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News Article | February 15, 2017
Site: www.eurekalert.org

WASHINGTON - Clinical trials for genome editing of the human germline - adding, removing, or replacing DNA base pairs in gametes or early embryos - could be permitted in the future, but only for serious conditions under stringent oversight, says a new report from the National Academy of Sciences and the National Academy of Medicine. The report outlines several criteria that should be met before allowing germline editing clinical trials to go forward. Genome editing has already entered clinical trials for non-heritable applications, but should be allowed only for treating or preventing diseases or disabilities at this time. Genome editing is not new. But new powerful, precise, and less costly genome editing tools, such as CRISPR/Cas9, have led to an explosion of new research opportunities and potential clinical applications, both heritable and non-heritable, to address a wide range of human health issues. Recognizing the promise and the concerns related to this technology, NAS and NAM appointed a study committee of international experts to examine the scientific, ethical, and governance issues surrounding human genome editing. Human genome editing is already widely used in basic research and is in the early stages of development and trials for clinical applications that involve non-heritable (somatic) cells. These therapies affect only the patient, not any offspring, and should continue for treatment and prevention of disease and disability, using the existing ethical norms and regulatory framework for development of gene therapy. Oversight authorities should evaluate safety and efficacy of proposed somatic applications in the context of the risks and benefits of intended use. However, there is significant public concern about the prospect of using these same techniques for so-called "enhancement" of human traits and capacities such as physical strength, or even for uses that are not possible, such as improving intelligence. The report recommends that genome editing for enhancement should not be allowed at this time, and that broad public input and discussion should be solicited before allowing clinical trials for somatic genome editing for any purpose other than treating or preventing disease or disability. "Human genome editing holds tremendous promise for understanding, treating, or preventing many devastating genetic diseases, and for improving treatment of many other illnesses," said Alta Charo, co-chair of the study committee and Sheldon B. Lubar Distinguished Chair and Warren P. Knowles Professor of Law and Bioethics, University of Wisconsin-Madison. "However, genome editing to enhance traits or abilities beyond ordinary health raises concerns about whether the benefits can outweigh the risks, and about fairness if available only to some people." Germline genome editing, in contrast, is contentious because genetic changes would be inherited by the next generation. Many view germline editing as crossing an "ethically inviolable" line, the report says. Concerns raised include spiritual objections to interfering with human reproduction to speculation about effects on social attitudes toward people with disabilities to possible risks to the health and safety of future children. But germline genome editing could provide some parents who are carriers of genetic diseases with their best or most acceptable option for having genetically related children who are born free of these diseases. Heritable germline editing is not ready to be tried in humans. Much more research is needed before it could meet the appropriate risk and benefit standards for clinical trials. The technology is advancing very rapidly, though, making heritable genome editing of early embryos, eggs, sperm, or precursor cells in the foreseeable future "a realistic possibility that deserves serious consideration," the report says. Although heritable germline genome editing trials must be approached with caution, the committee said, caution does not mean prohibition. At present, heritable germline editing is not permissible in the United States, due to an ongoing prohibition on the U.S. Food and Drug Administration's ability to use federal funds to review "research in which a human embryo is intentionally created or modified to include a heritable genetic modification." A number of other countries have signed an international convention that prohibits germline modification. If current restrictions are removed, and for countries where germline editing would already be permitted, the committee recommended stringent criteria that would need to be met before going forward with clinical trials. They include: (1) absence of reasonable alternatives; (2) restriction to editing genes that have been convincingly demonstrated to cause or strongly predispose to a serious disease or condition; (3) credible pre-clinical and/or clinical data on risks and potential health benefits; (4) ongoing, rigorous oversight during clinical trials; (5) comprehensive plans for long-term multigenerational follow-up; and (6) continued reassessment of both health and societal benefits and risks, with wide-ranging, ongoing input from the public. Policymaking surrounding human genome editing applications should incorporate public participation, and funding of genome editing research should include support to study the socio-political, ethical, and legal aspects and evaluate efforts to build public communication and engagement on these issues. "Genome editing research is very much an international endeavor, and all nations should ensure that any potential clinical applications reflect societal values and be subject to appropriate oversight and regulation," said committee co-chair Richard Hynes, Howard Hughes Medical Institute Investigator and Daniel K. Ludwig Professor for Cancer Research, Massachusetts Institute of Technology. "These overarching principles and the responsibilities that flow from them should be reflected in each nation's scientific community and regulatory processes. Such international coordination would enhance consistency of regulation." The study was funded by the Defense Advanced Research Projects Agency, the Greenwall Foundation, the John D. and Catherine T. MacArthur Foundation, U.S. Department of Health and Human Services, U.S. Food and Drug Administration, and the Wellcome Trust, with additional support from the National Academies' Presidents' Circle Fund and the National Academy of Sciences W.K. Kellogg Foundation Fund. The National Academy of Sciences and the National Academy of Medicine are private, nonprofit institutions that, along with the National Academy of Engineering, provide independent, objective analysis and advice to the nation to solve complex problems and inform public policy decisions related to science, technology, and medicine. The Academies operate under an 1863 congressional charter to the National Academy of Sciences, signed by President Lincoln. For more information, visit http://www. . Copies of Human Genome Editing: Science, Ethics, and Governance are available at http://www. or by calling 202-334-3313 or 1-800-624-6242. Reporters may obtain a copy from the Office of News and Public Information (contacts listed above). R. Alta Charo1 (co-chair) Sheldon B. Lubar Distinguished Chair and Warren P. Knowles Professor of Law and Bioethics University of Wisconsin Madison Richard O. Hynes1,2 (co-chair) Investigator Howard Hughes Medical Institute, and Daniel K. Ludwig Professor for Cancer Research Massachusetts Institute of Technology Cambridge Ellen Wright Clayton1 Craig Weaver Professor of Pediatrics, and Professor of Law Vanderbilt University Nashville, Tenn. Barry S. Coller1,2 David Rockefeller Professor of Medicine, Physician in Chief, and Head Allen and Frances Adler Laboratory of Blood and Vascular Biology Rockefeller University New York City Ephrat Levy-Lahad Director Fuld Family Department of Medical Genetics Shaare Zedek Medical Center Faculty of Medicine Hebrew University of Jerusalem Jerusalem Luigi Naldini Professor of Cell and Tissue Biology and of Gene and Cell Therapy San Raffaele University, and Director San Raffaele Telethon Institute for Gene Therapy Milan Duanqing Pei Professor and Director General Guangzhou Institute of Biomedicine and Health Chinese Academy of Sciences Guangzhou, China Janet Rossant2 Senior Scientist and Chief of Research Emeritus Hospital for Sick Children University of Toronto Toronto Dietram A. Scheufele John E. Ross Professor in Science Communication and Vilas Distinguished Achievement Professor University of Wisconsin Madison Jonathan Weissman2 Professor Department of Cellular and Molecular Pharmacology University of California San Francisco Keith R. Yamamoto1,2 Vice Chancellor for Science Policy and Strategy University of California San Francisco


