Absorption of Calcium, Vitamin B12, Iron, and Magnesium. Current Gastroenterology Reports, 12(6): 448–457. doi:  10.1007/s11894-010-0141-0


News Article | December 15, 2016
Site: www.eurekalert.org

NEW YORK NY (December 15, 2016)--Gastric tumors are started by specialized cells in the stomach that signal nerves to make more acetylcholine, according to a study in mice. The multinational team of researchers who conducted the study also identified a substance called nerve growth factor that stimulates nerve development and, when blocked, inhibits stomach cancer development. The findings were published today in Cancer Cell. Previous studies have shown that nerves are abundant in the gastric tumor microenvironment. In an earlier paper, the researchers demonstrated that inhibiting signaling by the neurotransmitter acetylcholine, by severing the vagus nerve in the stomach or treating with Botulinum toxin, shrank or prevented the growth of gastric tumors in mouse models. "Nerves and acetylcholine clearly play a key role in regulating the development and growth of cancer cells, particularly cancer stem cells, in the gastric tumor microenvironment," said Timothy C. Wang, MD, the Dorothy L. and Daniel H. Silberberg Professor of Medicine at Columbia University Medical Center (CUMC) and senior author of the paper. "But little is known about what is driving cancer in the earliest stage of development, before the expansion of nerves in the microenvironment. We also wanted to find out where acetylcholine is coming from before the growth of nerves." Through a series of experiments in mouse models, the researchers determined that a neurotrophin (substance that triggers nerve growth) called nerve growth factor is highly expressed in gastric cancer cells. They also discovered that tuft cells--specialized cells found in the lining of the digestive tract that, like nerves, communicate with other cells--provide another source of acetylcholine for cancer cell growth, particularly during the formation of tumors. "We learned that tuft cells are increased during the earliest stage of gastric tumor development, making acetylcholine and stimulating the production of nerve growth factor within the lining of the stomach," said Dr. Wang. "As nerves grow in around the tumor, tuft cells decrease." In additional experiments, the scientists showed that overexpression of nerve growth factor in the mouse stomach drove tumorigenesis. Furthermore, administration of a nerve growth factor receptor inhibitor prevented stomach cancer in the mice. "Our study provides some insight into the cellular crosstalk that leads to the development of stomach cancer, and points to a viable therapeutic target for this type of cancer," said Dr. Wang. "Using our findings as a paradigm, additional studies can be done to identify the specific neurotrophins and neurotransmitters that are involved in tumor development in other areas of the body." The study is titled, "Nerve growth factor promotes gastric tumorigenesis through aberrant cholinergic signaling." The other contributors are: Yoku Hayakawa (University of Tokyo, Tokyo, Japan), Kosuke Sakitani (University of Tokyo), Mitsuru Konishi (University of Tokyo), Samuel Asfaha (University of Western Ontario, Ontario, Canada), Ryota Niikura (University of Tokyo), Hiroyuki Tomita (Gifu University Graduate School of Medicine, Gifu, Japan), Bernhard W. Renz (Hospital of the University of Munich, Munich, Germany), Yagnesh Taylor (CUMC), Marina Macchini (CUMC). Moritz Middlehoff (CUMC), Zhengyu Jiang (CUMC), Takayuki Tenaka (CUMC), Zinaida A. Dubeykovskaya (CUMC), Woosook Kim (CUMC), Xiaowei Chen (CUMC), Aleksandra M. Urbanska (CUMC), Karan Nagar (CUMC), Christoph B. Westphalen (Klinikum der Universität München, Munich, Germany), Michael Quante (Technische Universität München, Munich, Germany), Chyuan-Sheng Lin (CUMC), Michael D. Gershon (CUMC), Akira Hara (Gifu University Graduate School of Medicine), Chun-Mei Zhao (Norwegian University of Science and Technology, Trondheim. Norway), Duan Chen (Norwegian University of Science and Technology), Daniel L. Worthley (University of Aidelaide, Australia), and Kazuhiko Koike (University of Tokyo). The study was supported by grants from the National Institutes of Health (U54CA126513, R01CA093405, R01CA120979, and R01DK052778), the Clyde Wu Family Foundation, the Nakayama Cancer Research Institute, the Okinaka Memorial Institute for Medical Research, and the Project for Cancer Research and Therapeutic Evolution from the Japan Agency of Medical Research and Development. Y.H. and K.S. were supported by Japan Society for the Promotion of Science, and Y.H. and T.T. were supported by Uehara Memorial Foundation. The authors declare no conflicts of interest. Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. The campus that Columbia University Medical Center shares with its hospital partner, NewYork-Presbyterian, is now called the Columbia University Irving Medical Center. For more information, visit cumc.columbia.edu or columbiadoctors.org.


