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PARG inhibition halts cholangiocarcinoma progression via the Hippo pathway and enhances response to chemotherapy and immunotherapy

PARG inhibition potentiates the efficacy of chemotherapy and PD-1 blockade in murine cholangiocellular carcinoma models.

PARG (poly(ADP-ribose) glycohydrolase) plays a key role in cancer cells by regulating poly(ADP-ribose) turnover and DNA damage responses, thereby supporting genomic stability, transcriptional programs, and survival pathways that enable tumour growth and treatment resistance. Yu, Xie, Yu, Zhao, Xu, Yang, Wei and coworkers evaluated the role of PARG in the development, progression and resistance to therapy in cholangiocarcinoma. In a cohort of 275 patients with cholangiocellular carcinoma (CCA), they observed that the levels of PARG are hyperactivated in the tumour tissue, and higher levels of PARG are associated with worse prognosis. Pharmacological or genetic inhibition of PARG in murine CCA models suppresses tumour growth by activating the Hippo pathway, leading to YAP/TAZ inactivation and reduced proliferative and stemness programs in cholangiocarcinoma cells. Notably, PARG inhibition synergizes with standard chemotherapy and enhances responsiveness to immunotherapy in mice, suggesting a role in modulating tumour cell–intrinsic survival pathways and the tumour immune microenvironment. Key open questions include the safety and specificity of sustained PARG inhibition in chronic liver disease and whether Hippo pathway activation and immune sensitization observed in models will translate into durable clinical benefit in heterogeneous human tumours.

Full text here: https://www.journal-of-hepatology.eu/article/S0168-8278(…0/fulltext.

EASL — the home of hepatology.

Cholangiocarcinoma (CCA) is a lethal malignancy with limited therapeutic options. We investigated the oncogenic role of poly(ADP-ribose) glycohydrolase (PARG) and evaluated potential therapeutic strategies.

Colonizing Brown Dwarfs — Life Around Failed Stars

Colonizing brown dwarfs: habitats, megastructures, and hidden homes around failed stars. Could these dim embers power civilizations for trillions of years?

Get Nebula using my link for 50% off an annual subscription: https://go.nebula.tv/isaacarthur.
Watch my exclusive video Lazarus Protocols: https://nebula.tv/videos/isaacarthur–… out 17 Pages: https://nebula.tv/17pages?ref=isaacar… and A Bit Obscure https://nebula.tv/abitfrank/a-bit-obs… 🛒 SFIA Merchandise: https://isaac-arthur-shop.fourthwall… 🌐 Visit our Website: http://www.isaacarthur.net ❤️ Support us on Patreon: / isaacarthur ⭐ Support us on Subscribestar: https://www.subscribestar.com/isaac-a… 👥 Facebook Group: / 1,583,992,725,237,264 📣 Reddit Community: / isaacarthur 🐦 Follow on Twitter / X: / isaac_a_arthur 💬 SFIA Discord Server: / discord Credits: Colonizing Brown Dwarfs – Life Around Failed Stars Written, Produced & Narrated by: Isaac Arthur Graphics from Fishy Tree, Jeremy Jozwik, Udo Schroeter Music Courtesy of Chris Zabriskie & Stellardrone Select imagery/video supplied by Getty Images Chapters 0:00 Intro 1:56 WHAT A BROWN DWARF IS 7:15 L Dwarfs 11:57 T-Dwarfs 17:04 Nebula 18:15 Habitable Zones 22:12 Megastructures.
Check out 17 Pages: https://nebula.tv/17pages?ref=isaacar…
and A Bit Obscure https://nebula.tv/abitfrank/a-bit-obs…

🛒 SFIA Merchandise: https://isaac-arthur-shop.fourthwall…
🌐 Visit our Website: http://www.isaacarthur.net.
❤️ Support us on Patreon: / isaacarthur.
⭐ Support us on Subscribestar: https://www.subscribestar.com/isaac-a…
👥 Facebook Group: / 1583992725237264
📣 Reddit Community: / isaacarthur.
🐦 Follow on Twitter / X: / isaac_a_arthur.
💬 SFIA Discord Server: / discord.
Credits:
Colonizing Brown Dwarfs – Life Around Failed Stars.
Written, Produced & Narrated by: Isaac Arthur.
Graphics from Fishy Tree, Jeremy Jozwik, Udo Schroeter.
Music Courtesy of Chris Zabriskie & Stellardrone.
Select imagery/video supplied by Getty Images.

Chapters.
0:00 Intro.
1:56 WHAT A BROWN DWARF IS
7:15 L Dwarfs.
11:57 T-Dwarfs.
17:04 Nebula.
18:15 Habitable Zones.
22:12 Megastructures

Read more

Biological and Clinical Staging of Alzheimer Disease Pathology in Down Syndrome

Among adults with DownSyndrome, clinical and biological staging of AlzheimerDisease showed greater concordance compared to sporadic cases, supporting the use of cognition-based staging for clinical trial enrollment. Most discordant cases exhibited more advanced pathology than clinical stage, highlighting resilience mechanisms in this population.

This cross-sectional study examines data for participants in the Alzheimer Biomarker Consortium–Down Syndrome study to gauge the concordance of clinical and biological Alzheimer disease staging.

ACSL4-associated lipid metabolism is a distinct therapeutic vulnerability in KMT2A-rearranged acute myeloid leukemia

Schäfer et al. identify ACSL4 as a selective vulnerability in KMT2A-rearranged AML. ACSL4 knockdown impairs leukemic growth in vitro and in vivo by reprogramming lipid metabolism, which can be rescued by polyunsaturated fatty acids (PUFAs). A KRADS12 signature derived from ACSL4-dependent cells is associated with poor patient survival.