News Article | October 26, 2016
Site: www.nanotech-now.com

Home > Press > Imaging where cancer drugs go in the body could improve treatment Abstract: Nanomedicine has the potential to help personalize cancer treatments and reduce side effects of therapeutic drugs. While some progress has been made toward the latter goal, customized treatments are still hard to come by. Now scientists report in the journal ACS Nano a new step toward seeing where certain cancer drugs accumulate in the body in order to better treat patients. They tested their drug-carrying, lipid-based nanoparticles in animals. Recent research has shown just how complicated it is to customize treatment for cancer patients. As one might expect, the same drug will accumulate in tumors at varying concentrations in patients with different cancers. But this also happens in patients with the same kind of cancer. To better evaluate which patients would benefit from particular nanomedicines such as DOXIL® or other liposomal drugs, it would be helpful to determine early on in a patient's treatment if a drug is targeting the right places at effective concentrations. Rafael T. M. de Rosales, Alberto Gabizon and colleagues sought to address this challenge. The researchers developed a simple method to attach labels to aminobisphosphonates, which are metal-binding cancer drugs commonly used in the treatment of bone metastases, packaged in liposomes. They extended the method to liposome-entrapped doxorubicin, another metal-binding drug widely used in cancer chemotherapy and present in various liposome-based nanomedicines. The labels -- and thus the liposomal drugs -- could then be tracked using positron emission tomography (PET) to see where they go within the body. Imaging with PET in mouse models of breast and ovarian cancer shows the drugs accumulated in tumors and metastatic tissues in varying concentrations and, in most cases, at levels well above those in normal tissues, the researchers report. In one mouse strain, the nanomedicines unexpectedly showed up in uteruses, a result that wouldn't have been detected without conducting the imaging study, according to the researchers. This type of imaging data may help predict how much drug will be delivered to cancer tissues in specific patients, and whether the nanomedicine is reaching all the patient's tumors in therapeutic concentrations. ### The authors acknowledge funding from the EPSRC/CRUK King's College London and UCL Comprehensive Cancer Imaging Centre, the Wellcome Trust/EPSRC Medical Engineering Centre at King's College London, the National Institute for Health Research (U.K.), and the Shaare Zedek Medical Center (Jerusalem, Israel). About American Chemical Society The American Chemical Society is a nonprofit organization chartered by the U.S. Congress. With nearly 157,000 members, ACS is the world's largest scientific society and a global leader in providing access to chemistry-related research through its multiple databases, peer-reviewed journals and scientific conferences. Its main offices are in Washington, D.C., and Columbus, Ohio. 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.


