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Written by: Levi Gadye

Published: 16 March 2024

UC San Francisco researchers have designed a candidate drug that could help make pancreatic cancer, which is almost always fatal, a treatable, perhaps even curable, condition.

The new drug candidate permanently modifies a wily cancer-causing mutation, called K-Ras G12D, that is responsible for nearly half of all pancreatic cancer cases and appears in some forms of lung, breast and colon cancer.

Pancreatic cancer is less common than these other cancers, but the lack of treatment options makes it more deadly, and it claims more than 50,000 lives each year in the United States.

“We’ve worked for 10 years to bring pancreatic cancer therapies up to speed with therapies for other cancers,” said Kevan Shokat, PhD, a professor in the Department of Cellular and Molecular Pharmacology who led the work. “This breakthrough is the first to target G12D and gives us a firm foothold to fight this devastating mutation.”

The findings appear March 5, 2024, in Nature Chemical Biology.

Shokat and his colleagues developed the first cancer drugs to stop a different K-Ras mutation, G12C, in 2013. Since then, two therapies have been approved for use in lung and breast cancer, but the advance didn’t move the needle for treating pancreatic cancer.

An extremely common mutation

K-Ras mutations are extremely common in pancreatic cancer, explaining 90% of cases. About half of these mutations are G12D, which differs from most other K-Ras mutations by a single amino acid substitution.

This difference between healthy and cancer-causing proteins, in which glycine (G) becomes aspartate (D), presented a monumental challenge for chemists.

“There are very few molecules out there that can sense the difference between the cancer-causing aspartate and the glycine,” Shokat said. “To make good therapies, we need drugs that work on the tumor cells only, without affecting healthy cells.”

Shokat’s team envisioned a molecule that fit into a pocket of the K-Ras protein, then firmly – and irreversibly – bound to the rogue aspartate. The explosion of research that followed Shokat’s 2013 discovery enabled them to develop a template for chemicals that reliably found their way into that corner of the protein.

“Once we had that structure for our molecules, we knew they were sitting in the protein at the right spot,” Shokat said. “Then we could explore the little nooks and crannies that we needed to discover the chemistry of the aspartate.”

Could a bend in a molecule lead to a cure?

The scientists went through dozens of chemicals.

“It’s like climbing a new route on a mountain, you may be strong but the lengths of your arms limit what you can do,” Shokat said. “It was a lot of trial and error, tweaking the branches of these molecules to position them in this incredibly tight space around G12D. Some got close, then failed, and we would start over.”

Eventually, they found a winning molecule. It settled into the appropriate corner of K-Ras and bent into a new shape that reacted strongly with the aspartate.

The molecule put the brakes on tumor growth from G12D in cancer cell lines, as well as an animal model of human cancer. And it never attacked healthy proteins.

The scientists are now optimizing the molecule to be durable enough to fight cancer in the human body. With the traction gained from this study, Shokat said, new therapies for pancreatic cancer could enter clinical trials in as little as two to three years.

“We’ve learned a lot from other targeted therapies and know how to quickly translate discoveries like these for the clinic,” said Margaret Tempero, MD, director of the UCSF Pancreas Center. “An effective drug targeting K-RAS G12D could be transformative for patients with pancreatic cancer.”

For funding and disclosures, see the paper. Other UCSF authors are Quinheng Zheng, Ziyang Zhang, and Keelan Z. Guiley. Zhang is now a professor at UC Berkeley.

Levi Gadye writes for the University of California, San Francisco.

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Written by: EUROPEAN SOUTHERN OBSERVATORY

Published: 16 March 2024

In a series of studies, a team of astronomers has shed new light on the fascinating and complex process of planet formation. The stunning images, captured using the European Southern Observatory's Very Large Telescope (ESO’s VLT) in Chile, represent one of the largest ever surveys of planet-forming discs. The research brings together observations of more than 80 young stars that might have planets forming around them, providing astronomers with a wealth of data and unique insights into how planets arise in different regions of our galaxy.

“This is really a shift in our field of study,” says Christian Ginski, a lecturer at the University of Galway, Ireland, and lead author of one of three new papers published today in Astronomy & Astrophysics. “We’ve gone from the intense study of individual star systems to this huge overview of entire star-forming regions.”

