Emerging roles and therapeutic potentials of sphingolipids in pathophysiology: emphasis on fatty acyl heterogeneity.

Sphingolipids not only exert structural roles in cellular membranes, but also act as signaling molecules in various physiological and pathological processes. A myriad of studies have shown that abnormal levels of sphingolipids and their metabolic enzymes are associated with a variety of human diseases. Moreover, blood sphingolipids can also be used as biomarkers for disease diagnosis. This review summarizes the biosynthesis, metabolism, and pathological roles of sphingolipids, with emphasis on the biosynthesis of ceramide, the precursor for the biosynthesis of complex sphingolipids with different fatty acyl chains. The possibility of using sphingolipids for disease prediction, diagnosis, and treatment is also discussed. Targeting endogenous ceramides and complex sphingolipids along with their specific fatty acyl chain to promote future drug development will also be discussed.

Erratum to "Lipidome Atlas of the Developing Heart Uncovers Dynamic Membrane Lipid Attributes Underlying Cardiac Structural and Metabolic Maturation".

[This corrects the article DOI: 10.34133/research.0006.].

Obesity-Induced miR-455 Upregulation Promotes Adaptive Pancreatic ß-Cell Proliferation Through the CPEB1/CDKN1B Pathway.

Pancreatic ß-cells adapt to compensate for increased metabolic demand during obesity. Although the miRNA pathway has an essential role in ß-cell expansion, whether it is involved in adaptive proliferation is largely unknown. First, we report that EGR2 binding to the miR-455 promoter induced miR-455 upregulation in the pancreatic islets of obesity mouse models. Then, in vitro gain- or loss-of-function studies showed that miR-455 overexpression facilitated ß-cell proliferation. Knockdown of miR-455 in ob/ob mice via pancreatic intraductal infusion prevented compensatory ß-cell expansion. Mechanistically, our results revealed that increased miR-455 expression inhibits the expression of its target cytoplasmic polyadenylation element binding protein 1 (CPEB1), an mRNA binding protein that plays an important role in regulating insulin resistance and cell proliferation. Decreased CPEB1 expression inhibits elongation of the poly(A) tail and the subsequent translation of Cdkn1b mRNA, reducing the CDKN1B expression level and finally promoting ß-cell proliferation. Taken together, our results show that the miR-455/CPEB1/CDKN1B pathway contributes to adaptive proliferation of ß-cells to meet metabolic demand during obesity.

Obesity-induced overexpression of miR-802 impairs insulin transcription and secretion.

B cell dysfunction due to obesity can be associated with alterations in the levels of micro-RNAs (miRNAs). However, the role of miRNAs in these processes remains elusive. Here, we show that miR-802 is increased in the pancreatic islets of obese mouse models and demonstrate that inducible transgenic overexpression of miR-802 in mice causes impaired insulin transcription and secretion. We identify Foxo1 as a transcription factor of miR-802 promoting its transcription, and NeuroD1 and Fzd5 as targets of miR-802-dependent silencing. Repression of NeuroD1 in ß cell and primary islets impairs insulin transcription and reduction of Fzd5 in ß cell, which, in turn, impairs Ca2+ signaling, thereby repressing calcium influx and decreasing insulin secretion. We functionally create a novel network between obesity and ß cell dysfunction via miR-802 regulation. Elucidation of the impact of obesity on microRNA expression can broaden our understanding of pathophysiological development of diabetes.

Chair Heterogeneity Index: Describing the dose heterogeneity inside the tumor volume where there is a boost volume.

