Monday, December 3rd, 2018

Time	Event
10:34a	New drug combination could be more effective against melanoma A class of cancer drugs called protein kinase inhibitors is one of the most effective treatments for melanoma. However, in many cases, tumors eventually become resistant to the drugs and cause a relapse in the patient. A new study from MIT suggests that combining kinase inhibitors with experimental drugs known as ribonucleases could lead to better results. In tests with human cancer cells, the researchers found that the two drugs given together kill cells much more effectively than either drug does on its own. The combination could also help to prevent tumors from developing drug resistance, says Ronald Raines, the Firmenich Professor of Chemistry at MIT. “We discovered that this ribonuclease drug could be paired favorably with other cancer chemotherapeutic agents, and not only that, the pairing made logical sense in terms of the underlying biochemistry,” Raines says. Raines is the senior author of the study, which appears in the Dec. 3 issue of Molecular Cancer Therapeutics and was posted in the journal’s “online first” section on Nov. 20. Trish Hoang, a former graduate student at the University of Wisconsin at Madison, is the lead author of the study. Unexpected link Ribonucleases are enzymes produced by all human cells that break down RNA molecules. They degrade cellular RNA that is no longer needed, and they help to defend against viral RNA. Because of ribonucleases’ ability to kill cells by damaging their RNA, Raines has been working on developing these enzymes as cancer drugs for about two decades. His lab has also been studying the protein that has evolved to help cells defend against ribonucleases, which can be very destructive if unchecked. This protein, called ribonuclease inhibitor, binds to ribonucleases with a half-life of at least three months — the strongest naturally occurring protein-binding interaction ever recorded. “That means that should ribonuclease invade cells, there is an unbelievable defense system,” Raines says. To create a ribonuclease drug for testing, the researchers modified it so that ribonuclease inhibitors don’t bind as tightly — the half-life for the interaction is only a few seconds. One version of this drug is now in a phase 1 clinical trial, where it has stabilized the disease in about 20 percent of patients. In the new study, the researchers found an unexpected link between ribonucleases and enzymes called protein kinases (the targets of protein kinase inhibitors), which led them to discover that the two drugs can kill cancer cells much better when used together than either one can alone.  The discovery came about when Hoang decided to try to produce the ribonuclease inhibitor protein in human cells instead of in E. coli, which Raines’ lab normally uses to produce the protein. She found that the human-cell-produced version, though identical in amino acid sequence to the protein produced by bacteria, bound to ribonucleases 100 times more strongly. This boosted the half-life of the interaction from months to decades — a protein-binding strength previously unheard of. The researchers hypothesized that human cells were somehow modifying the inhibitor in a way that made it bind more tightly. Their studies revealed that, indeed, the inhibitor produced by human cells had phosphate groups added to it. This “phosphorylation” made the inhibitor bind much more strongly than anyone had previously suspected. The researchers also discovered that phosphorylation was being carried out by protein kinases that are part of a cell signaling pathway called ERK. This pathway, which controls how cells respond to growth factors, is often overactive in cancer cells. The protein kinase inhibitors trametinib and dabrafenib, used to treat melanoma, can shut off the ERK pathway. “This was a fortuitous intersection of two different strategies, because we reasoned that if we could use these drugs to deter the phosphorylation of ribonuclease inhibitor, then we could make the ribonucleases more potent at killing cancer cells,” Raines says. Combating resistance Tests of human melanoma cells supported this idea. The combination of a kinase inhibitor plus a ribonuclease was much deadlier to cancer cells, and the drugs were effective at lower concentrations. The kinase inhibitor prevented the ribonuclease inhibitor from being phosphorylated, making it weaker and allowing the ribonuclease more freedom to perform its function and destroy RNA. If the same holds true in human patients, this approach could lead to reduced side effects and a lower chance of tumor cells becoming drug-resistant, Raines says. The researchers now hope to test this drug combination in mice, as a step toward testing the combination in clinical trials.  “We’re hoping that we can explore relationships with some of the many pharmaceutical companies that develop ERK pathway inhibitors, to team up and use our ribonuclease drug in concert with kinase inhibitors,” Raines says. The researchers have also engineered mice that do not produce ribonucleases, which they plan to use to further study the biological functions of these enzymes. The research was funded by the National Institutes of Health. (Comment on this)
2:00p	LIGO and Virgo announce four new gravitational-wave detections The following news article is adapted from a press release issued by the Laser Interferometer Gravitational-wave Observatory (LIGO) Laboratory, in partnership with the LIGO Scientific Collaboration (LSC) and Virgo Collaboration. LIGO is funded by the National Science Foundation (NSF) and operated by Caltech and MIT, which conceived and built the project. Presently, David Shoemaker, senior research scientist in MIT's Kavli Institute for Astrophysics and Space Research, serves as the elected Spokesperson for the LSC. On Saturday, Dec. 1, scientists attending the Gravitational Wave Physics and Astronomy Workshop in College Park, Maryland, presented new results from the National Science Foundation's LIGO (Laser Interferometer Gravitational-Wave Observatory) and the European-based VIRGO gravitational-wave detector regarding their searches for coalescing cosmic objects, such as pairs of black holes and pairs of neutron stars. The LIGO and Virgo collaborations have now confidently detected gravitational waves from a total of 10 stellar-mass binary black hole mergers and one merger of neutron stars, which are the dense, spherical remains of stellar explosions. Six of the black hole merger events had been reported before, while four are newly announced. From Sept. 12, 2015, to