ADT-1004: a first-in-class, oral pan-RAS inhibitor with robust antitumor activity in preclinical models of pancreatic ductal adenocarcinoma.

Background: Oncogenic KRAS mutations occur in nearly, 90% of patients with pancreatic ductal adenocarcinoma (PDAC). Targeting KRAS has been complicated by mutational heterogeneity and rapid resistance. We developed a novel pan-RAS inhibitor, ADT-1004 (an oral prodrug of ADT-007) and evaluated antitumor activity in murine and human PDAC models.

Potency and selectivity of a novel pan-RAS inhibitor in 3D bioprinted organoid tumor models.

Background: Colorectal cancer (CRC) remains a significant global health burden, with KRAS mutations driving ∼40% of cases. Efficacy of recently approved, mutant-specific KRAS inhibitors is limited by intrinsic and adaptive resistance mechanisms. Pan-RAS inhibitors, such as ADT-007, offer broader therapeutic potential by targeting multiple RAS isoforms.

Investigating Sensitivity to Shared Information and Personal Experience in Children's Use of Majority Information.

Children and adults alike rely on others to learn about the world, but also need to be able to determine the strength of both their own evidence as well as the evidence that other people provide, particularly when different sources of information disagree. For example, if two informants agree on a belief but share the same evidence, their testimony is statistically dependent on each other, and may be weaker evidence for that belief than two informants who draw on different pieces of evidence to support that belief. Across three experiments (total = 492), we examine how 4- and 5-year-old children evaluate statistical dependency on a task where they must determine which of two jars that toys were drawn from.

A Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth and Induces Antitumor Immunity in Gastrointestinal Cancer.

Activated RAS is a common driver of cancer that was considered undruggable for decades. Recent advances have enabled the development of RAS inhibitors, but the efficacy of these inhibitors remains limited by resistance. In this study, we developed a pan-RAS inhibitor, ADT-007, (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide, that binds nucleotide-free RAS to block GTP activation of effector interactions and MAPK/AKT signaling, resulting in mitotic arrest and apoptosis.

Synchronous citizen science with dogs.

Citizen science approaches have grown in popularity over the years, partly due to their ability to reach a wider audience and produce more generalizable samples. In dogs, these studies, though, have been limited in their controls over materials or experimental protocols, with guardians typically reporting results without researcher supervision. Over two studies, we explored and validated a synchronous citizen science approach.

BET inhibition decreases HMGCS2 and sensitizes resistant pancreatic tumors to gemcitabine.

Efforts to develop targetable molecular bases for drug resistance for pancreatic ductal adenocarcinoma (PDAC) have been equivocally successful. Using RNA-seq and ingenuity pathway analysis we identified that the superpathway of cholesterol biosynthesis is upregulated in gemcitabine resistant (gemR) tumors using a unique PDAC PDX model with resistance to gemcitabine acquired in vivo. Analysis of additional in vitro and in vivo gemR PDAC models showed that HMG-CoA synthase 2 (HMGCS2), an enzyme involved in cholesterol biosynthesis and rate limiting in ketogenesis, is overexpressed in these models.

A Novel Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth in Mouse Models of GI Cancer.

Unlabelled: Here, we describe a novel pan-RAS inhibitor, ADT-007, that potently inhibited the growth of RAS mutant cancer cells irrespective of the RAS mutation or isozyme. RAS cancer cells with GTP-activated RAS from upstream mutations were equally sensitive. Conversely, RAS cancer cells harboring downstream BRAF mutations and normal cells were essentially insensitive to ADT-007.

How can I find what I want? Can children, chimpanzees and capuchin monkeys form abstract representations to guide their behavior in a sampling task?

concepts are a powerful tool for making wide-ranging predictions in new situations based on little experience. Whereas looking-time studies suggest an early emergence of this ability in human infancy, other paradigms like the relational match to sample task often fail to detect abstract concepts until late preschool years. Similarly, non-human animals show difficulties and often succeed only after long training regimes.

