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PubMed | IFOM, National University of Singapore, French National Center for Scientific Research, French Institute of Health and Medical Research and The Barcelona Institute of Science and Technology
Type: | Journal: Journal of cell science | Year: 2016

Biomimetic materials have long been the (he)art of bioengineering. They usually aim at mimicking in vivo conditions to allow in vitro culture, differentiation and expansion of cells. The past decade has witnessed a considerable amount of progress in soft lithography, bio-inspired micro-fabrication and biochemistry, allowing the design of sophisticated and physiologically relevant micro- and nano-environments. These systems now provide an exquisite toolbox with which we can control a large set of physicochemical environmental parameters that determine cell behavior. Bio-functionalized surfaces have evolved from simple protein-coated solid surfaces or cellular extracts into nano-textured 3D surfaces with controlled rheological and topographical properties. The mechanobiological molecular processes by which cells interact and sense their environment can now be unambiguously understood down to the single-molecule level. This Commentary highlights recent successful examples where bio-functionalized substrates have contributed in raising and answering new questions in the area of extracellular matrix sensing by cells, cell-cell adhesion and cell migration. The use, the availability, the impact and the challenges of such approaches in the field of biology are discussed.

News Article | February 16, 2017
Site: www.eurekalert.org

What if you could lose weight and reduce your risk of life-threatening disease without any changes in what you eat -- other than a five-day special diet once every few months? That's what happened for 71 adults who were placed on three cycles of a low-calorie, "fasting-mimicking" diet. The phase II trial, conducted by researchers at the USC Leonard Davis School of Gerontology, demonstrated a host of benefits from the regimen. The diet reduced cardiovascular risk factors including blood pressure, signs of inflammation (measured by C-reactive protein levels), as well as fasting glucose and reduced levels of IGF-1, a hormone that affects metabolism. It also shrank waistlines and resulted in weight loss, both in total body fat and trunk fat, but not in muscle mass. In effect, the diet reduced the study participants' risks for cancer, diabetes, heart disease and other age-related diseases, according to the findings published Feb. 15 in Science Translational Medicine. "This study provides evidence that people can experience significant health benefits through a periodic, fasting-mimicking diet that is designed to act on the aging process," said Valter Longo, director of the USC Longevity Institute and a professor of biological sciences for USC Davis and Dornsife. "Prior studies have indicated a range of health benefits in mice, but this is the first randomized clinical trial with enough participants to demonstrate that the diet is feasible, effective and safe for humans. "Larger FDA studies are necessary to confirm its effects on disease prevention and treatment," he added. One hundred people participated in the trial from April 2013 to July 2015. The participants, ages 20 to 70 and all generally healthy, were divided into two groups for the randomized trial. Participants in the first group, the control group, were asked to continue their normal eating habits for three months. People in the second group were placed on a three-month test of the fasting-mimicking diet. Those on the special diet were required to eat food products supplied by the nutrition company L-Nutra during the fasting periods of five days each month. The diet, which was designed to mimic the results of a water-only fast, allowed for participants to consume between 750 and 1,100 calories per day. The meals for the fast-mimicking diet contained precise proportions of proteins, fats and carbohydrates. After three months, participants in the control group were moved onto the special diet. The researchers found that participants on the fasting-mimicking diet lost an average of about 6 pounds. Their waistlines shrank by 1 to 2 inches. Their systolic blood pressure, which was in the normal range when the study began, dropped by 4.5 mmHG, while their diastolic blood pressure dropped by 3.1 mmHg. Also, their levels of IGF-1 dropped to between 21.7 ng/mL and 46.2 ng/mL, reaching a range associated with lower cancer risk. "After the first group completed their three months on the fasting diet, we moved over participants in the control group to see if they also would experience similar results," Longo said. "We saw similar outcomes, which provides further evidence that a fasting-mimicking diet has effects on many metabolic and disease markers. Our mouse studies using a similar fasting-mimicking diet indicate that these beneficial effects are caused by multi-system regeneration and rejuvenation in the body at the cellular and organ levels. "Our participants retained those effects, even when they returned to their normal daily eating habits," he added. The researchers also noted that participants considered "at risk" because they had risk factors such as high IGF-1, cholesterol, blood pressure or blood sugar levels, made significant progress toward better health. For example, baseline fasting glucose levels for participants with high blood sugar levels (putting them at risk for diabetes) dropped into the healthy range, below 99 mg/dl -- but these levels didn't drop among participants who already had healthy levels at the beginning of the study. Cholesterol was reduced by 20 mg/dl in those with high cholesterol levels, and by about 5 mg/dl in all participants. "Fasting seems to be the most beneficial for patients who have the great risk factors for disease, such as those who have high blood pressure or pre-diabetes or who are obese," Longo said. The researchers had invited participants in the study for one last set of tests three months later, at the end of the diet. The research team found that the beneficial effects -- from weight loss, smaller waistlines and lower glucose, blood pressure and IGF-1 levels -- were sustained. The next step for researchers is a large, FDA phase III clinical trial to test the FMD on patients diagnosed with age-related diseases or at high risk for them. The researchers said further investigation will determine whether the benefits of the diet can continue for several months. The work was funded by the USC Edna M. Jones Chair in Gerontology fund, as well as through a National Institutes of Health grant to co-author Wendy Mack at the Keck School of Medicine of USC, through the Southern California Clinical and Translational Science Institute. Study co-authors from USC Davis were Min Wei and Sebastian Brandhorst (lead co-authors) and Mahshid Shelehchi, Hamed Mirzaei, Chia Wei Cheng, Julia Budniak, Esra Guen, Stefano Di Biase, Pinchas Cohen and Todd Morgan. Others were Tanya Dorff of USC Norris Comprehensive Cancer Center; Kurt Hong, of the Keck School of Medicine; Andreas Michalsen of Charité University Medical Center in Germany; and Alessandro Laviano at IFOM, the FIRC Institute of Molecular Oncology. Longo is the founder of L-Nutra, whose food products were used in the study. His interest in L-Nutra has been disclosed and managed per USC's conflicts of interest policies to assure objectivity and a lack of bias in the conduct and reporting of his research. USC also has an ownership interest in L-Nutra, and the potential to receive royalty payments from L-Nutra. USC's financial interest in the company has been disclosed and managed under USC's institutional conflict of interest policies.

