WRAD core perturbation impairs DNA replication fidelity promoting immunoediting in pancreatic cancer.

It is unclear how cells counteract the potentially harmful effects of uncoordinated DNA replication in the context of oncogenic stress. Here, we identify the WRAD (WDR5/RBBP5/ASH2L/DPY30) core as a modulator of DNA replication in pancreatic ductal adenocarcinoma (PDAC) models. Molecular analyses demonstrated that the WRAD core interacts with the replisome complex, with disruption of DPY30 resulting in DNA re-replication, DNA damage, and chromosomal instability (CIN) without affecting cancer cell proliferation.

Therapeutic targeting of Syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers.

The therapeutic benefit of recently developed mutant KRAS (mKRAS) inhibitors has been limited by the rapid onset of resistance. Here, we aimed to delineate the mechanisms underlying acquired resistance to mKRAS inhibition and identify actionable targets for overcoming this clinical challenge. Previously, we identified Syndecan-1 (SDC1) as a key effector for pancreatic cancer progression whose surface expression is driven by mKRAS.

Co-targeting SOS1 enhances the antitumor effects of KRAS inhibitors by addressing intrinsic and acquired resistance.

Combination approaches are needed to strengthen and extend the clinical response to KRAS inhibitors (KRASi). Here, we assessed the antitumor responses of KRAS mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRAS inhibitor, adagrasib. We found that responses to BI-3406 plus adagrasib were stronger than to adagrasib alone, comparable to adagrasib with SHP2 (SHP2i) or EGFR inhibitors and correlated with stronger suppression of RAS-MAPK signaling.

Application of CRISPR/Cas12a in miRNA-155 detection: A novel homogeneous electrochemiluminescence biosensor.

Background: MicroRNAs (miRNAs) are important non-coding RNA entities that affect gene expression and function by binding to target mRNAs, leading to degradation of the mRNAs or inhibiting their translation. MiRNAs are widely involved in a variety of biological processes, such as cell differentiation, development, metabolism, and apoptosis. In addition, miRNAs are associated with many diseases, including cancer.

Clonal dominance defines metastatic dissemination in pancreatic cancer.

Tumors represent ecosystems where subclones compete during tumor growth. While extensively investigated, a comprehensive picture of the interplay of clonal lineages during dissemination is still lacking. Using patient-derived pancreatic cancer cells, we created orthotopically implanted clonal replica tumors to trace clonal dynamics of unperturbed tumor expansion and dissemination.

SMARCB1 regulates the hypoxic stress response in sickle cell trait.

Renal medullary carcinoma (RMC) is an aggressive kidney cancer that almost exclusively develops in individuals with sickle cell trait (SCT) and is always characterized by loss of the tumor suppressor . Because renal ischemia induced by red blood cell sickling exacerbates chronic renal medullary hypoxia in vivo, we investigated whether the loss of SMARCB1 confers a survival advantage under the setting of SCT. Hypoxic stress, which naturally occurs within the renal medulla, is elevated under the setting of SCT.

Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis.

Mitochondria are hubs where bioenergetics, redox homeostasis, and anabolic metabolism pathways integrate through a tightly coordinated flux of metabolites. The contributions of mitochondrial metabolism to tumor growth and therapy resistance are evident, but drugs targeting mitochondrial metabolism have repeatedly failed in the clinic. Our study in pancreatic ductal adenocarcinoma (PDAC) finds that cellular and mitochondrial lipid composition influence cancer cell sensitivity to pharmacological inhibition of electron transport chain complex I.

Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials.

Although targeting oxidative phosphorylation (OXPHOS) is a rational anticancer strategy, clinical benefit with OXPHOS inhibitors has yet to be achieved. Here we advanced IACS-010759, a highly potent and selective small-molecule complex I inhibitor, into two dose-escalation phase I trials in patients with relapsed/refractory acute myeloid leukemia (NCT02882321, n = 17) and advanced solid tumors (NCT03291938, n = 23). The primary endpoints were safety, tolerability, maximum tolerated dose and recommended phase 2 dose (RP2D) of IACS-010759.

