Ketogenic diet (KD) is popular in diabetic patients but its cardiac safety and efficiency on the heart are unknown. The aim of the present study is to determine the effects and the underlined mechanisms of KD on cardiac function in diabetic cardiomyopathy (DCM). We used db/db mice to model DCM, and different diets (regular or KD) were used. Cardiac function and interstitial fibrosis were determined. T-regulatory cell (Treg) number and functions were evaluated. The effects of ketone body (KB) on fatty acid (FA) and glucose metabolism, mitochondria-associated endoplasmic reticulum membranes (MAMs), and mitochondrial respiration were assessed. The mechanisms via which KB regulated MAMs and Tregs were addressed. KD improved metabolic indices in db/db mice. However, KD impaired cardiac diastolic function and exacerbated ventricular fibrosis. Proportions of circulatory CD4+CD25+Foxp3+ cells in whole blood cells and serum levels of IL-4 and IL-10 were reduced in mice fed with KD. KB suppressed the differentiation to Tregs from naive CD4+ T cells. Cultured medium from KB-treated Tregs synergically activated cardiac fibroblasts. Meanwhile, KB inhibited Treg proliferation and productions of IL-4 and IL-10. Treg MAMs, mitochondrial respiration and respiratory complexes, and FA synthesis and oxidation were all suppressed by KB while glycolytic levels were increased. L-carnitine reversed Treg proliferation and function inhibited by KB. Proportions of ST2L+ cells in Tregs were reduced by KB, as well as the production of ST2L ligand, IL-33. Reinforcement expressions of ST2L in Tregs counteracted the reductions in MAMs, mitochondrial respiration, and Treg proliferations and productions of Treg cytokines IL-4 and IL-10. Therefore, despite the improvement of metabolic indices, KD impaired Treg expansion and function and promoted cardiac fibroblast activation and interstitial fibrosis. This could be mainly mediated by the suppression of MAMs and fatty acid metabolism inhibition via blunting IL-33/ST2L signaling.

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Background: Tangential irradiation is the most popular postoperative radiotherapy technique for breast cancer. However, irradiation has been related to symptomatic radiation pneumonitis (SRP), which decreases the quality of life of patients. This study investigated the clinical features and dosimetric parameters related to SRP of the ipsilateral lung to identify risk factors for SRP in breast cancer patients after three-dimensional conformal radiation therapy (3D-CRT) with tangential fields.Material and Methods: A total of 515 breast cancer patients were evaluated and divided into two groups: the local-regional irradiation group (259 patients) and the simple local irradiation group (256 patients). Clinical symptoms were registered and patient data collected. The relationship between the incidence of SRP and dosimetric parameters for the ipsilateral lung was assessed within 6 months after 3D-CRT. Dosimetric parameters were compared using t tests. The dosimetric predictors for SRP were estimated using a logistic regression model and receiver operating characteristic curve analysis.Results: In total, 19 patients (3.7%) developed grade 2 SRP. In the local-regional irradiation group, the probability of SRP in the lung body was greater than that in the lung apex (3.9% vs. 1.5%). V20 and V30 were independent predictors for SRP in the local-regional irradiation group (odds ratio = 1.152 and 1.439, both p = 0.030), whereas only V20 was an independent predictor of SRP in the simple local irradiation group (odds ratio = 1.351, p = 0.001). With 39.8% as the optimal threshold for V20 and 25.7% for V30 for local-regional irradiation, SRP could be predicted with an accuracy of 80.3% and 79.9%, a sensitivity of 61.5% and 69.2%, and a specificity of 81.3% and 80.5%, respectively. With 20.2% as the optimal V20 threshold for simple local irradiation, SRP could be predicted with an accuracy of 88.7%, a sensitivity of 83.3% and a specificity of 89.6%.Conclusions: SRP has become a rare complication with mild symptoms and occurs mainly in the lung body. V20 and V30 may be useful dosimetric predictors to evaluate SRP risk of the ipsilateral lung in breast cancer.

Purpose To investigate the fixed‐jaw intensity‐modulated radiotherapy (F‐IMRT) and tangential partial volumetric modulated arc therapy (tP‐VMAT) treatment plans for synchronous bilateral breast cancer (SBBC). Materials and method Twelve SBBC patients with pTis‐2N0M0 stages who underwent whole‐breast irradiation after breast‐conserving surgery were planned with F‐IMRT and tP‐VMAT techniques prescribing 42.56 Gy (2.66 Gy*16f) to the breast. The F‐IMRT used 8‐12 jaw‐fixed tangential fields with single (sF‐IMRT) or two (F‐IMRT) isocenters located under the sternum or in the center of the left and right planning target volumes (PTVs), and tP‐VMAT used 4 tangential partial arcs with two isocenters located in the center of the left and right PTVs. Plan evaluation was based on dose‐volume histogram (DVH) analysis. Dosimetric parameters were calculated to evaluate plan quality; total monitor units (MUs), and the gamma analysis for patient‐specific quality assurance (QA) were also evaluated. Results For PTVs, the three plans had similar Dmean and conformity index (CI) values. F‐IMRT showed a slightly better target coverage according to the V100% values and demonstrated an obvious reduction in V105% and Dmax compared with the values observed for sF‐IMRT and tP‐VMAT. Compared with tP‐VMAT, sF‐IMRT was slightly better in terms of V100%, V105% and Dmax. In addition, F‐IMRT achieved the best homogeneity index (HI) values for PTVs. Concerning healthy tissue, tP‐VMAT had an advantage in minimizing the high dose volume. The MUs of the tP‐VMAT plan were decreased approximately 1.45 and 1 times compared with the sF‐IMRT and F‐IMRT plans, respectively, and all plans passed QA. For the lungs, heart and liver, F‐IMRT achieved the smallest values in terms of Dmean and showed a significant difference compared with tP‐VMAT. Simultaneously, sF‐IMRT was also superior to tP‐VMAT. For the coronary artery, tP‐VMAT achieved the lowest Dmean, while the value for F‐IMRT was 2.24% lower compared with sF‐IMRT. For all organs at risk (OARs), tP‐VMAT was superior at the high dose level. In contrast, sF‐IMRT and F‐IMRT were obviously superior at the low dose level. The sF‐IMRT and F‐IMRT plans showed consistent trends. Conclusion All treatment plans for the provided techniques were of high quality and feasible for SBBC patients. However, we recommend F‐IMRT with a single isocenter as a priority technique because of the tremendous advantage of local hot spot control in PTVs and the reduced dose to OARs at low dose levels. When the irradiated dose to the lungs and heart exceed the clinical restriction, two isocenter F‐IMRT can be used to maximize OAR sparing. Additionally, tP‐VMAT can be adopted for improving cold spots in PTVs or high‐dose exposure to normal tissue when the interval between PTVs is narrow.