Jan. 19, 2016, during the first LIGO observing run since undergoing upgrades in a program called Advanced LIGO, gravitational waves from three binary black hole mergers were detected. The second observing run, which lasted from Nov. 30, 2016 to Aug. 25, 2017, yielded one binary neutron star merger and seven additional binary black hole mergers, including the four new gravitational-wave events being reported now. The new events are known as GW170729, GW170809, GW170818, and GW170823, in reference to the dates they were detected. All of the events are included in a new catalog, also released Saturday, with some of the events breaking records. For instance, the new event GW170729, detected in the second observing run on July 29, 2017, is the most massive and distant gravitational-wave source ever observed. In this coalescence, which happened roughly 5 billion years ago, an equivalent energy of almost five solar masses was converted into gravitational radiation. GW170814 was the first binary black hole merger measured by the three-detector network, and allowed for the first tests of gravitational-wave polarization (analogous to light polarization). The event GW170817, detected three days after GW170814, represented the first time that gravitational waves were ever observed from the merger of a binary neutron star system. What's more, this collision was seen in gravitational waves and light, marking an exciting new chapter in multimessenger astronomy, in which cosmic objects are observed simultaneously in different forms of radiation. One of the new events, GW170818, which was detected by the global network formed by the LIGO and Virgo observatories, was very precisely pinpointed in the sky. The position of the binary black holes, located 2.5 billion light-years from Earth, was identified in the sky with a precision of 39 square degrees. That makes it the next best localized gravitational-wave source after the GW170817 neutron star merger. Caltech’s Albert Lazzarini, deputy director of the LIGO Laboratory, says “The release of four additional binary black hole mergers further informs us of the nature of the population of these binary systems in the universe and better constrains the event rate for these types of events." "In just one year, LIGO and VIRGO working together have dramatically advanced gravitational-wave science, and the rate of discovery suggests the most spectacular findings are yet to come,” says Denise Caldwell, director of NSF's Division of Physics. "The accomplishments of NSF's LIGO and its international partners are a source of pride for the agency, and we expect even greater advances as LIGO's sensitivity becomes better and better in the coming year." "The next observing run, starting in Spring 2019, should yield many more gravitational-wave candidates, and the science the community can accomplish will grow accordingly,” says David Shoemaker, spokesperson for the LIGO Scientific Collaboration and senior research scientist in MIT’s Kavli Institute for Astrophysics and Space Research. “It’s an incredibly exciting time.” “It is gratifying to see the new capabilities that become available through the addition of Advanced Virgo to the global network,” says Jo van den Brand of Nikhef (the Dutch National Institute for Subatomic Physics) and VU University Amsterdam, who is the spokesperson for the Virgo Collaboration. “Our greatly improved pointing precision will allow astronomers to rapidly find any other cosmic messengers emitted by the gravitational-wave sources.” The enhanced pointing capability of the LIGO-Virgo network is made possible by exploiting the time delays of the signal arrival at the different sites and the so-called antenna patterns of the interferometers. “The new catalog is another proof of the exemplary international collaboration of the gravitational wave community and an asset for the forthcoming runs and upgrades” adds EGO Director Stavros Katsanevas. The scientific papers describing these new findings, which are being initially published on the arXiv repository of electronic preprints, present detailed information in the form of a catalog of all the gravitational wave detections and candidate events of the two observing runs as well as describing the characteristics of the merging black hole population. Most notably, we find that almost all black holes formed from stars are lighter than 45 times the mass of the Sun. Thanks to more advanced data processing and better calibration of the instruments, the accuracy of the astrophysical parameters of the previously announced events increased considerably. Laura Cadonati, deputy spokesperson for the LIGO Scientific Collaboration, says “These new discoveries were only made possible through the tireless and carefully coordinated work of the detector commissioners at all three observatories, and the scientists around the world responsible for data quality and cleaning, searching for buried signals, and parameter estimation for each candidate — each a scientific specialty requiring enormous expertise and experience.” LIGO is funded by NSF and operated by Caltech and MIT, which conceived of LIGO and led the Initial and Advanced LIGO projects. Financial support for the Advanced LIGO project was led by the NSF with Germany (Max Planck Society), the U.K. (Science and Technology Facilities Council) and Australia (Australian Research Council-OzGrav) making significant commitments and contributions to the project. More than 1,200 scientists from around the world participate in the effort through the LIGO Scientific Collaboration, which includes the GEO Collaboration. A list of additional partners is available at https://my.ligo.org/census.php. The Virgo collaboration consists of more than 300 physicists and engineers belonging to 28 different European research groups: six from Centre National de la Recherche Scientifique (CNRS) in France; 11 from the Istituto Nazionale di Fisica Nucleare (INFN) in Italy; two in the Netherlands with Nikhef; the MTA Wigner RCP in Hungary; the POLGRAW group in Poland; Spain with IFAE and the Universities of Valencia and Barcelona; two in Belgium with the Universities of Liege and Louvain; Jena University in Germany; and the European Gravitational Observatory (EGO), the laboratory hosting the Virgo detector near Pisa in Italy, funded by CNRS, INFN, and Nikhef. A list of the Virgo Collaboration can be found at http://public.virgo-gw.eu/the-virgo-collaboration/. Papers available on the arXiv and the LIGO DCC (Document Control Center), https://dcc.ligo.org/. (Comment on this)

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