Vitamin C inhibits ACSL4 to alleviate ferro-aging in primates

Liu et al. identify that an iron-triggered aging pathway, termed ferro-aging, is orchestrated by ACSL4. Vitamin C directly targets and inhibits ACSL4, thereby blocking ferro-aging. Their further research shows that long-term supplementation in non-human primates systemically attenuates aging and improves metabolic and neurological function.

A direct auditory subcortical route to the amygdala associated with fear in humans

New in JNeurosci from Kosteletou-Kassotaki et al: A white matter tract connecting the inferior colliculus to the basolateral amygdala via the MGB of the thalamus is linked to better hearing ability and higher self-reported fearfulness in people.

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Rapid and efficient fear processing is essential for survival. In vision, this function is supported by a well-characterized subcortical pathway consisting of direct projections from the pulvinar of the thalamus to the amygdala in the human brain. In contrast, the existence of an analogous shortcut for fear in audition has been demonstrated in non-human animals, but remains unconfirmed in humans. To address this question, we used probabilistic streamline tractography and fixel-based analysis on diffusion-weighted images from Human Connectome Project participants of either sex, to reconstruct candidate auditory subcortical pathways and examine their associations with affective and auditory behavioral measures. Our findings revealed a robust white matter tract connecting the inferior colliculus to basolateral amygdala via the medial geniculate body (MGB) of the thalamus. Remarkably, higher fiber density in this tract was associated with better hearing ability in noise and increased self-reported fearfulness, supporting its role in auditory and affective function. Conversely, a control analysis of the core thalamocortical pathway from ventral MGB to primary auditory cortex (PAC), representing the main route for auditory processing, was associated with auditory ability but not with affective measures. These findings provide previously unreported evidence for an auditory colliculo-geniculo-amygdala “low road” in humans, aligning with evolutionarily conserved pathways for fear described in non-human species.

Significance Statement Rapid fear processing is crucial for survival. While a visual subcortical “low road” for fear is well characterized in humans, the existence of an analogous human auditory shortcut remains undetermined. Using diffusion magnetic resonance imaging tractography, we provide evidence for a white matter tract connecting the inferior colliculus to basolateral amygdala via the medial geniculate body of the thalamus, which is associated with hearing ability and self-reported fearfulness. Our findings provide novel evidence for an auditory colliculo-geniculo-amygdala direct route in humans, revealing an evolutionarily conserved pathway for fear previously described in non-human species.

Single-cell analysis identifies RETN+ monocyte-derived Resistin as a therapeutic target in hepatitis B virus-related acute-on-chronic liver failure

GUTImage from the paper by Xu et al entitled.

via.

HepatitisB HBV

Background Acute-on-chronic liver failure (ACLF) is characterised by intense systemic inflammation and high short-term mortality, yet effective targeted therapies are lacking.

Objective To explore monocyte heterogeneity in HBV-related ACLF (HBV-ACLF) to identify specific subsets and associated therapeutic targets.

Design Peripheral blood mononuclear cells from healthy controls (n=4), patients with acute decompensation (n=5), and patients with ACLF (n=9) underwent single-cell RNA sequencing (scRNA-seq). Findings were integrated with hepatic scRNA-seq, bulk transcriptomics, multiplex immunohistochemistry and in vitro functional assays. The in vivo roles of candidate targets were validated in two murine ACLF models.

Continue reading “Single-cell analysis identifies RETN+ monocyte-derived Resistin as a therapeutic target in hepatitis B virus-related acute-on-chronic liver failure” | >

GLP-1 medications used to treat diabetes and obesity may also help alleviate symptoms of anxiety and depression

GLP-1 medications used to treat diabetes and obesity were associated with a reduced need for hospital care and sickness absence due to psychiatric reasons, a new study shows. The large register-based study was carried out in collaboration between the University of Eastern Finland, Karolinska Institutet in Stockholm and Griffith University in Australia.

Diabetes and obesity are associated with an increased risk of mental health symptoms, and similarly, individuals with mental disorders have an elevated risk of metabolic diseases such as obesity and diabetes. Researchers have long been interested in the connections between these conditions and in how pharmacological treatments may affect both metabolic and mental health disorders.

The present study included nearly 100,000 participants, more than 20,000 of whom had used GLP-1 medications. Participants were followed through Swedish national registers between 2009 and 2022. The study’s findings were published in The Lancet Psychiatry.

Fossil X-ray reveals new species of baby dino named for iconic Korean cartoon

Cute, green, and sporting two sprigs of hair on his head, a mischievous baby dinosaur named Dooly is one of the most beloved cartoon characters in South Korea. So, when researchers from The University of Texas at Austin and the Korean Dinosaur Research Center discovered a new species of baby dinosaur from Korea’s Aphae Island, they knew exactly what to call it: Doolysaurus.

“Dooly is one of the very famous, iconic dinosaur characters in Korea. Every generation in Korea knows this character,” said Jongyun Jung, a visiting postdoctoral researcher at UT’s Jackson School of Geosciences who led the research. “And our specimen is also a juvenile or ‘baby,’ so it’s perfect for our dinosaur species name to honor Dooly.”

The baby dinosaur is the first new dinosaur species discovered in Korea in 15 years and the first Korean dinosaur fossil found with portions of its skull. The skull bones were revealed when the fossil underwent a scientific micro-CT scan at the University of Texas High-Resolution X-ray Computed Tomography (UTCT) facility.

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