News Article | February 27, 2017
Site: phys.org

Soft tissues such as organs and blood vessels are nearly impossible to examine in X-ray images. To detect a narrowing or other changes in coronary blood vessels, patients are therefore usually injected with an iodinated contrast agent. These substances can sometimes be hazardous to health, however: "Particularly in patients with kidney insufficiency, complications may arise, in some cases even kidney failure," explains Dr. Daniela Münzel, an adjunct teaching professor for radiology at TUM's Klinikum rechts der Isar. "That is why we are studying possibilities of using lower concentrations of contrast agents." One approach to reducing the dosage has now been developed by scientists from the Department of Diagnostic and Interventional Radiology at the Klinikum rechts der Isar, working in close cooperation with the Chair of Biomedical Physics at TUM's Department of Physics. The method, which they have described in a paper published in Nature Scientific Reports, is not based on new contrast agents. Instead it relies on special X-rays generated using the Munich Compact Light Source (MuCLS), the world's first mini-synchrotron, which was officially inaugurated at TUM at the end of 2015. "Conventional X-ray sources generate a relatively broad range of energy levels. By contrast, the energy of X-rays produced by the MuCLS can be controlled much more precisely," says physicist Elena Eggl, the first author of the paper. Contrast agents such as iodine and gadolinium have an absorption edge. That means that when the substance is exposed to X-rays of a certain energy, the contrast of the final image of the marked organ is particularly good. Below the absorption edge - about 30 kiloelectron volts (keV) for iodine - the contrast deteriorates rapidly. The contrast also becomes weaker at energies far above the absorption edge. As a result, when using conventional broad-spectrum X-ray sources, an adequate quantity of contrast agent must always be used in order to offset this effect and obtain a sufficiently sharp image for a diagnosis. The MuCLS can generate X-rays that have exactly the optimal energy level. The capability of producing such monoenergetic X-rays has existed for some time. In the past, however, this was possible only with circular particle accelerators with a diameter of several hundred meters. In contrast, the MuCLS is comparable in size to a car. The data shows that monoenergetic X-rays would make it possible to decrease the required concentration of iodine by about one third with no loss of contrast. For gadolinium, there would even be a somewhat greater reduction. A lot more research is needed, however, before real patients can be examined with monoenergetic X-rays. "We're still at the very beginning of the development of this technology," says Elena Eggl. The MuCLS is the very first machine of its kind. Moreover, it is designed for fundamental research, and not for examining patients. But with detailed computer simulations and tests with a pig's heart, using blood vessels dyed with iodine, the researchers were able to demonstrate feasibility of the method. Franz Pfeiffer, professor of biomedical physics at TUM, sees the team's results as a promising start for medical research with the compact synchrotron: "The MuCLS offers numerous possibilities for medical applications that we plan to continue researching with our partners in medical fields." More information: Elena Eggl et al, Mono-Energy Coronary Angiography with a Compact Synchrotron Source, Scientific Reports (2017). DOI: 10.1038/srep42211