Epithelial memory of inflammation limits tissue damage while promoting pancreatic tumorigenesis.

Inflammation is a major risk factor for pancreatic ductal adenocarcinoma (PDAC). When occurring in the context of pancreatitis, KRAS mutations accelerate tumor development in mouse models. We report that long after its complete resolution, a transient inflammatory event primes pancreatic epithelial cells to subsequent transformation by oncogenic KRAS.

Medium-Chain Acyl-CoA Dehydrogenase Protects Mitochondria from Lipid Peroxidation in Glioblastoma.

Glioblastoma (GBM) is highly resistant to chemotherapies, immune-based therapies, and targeted inhibitors. To identify novel drug targets, we screened orthotopically implanted, patient-derived glioblastoma sphere-forming cells using an RNAi library to probe essential tumor cell metabolic programs. This identified high dependence on mitochondrial fatty acid metabolism.

Uncovering the chemistry of C-C bond formation in C-nucleoside biosynthesis: crystal structure of a C-glycoside synthase/PRPP complex.

The enzyme ForT catalyzes C-C bond formation between 5'-phosphoribosyl-1'-pyrophosphate (PRPP) and 4-amino-1H-pyrazole-3,5-dicarboxylate to make a key intermediate in the biosynthesis of formycin A 5'-phosphate by Streptomyces kaniharaensis. We report the 2.5 Å resolution structure of the ForT/PRPP complex and locate active site residues critical for PRPP recognition and catalysis.

PMP-diketopiperazine adducts form at the active site of a PLP dependent enzyme involved in formycin biosynthesis.

ForI is a PLP-dependent enzyme from the biosynthetic pathway of the C-nucleoside antibiotic formycin. Cycloserine is thought to inhibit PLP-dependent enzymes by irreversibly forming a PMP-isoxazole. We now report that ForI forms novel PMP-diketopiperazine derivatives following incubation with both d and l cycloserine.

Exposure to artificial light at night increases innate immune activity during development in a precocial bird.

Humans have greatly altered Earth's night-time photic environment via the production of artificial light at night (ALAN; e.g. street lights, car traffic, billboards, lit buildings).

The causative effects of corticosterone on innate immunity during the stress response in the House Sparrow, Passer domesticus.

Stress-induced inhibition of innate immune activity has been observed in a variety of wild birds and may increase chances of infection because this activity constitutes the first line of defense against pathogens. We previously reported that the transient elevation of plasma corticosterone (CORT; the primary avian glucocorticoid) that occurs during stress is necessary for stress-induced suppression of natural antibody-mediated, complement-mediated, and bactericidal activity. Here, we further investigated the regulatory role of CORT during this suppression.

Oxidation of the Cyanobactin Precursor Peptide Is Independent of the Leader Peptide and Operates in a Defined Order.

The five-membered nitrogen plus heteroatom rings known as azolines or in their oxidized form as azoles are very common in natural products and drugs. The oxidation of thiazoline to thiazole in the cyanobactin class of natural products is one of the several important transformations that are known to alter the biological properties of the compound. The ordering of the various chemical reactions that occur during cyanobactin biosynthesis is not fully understood.

Circulating corticosterone levels vary during exposure to anthropogenic stimuli and show weak correlation with behavior across an urban gradient in house finches (Haemorhous mexicanus).

Urban environments are rapidly expanding and presenting animal populations with novel challenges, many of which are thought to be stressors that contribute to low biodiversity. However, studies on stress responses in urban vs rural populations have produced mixed results, and many of these studies use a standard stressor that cannot be replicated in the wild (e.g.

Glucocorticoid receptor selectively mediates stress-induced suppression of innate immunity in the House Sparrow, Passer domesticus.