News Article | October 26, 2016
Site: www.eurekalert.org

Nanomedicine has the potential to help personalize cancer treatments and reduce side effects of therapeutic drugs. While some progress has been made toward the latter goal, customized treatments are still hard to come by. Now scientists report in the journal ACS Nano a new step toward seeing where certain cancer drugs accumulate in the body in order to better treat patients. They tested their drug-carrying, lipid-based nanoparticles in animals. Recent research has shown just how complicated it is to customize treatment for cancer patients. As one might expect, the same drug will accumulate in tumors at varying concentrations in patients with different cancers. But this also happens in patients with the same kind of cancer. To better evaluate which patients would benefit from particular nanomedicines such as DOXIL® or other liposomal drugs, it would be helpful to determine early on in a patient's treatment if a drug is targeting the right places at effective concentrations. Rafael T. M. de Rosales, Alberto Gabizon and colleagues sought to address this challenge. The researchers developed a simple method to attach labels to aminobisphosphonates, which are metal-binding cancer drugs commonly used in the treatment of bone metastases, packaged in liposomes. They extended the method to liposome-entrapped doxorubicin, another metal-binding drug widely used in cancer chemotherapy and present in various liposome-based nanomedicines. The labels -- and thus the liposomal drugs -- could then be tracked using positron emission tomography (PET) to see where they go within the body. Imaging with PET in mouse models of breast and ovarian cancer shows the drugs accumulated in tumors and metastatic tissues in varying concentrations and, in most cases, at levels well above those in normal tissues, the researchers report. In one mouse strain, the nanomedicines unexpectedly showed up in uteruses, a result that wouldn't have been detected without conducting the imaging study, according to the researchers. This type of imaging data may help predict how much drug will be delivered to cancer tissues in specific patients, and whether the nanomedicine is reaching all the patient's tumors in therapeutic concentrations. The authors acknowledge funding from the EPSRC/CRUK King's College London and UCL Comprehensive Cancer Imaging Centre, the Wellcome Trust/EPSRC Medical Engineering Centre at King's College London, the National Institute for Health Research (U.K.), and the Shaare Zedek Medical Center (Jerusalem, Israel). The paper's abstract will be available on Oct. 26 here: The American Chemical Society is a nonprofit organization chartered by the U.S. Congress. With nearly 157,000 members, ACS is the world's largest scientific society and a global leader in providing access to chemistry-related research through its multiple databases, peer-reviewed journals and scientific conferences. Its main offices are in Washington, D.C., and Columbus, Ohio. To automatically receive news releases from the American Chemical Society, contact newsroom@acs.org.


Patent
Shaare Zedek Medical Center and Hebrew University of Jerusalem | Date: 2012-07-07

The present disclosure provides liposomes comprising a membrane and an intraliposomal aqueous water phase, the membrane comprising at least one liposome forming lipid and the intraliposomal aqueous water phase comprises a salt of a bisphosphonate together with an amphipathic weak base agent (PLAD). An example of a liposome is one comprising co encapsulated in the intraliposomal aqueous water phase N-containing bisphosphonate, such as alendronate, and an anthracycline such as doxorubicin which was shown to increase survival as compared to Doxil or to administrations of liposomal alendronate (PLA) and Doxil (separate liposomes). Such liposomes may carry a targeting moiety exposed at the liposomes outer surface, for example, conjugate of folic acid as a targeting moiety to folate receptor (FT-PLAD). Also provided by the present disclosure is a method of preparing the liposomes and methods of use of the liposomes, at times, in combination with additional active ingredients, such as T-cells.