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

The most prevalent method for obtaining images of clogged coronary vessels is coronary angiography. For some patients, however, the contrast agents used in this process can cause health problems. A team at the Technical University of Munich (TUM) has now demonstrated that the required quantity of these substances can be significantly reduced if monoenergetic X-rays from a miniature particle accelerator are used. Soft tissues such as organs and blood vessels are nearly impossible to examine in X-ray images. To detect a narrowing or other changes in coronary blood vessels, patients are therefore usually injected with an iodinated contrast agent. These substances can sometimes be hazardous to health, however: "Particularly in patients with kidney insufficiency, complications may arise, in some cases even kidney failure," explains Dr. Daniela Münzel, an adjunct teaching professor for radiology at TUM's Klinikum rechts der Isar. "That is why we are studying possibilities of using lower concentrations of contrast agents." One approach to reducing the dosage has now been developed by scientists from the Department of Diagnostic and Interventional Radiology at the Klinikum rechts der Isar, working in close cooperation with the Chair of Biomedical Physics at TUM's Department of Physics. The method, which they have described in a paper published in Nature Scientific Reports, is not based on new contrast agents. Instead it relies on special X-rays generated using the Munich Compact Light Source (MuCLS), the world's first mini-synchrotron, which was officially inaugurated at TUM at the end of 2015. "Conventional X-ray sources generate a relatively broad range of energy levels. By contrast, the energy of X-rays produced by the MuCLS can be controlled much more precisely," says physicist Elena Eggl, the first author of the paper. Contrast agents such as iodine and gadolinium have an absorption edge. That means that when the substance is exposed to X-rays of a certain energy, the contrast of the final image of the marked organ is particularly good. Below the absorption edge - about 30 kiloelectron volts (keV) for iodine - the contrast deteriorates rapidly. The contrast also becomes weaker at energies far above the absorption edge. As a result, when using conventional broad-spectrum X-ray sources, an adequate quantity of contrast agent must always be used in order to offset this effect and obtain a sufficiently sharp image for a diagnosis. The MuCLS can generate X-rays that have exactly the optimal energy level. The capability of producing such monoenergetic X-rays has existed for some time. In the past, however, this was possible only with circular particle accelerators with a diameter of several hundred meters. In contrast, the MuCLS is comparable in size to a car. The data shows that monoenergetic X-rays would make it possible to decrease the required concentration of iodine by about one third with no loss of contrast. For gadolinium, there would even be a somewhat greater reduction. A lot more research is needed, however, before real patients can be examined with monoenergetic X-rays. "We're still at the very beginning of the development of this technology," says Elena Eggl. The MuCLS is the very first machine of its kind. Moreover, it is designed for fundamental research, and not for examining patients. But with detailed computer simulations and tests with a pig's heart, using blood vessels dyed with iodine, the researchers were able to demonstrate feasibility of the method. Franz Pfeiffer, professor of biomedical physics at TUM, sees the team's results as a promising start for medical research with the compact synchrotron: "The MuCLS offers numerous possibilities for medical applications that we plan to continue researching with our partners in medical fields." The research was funded by the German Research Foundation (DFG), Munich Centre for Advanced Photonics (MAP) cluster of excellence, the Center for Advanced Laser Applications (CALA), the Ministry for Education and Research, and the DFG Gottfried Wilhelm Leibniz Program. PD Dr. med Daniela Münzel Department of Diagnostic and Interventional Radiology Klinikum rechts der Isar Technical University of Munich Email: daniela.muenzel@tum.de


News Article | November 15, 2016
Site: www.eurekalert.org

A new bioinformatic framework developed by researchers at University of California San Diego School of Medicine has identified key proteins significantly altered at the gene-expression level in biopsied tissue from patients with diabetic kidney disease, a result that may reveal new therapeutic targets. In a recently published paper in JCI Insights, researchers, led by Kumar Sharma, MD, professor of medicine at UC San Diego School of Medicine, revealed that the protein MDM2 was consistently down-regulated and played a key role in diabetic kidney disease progression. The researchers used the new "MetBridge Generator" bioinformatics framework to identify the relevant enzymes and bridge proteins that link human metabolomics data to the pathophysiology of diabetic kidney disease at a molecular level. "MetBridge Generator allows for efficient, focused analysis of urine metabolomics data from patients with diabetic kidney disease, providing researchers an opportunity to develop new hypotheses based on the possible cellular or physiological role of key proteins," said Sharma, senior author and director of the Institute for Metabolomic Medicine and the Center for Renal Translational Medicine at UC San Diego School of Medicine. "The framework may also be used in the interpretation of other metabolomic signatures from a variety of diseases. For example, MDM2 is also involved in regulating tumor protein p53, which is a target for cancer treatments." In a previous study, the authors identified 13 metabolites that were found to be altered in patients with diabetic kidney disease. Combining this information and publicly available data on metabolic pathways, the researchers tested an hypothesis that some proteins act as bridges creating less well-defined pathways. The framework then created a map of metabolic and protein-protein interaction (PPI) networks. This allowed the team to look deeper into relevant bridges with the greatest number of interactions with enzymes that regulate the 13-metabolite signature of diabetic kidney disease. The authors already identified protein-RNA interactions as possible sources for additional key pathways underlying disease progression that could be added to the MetBridge Generator network. This growth will continue to add to possible therapeutic targets for disease treatment. Study co-authors include: Rintaro Saito, Young-Hyun You, Manjula Darshi, Benjamin Van Espen, Satoshi Miyamoto, Jessica Pham, Minya Pu, Loki Natarajan, Keiichiro Ono, Trey Ideker, UC San Diego; Anaïs Rocanin-Arjo, Simone Romoli, Dana Thomasova, Shrikant R. Mulay, Hans Joachim Anders, Klinikum der Universität München, LMU Munich; Wenjun Ju, Matthias Kretzler, University of Michigan; Robert Nelson, National Institute of Diabetes and Digestive and Kidney Diseases; Vivette D'Agati, Columbia University; Ergin Beyret, and Juan Carlos Izpisua Belmonte, Salk Institute for Biological Studies. Disclosure: Sharma is the co-founder of ClinMet, Inc. He was on the board of directors, a scientific adviser and held an equity interest. Sharma's spouse is co-founder and was the president and chief operating officer and also held an equity interest.

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