Paul Geeleher

Our paper identifying evidence of off-target probe binding in the 10x Genomics Xenium Breast Gene Panel is now available as a reviewed preprint at #eLife

elifesciences.org/reviewed-pre...

We look forward to revising the paper to incorporate reviewer recommendations and other updates 🧵👇

Scientists solve mystery of how the drug retinoic acid works to treat neuroblastoma Neuroblastoma is a solid tumor that occurs in children. When high-risk, the disease has a poor prognosis. Decades ago, adding the drug retinoic acid to neuroblastoma treatment increased survival by 10–15%.

Retinoic acid effectively treats metastasized neuroblastoma by exploiting the BMP signaling pathway in the bone marrow microenvironment, offering insights for future combination therapies. doi.org/g86pzp

An integrated large-scale photonic accelerator with ultralow latency - Nature A large-scale photonic accelerator comprising more than 16,000 components integrated on a single chip to process MAC operations is described, demonstrating ultralow latency and reduced computing time compared with a commercially available GPU.

Nature research paper: An integrated large-scale photonic accelerator with ultralow latency

https://go.nature.com/3R7tyvL

The April (and #AACR25) issue of Cancer Discovery is now online! The cover features work by Ling Cai, Nia Hammond, @faubert.bsky.social, @rjdlab.bsky.social & colleagues showing high glucose contribution to the TCA cycle is a feature of aggressive NSCLC - more here: aacrjournals.org/cancerdiscov...

A natural experiment on the effect of herpes zoster vaccination on dementia - Nature Using a natural experiment that avoids common bias concerns, this study finds that the live-attenuated shingles vaccine reduced the probability of a new dementia diagnosis within a follow-up period of 7 years by approximately one-fifth.

Nature research paper: A natural experiment on the effect of herpes zoster vaccination on dementia

https://go.nature.com/3XHRhq5

Itai Yanai is now putting together with Oded Rechavi and others the Woodstock of Biology 2 & Night Science conference to integrate some of Itai's ideas into a scientific meeting. #theconferencetoendallconferences

More info & registration here: woodstock.img.cas.cz

In a new Science study, cryo–electron tomography captures the in-cell architecture of the mitochondrial respiratory chain, illuminating how the coordinated action of molecular machines drives life’s fundamental energy conversion.

Learn more in this week's issue: scim.ag/3FA3Ygq

Anti-icing properties of polar bear fur Polar bears are able to minimize ice accumulation thanks to their hair oil.

Polar bear fur remains ice-free in the Arctic cold thanks to the unique array of ingredients in its fur sebum, or hair grease, a #ScienceAdvances study finds.

Learn more on #WorldBearDay:

Can Earth’s rotation generate power? Physicists divided over controversial claim Experiments suggest that an unusual magnetic material can help harness energy from the planet’s rotation. But not everyone is convinced.

Experiments suggest that an unusual magnetic material can help harness energy from the planet’s rotation. But not everyone is convinced.

https://go.nature.com/4ixBNxj

So proud of this work, this was a great collaboration and I highly recommend this read and tool. My own tweetorial shortly but @steglelab.bsky.social tutorial is great.

Man survives with titanium heart for 100 days – a world first Nature - The device, to be tested in more people, could be used as a temporary measure for those waiting for a donor organ.

An Australian man in his forties has become the first person in the world to leave hospital with an artificial heart made of titanium

The device could be a temporary measure for those waiting for a donor organ

https://go.nature.com/427bLLh

This is very much fitting, and exciting, for my first Blusky post 🤩
Thrilled to share our new study on CAFs and NK cells, now online 🌟 in CD_AACR!! t.co/vmq8ZyQ3KV

Bone morphogenetic protein signaling reported to be responsible for determining neuroblastoma cell fate and sensitivity to retinoic acid treatment doi.org/10.1038/s414... #CancerResearch

Big news: we are setting up a new non-profit organization to run bioRxiv and medRxiv. It's called openRxiv [no it's not a new preprint server; it's dedicated organization to oversee the servers] openrxiv.org 1/n

Clonal dynamics and somatic evolution of haematopoiesis in mouse - Nature Isolating and studying haematopoietic stem cells in young and aged mice demonstrates evolutionary processes related to blood production and provides a framework for interpreting future work using labo...