To date more than 5000 planets have been discovered orbiting stars other than the Sun, often within systems markedly different from our own Solar System. To understand where and how this diversity arises, astronomers must observe the dust- and gas-rich discs that envelop young stars — the very cradles of planet formation. These are best found in huge gas clouds where the stars themselves are forming.

Much like mature planetary systems, the new images showcase the extraordinary diversity of planet-forming discs. “Some of these discs show huge spiral arms, presumably driven by the intricate ballet of orbiting planets,” says Ginski. “Others show rings and large cavities carved out by forming planets, while yet others seem smooth and almost dormant among all this bustle of activity,” adds Antonio Garufi, an astronomer at the Arcetri Astrophysical Observatory, Italian National Institute for Astrophysics (INAF), and lead author of one of the papers.

The team studied a total of 86 stars across three different star-forming regions of our galaxy: Taurus and Chamaeleon I, both around 600 light-years from Earth, and Orion, a gas-rich cloud about 1600 light-years from us that is known to be the birthplace of several stars more massive than the Sun. The observations were gathered by a large international team, comprising scientists from more than 10 countries.

The team was able to glean several key insights from the dataset. For example, in Orion they found that stars in groups of two or more were less likely to have large planet-forming discs. This is a significant result given that, unlike our Sun, most stars in our galaxy have companions.

As well as this, the uneven appearance of the discs in this region suggests the possibility of massive planets embedded within them, which could be causing the discs to warp and become misaligned.

While planet-forming discs can extend for distances hundreds of times greater than the distance between Earth and the Sun, their location several hundreds of light-years from us makes them appear as tiny pinpricks in the night sky.

To observe the discs, the team employed the sophisticated Spectro-Polarimetric High-contrast Exoplanet REsearch instrument, or SPHERE, mounted on ESO’s VLT. SPHERE’s state-of-the-art extreme adaptive optics system corrects for the turbulent effects of Earth’s atmosphere, yielding crisp images of the discs.

This meant the team were able to image discs around stars with masses as low as half the mass of the Sun, which are typically too faint for most other instruments available today.

Additional data for the survey were obtained using the VLT’s X-shooter instrument, which allowed astronomers to determine how young and how massive the stars are. The Atacama Large Millimeter/submillimeter Array, or ALMA, in which ESO is a partner, on the other hand, helped the team understand more about the amount of dust surrounding some of the stars.

As technology advances, the team hopes to delve even deeper into the heart of planet-forming systems. The large 39-meter mirror of ESO’s forthcoming Extremely Large Telescope (ELT), for example, will enable the team to study the innermost regions around young stars, where rocky planets like our own might be forming.

For now, these spectacular images provide researchers with a treasure trove of data to help unpick the mysteries of planet formation.

“It is almost poetic that the processes that mark the start of the journey towards forming planets and ultimately life in our own Solar System should be so beautiful,” concludes Per-Gunnar Valegård, a doctoral student at the University of Amsterdam, the Netherlands, who led the Orion study.

Valegård, who is also a part-time teacher at the International School Hilversum in the Netherlands, hopes the images will inspire his pupils to become scientists in the future.

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Written by: Lake County News reports

Published: 15 March 2024

THIS STORY HAS BEEN UPDATED.

LAKE COUNTY, Calif. — The Lake County Registrar of Voters Office on Thursday offered an update on the work to complete the official canvass for the March 5 presidential primary.

The 28-day canvass period began the day after the election. Until it is complete and the election is certified, the election results are not final.

Since the last update, the March 12 deadline passed to receive ballots postmarked by the end of Election Day.

The elections office said that approximately 7,415 vote-by-mail, or absentee, ballots remain to be counted. That’s about 600 less than the last count, which was impacted by those additional ballots continuing to come in by mail.

There also are 266 provisional or conditional ballots, and 266 vote-by-mail ballots that require further review for various reasons, the agency reported.

The elections office said the grand total of ballots remaining to be counted as of Thursday was 7,947.

Effective this year, AB 63 requires that the elections office update vote results and unprocessed ballot counts at least once per week and post the updated information on its website.

Registrar of Voters Maria Valadez said her office may stop posting results if the only ballots left to count are the ballots for which voters have the opportunity to either verify their signature or provide a signature, or until they certify election results.

For more information, visit the Lake County Registrar of Voters website or call 707-263-2372 OR toll-free at 888-235-6730.

Editor’s note: This story has been corrected to state that the canvass period is 28 days, not 30, and to add information about AB 63.