In this report, Chair Heterogeneity Index (CHI) was introduced to assess the dose heterogeneity inside the target with a boost volume. CHI was defined by dividing (V Rx - V Dl ) by (V Dm - V Dh ): V Rx , V Dl , V Dm and V Dh were four points selected from the target cumulative dose volume histogram curve. The effectiveness of CHI was validated by assessing the treatment plans for nasopharyngeal cancer (NPC, 12 cases), breast cancer after breast-conserving-surgery (BC, 10 cases), and stereotactic radiosurgery after whole brain irradiation (SRS, 9 cases). Our results indicate that both CHI and HI of the target can distinguish Volumetric Modulated Arc Therapy (VMAT) from Intensity Modulated Radiation Therapy (IMRT, p < 0.05) while the mean differences in CHI (NPC 1.16, BC 1.19 and SRS 3.3) were larger than those in HI (NPC 0.03, BC 0.02 and SRS 0.02). In addition, CHI of the combination volume (the target minus the boost) were statistically higher in VMAT than IMRT in all three kinds of cancer. In conclusion, CHI was effective in assessing the dose heterogeneity inside a target containing a boost volume.

Advantages of a technique using two 50 degree arcs in simultaneous integrated boost radiotherapy for left-sidebreast cancer.

This study evaluated radiotherapy techniques with 15 cases for simultaneous integrated boost to treat whole left breast and tumor bed following breast conserving surgery. Treatment plans were generated using three techniques: volumetric modulated arc therapy (VMAT) with a partial arc of 190° (1ARC), VMAT with two tangential mini-arcs of 50° each (2TARC) and intensity modulated radiation therapy with four fixed angle fields (4IMRT). Dosimetric parameters for the whole breast (Target), the boost tumor bed (Boost), and surrounding normal organs were compared. Chair Index (CHI) was introduced to evaluate the dose homogeneity in Target given the two levels of prescription dose. The dose coverage in Target was better in 1ARC and 2TARC than that in 4IMRT. The mean CHI in 1ARC (2.47) and 2TARC (2.62) were higher than that in 4IMRT (1.71, p < 0.05), and this indicated the dose homogeneity of Target was better in 1ARC and 2TARC than that in 4IMRT. The mean doses to right lung, and contralateral breast in 4IMRT were lower than those in 2TARC but the differences between them were small. 2TARC was better than 4IMRT with respect to the dose to ipsilateral lung and heart. Overall, 2TARC was optimal among three techniques.

A dosimetric comparison of double-arc volumetric arc therapy, step-shoot intensity modulated radiotherapy and 3D-CRT for left-sided breast cancer radiotherapy after breast-conserving surgery.

OBJECTIVE: To compare the dosimetric and efficiency differences for left-sided breast cancer radiotherapy after breast-conserving surgery among three different planning techniques: double-arc volumetric-modulate arc therapy (VMAT), step-shoot intensity-modulated radiotherapy (sIMRT) and three-dimensional conformal radiation therapy (3D-CRT). MATERIALS AND METHODS: A total of 17 female patients with left-sided breast cancer who underwent breast-conserving surgery were selected; the prescription doses were 50 Gy in 25 fractions. For every patient VMAT, sIMRT and 3D-CRT plans were generated within the Monaco treatment planning system for an Axesse™ accelerator equipped with the Agility MLC. The Conformity Index (CI), the Homogeneity Index (HI), the dose volume histogram (DVH) parameters for the organs at risk and the delivery efficiency were evaluated. RESULTS: The VMAT plans showed on average higher CI of PTV (0.77 ± 0.03) than both sIMRT (0.68 ± 0.02) and 3D-CRT (0.55 ± 0.04) plans (P< 0.05). The HI values in the VMAT, sIMRT and 3D-CRT plans were 0.10 ± 0.01 0.09 ± 0.01 and 0.13 ± 0.01 (P> 0.05), respectively, and the differences among the three techniques were not statistically significant. In the ipsilateral lung, the VMAT plans showed lower Dmean, V30, V20, and V10 than the sIMRT and 3D-CRT (P< 0.05); however, there was no significant difference in V5. In the heart, the VMAT plans had lower V30 and V20 than the sIMRT and 3D-CRT plans (P< 0.05), but there was no significant difference in the Dmean and V5. In the contralateral lung, the VMAT plans showed higher Dmean and V5 than sIMRT and 3D-CRT (P< 0.05). In the contralateral breast, the VMAT plans had a higher V5 than the sIMRT and 3D-CRT plans (P< 0.05). The VMAT plans had higher MU's than sIMRT and 3D-CRT, while the treatment times were lower than that of sIMRT. CONCLUSION: For left-sided breast cancer radiotherapy after breast-conserving surgery, the VMAT plans had a better CI than the sIMRT and 3D-CRT plans. The VMAT and the sIMRT plans had better HI than the 3D-CRT plans, but no significant difference was observed between VMAT and sIMRT.