Delighted to share my PhD thesis work is now published in @nature.com! This study tracks the journey of blood stem cells in aging mice, examining how the clonal dynmics of blood production change over time. A short 🧵1/n #aging #stemcells #clonalhematopoiesis
www.nature.com/articles/s41...

Microsoft quantum computing 'breakthrough' faces fresh challenge Analysis pokes holes in protocol that underpins Microsoft’s claim to have created the first topological qubits.

A physicist has published an analysis that pokes holes in the protocol that underpins Microsoft’s claim to have created the first topological qubits. The critique comes amid mounting speculation about the validity of Microsoft’s claim.
https://go.nature.com/4byvwyl

Transcriptomic plasticity is a hallmark of metastatic pancreatic cancer Metastasis is the leading cause of cancer deaths; nonetheless, how tumor cells adapt to vastly different organ contexts is largely unknown. To investigate this question, we generated a transcriptomic ...

1) I am delighted to share a manuscript long in the making (7 years), elucidating the forces that shape metastatic adaptation PDAC using scRNA-seq across multiple organs from a rapid autopsy combined with a powerful new clonal phylogeny inference algorithm www.biorxiv.org/content/10.1...

Seven New Cancer Grand Challenges Announced

www.cancergrandchallenges.org/new-challenges

With awards of up to £20m ($25m). Expressions of Interest are now open.

@cancergrand.bsky.social #CancerGrandChallenges

Fascinatingly, the relationship between BMP and natural retinoic acid is well established in NORMAL DEVELOPMENT, tipping cells between apoptosis and differentiation. This mechanism can seemingly be preserved in neuroblastoma CANCER CELLS and exploited to kill them! 🤯🤯 10/n

Remarkably, using single-cell RNA-seq and IF we found that BMP signaling activity is dramatically higher in disseminated neuroblastoma cells in patient bone marrow. This seems to explain the unusual clinical observation of site-specific drug activity! 🤯 9/n

Retinoic acid has other seemingly unique activities. For example, while it has little activity against established bulky tumors in vivo, it has been shown to clear metastatic cells from the bone marrow in patients. Could this paradox stem from differential BMP activity? 8/n

We then showed that amplifying BMP signaling activity (e.g. by adding exogenous BMP to cells) can potentiate the apoptosis/senescence cell fate choice upon exposure to retinoic acid. Blocking BMP tipped the cells towards differentiation, and a comparatively weaker response. 7/n

We performed a genome-wide CRISPR screen in a retinoic acid-treated hyper-responsive neuroblastoma cell line, finding that BMP signaling genes (ACVR1, BMP, SMAD, etc) were heavily affecting response to retinoic acid. 6/n

No. The hyper-responsive cell lines are predominantly undergoing either apoptosis or senescence, before (or in parallel with) differentiation... 5/n

However, we now have data from much larger preclinical screens. Using these data, we observed that, curiously, some cell lines behave as extreme outliers in their response to retinoic acid. Are these cells (arrows below) mega-differentiating!? 4/n

Spurred by these observations, clinical trials in the 90s showed a dramatic improvement in neuroblastoma patient survival when retinoic acid was added as post-chemo maintenance therapy – seemingly confirming that differentiation is effective 3/n

The idea that retinoids are effective because of differentiation stems from the 1980s when these compounds were shown to make cancer cells differentiate in vitro. Differentiation is particularly striking in some pediatric neuroblastoma cell lines. 2/n

Bone morphogenetic protein (BMP) signaling determines neuroblastoma cell fate and sensitivity to retinoic acid - Nature Communications Retinoic acid is known to be effective against bone marrow metastatic neuroblastoma cells, but not primary tumors. Here, authors discover that bone morphogenetic protein signaling is responsible for d...

Can we treat cancer by forcing cancer cells to differentiate?

Retinoids are unique cancer drugs that, according to textbooks, make cancer cells mature and lose their malignant behavior. In our new paper, we reveal there’s more to how they really work… 1/n
www.nature.com/articles/s41...

St. Jude scientists solve mystery of how the drug retinoic acid works to treat neuroblastoma Find new research showing how retinoic acid hijacks a developmental pathway in metastasized neuroblastoma in the bone marrow, solving a 50 year-long mystery.

Researchers at St. Jude Children's Research Hospital have uncovered the mechanism behind retinoic acid's selective killing of metastatic neuroblastoma cells. This discovery may pave the way for improved combination therapies. ow.ly/PgBl50V8hZn