Small-molecule CBP/p300 histone acetyltransferase inhibition mobilizes leukocytes from the bone marrow via the endocrine stress response.

Mutations of the CBP/p300 histone acetyltransferase (HAT) domain can be linked to leukemic transformation in humans, suggestive of a checkpoint of leukocyte compartment sizes. Here, we examined the impact of reversible inhibition of this domain by the small-molecule A485. We found that A485 triggered acute and transient mobilization of leukocytes from the bone marrow into the blood. Leukocyte mobilization by A485 was equally potent as, but mechanistically distinct from, granulocyte colony-stimulating factor (G-CSF), which allowed for additive neutrophil mobilization when both compounds were combined. These effects were maintained in models of leukopenia and conferred augmented host defenses. Mechanistically, activation of the hypothalamus-pituitary-adrenal gland (HPA) axis by A485 relayed shifts in leukocyte distribution through corticotropin-releasing hormone receptor 1 (CRHR1) and adrenocorticotropic hormone (ACTH), but independently of glucocorticoids. Our findings identify a strategy for rapid expansion of the blood leukocyte compartment via a neuroendocrine loop, with implications for the treatment of human pathologies.

Endocrine health in survivors of adult-onset cancer.

Long-term survivors of cancer (ie, the patient who is considered cured or for whom the disease is under long-term control and unlikely to recur) are at an increased risk of developing endocrine complications such as hypothalamic-pituitary dysfunctions, hypogonadisms, osteoporosis, or metabolic disorders, particularly when intensive tumour-directed therapies are applied. Symptom severity associated with these conditions ranges from mild and subclinical to highly detrimental, affecting individual health and quality of life. Although they are usually manageable, many of these endocrine pathologies remain underdiagnosed and untreated for years. To address this challenge, a higher degree of awareness, standardised screening tools, comprehensible treatment algorithms, and a close collaborative effort between endocrinologists and oncologists are essential to early identify patients who are at risk, and to implement appropriate treatment protocols. This Review highlights common symptoms and conditions related to endocrine disorders among survivors of adult-onset cancer, provides a summary of the currently available practice guidelines, and proposes a practical approach to diagnose affected patients among this group.

The neurocircuitry of fasting-induced glucocorticoid release.

Activation of the hypothalamus-pituitary-adrenal gland (HPA) axis confers adaptations to homeostatic perturbations including food scarcity. A comprehensive new study by Douglass et al. disentangled how agouti-related peptide (AgRP)-expressing neurons of the arcuate nucleus (ARC) trigger rapid HPA-axis activation in response to fasting, which is mediated by repression of a tonic, inhibitory neuro circuit.

Cancer cachexia as a blueprint for treating obesity.

Effective pharmacological treatments to achieve significant and sustained weight loss in obese individuals remain limited. Here, we apply a 'reverse engineering' approach to cancer cachexia, an extreme form of dysregulated energy balance resulting in net catabolism. We discuss three phenotypic features of the disease, summarize the underlying molecular checkpoints, and explore their translation to obesity research. We then provide examples for established pharmaceuticals, which follow a reverse engineering logic, and propose additional targets that may be of relevance for future studies. Finally, we argue that approaching diseases from this perspective may prove useful as a generic strategy to fuel the development of innovative therapies.

Dickkopf1 fuels inflammatory cytokine responses.

Many human diseases, including cancer, share an inflammatory component but the molecular underpinnings remain incompletely understood. We report that physiological and pathological Dickkopf1 (DKK1) activity fuels inflammatory cytokine responses in cell models, mice and humans. DKK1 maintains the elevated inflammatory tone of cancer cells and is required for mounting cytokine responses following ligation of toll-like and cytokine receptors. DKK1-controlled inflammation derives from cell-autonomous mechanisms, which involve SOCS3-restricted, nuclear RelA (p65) activity. We translate these findings to humans by showing that genetic DKK1 variants are linked to elevated cytokine production across healthy populations. Finally, we find that genetic deletion of DKK1 but not pharmacological neutralization of soluble DKK1 ameliorates inflammation and disease trajectories in a mouse model of endotoxemia. Collectively, our study identifies a cell-autonomous function of DKK1 in the control of the inflammatory response, which is conserved between malignant and non-malignant cells. Additional studies are required to mechanistically dissect cellular DKK1 trafficking and signaling pathways.

Circulating Dickkopf1 Parallels Metabolic Adaptations and Predicts Disease Trajectories in Patients With COVID-19.

CONTEXT AND AIMS: Coronavirus disease 19 (COVID-19) trajectories show high interindividual variability, ranging from asymptomatic manifestations to fatal outcomes, the latter of which may be fueled by immunometabolic maladaptation of the host. Reliable identification of patients who are at risk of severe disease remains challenging. We hypothesized that serum concentrations of Dickkopf1 (DKK1) indicate disease outcomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals. METHODS: We recruited hospitalized patients with PCR-confirmed SARS-CoV-2 infection and included 80 individuals for whom blood samples from 2 independent time points were available. DKK1 serum concentrations were measured by ELISA in paired samples. Clinical data were extracted from patient charts and correlated with DKK1 levels. Publicly available datasets were screened for changes in cellular DKK1 expression on SARS-CoV-2 infection. Plasma metabolites were profiled by nuclear magnetic resonance spectroscopy in an unbiased fashion and correlated with DKK1 data. Kaplan-Meier and Cox regression analysis were used to investigate the prognostic value of DKK1 levels in the context of COVID-19. RESULTS: We report that serum levels of DKK1 predict disease outcomes in patients with COVID-19. Circulating DKK1 concentrations are characterized by high interindividual variability and change as a function of time during SARS-CoV-2 infection, which is linked to platelet counts. We further find that the metabolic signature associated with SARS-CoV-2 infection resembles fasting metabolism and is mirrored by circulating DKK1 abundance. Patients with low DKK1 levels are twice as likely to die from COVID-19 than those with high levels, and DKK1 predicts mortality independent of markers of inflammation, renal function, and platelet numbers. CONCLUSION: Our study suggests a potential clinical use of circulating DKK1 as a predictor of disease outcomes in patients with COVID-19. These results require validation in additional cohorts.

Stress-induced muscle-to-CNS signaling.

Soluble mediators secreted by skeletal muscles (collectively referred to as myokines) exert systemic effects by signaling to distant organs. Rai et al. have now uncovered a muscle-to-central nervous system (CNS) signaling axis, which is engaged in response to proteostatic stress. These adaptations confer protection against pathological protein accumulation in the CNS, a hallmark of neurodegenerative diseases.

Challenges in Preventing Bone Loss Induced by Aromatase Inhibitors.

CONTEXT: Aromatase inhibitors have become a mainstay in the adjuvant treatment regimen in postmenopausal women with hormone receptor-positive breast cancer. While many of these patients have an excellent long-term prognosis, adverse effects on bone represent an emerging complication of aromatase inhibitor treatment, resulting in substantial bone loss and fragility fractures. Treatment approaches to prevent aromatase inhibitor-induced bone loss typically consist of an antiresorptive approach with bisphosphonates or the RANKL antibody denosumab. However, different guidelines vary with respect to treatment thresholds, duration, and dosing. The choice of antiresorptive regime is further complicated by comorbidities and potential disease-modifying effects of individual agents. OBJECTIVE: This review summarizes the evidence of how aromatase inhibitors affect bone health and provides an update of clinical approaches to preserve bone strength in affected women. (J Clin Endocrinol Metab XX: 0-0, 2020).