Dosimetric comparison between step-shoot intensity-modulated radiotherapy and volumetric-modulated arc therapy for upper thoracic and cervical esophageal carcinoma.

To compare and analyze the dosimetric characteristics of volumetric modulated arc therapy (VMAT) vs step-shoot intensity-modulated radiation therapy (sIMRT) for upper thoracic and cervical esophageal carcinoma. Single-arc VMAT (VMAT1), dual-arc VMAT (VMAT2), and 7-field sIMRT plans were designed for 30 patients with upper thoracic or cervical esophageal carcinoma. Planning target volume (PTV) was prescribed to 50.4Gy in 28 fractions, and PTV1 was prescribed to 60Gy in 28 fractions. The parameters evaluated included dose homogeneity and conformality, dose to organs at risk (OARs), and delivery efficiency. (1) In comparison to sIMRT, VMAT provided a systematic improvement in PTV1 coverage. The homogeneity index of VMAT1 was better than that of VMAT2. There were no significant differences among sIMRT, VMAT1, and VMAT2 in PTV coverage. (2) VMAT1 and VMAT2 reduced the maximum dose of spinal cord as compared with sIMRT (p < 0.05). The rest dose-volume characteristics of OARs were similar. (3) Monitor units of VMAT2 and VMAT1 were more than sIMRT. However, the treatment time of VMAT1, VMAT2, and sIMRT was (2.0 ± 0.2), (2.8 ± 0.3), and (9.8 ± 0.8) minutes, respectively. VMAT1 was the fastest, and the difference was statistically significant. In the treatment of upper thoracic and cervical esophageal carcinoma by the AXESSE linac, compared with 7-field sIMRT, VMAT showed better PTV1 coverage and superior spinal cord sparing. Single-arc VMAT had similar target volume coverage and the sparing of OAR to dual-arc VMAT, with shortest treatment time and highest treatment efficiency in the 3 kinds of plans.

Collimator rotation in volumetric modulated arc therapy for craniospinal irradiation and the dose distribution in the beam junction region.

PURPOSE: The purpose of this study was to investigate the role of beam collimator rotation in Volumetric Modulated Arc Therapy (VMAT) for craniospinal irradiation (CSI), and the impact on dose distribution in the beam junctions. METHODS: Six adult patients were selected for the study. Six VMAT plans with different collimator angles were generated for each patient. The patients were treated in supine position with two beam isocenters. The plans were evaluated by analysis of Dose-Volume Histogram (DVHs) data for planning target volume (PTV) and organs at risk (OAR), and conformity index (CI) and homogeneity index (HI) for the target. Dose distributions in the beam junctions were examined carefully and experimentally validated in phantom, with measurement using an ion chamber array and film. RESULTS: The mean values of HI and CI for the plans with different beam collimator angles were not significantly different. The numbers of segments, monitor units (MUs) and the delivery time of the plans with 45° beam collimator were obviously higher than those in plans with other beam collimator angles. When collimator angle for both sets of beams were set at 0°, there was a 1 mm low dose gap measured in the junction region. CONCLUSIONS: By setting the collimator angle to 45°, only two isocenters were needed for the treatment of a target with the length up to 90 cm. The HI and CI of the plans were almost the same, regardless if the collimator angles were at 0°. The collimator angles for at least one set of beams should be off 0° in order to avoid a dose gap in the beam junction region.

Frameless stereotactic body radiation therapy for multiple lung metastases.