Stress-induced inhibition of innate immune activity is widespread in free-ranging birds, but the mechanisms that are responsible for this inhibition are poorly understood. We previously demonstrated that an increase in plasma corticosterone (CORT), the primary avian glucocorticoid, is necessary for the inhibition of natural antibody- and complement-mediated as well as bactericidal activities to occur during stress. Here we investigated the role of glucocorticoid receptors in stress-induced inhibition of natural antibody- and complement-mediated activities and bactericidal activity within non-genomic (<10 min) and genomic (<120 min) time frames in male House Sparrows, Passer domesticus.

Roles and Mechanistic Bases of Glucocorticoid Regulation of Avian Reproduction.

To maximize fitness, organisms must invest energetic and nutritional resources into developing, activating, and maintaining reproductive physiology and behavior. Corticosterone (CORT), the primary avian glucocorticoid, regulates energetic reserves to meet metabolic demands. At low (baseline) plasma levels, CORT activates avian mineralocorticoid receptors and may stimulate lipid mobilization, foraging activity, and feeding behavior.

Corticosterone rapidly suppresses innate immune activity in the house sparrow (Passer domesticus).

Stress-induced effects on innate immune activity in wild birds have been difficult to predict. These difficulties may arise from the frequent assumptions that (1) the stress response influences different components of the immune response similarly, (2) stress-induced effects do not change over the course of the stress response and (3) glucocorticoids are the primary regulators of stress-induced changes of immune activity. We tested the first two assumptions by measuring three components of innate immunity at two times during the stress response in captive adult male house sparrows, Passer domesticus Acute stress resulting from handling and restraint suppressed plasma lytic and microbicidal activity within 10 min and reduced plasma agglutination ability within 120 min.

Endocrine, metabolic, and behavioral effects of and recovery from acute stress in a free-ranging bird.

Acute stress in vertebrates generally stimulates the hypothalamo-pituitary-adrenal axis and is often associated with multiple metabolic changes, such as increased gluconeogenesis, and with behavioral alterations. Little information is available, especially in free-ranging organisms, on the duration of these reversible effects once animals are no longer exposed to the stressor. To investigate this question, we exposed free-ranging adult male Rufous-winged Sparrows, Peucaea carpalis, in breeding condition to a standard protocol consisting of a social challenge (conspecific song playback) followed with capture and restraint for 30min, after which birds were released on site.

The seasonal glucocorticoid response of male Rufous-winged Sparrows to acute stress correlates with changes in plasma uric acid, but neither glucose nor testosterone.

We sought to clarify functional relationships between baseline and acute stress-induced changes in plasma levels of the stress hormone corticosterone (CORT) and the reproductive hormone testosterone (T), and those of two main metabolites, uric acid (UA) and glucose (GLU). Acute stress in vertebrates generally stimulates the secretion of glucocorticoids, which in birds is primarily CORT. This stimulation is thought to promote behavioral and metabolic changes, including increased glycemia.

Negative energy balance in a male songbird, the Abert's towhee, constrains the testicular endocrine response to luteinizing hormone stimulation.

Energy deficiency can suppress reproductive function in vertebrates. As the orchestrator of reproductive function, endocrine activity of the hypothalamo-pituitary-gonadal (HPG) axis is potentially an important mechanism mediating such effects. Previous experiments in wild-caught birds found inconsistent relationships between energy deficiency and seasonal reproductive function, but these experiments focused on baseline HPG axis activity and none have investigated the responsiveness of this axis to endocrine stimulation.

Negative energy balance in a male songbird, the Abert's Towhee, constrains the testicular endocrine response to luteinizing hormone stimulation.

Energy deficiency can suppress reproductive functions in vertebrates. As the orchestrator of reproductive function, endocrine activity of the hypothalamo-pituitary-gonadal (HPG) axis is potentially an important mechanism mediating such effects. Previous experiments in wild-caught birds found inconsistent relationships between energy deficiency and seasonal reproductive function, but these experiments focused on baseline HPG axis activity and none has investigated the responsiveness of this axis to endocrine stimulation.