Grant
Agency: European Commission | Branch: H2020 | Program: RIA | Phase: PHC-18-2015 | Award Amount: 6.00M | Year: 2016

The incidence of paediatric onset Inflammatory Bowel Diseases (PIBD) has risen dramatically in recent decades. Compared to adult forms, PIBD reflects a more severe disease, more often requiring aggressive treatment with immunomodulators, and thereby exposing children to a life-long risk of serious disease and treatment-related adverse events, such as infections and malignancies. Therefore, there is an urgent need to develop strategies which balance, on an individual basis, therapeutic effectiveness with risks of treatment. The overall goal of this proposal is to develop and validate a treatment algorithm for PIBD based on high or low risk predictors for early complicated or relapsing disease. This will improve effectiveness, while reducing treatment related risks and life-long complications due to uncontrolled disease progression. To attain this goal 3 specific aims are proposed under the umbrella of an international network, the PIBD-net: 1) Development of an accessible and feasible risk-stratified treatment algorithm for new onset paediatric IBD on an existing inception cohort and validation in an independent cohort 2) Generation of a prospective large longterm real world inception cohort in a registry designed to analyze effectiveness and safety signals and correlate them to individual risk factors 3) Design and performance of a risk algorithm-based prospective large-scale multicenter randomized clinical trial (RCT) (stratification into high or low risk groups based on specific aim#1) in order to provide optimal personalized therapy: low risk azathioprine vx. methotrexate, high risk : methotrexate vx. adalimumab This project will translate into the first risk-stratified PIBD treatment algorithms allowing optimization of medical therapy while minimizing treatment-related risk (personalized medicine).


Cherny N.,Shaare Zedek Medical Center
Seminars in Oncology | Year: 2011

This article seeks to address the question: Is best supportive care (BSC) in research a euphemism for no care or a standard of good care? The data regarding the ethical and methodological validity of BSC studies are reviewed. Most of the BSC studies published over the past 25 years are really treatment versus no treatment studies represented as BSC studies. By ignoring the best contemporaneous standards of BSC, standardizing practices in multicenter studies, validating participating centers, or documenting treatment delivery, researchers belie the stated intention of studying BSC. Most studies sought to evaluate if there was any benefit of a new anti-tumor treatment versus discontinuation of anti-tumor therapies. Overwhelmingly, and with few exceptions, the impact of BSC practices was not really part of the key research question. To be ethical and methodologically valid, BSC studies must incorporate standards consistent with contemporaneous, proven BSC practice standards. Work is underway to develop widely validated standards of practice for the control arm of best supportive care studies. These can be readily incorporated in to study development and evaluation. © 2011 Elsevier Inc.


Hershko C.,Shaare Zedek Medical Center
Annals of the New York Academy of Sciences | Year: 2010

In thalassemia major, iron overload is the joint outcome of multiple blood transfusions and an inappropriately increased iron absorption associated with ineffective erythropoiesis. Threshold values for iron toxicity are a liver iron concentration exceeding 440 mmolesg dry weight, serum ferritin >2500 ngmL, DFO urinary iron excretion >20 mgday, and transferrin saturation >75%. The outpouring of catabolic iron that exceeds the iron-carrying capacity of transferrin results in the emergence of non-transferrin-bound iron (NTBI). NTBI is cleared preferentially by the liver and myocardium at a rate exceeding 200 times that of transferrin iron. NTBI catalyzes the formation of free radicals, resulting in oxidative stress and damage to mitochondria, lysosomes, lipid membranes, proteins, and DNA. The long-term consequences of iron toxicity, including cirrhosis, myocardiopathy, and endocrine disorders, are preventable and mostly reversible by effective iron chelation therapy. Recent technologic advances in the documentation of organ-specific siderosis and the improved efficiency of iron chelating programs resulted in a spectacular improvement in the prevention of iron-induced end-organ failure and improved survival in thalassemic patients. © 2010 New York Academy of Sciences.