Two patients with multiple lung metastases (≥ 5) were treated using frameless stereotactic body radiation therapy (SBRT) on an Elekta Axesse linear accelerator equipped with an interdigitation-capable multileaf collimator and four-dimensional cone-beam CT (4D CBCT). The technique and the early clinical outcomes were evaluated. Patient A with five lung metastases and Patient B with seven lung metastases underwent SBRT (48 Gy/8 fractions for Patient A, 42 Gy/7 fractions for Patient B). The treatments were administered using a 6 MV photon beam. The nominal dose rate was 660 MUs/min. Patients were positioned and immobilized using thermoplastic masks and image guidance was done using 4D CBCT. The targets were delineated on the images of the 4D CT, and the positron emission tomography-computed tomography (PET-CT) images were taken as references. A two-step, volumetric-modulated arc therapy (VMAT) plan was designed for each patient. Step 1: the lesions in one lung were irradiated by a 210° arc field; Step 2: the rest of the lesions in the other lung were irradiated by a 120° arc field. Plans were evaluated using conformity index (CI) and homogeneity index (HI). Patients were followed up and adverse events were graded according to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE v4.0). The beam-on time of each treatment was less than 10 min. The CI and HI for the two plans were 0.562, 0.0709 and 0.513, 0.0794, respectively. Pulmonary function deteriorated slightly in both patients, and the patient with seven lung lesions was confirmed to have Grade 1 radiation pneumonitis. The technique was fast, accurate, and well tolerated by patients, and the two-step plan is a helpful design in reducing the dose to the lungs.

Single arc volumetric-modulated arc therapy is sufficient for nasopharyngeal carcinoma: a dosimetric comparison with dual arc VMAT and dynamic MLC and step-and-shoot intensity-modulated radiotherapy.

BACKGROUND: The performance of single arc VMAT (VMAT1) for nasopharyngeal carcinoma (NPC) on the Axesse linac has not been well described in previous studies. The purpose of this study is to assess the feasibility of VMAT1 for NPC by comparing the dosimetry, delivery efficiency, and accuracy with dual arc VMAT (VMAT2), dynamic MLC intensity-modulated radiotherapy (dIMRT), and step-and-shoot intensity-modulated radiotherapy (ssIMRT). METHODS: Twenty consecutive patients with non-metastatic NPC were selected to be planned with VMAT1, VMAT2, dIMRT and ssIMRT using Monaco 3.2 TPS on the Axesse™ linear accelerator. Three planning target volumes (PTVs), contoured as high risk, moderate risk and low risk regions, were set to receive median absorbed-dose (D50%) of 72.6 Gy, 63.6 Gy and 54 Gy, respectively. The Homogeneity Index (HI), Conformity Index (CI), Dose Volume Histograms (DVHs), delivery efficiency and accuracy were all evaluated. RESULTS: Mean HI of PTV72.6 is better with VMAT1(0.07) and VMAT2(0.07) than dIMRT(0.09) and ssIMRT(0.09). Mean HI of PTV63.6 is better with VMAT1(0.21) and VMAT2(0.21) than dIMRT and ssIMRT. Mean CI of PTV72.6 is also better with VMAT1(0.57) and VMAT2(0.57) than dIMRT(0.49) and ssIMRT(0.5). Mean CI of PTV63.6 is better with VMAT1(0.76) and VMAT2(0.76) than dIMRT(0.73) and ssIMRT(0.73). VMAT had significantly improved homogeneity and conformity compared with IMRT. There was no significant difference between VMAT1 and VMAT2 in PTV coverage. Dose to normal tissues was acceptable for all four plan groups. VMAT1 and VMAT2 showed no significant difference in normal tissue sparring, whereas the mean dose of the parotid gland of dIMRT was significantly reduced compared to VMAT1 and VMAT2. The mean delivery time for VMAT1, VMAT2, dIMRT and ssIMRT was 2.7 min, 3.9 min, 5.7 min and 14.1 min, respectively. VMAT1 reduced the average delivery time by 29.8%, 51.1% and 80.8% compared with VMAT2, dIMRT and ssIMRT, respectively. VMAT and IMRT could all be delivered accurately based on our quality assurance standards. CONCLUSIONS: In the treatment of NPC using the Axesse™ linear accelerator, single arc VMAT has shown superiority to double arc VMAT, dIMRT and ssIMRT in delivery efficiency, without compromise to the PTV coverage. However, there is still room for improvement in terms of OAR sparing.