Environmental endocrine disruptor Bisphenol A induces metabolic derailment and obesity via upregulating IL-17A in adipocytes.

BACKGROUND: Bisphenol A (BPA), a ubiquitous environmental endocrine disruptor, has been extensively demonstrated to be associated with metabolic disorders, including obesity and type 2 diabetes mellitus. However, the underlying mechanism underpinning the environmental etiology of chronic metabolic disorders has not been sufficiently elucidated. OBJECTIVES: This study is designed to explore the toxicological pathogenesis of chronic inflammation in BPA exposure during obesity. METHODS: We investigated the role of IL-17A in the association of BPA exposure and obesity from human cross-sectional study to animal models, including genetically modified IL-17A-/- mice. RESULTS: Here, our work started from case-control observation that BPA exposure was significantly associated with risk of obesity (odds ratio = 4.72, 95%CI: 3.18 - 11.18, P < 0.01), metabolic disorder and levels of interleukin-17A (IL-17A) in human adipose (estimated changes ß = 0.46, 95%CI: 0.15 - 1.01, P < 0.01) with bariatric surgery. Animal model fed with high-fat diet (HFD) confirmed that BPA exposure aggravated body weight gain and insulin resistance, concurrent with much heightened inflammatory responses in the adipose tissue including increase in IL-17A and macrophage polarization towards M1 stage. Genetically modified IL-17A ablated mice (IL-17A-/-) showed reversed adipose tissue inflammation response, improved macrophage polarization homeostasis, along with insulin sensitivity in both HFD group alone or much more significantly the HFD + BPA group. Moreover, mediation analysis in human epidemiological investigation demonstrated that plasma IL-17A attributed up to 30.01% mediating role in the associations between BPA exposure and obesity risk. DISCUSSION: This research paradigm from human to animal provides strong evidence for the elucidation of IL-17A moderating inflammation and insulin resistance in obesity. Such findings reiterate the obesogenic role of environmental endocrine disruptor BPA in metabolic disorders and unveils the potential toxicological mechanisms underpinning such effect.

Dosimetric feasibility on hypofractionated intensity-modulated radiotherapy and simultaneous integrated boost for locally advanced unresectable pancreatic cancer with helical tomotherapy.

BACKGROUND: This dosimetric study on locally advanced pancreatic cancer (LAPC) and the surrounding gastrointestinal organs at risk (OARs) aimed at exploring the potential of further improving the internal dose and reducing the fractionation number by concurrent hypofractionated simultaneous integrated boost (SIB) radiotherapy using helical tomotherapy (HT). METHODS: We collected computed tomography positioning images from a LAPC study of 17 consecutive patients. Gross tumor volume (GTV)1, GTV2, and GTV3 were defined as the GTV minus a margin of 3, 6, and 9 mm from the external part in all directions, respectively. Under the same physical parameters and limited dose on normal organs, each case had 4 sets of SIB radiotherapy plans. Upon dose escalation, we statistically analyzed the difference of dosimetric parameters received by the OARs between group A [planning target volume (PTV)/GTV=50 Gy/70 Gy] and the other groups. According to the equivalent bioradiotherapy formula, we calculated the hypofractionated standard dose by converting the average tolerated dose of each OAR with the corresponding number of fractions. Then, we compared the dose and volume parameters of the gastrointestinal tract from the less-than-20-fraction modes with the corresponding gastrointestinal hypofractionated standard dose. RESULTS: For dose escalation, although there were a few differences in the parameters of the OAR between group A and group D, all OAR doses of group D (PTV/GTV/GTV1/GTV2/GTV3=50 Gy/70 Gy/80 Gy/90 Gy/100 Gy) were within the limited dose range. In the hypofractionated mode, there was a statistically significant difference between the gastrointestinal dose-volume parameters and the dose-limiting reference standard when the fraction number was less than 14 or 15 for group A or D, respectively. CONCLUSIONS: The dose of the internal target can be increased to 100 Gy with 15 fractions in the hypofractionated SIB radiotherapy for LAPC with HT. The corresponding tolerance dose of OARs may also be acceptable.

Influence of computed tomography contrast agent on radiotherapy dose calculation for pancreatic carcinoma: A dosimetric study based on tomotherapy and volumetric-modulated arc therapy techniques.

The main purpose of our investigation was to quantify the dosimetric influence of intravenous contrast agent for pancreatic cancer radiotherapy treatment. This study focused on complex modulated irradiation techniques of tomotherapy (TOMO) and volumetric-modulated arc therapy (VMAT) to investigate if novel conformal treatment methods could reduce the influence of contrast agent. In our study, patients with pancreatic cancer were enrolled to have 2 computed tomography (CT) scans in the same position without and with intravenous contrast agent for treatment planning. Then tumors and organ at risks were countered on contrast-enhanced CT (CECT) images. Each patient's CECT was assigned a TOMO plan and a VMAT plan. Then these plans were copied onto the non-CECT image and dose distribution was calculated with the same algorithm and structure sets. Finally, the dose distribution and the dose difference were analyzed for the target volume and organs at risk between the 2 sets of images. The statistic dosimetric result showed that for both TOMO and VMAT, no significant dose difference between CECT and non-CECT-based plan was observed. Dose difference was clinically negligible because the average relative percentage dose difference was 1% ± 1% for target volume, except a blurring effect at the higher dose region of the target volume. It implied that intravenous contrast agent will not affect dose calculation for pancreatic cancer radiotherapy significantly. Also the dose deviation based on TOMO showed no statistical difference compared with that on VMAT. For both superposition/conversation algorithm used by TOMO and Monte Carlo algorithm used by VMAT, the dosimetric difference was nonsignificant. A full analysis demonstrated a negligible dose difference of less than 1% between CECT-based plan and non-CECT-based plan. Therefore, contrast-enhanced CT image can be used directly for dose calculation of TOMO and VMAT plans for pancreatic cancer. It is unnecessary to scan twice then make a fusion of CECT and non-CECT, which would result to additional unnecessary radiation dose to patient and decrease work efficiency.

[Investigation of field width and pitch in tomotherapy treatment plans for brain metastases from lung cancer].

Tomotherapy plans were produced using a combination of field widths (1 cm, 2.5 cm and 5 cm) and pitches (0.15, 0.30, and 0.45) for seven patients with brain metastases from lung cancer, the plans were compared with dosimetric parameters, protection of organs at risk (OAR) dose and treatment times. All plans were defined that CTV with 30Gy and GTV 50 Gy by ten fraction synchronously. The results showed that the mean dose and CI for GTV was statistical difference (P = 0.002 1, P = 0.012 8), OARs were within the normal range, the treatment time increased inversely proportional to the jaw width, but had lesser impact on the pitch. This study showed plans produced with 5 cm jaw was an effective method for patients with brain metastases from lung cancer.

[Dosimetric comparison of treatment plans of pancreatic carcinoma treated with body gamma knife and tomotherapy].

Fourteen patients with pancreatic carcinoma were selected. Two treatment plans were designed for each patient, including gamma knife and Tomotherapy. The dose characteristics were evaluated by DVH and were compared. The results showed that the gamma knife plan had the higher maximal and mean target dose than Tomotherapy. Body gamma knife can increase the target dose significantly, and decrease the OAR dose. Tomotherapy had excellent dose-target conformality, and it can control doses of duodenum and stomach easily, but it had larger low dose region.