CCR4 is a determinant of melanoma brain metastasis.

We previously identified the chemokine receptor CCR4 as part of the molecular signature of melanoma brain metastasis. The aim of this study was to determine the functional significance of CCR4 in melanoma brain metastasis. We show that CCR4 is more highly expressed by brain metastasizing melanoma cells than by local cutaneous cells from the same melanoma. Moreover, we found that the expression of CCR4 is significantly higher in paired clinical specimens of melanoma metastases than in samples of primary tumors from the same patients. Notably, the expression of the CCR4 ligands, Ccl22 and Ccl17 is upregulated at the earliest stages of brain metastasis, and precedes the infiltration of melanoma cells to the brain. In-vitro, CCL17 induced migration and transendothelial migration of melanoma cells. Functionally, human melanoma cells over-expressing CCR4 were more tumorigenic and produced a higher load of spontaneous brain micrometastasis than control cells. Blocking CCR4 with a small molecule CCR4 antagonist in-vivo, reduced the tumorigenicity and micrometastasis formation of melanoma cells. Taken together, these findings implicate CCR4 as a driver of melanoma brain metastasis

A Non-stop identity complex (NIC) supervises enterocyte identity and protects from premature aging

A hallmark of aging is loss of differentiated cell identity. Age

Inflammatory Activation of Astrocytes Facilitates Melanoma Brain Tropism via the CXCL10-CXCR3 Signaling Axis

Melanoma is the deadliest skin cancer due to its high rate of metastasis, frequently to the brain. Brain metastases are incurable; therefore, understanding melanoma brain metastasis is of great clinical importance. We used a mouse model of spontaneous melanoma brain metastasis to study the interactions of melanomas with the brain microenvironment. We find that CXCL10 is upregulated in metastasis-associated astrocytes in mice and humans and is functionally important for the chemoattraction of melanoma cells. Moreover, CXCR3, the receptor for CXCL10, is upregulated in brain-tropic melanoma cells. Targeting melanoma expression of CXCR3 by nanoparticle-mediated siRNA delivery or by shRNA transduction inhibits melanoma cell migration and attenuates brain metastasis in vivo. These findings suggest that the instigation of pro-inflammatory signaling in astrocytes is hijacked by brain-metastasizing tumor cells to promote their metastatic capacity and that the CXCL10-CXCR3 axis may be a potential therapeutic target for the prevention of melanoma brain metastasis

Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9-RAGE-NF-κB-JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.info:eu-repo/semantics/publishedVersio

Hypothyroidism and diabetes mellitus – a risky dual gestational endocrinopathy

Objectives. Diabetes mellitus (DM) and hypothyroidism are each associated with increased rate of pregnancy complications. However, their combined morbidity during gestation is poorly studied. Therefore, the aims of this study were to determine the prevalence of the combined morbidity of DM & hypothyroidism and whether it is associated with adverse maternal and neonatal outcome.Study design. This population based retrospective cohort study included 87,213 women who had 232,293 deliveries. All deliveries were divided into the following groups: (1) hypothyroidism & DM (n = 171); (2) hypothyroidism (n = 1502); (3) DM (n = 13,324); and (4) deliveries of women with neither endocrinopathy, who served as a control group (n = 217, 296).Results. The prevalence of DM & hypothyroidism in our population was 0.17%. In comparisons to the other study groups, women with DM & hypothyroidism had higher rates of infertility (p < 0.001), preeclampsia (p < 0.001), chronic hypertension (p < 0.001), preterm birth (p < 0.001), and cesarean deliveries (p < 0.001). In Generalized Estimating Equations (GEE) model, hypothyroidism & DM was an independent risk factor for cesarean section (OR 3.46; 95% CI 2.53–4.75) and for preeclampsia (OR 1.82; 95%CI 1.16–2.84).Conclusion. The combination of DM & hypothyroidism is rare, yet it is associated with higher rate of infertility, cesarean sections, preterm deliveries, and hypertensive disorders of pregnancy than the rest of the population. This dual endocrinological combination is an independent risk factor for preeclampsia and cesarean section. These findings suggest that these patients are at risk for perinatal complications and should be followed and delivered as high risk pregnancies