ST6GAL1 sialyltransferase promotes acinar to ductal metaplasia and pancreatic cancer progression.

The role of aberrant glycosylation in pancreatic ductal adenocarcinoma (PDAC) remains an under-investigated area of research. In this study, we determined that ST6 β-galactoside α2,6 sialyltransferase 1 (ST6GAL1), which adds α2,6-linked sialic acids to N-glycosylated proteins, was upregulated in patients with early-stage PDAC and was further increased in advanced disease. A tumor-promoting function for ST6GAL1 was elucidated using tumor xenograft experiments with human PDAC cells.

One- and two-year-olds grasp that causes must precede their effects.

Knowing the temporal direction of causal relations is critical for producing desired outcomes and explaining events. Existing evidence suggests that children start to grasp that causes must precede their effects (the temporal priority principle) by age 3; however, whether younger children also understand this has, to our knowledge, not previously been tested. Given the importance of temporal priority in making sense of the world, we explored when knowledge of this principle develops.

Evidence for abstract representations in children but not capuchin monkeys.

The use of abstract higher-level knowledge (also called overhypotheses) allows humans to learn quickly from sparse data and make predictions in new situations. Previous research has suggested that humans may be the only species capable of abstract knowledge formation, but this remains controversial. There is also mixed evidence for when this ability emerges over human development.

Causal learning, counterfactual reasoning and pretend play: a cross-cultural comparison of Peruvian, mixed- and low-socioeconomic status U.S. children.

Pretend play universally emerges during early childhood and may support the development of causal inference and counterfactual reasoning. However, the amount of time spent pretending, the value that adults place on pretence and the scaffolding adults provide vary by both culture and socioeconomic status (SES). In middle class U.

Head-mounted mobile eye-tracking in the domestic dog: A new method.

Humans rely on dogs for countless tasks, ranging from companionship to highly specialized detection work. In their daily lives, dogs must navigate a human-built visual world, yet comparatively little is known about what dogs visually attend to as they move through their environment. Real-world eye-tracking, or head-mounted eye-tracking, allows participants to freely move through their environment, providing more naturalistic results about visual attention while interacting with objects and agents.

Pan-RAS inhibitors: Hitting multiple RAS isozymes with one stone.

Mutations in the three RAS oncogenes are present in approximately 30% of all human cancers that drive tumor growth and metastasis by aberrant activation of RAS-mediated signaling. Despite the well-established role of RAS in tumorigenesis, past efforts to develop small molecule inhibitors have failed for various reasons leading many to consider RAS as "undruggable." Advances over the past decade with KRAS(G12C) mutation-specific inhibitors have culminated in the first FDA-approved RAS drug, sotorasib.

Searching high and low: domestic dogs' understanding of solidity.

Physical reasoning appears central to understanding how the world works, suggesting adaptive function across the animal kingdom. However, conclusive evidence for inferential reasoning about physical objects is limited to primates. We systematically tested a central feature-understanding of solidity-in domestic dogs, by adapting a validated procedure (the shelf task) previously used to test children and non-human primates.

What's the point? Domestic dogs' sensitivity to the accuracy of human informants.

Dogs excel at understanding human social-communicative gestures like points and can distinguish between human informants who vary in characteristics such as knowledge or familiarity. This study explores if dogs, like human children, can use human social informants' past accuracy when deciding whom to trust. Experiment 1 tested whether dogs would behave differently in the presence of an accurate (vs.

Glycosyltransferase ST6Gal-I promotes the epithelial to mesenchymal transition in pancreatic cancer cells.