News Article | December 13, 2016
Site: globenewswire.com

IBA signs two new Proteus®ONE contracts with Proton Partners International Louvain-La-Neuve, Belgium, 13 December 2016 - IBA (Ion Beam Applications S.A., EURONEXT), the world's leading provider of proton therapy solutions for the treatment of cancer, today announces it has signed two new contracts with Proton Partners International (PPI), to install two Proteus®ONE* compact proton therapy solutions in Reading and an undisclosed site in the UK. The contracts are effective as of today. The contracted Proteus®ONE solutions include Pencil Beam Scanning (PBS) and Cone Beam CT (CBCT) capabilities making Proteus®ONE the only compact solution ready for adaptive treatment. The contracts also include a maintenance agreement. The typical end-user price for a Proteus®ONE solution with a maintenance contract is between EUR 35 and 40 million. These new centers will be the fifth and sixth that IBA will install for PPI. Previously-ordered centers by PPI are currently being installed in Wales (Newport), in England (Northumberland and London) and in Abu Dhabi, UAE. These latest contracted Proteus®ONE will be the 15th and 16th installation of IBA's compact single-room proton therapy solution, globally. IBA has now sold 45 proton therapy centers worldwide. These projects are a result of the framework agreement with Philips that has been in place since September 2014, demonstrating the benefit of this relationship in bringing new international contracts to fruition. Olivier Legrain, Chief Executive Officer of IBA, commented: "We are delighted to partner with PPI, the institution that leads proton therapy penetration in UK and in the United Arab Emirates. PPI's choice of IBA and our compact solution demonstrates the increasing demand for this cutting edge treatment modality. At present, proton therapy represents only 1% of all radiotherapy treatments, however, studies estimate that 20% of patients treated by radiotherapy would benefit from being treated with proton therapy." Mike Moran, Chief Executive Officer of Proton Partners International Limited, added: "We are very pleased to further expand our collaboration with IBA following the highly professional support and responsiveness that it has demonstrated to date. Cancer incidence is rising dramatically, globally, and more innovation is needed to deal with this disease. Our strategy of building a strong international network of proton therapy centers will guarantee high-quality treatment throughout our network, enabling more patients to benefit from cutting-edge proton therapy. Every cancer patient in UK deserves the best possible care without needing to travel far." About Proteus®ONE Proteus®ONE is the compact intensity modulated proton therapy (IMPT) solution from IBA. It benefits from the latest technologies developed with renowned clinical institutions. Proteus®ONE is smaller, more affordable, easier to install and to operate. It is ultimately easier to finance, making this advanced radiation therapy modality available to more institutions and patients worldwide. Proteus®ONE makes proton therapy easy. * Proteus®ONE is the brand name of Proteus®235 in the US and Europe and a certified product in Japan. About IBA IBA (Ion Beam Applications S.A.) is a global medical technology company focused on bringing integrated and innovative solutions for the diagnosis and treatment of cancer. The company is the worldwide technology leader in the field of proton therapy, considered to be the most advanced form of radiation therapy available today. IBA's proton therapy solutions are flexible and adaptable, allowing customers to choose from universal full-scale proton therapy centers as well as compact, single room solutions. In addition, IBA also has a radiation dosimetry business and develops particle accelerators for the medical world and industry. Headquartered in Belgium and employing about 1,500 people worldwide, IBA has installed systems across the world. IBA is listed on the pan-European stock exchange NYSE EURONEXT (IBA: Reuters IBAB.BR and Bloomberg IBAB.BB). More information can be found at: www.iba-worldwide.com About Proton Partners International Limited Proton Partners International is a private limited company, registered in Wales. The company was formed following discussions between Professor Karol Sikora, former head of the World Health Organisation's cancer programme, Professor Sir Chris Evans, the leading life sciences entrepreneur, and Neil Woodford, founding partner of Woodford Investment Management. Institutional and private investors have committed to almost £100m equity finance in the company. Professor Gordon McVie, Clinical Research Adviser to the FIRC Institute of Molecular Oncology (IFOM), is non-executive chairman and Professor Karol Sikora is chief medical officer to the company. The Welsh Government's Life Sciences Investment Fund is a key investor in Proton Partners International. For more information on Proton Partners, please visit: www.proton-int.com For further information, please contact:

Palazzo L.,University of Naples Federico II | Palazzo L.,University of Oxford | Della Monica R.,University of Naples Federico II | Visconti R.,CNR Institute Experimental Endocrinology and Oncology Gaetano Salvatore | And 2 more authors.
Cell Cycle | Year: 2014

The recessive ataxia-telangiectasia (A-T) syndrome is characterized by cerebellar degeneration, immunodeficiency, cancer susceptibility, premature aging, and insulin-resistant diabetes and is caused by loss of function of the ATM kinase, a member of the phosphoinositide 3-kinase-like protein kinases (PIKKs) family. ATM plays a crucial role in the DNA damage response (DDR); however, the complexity of A-T features suggests that ATM may regulate other cellular functions. Here we show that ATM affects proper bipolar mitotic spindle structure independently of DNA damage. In addition, we find that in mitosis ATM forms a complex with the poly(ADP)ribose (PAR) polymerase Tankyrase (TNKS) 1, the spindle pole protein NuMA1, and breast cancer susceptibility protein BRCA1, another crucial DDR player. Our evidence indicates that the complex is required for efficient poly(ADP)ribosylation of NuMA1. We find further that a mutant NuMA1 version, non-phosphorylatable at potential ATM-dependent phosphorylation sites, is poorly PARylated and induces loss of spindle bipolarity. Our findings may help to explain crucial A-T features and provide further mechanistic rationale for TNKS inhibition in cancer therapy. © 2014 Landes Bioscience.

Bonner J.N.,Sloan Kettering Cancer Center | Choi K.,Sloan Kettering Cancer Center | Xue X.,Yale University | Torres N.P.,University of Toronto | And 9 more authors.
Cell Reports | Year: 2016

Timely removal of DNA recombination intermediates is critical for genome stability. The DNA helicase-topoisomerase complex, Sgs1-Top3-Rmi1 (STR), is the major pathway for processing these intermediates to generate conservative products. However, the mechanisms that promote STR-mediated functions remain to be defined. Here we show that Sgs1 binds to poly-SUMO chains and associates with the Smc5/6 SUMO E3 complex in yeast. Moreover, these interactions contribute to the sumoylation of Sgs1, Top3, and Rmi1 upon the generation of recombination structures. We show that reduced STR sumoylation leads to accumulation of recombination structures, and impaired growth in conditions when these structures arise frequently, highlighting the importance of STR sumoylation. Mechanistically, sumoylation promotes STR inter-subunit interactions and accumulation at DNA repair centers. These findings expand the roles of sumoylation and Smc5/6 in genome maintenance by demonstrating that they foster STR functions in the removal of recombination intermediates. Bonner et al. show that the Smc5/6 SUMO ligase complex interacts with and promotes the sumoylation of the DNA helicase Sgs1 and its partner proteins Top3 and Rmi1. Sgs1-Top3-Rmi1 (STR) sumoylation fosters the removal of recombination intermediates, in part by stimulating STR inter-subunit interaction and STR accumulation at DNA repair centers. © 2016.

