No abstract

In many biological systems, cells display spontaneous calcium oscillations (CaOs) and repetitive action-potential firing. These phenomena have been described separately by models for intracellular inositol trisphosphate (IP3)-mediated CaOs and for plasma membrane excitability. In this study, we present an integrated model that combines an excitable membrane with an IP3-mediated intracellular calcium oscillator. The IP3 receptor is described as an endoplasmic reticulum (ER) calcium channel with open and close probabilities that depend on the cytoplasmic concentration of IP3 and Ca2+. We show that simply combining this ER model for intracellular CaOs with a model for membrane excitability of normal rat kidney (NRK) fibroblasts leads to instability of intracellular calcium dynamics. To ensure stable long-term periodic firing of action potentials and CaOs, it is essential to incorporate calcium transporters controlled by feedback of the ER store filling, for example, store-operated calcium channels in the plasma membrane. For low IP3 concentrations, our integrated NRK cell model is at rest at -70 mV. For higher IP3 concentrations, the CaOs become activated and trigger repetitive firing of action potentials. At high IP3 concentrations, the basal intracellular calcium concentration becomes elevated and the cell is depolarized near -20 mV. These predictions are in agreement with the different proliferative states of cultures of NRK fibroblasts. We postulate that the stabilizing role of calcium channels and/or other calcium transporters controlled by feedback from the ER store is essential for any cell in which calcium signaling by intracellular CaOs involves both ER and plasma membrane calcium fluxes.

Unfortunately, parts of the 'Materials and Methods section' and a sentence in the 'Discussion section' had to be corrected. On page 3, left column, the complete first paragraph was corrected and now reads as follows: Auto-Planning is fully integrated into Pinnacle v.9.10 TPS to automate the inverse planning process [11-13]. On page 3, left column, the complete third paragraph was corrected and now reads as follows: Thus, Auto-planning is designed to automatically perform many of the manual operations in the IMRT planning process. On page 3, right column, second paragraph to page 4 left column, first paragraph, the complete section was corrected and now reads as follows: Table 2 shows the Auto-Planning optimization preset used for the patients in this study. In the Advanced Setting Tab (see also Ref. 20

The Auto-Planning module was able to produce clinically acceptable head and neck IMRT plans with consistent quality.

BackgroundTo report on the acute toxicity in children with medulloblastoma undergoing intensity-modulated radiation therapy (IMRT) with daily intrafractionally modulated junctions.MethodsNewly diagnosed patients, aged 3–21, with standard-risk (SR) or high-risk (HR) medulloblastoma were eligible. A dose of 23.4 or 36.0Gy in daily fractions of 1.8Gy was prescribed to the craniospinal axis, followed by a boost to the primary tumor bed (54 or 55.8Gy) and metastases (39.6–55.8Gy), when indicated. Weekly, an intravenous bolus of vincristine was combined for patients with SR medulloblastoma and patients participating in the COG-ACNS-0332 study. Common toxicity criteria (CTC, version 2.0) focusing on skin, alopecia, voice changes, conjunctivitis, anorexia, dysphagia, gastro-intestinal symptoms, headache, fatigue and hematological changes were scored weekly during radiotherapy.ResultsFrom 2010 to 2014, data from 15 consecutive patients (SR, n = 7; HR, n = 8) were collected. Within 72 h from onset of treatment, vomiting (66 %) and headache (46 %) occurred. During week 3 of treatment, a peak incidence in constipation (33 %) and abdominal pain/cramping (40 %) was observed, but only in the subgroup of patients (n = 9) receiving vincristine (constipation: 56 vs 0 %, P = .04; pain/cramping: 67 vs 0 %, P = .03). At week 6, 73 % of the patients developed faint erythema of the cranial skin with dry desquamation (40 %) or moist desquamation confined to the skin folds of the auricle (33 %). No reaction of the skin overlying the spinal target volume was observed.ConclusionsHeadache at onset and gastro-intestinal toxicity, especially in patients receiving weekly vincristine, were the major complaints of patients with medulloblastoma undergoing craniospinal irradiation with IMRT.