ST6Gal-I, an enzyme upregulated in numerous malignancies, adds α2-6-linked sialic acids to select membrane receptors, thereby modulating receptor signaling and cell phenotype. In this study, we investigated ST6Gal-I's role in epithelial to mesenchymal transition (EMT) using the Suit2 pancreatic cancer cell line, which has low endogenous ST6Gal-I and limited metastatic potential, along with two metastatic Suit2-derived subclones, S2-013 and S2-LM7AA, which have upregulated ST6Gal-I. RNA-Seq results suggested that the metastatic subclones had greater activation of EMT-related gene networks than parental Suit2 cells, and forced overexpression of ST6Gal-I in the Suit2 line was sufficient to activate EMT pathways.

Enhancing anticancer activity of checkpoint immunotherapy by targeting RAS.

Approximately 30% of human cancers harbor a gain-in-function mutation in the RAS gene, resulting in constitutive activation of the RAS protein to stimulate downstream signaling, including the RAS-mitogen activated protein kinase pathway that drives cancer cells to proliferate and metastasize. RAS-driven oncogenesis also promotes immune evasion by increasing the expression of programmed cell death ligand-1, reducing the expression of major histocompatibility complex molecules that present antigens to T-lymphocytes and altering the expression of cytokines that promote the differentiation and accumulation of immune suppressive cell types such as myeloid-derived suppressor cells, regulatory T-cells, and cancer-associated fibroblasts. Together, these changes lead to an immune suppressive tumor microenvironment that impedes T-cell activation and infiltration and promotes the outgrowth and metastasis of tumor cells.

STAT3 and GR Cooperate to Drive Gene Expression and Growth of Basal-Like Triple-Negative Breast Cancer.

Breast cancers are divided into subtypes with different prognoses and treatment responses based on global differences in gene expression. Luminal breast cancer gene expression and proliferation are driven by estrogen receptor alpha, and targeting this transcription factor is the most effective therapy for this subtype. By contrast, it remains unclear which transcription factors drive the gene expression signature that defines basal-like triple-negative breast cancer, and there are no targeted therapies approved to treat this aggressive subtype.

PDE5 and PDE10 inhibition activates cGMP/PKG signaling to block Wnt/β-catenin transcription, cancer cell growth, and tumor immunity.

Although numerous reports conclude that nonsteroidal anti-inflammatory drugs (NSAIDs) have anticancer activity, this common drug class is not recommended for long-term use because of potentially fatal toxicities from cyclooxygenase (COX) inhibition. Studies suggest the mechanism responsible for the anticancer activity of the NSAID sulindac is unrelated to COX inhibition but instead involves an off-target, phosphodiesterase (PDE). Thus, it might be feasible develop safer and more efficacious drugs for cancer indications by targeting PDE5 and PDE10, which are overexpressed in various tumors and essential for cancer cell growth.

PAICS, a De Novo Purine Biosynthetic Enzyme, Is Overexpressed in Pancreatic Cancer and Is Involved in Its Progression.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with an extremely poor prognosis. There is an urgent need to identify new therapeutic targets and also understand the mechanism of PDAC progression that leads to aggressiveness of the disease. To find therapeutic targets, we analyzed data related to PDAC transcriptome sequencing and found overexpression of the de novo purine metabolic enzyme phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS).

Inhibition of the Wnt/β-catenin pathway enhances antitumor immunity in ovarian cancer.

Background: The Wnt/β-catenin pathway is linked to tumorigenesis in a variety of tumors and promotes T cell exclusion and resistance to checkpoint inhibitors. We sought to determine whether a small molecule inhibitor of this pathway, WNT974, would impair tumor growth, affect gene expression patterns, and improve the immune response in human and murine ovarian cancer models.

Methods: Human ovarian cancer cells were treated with WNT974 .

Belief as a non-epistemic adaptive benefit.

Although rationalization about one's own beliefs and actions can improve an individual's future decisions, beliefs can provide other benefits unrelated to their epistemic truth value, such as group cohesion and identity. A model of resource-rational cognition that accounts for these benefits may explain unexpected and seemingly irrational thought patterns, such as belief polarization.