Objective: To evaluate the attitudes of the European Oncologists to information disclosure to patients with advanced cancer, their self-reported behaviors, and the factors that influence both attitudes and behaviors. Methods: ESMO members were invited to complete an online questionnaire to evaluate both attitudes and clinical behaviors relating to the disclosure of information to patients with advanced cancer. Data were analyzed to evaluate demographic, educational and social factors influencing attitudes and behaviors. Results: Two hundred and ninety-eight completed surveys were returned. The survey demonstrated strong internal consistency construct validity. The responses indicate that individual clinicians generally display a range of behaviors including non-disclosive as well as disclosive behaviors depending on the dynamics of individual interactions between oncologist and specific patient. Although regional cultural norms influence oncologists' attitudes toward disclosure and, indirectly, their self-reported behaviors, the impact is influenced by other factors: in particular, perceived institutional professional norms, the degree of training in breaking bad news and the frequency of exposure to requests by family members to withhold information from the patient. Conclusions: Positive attitudes regarding disclosure of information to patients and disclosive behaviors can be encouraged, even in non-Western countries, by the development of strong professional norms and education in breaking bad news and coping with the emotional responses of patients. Copyright © 2010 John Wiley & Sons, Ltd.


Cherny N.,Shaare Zedek Medical Center
Palliative Medicine | Year: 2011

Aim: To address the question: is oral methadone better than placebo, or other oral/transdermal opioids in the management of cancer pain?Method: A literature search was performed to identify relevant studies. Search strategies included: (1) methadone (title) AND placebo (title or abstract) AND pain (title or abstract); (2) methadone (title) AND randomized (title or abstract) AND pain (title or abstract) AND cancer (title or abstract). Papers were reviewed for relevance to first-line opioid therapy.Results: No studies were identified comparing methadone to placebo for cancer pain. A single study compared methadone to placebo for neuropathic pain and demonstrated evidence of analgesic effect at a dose of 20 mg/day but not at a dose of 10 mg/day.Four studies compared oral methadone to either oral morphine, or oral morphine and transdermal fentanyl in a first-line setting: Gourlay 1986 (N = 18), Ventafridda 1986 (N = 54), Bruera 2004 (N = 106) and Mercadante 2008 (N = 108). All studies demonstrated comparable, but not superior, analgesia with, overall, a comparable adverse effect profile. The duration of the study period for the three largest studies was 28 days. Two of these studies, Ventafridda 1986 and Mercadante 2008, indicated that, over time, the opioid escalation index was lower for methadone than for morphine. One study that used a 2:1 dose ratio between morphine and methadone was associated with a high attrition rate in the first week because of excessive sedation. This effect was not seen in the study that used a 4:1 morphine to methadone dose ratio with dose titration.Conclusion: This limited data suggests that (1) methadone may be an equally effective candidate for first-line opioid therapy, (2) that it is possibly less expensive, (3) that there may be a propensity to sedation and dose accumulation unless there is close monitoring and conservative dose selection and (4) that it should be initiated with a calculated dose based on a morphine to methadone dose ratio of not less than 4:1. © 2011 The Author(s).


Korn-Lubetzki I.,Shaare Zedek Medical Center
Journal of the American Heart Association | Year: 2013

One of the most daunting complications of cardiac catheterization is a cerebrovascular event (CVE). We aimed to assess the real-life incidence, etiology, and risk factors of cardiac catheterization-related acute CVEs in a large cohort of patients treated in a single center. We undertook a retrospective analysis of 43,350 coronary procedures performed on 30,907 procedure days over the period 1992-2011 and compared patient and procedural characteristics of procedures complicated by CVEs with the remaining cohort. CVEs occurred in 47 cases: 43 were ischemic, 3 intracerebral hemorrhages, and 1 undetermined. The overall CVE rate was 0.15%, with percutaneous coronary intervention (PCI) and diagnostic coronary angiography rates 0.23% and 0.09%, respectively. Using a forward stepwise multivariate logistic regression model including patient demographic and procedural characteristics, a total of 5 significant predictors were defined: prior stroke (OR=15.09, 95% CI [8.11 to 28.08], P<0.0001), presence of coronary arterial thrombus (OR=2.79, 95% CI [1.25 to 6.22], P=0.012), age >75 years (OR=3.33, 95% CI [1.79 to 6.19], P<0.0001), triple vessel disease (OR=2.24, 95% CI [1.20 to 4.18], P=0.011), and performance of intervention (OR=2.21, 95% CI [1.12 to 4.33], P=0.021). An additional analysis excluded any temporal change of CVE rates but demonstrated a significant increase of all high-risk patient features. In a single-center, retrospective assessment over nearly 20 years, cardiac catheterization-related CVEs were very rare and nearly exclusively ischemic. The independent predictors for these events were found to be the performance of an intervention and those associated with increased atherosclerotic burden, specifically older age, triple vessel disease, and prior stroke. The presence of intracoronary thrombus appears also to raise the risk of procedure-related CVE.

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