Morelli E.,IFOM | Mastrodonato V.,IFOM | Beznoussenko G.V.,IFOM | Mironov A.A.,IFOM | And 2 more authors.
EMBO Journal | Year: 2016

The kinetochore is an essential structure that mediates accurate chromosome segregation in mitosis and meiosis. While many of the kinetochore components have been identified, the mechanisms of kinetochore assembly remain elusive. Here, we identify a novel role for Snap29, an unconventional SNARE, in promoting kinetochore assembly during mitosis in Drosophila and human cells. Snap29 localizes to the outer kinetochore and prevents chromosome mis-segregation and the formation of cells with fragmented nuclei. Snap29 promotes accurate chromosome segregation by mediating the recruitment of Knl1 at the kinetochore and ensuring stable microtubule attachments. Correct Knl1 localization to kinetochore requires human or Drosophila Snap29, and is prevented by a Snap29 point mutant that blocks Snap29 release from SNARE fusion complexes. Such mutant causes ectopic Knl1 recruitment to trafficking compartments. We propose that part of the outer kinetochore is functionally similar to membrane fusion interfaces. © 2016 EMBO.

Hang L.E.,Sloan Kettering Cancer Center | Hang L.E.,Rockefeller University | Peng J.,SUNY Upstate Medical University | Tan W.,Sloan Kettering Cancer Center | And 7 more authors.
Molecular Cell | Year: 2015

Elucidating the individual and collaborative functions of genome maintenance factors is critical for understanding how genome duplication is achieved. Here, we investigate a conserved scaffold in budding yeast, Rtt107, and its three partners: a SUMO E3 complex, a ubiquitin E3 complex, and Slx4. Biochemical and genetic findings show that Rtt107 interacts separately with these partners and contributes to their individual functions, including a role in replisome sumoylation. We also provide evidence that Rtt107 associates with replisome components, and both itself and its associated E3s are important for replicating regions far from initiation sites. Corroborating these results, replication defects due to Rtt107 loss and genotoxic sensitivities in mutants of Rtt107 and its associated E3s are rescued by increasing replication initiation events through mutating two master repressors of late origins, Mrc1 and Mec1. These findings suggest that Rtt107 functions as a multi-functional platform to support replication progression with its partner E3 enzymes. © 2015 Elsevier Inc.

Boniolo G.,University of Milan | Di Fiore P.P.,IFOM | Pece S.,University of Milan
Bioethics | Year: 2012

We argue that, in the case of research biobanks, there is a need to replace the currently used informed consent with trusted consent. Accordingly, we introduce a proposal for the structure of the latter. Further, we discuss some of the issues that can be addressed effectively through our proposal. In particular, we illustrate: i) which research should be authorized by donors; ii) how to regulate access to information; iii) the fundamental role played by a Third Party Authority in assuring compliance with the reciprocal expectations and obligations of donors and scientists. Finally, we briefly analyse two issues that might represent important elements of a 'new alliance' between researchers and donors to which the trusted consent could pave the way: i) the correlations between needs and rights of the two parties, and ii) possible economic transactions. © 2010 Blackwell Publishing Ltd.

PubMed | Sloan Kettering Cancer Center, IFOM, SUNY Upstate Medical University and Georgia Institute of Technology
Type: Journal Article | Journal: Molecular cell | Year: 2015

Elucidating the individual and collaborative functionsof genome maintenance factors is critical for understanding how genome duplication is achieved. Here, we investigate a conserved scaffold in budding yeast, Rtt107, and its three partners: a SUMO E3 complex, a ubiquitin E3 complex, and Slx4. Biochemical and genetic findings show that Rtt107 interacts separately with these partners and contributes to their individual functions, including a role in replisome sumoylation. We also provide evidence that Rtt107 associates with replisome components, and both itself and its associated E3s are important for replicating regions far from initiation sites. Corroborating these results, replication defects due to Rtt107 loss and genotoxic sensitivities in mutants of Rtt107 and its associated E3s are rescued by increasing replication initiation events through mutating two master repressors of late origins, Mrc1 and Mec1. These findings suggest that Rtt107 functions as a multi-functional platform to support replication progression with its partner E3 enzymes.

PubMed | IFOM
Type: Journal Article | Journal: Circulation research | Year: 2010

Early stages of vascular development include endothelial cell differentiation in a network of arteries, veins, and lymphatics. Subsequently, to respond to the specific needs of the organs, endothelial cells acquire specialized properties such as permeability control, expression of specific transcellular transport systems, membrane adhesive molecules, and others. Endothelial cell differentiation depends on communication between the surrounding tissues, which is mediated by growth and differentiation factors able to activate specific gene expression programs. Recent reports underline the important role of the Wnt system in vascular morphogenesis in the embryo and in organ-specific endothelial differentiation. Wnt signaling regulates fundamental aspects of development, including cell fate specification, proliferation, and survival, and may use different receptors and signaling pathways. Both loss- and gain-of-function experiments of members of the Wnt signaling pathway were found to cause marked alterations of vascular development and endothelial cell specification. Furthermore, altered Wnt signaling in the endothelium may contribute to pathological conditions such as retinopathies, pulmonary arterial hypertension, stroke, and others. Continued progress in this field holds the potential to identify novel therapeutics for the treatment of these diseases.

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