A modeling study of functional magnetic resonance imaging to individualize target definition of seminal vesicles for external beam radiotherapy

Background Pre-treatment magnetic resonance imaging (MRI) can give patient-specific evaluation of 25 suspected pathologically-involved volumes in the seminal vesicles (SV) in prostate cancer patients. By 26 targeting this suspicious volume we hypothesize that radiotherapy is more efficient without introducing more 27 toxicity. In this study we evaluate the concept of using MRI-defined target volumes in terms of tumor 28 control probability (TCP) and rectal normal tissue complication probability (NTCP). Materials and methods Twenty-one high-risk prostate cancer patients were included. Pre-treatment CT 30 images, T2 weighted (T2w) MRI and two multi-parametric MRI were acquired. Overlap between a 31 suspicious volume in the SV observed on T2w images and a suspicious volume observed on either multi-32 parametric MRI was assumed to reflect a true malignant region (named “MRI positive”). In addition the 33 entire SV on the CT-scan was delineated. Three treatment plans of 2Gyx39 fractions were generated per 34 patient: one covering the MRI positive volume in SV and prostate with margin of 11 mm to the MRI positive 35 in the SV and two plans covering prostate and SV using 11mm and 7mm SV margin, respectively. All plans 36 prescribed the same PTV mean dose. Rectal NTCP grade≥2 was evaluated with the Lyman-Kutcher-Burman 37 model and TCP was estimated by a logistic model using the combined MRI positive volume in SV and 38 prostate as region-of-interest. Results 14/21 patients were classified as MRI positive, 6 of which had suspicious volumes in all three MRI 40 modalities. On average TCP for the plan covering prostate and the MRI positive volume was 3% higher (up 41 to 11%) than the two other plans which was statistically significant. The increased TCP was obtained without 42 increasing rectal NTCP grade≥2. Conclusion Using functional MRI for individualized target delineation in the seminal vesicles may improve 44 the treatment outcome in radiotherapy of prostate cancer without increasing the rectal toxicity.</p

Visual Cells Remember Earlier Applied Target: Plasticity of Orientation Selectivity

BACKGROUND: A canonical proposition states that, in mature brain, neurons responsive to sensory stimuli are tuned to specific properties installed shortly after birth. It is amply demonstrated that that neurons in adult visual cortex of cats are orientation-selective that is they respond with the highest firing rates to preferred oriented stimuli. METHODOLOGY/PRINCIPAL FINDINGS: In anesthetized cats, prepared in a conventional fashion for single cell recordings, the present investigation shows that presenting a stimulus uninterruptedly at a non-preferred orientation for twelve minutes induces changes in orientation preference. Across all conditions orientation tuning curves were investigated using a trial by trial method. Contrary to what has been previously reported with shorter adaptation duration, twelve minutes of adaptation induces mostly attractive shifts, i.e. toward the adapter. After a recovery period allowing neurons to restore their original orientation tuning curves, we carried out a second adaptation which produced three major results: (1) more frequent attractive shifts, (2) an increase of their magnitude, and (3) an additional enhancement of responses at the new or acquired preferred orientation. Additionally, we also show that the direction of shifts depends on the duration of the adaptation: shorter adaptation in most cases produces repulsive shifts, whereas adaptation exceeding nine minutes results in attractive shifts, in the same unit. Consequently, shifts in preferred orientation depend on the duration of adaptation. CONCLUSION/SIGNIFICANCE: The supplementary response improvements indicate that neurons in area 17 keep a memory trace of the previous stimulus properties, thereby upgrading cellular performance. It also highlights the dynamic nature of basic neuronal properties in adult cortex since repeated adaptations modified both the orientation tuning selectivity and the response strength to the preferred orientation. These enhanced neuronal responses suggest that the range of neuronal plasticity available to the visual system is broader than anticipated

The evolutionarily conserved residue A653 plays a key role in HERG channel closing

Human ether-a-go-go-related gene (HERG) encodes the rapid, outwardly rectifying K+ current IKr that is critical for repolarization of the cardiac action potential. Congenital HERG mutations or unintended pharmaceutical block of IKr can lead to life-threatening arrhythmias. Here, we assess the functional role of the alanine at position 653 (HERG-A653) that is highly conserved among evolutionarily divergent K+ channels. HERG-A653 is close to the ‘glycine hinge’ implicated in K+ channel opening, and is flanked by tyrosine 652 and phenylalanine 656, which contribute to the drug binding site. We substituted an array of seven (I, C, S, G, Y, V and T) amino acids at position 653 and expressed individual variants in heterologous systems to assess changes in gating and drug binding. Substitution of A653 resulted in negative shifts of the V1/2 of activation ranging from −23.6 (A653S) to −62.5 (A653V) compared to −11.2 mV for wild-type (WT). Deactivation was also drastically altered: channels with A653I/C substitutions exhibited delayed deactivation in response to test potentials above the activation threshold, while A653S/G/Y/V/T failed to deactivate under those conditions and required hyperpolarization and prolonged holding potentials at −130 mV. While A653S/G/T/Y variants showed decreased sensitivity to the IKr inhibitor dofetilide, these changes could not be correlated with defects in channel closure. Homology modelling suggests that in the closed state, A653 forms tight contacts with several residues from the neighbouring subunit in the tetramer, playing a key role in S6 helix packing at the narrowest part of the vestibule. Our study suggests that A653 plays an important functional role in the outwardly rectifying gating behaviour of HERG, supporting channel closure at membrane potentials negative to the channel activation threshold