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Neurons in the CNS do not regenerate following injury; regeneration is blocked by inhibitory proteins in myelin, such as myelin-associated glycoprotein (MAG). Elevating neuronal levels of the second messenger cAMP overcomes this blocked axonal outgrowth. One way to elevate cAMP is pretreating neurons with neurotrophins, such as brain-derived neurotrophic factor (BDNF). However, pleiotropic effects and poor bioavailability make exogenous administration of neurotrophins in vivo problematic; therefore, alternative targets must be considered. In neurons, two families of adenylyl cyclases synthesize cAMP, transmembrane adenylyl cyclases (tmACs), and soluble adenylyl cyclase (sAC). Here, we demonstrate that sAC is the essential source of cAMP for BDNF to overcome MAG-dependent inhibition of neurite outgrowth. Elevating sAC in rat and mouse neurons is sufficient to induce neurite outgrowth on myelin in vitro and promotes regeneration in vivo. These results suggest that stimulators of sAC might represent a novel therapeutic strategy to promote axonal growth and regeneration. [ABSTRACT FROM AUTHOR]

Through chemical screening, we identified a pyrazolone that reversibly blocked the activation of phagocyte oxidase (phox) in human neutrophils in response to tumor necrosis factor (TNF) or formylated peptide. The pyrazolone spared activation of phox by phorbol ester or bacteria, bacterial killing, TNF-induced granule exocytosis and phox assembly, and endothelial transmigration. We traced the pyrazolone's mechanism of action to inhibition of TNF-induced intracellular Ca2+ elevations, and identified a nontransmembrane ("soluble") adenylyl cyclase (sAC) in neutrophils as a Ca2+-sensing source of cAMP. A sAC inhibitor mimicked the pyrazolone's effect on phox. Both compounds blocked TNF-induced activation of Rapi1A, a phox-assoclated guanosine triphosphatase that is regulated by cAMP. Thus, TNF turns on phox through a Ca2+-triggered, sAC-dependent process that may involve activation of Rap1A. This pathway may offer opportunities to suppress oxidative damage during inflammation without blocking antimicrobial function. [ABSTRACT FROM AUTHOR]

Background/aim: Estrogen receptor (ER)-negative [ER(-)] invasive breast cancers (IBCs) are known to be more aggressive than their ER(+) counterparts. This is less well defined for ductal carcinoma in situ (DCIS). This study investigated the outcomes following the treatment of ER(-) DCIS., Patients and Methods: A total of 103 ER(-) DCIS patients diagnosed between 2004-2018 were retrospectively analyzed. Median follow-up was 63.9 months. Statistical analysis included descriptive statistics, non-parametric tests, T-test, logistic regression. The outcomes were compared to a group of 102 ER(+) DCIS patients from our institution., Results: Any breast event (BE) occurred in 10 (9.7%) patients at a median of 3.2 (1.7-7.2) years. The incidence of ipsilateral breast events (IBEs) was 5.8% (6/103). All IBE cases were ER(-) DCIS. All (n=4) contralateral breast events (CBEs) were ER(+) including 3 IBCs. Cumulative incidence of any BEs at 1, 2, and 5 years was 0%, 1.1%, and 9.1%, respectively. Among patients with ER(-) DCIS who developed BE, breast conserving surgery (BCS) had been performed for the initial DCIS in 90% of cases. In those without any BE, the BCS rate (vs. mastectomy) was 58.1% (p=0.08). Adjuvant radiotherapy after BCS was used less often among patients with vs. without subsequent BE (55.5% vs. 77.4%) (p=0.22). Predictors for BE occurrence were not identified. The incidence of any BE among patients with ER(+) DCIS was 6.9% and was not significantly different compared to ER(-) DCIS group (p=0.46)., Conclusion: ER(-) DCIS outcomes were similar to our institutional ER-positive DCIS group and the previously reported ones for predominantly ER-positive DCIS cohorts., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background and Purpose: Incidental thyroid gland irradiation frequently occurs in breast cancer patients who receive regional nodal irradiation (RNI) to the supraclavicular (SCV) region. Recent studies suggest hypothyroidism (HT) is a complication of radiation therapy (RT) that includes SCV fields. We retrospectively analyzed patients who received RNI to evaluate thyroid gland evolution following RT as well as its association with the development of HT., Materials and Methods: 61 breast cancer patients received SCV-directed RT between 2007 and 2019 and met inclusion criteria. Thyroid glands were retrospectively contoured on CT simulation and follow-up images. Individual dose-volume histograms were analyzed to determine thyroid volume within and outside specific isodose lines. Relative thyroid volume changes based on different radiation doses were estimated by fusing post-RT scans with CT simulation. Logistic regression was performed to assess thyroid volume changes as a factor in the development of HT., Results: Median pre-treatment thyroid volume was 11.8 cc (range: 6.3-74.1 cc) with a median of 42.2 % within the 20 Gy and 23.2 % within the 40 Gy isodose lines. A significant decrease in thyroid volume was noted by 1-year post-treatment (p < 0.0001) and thereafter. By 4 years post-treatment, average thyroid volume was decreased by 29.7 % (range: 2.3-64.4 %). Thyroid volume receiving 40 Gy or higher demonstrated a greater decrease compared to those receiving lower irradiation dosage. HT occurred in 17 patients (27.9 %). Patients who developed HT displayed a larger decrease in the thyroid volume receiving between 20 and 40 Gy at 12 months (p = 0.033)., Conclusion: Our study demonstrates for the first time that a reduction in thyroid volume may be seen as early as 6 months after SCV-directed RT for breast cancer, which correlates with development of clinical and subclinical HT. Furthermore, a dose-dependent correlation exists between thyroid subvolume reduction and SCV-directed RT in breast cancer patients. As feasible, efforts should be made to reduce the dose to the thyroid in patients who undergo RNI for breast cancer., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

In a model for neuronal movement, PC12 cells undergo fast migration in response to nerve growth factor (NGF) and phorbol ester (PMA). We previously showed that NGF increases intracellular cAMP via activation of soluble adenylyl cyclase (sAC). In this report, we demonstrate that sAC activation is an essential component of NGF- + PMA-induced fast migration in PC12 cells. Interestingly, PMA also raises intracellular cAMP but does so by stimulating transmembrane adenylyl cyclases (tmAC); however, this tmAC-generated cAMP does not contribute to fast migration. Therefore, cells must possess independent pools of cAMP capable of modulating distinct functions.