Delay-Dependent Robust Exponential Stability for Uncertain Neutral Stochastic Systems with Interval Time-Varying Delay

This paper discusses the mean-square exponential stability of uncertain neutral linear stochastic systems with interval time-varying delays. A new augmented Lyapunov-Krasovskii functional (LKF) has been constructed to derive improved delay-dependent robust mean-square exponential stability criteria, which are forms of linear matrix inequalities (LMIs). By free-weight matrices method, the usual restriction that the stability conditions only bear slow-varying derivative of the delay is removed. Finally, numerical examples are provided to illustrate the effectiveness of the proposed method

A Novel Aptamer LL4A Specifically Targets Vemurafenib-Resistant Melanoma through Binding to the CD63 Protein.

Melanoma is a highly aggressive tumor with a poor prognosis, and half of all melanoma patients harbor BRAF mutations. A BRAF inhibitor, vemurafenib (PLX4032), has been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) to treat advanced melanoma patients with BRAFV600E mutation. However, the efficacy of vemurafenib is impeded by adaptive resistance in almost all patients. In this study, using a cell-based SELEX (systematic evolution of ligands by exponential enrichment) strategy, we obtained a DNA aptamer (named LL4) with high affinity and specificity against vemurafenib-resistant melanoma cells. Optimized truncated form (LL4A) specifically binds to vemurafenib-resistant melanoma cells with dissociation constants in the nanomolar range and with excellent stability and low toxicity. Meanwhile, fluorescence imaging confirmed that LL4A significantly accumulated in tumors formed by vemurafenib-resistant melanoma cells, but not in control tumors formed by their corresponding parental cells in vivo. Further, a transmembrane protein CD63 was identified as the binding target of aptamer LL4A using a pull-down assay combined with the liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. CD63 formed a supramolecular complex with TIMP1 and β1-integrin, activated the nuclear factor кB (NF-кB) and mitogen-activated protein kinase (MAPK) signaling pathways, and contributed to vemurafenib resistance. Potentially, the aptamer LL4A may be used diagnostically and therapeutically in humans to treat targeted vemurafenib-resistant melanoma

Online dosimetric evaluation of larynx SBRT: A pilot study to assess the necessity of adaptive replanning

PURPOSE: We have initiated a multi-institutional phase I trial of 5-fraction stereotactic body radiotherapy (SBRT) for Stage III-IVa laryngeal cancer. We conducted this pilot dosimetric study to confirm potential utility of online adaptive replanning to preserve treatment quality. METHODS: We evaluated ten cases: five patients enrolled onto the current trial and five patients enrolled onto a separate phase I SBRT trial for early-stage glottic larynx cancer. Baseline SBRT treatment plans were generated per protocol. Daily cone-beam CT (CBCT) or diagnostic CT images were acquired prior to each treatment fraction. Simulation CT images and target volumes were deformably registered to daily volumetric images, the original SBRT plan was copied to the deformed images and contours, delivered dose distributions were re-calculated on the deformed CT images. All of these were performed on a commercial treatment planning system. In-house software was developed to propagate the delivered dose distribution back to reference CT images using the deformation information exported from the treatment planning system. Dosimetric differences were evaluated via dose-volume histograms. RESULTS: We could evaluate dose within 10 minutes in all cases. Prescribed coverage to gross tumor volume (GTV) and clinical target volume (CTV) was uniformly preserved; however, intended prescription dose coverage of planning treatment volume (PTV) was lost in 53% of daily treatments (mean: 93.9%, range: 83.9-97.9%). Maximum bystander point dose limits to arytenoids, parotids, and spinal cord remained respected in all cases, although variances in carotid artery doses were observed in a minority of cases. CONCLUSIONS: Although GTV and CTV SBRT dose coverage is preserved with in-room three-dimensional image guidance, PTV coverage can vary significantly from intended plans and dose to critical structures may exceed tolerances. Online adaptive treatment re-planning is potentially necessary and clinically applicable to fully preserve treatment quality. Confirmatory trial accrual and analysis remains ongoing

Technical note: Comparison of the internal target volume (ITV) contours and dose calculations on 4DCT, average CBCT, and 4DCBCT imaging for lung stereotactic body radiation therapy (SBRT)

PURPOSE: To investigate the differences between internal target volumes (ITVs) contoured on the simulation 4DCT and daily 4DCBCT images for lung cancer patients treated with stereotactic body radiotherapy (SBRT) and determine the dose delivered on 4D planning technique. METHODS: For nine patients, 4DCBCTs were acquired before each fraction to assess tumor motion. An ITV was contoured on each phase of the 4DCBCT and a union of the 10 ITVs was used to create a composite ITV. Another ITV was drawn on the average 3DCBCT (avgCBCT) to compare with current clinical practice. The Dice coefficient, Hausdorff distance, and center of mass (COM) were averaged over four fractions to compare the ITVs contoured on the 4DCT, avgCBCT, and 4DCBCT for each patient. Planning was done on the average CT, and using the online registration, plans were calculated on each phase of the 4DCBCT and on the avgCBCT. Plan dose calculations were tested by measuring ion chamber dose in the CIRS lung phantom. RESULTS: The Dice coefficients were similar for all three comparisons: avgCBCT-to-4DCBCT (0.7 ± 0.1), 4DCT-to-avgCBCT (0.7 ± 0.1), and 4DCT-to-4DCBCT (0.7 ± 0.1); while the mean COM differences were also comparable (2.6 ± 2.2mm, 2.3 ± 1.4mm, and 3.1 ± 1.1mm, respectively). The Hausdorff distances for the comparisons with 4DCBCT (8.2 ± 2.9mm and 8.1 ± 3.2mm) were larger than the comparison without (6.5 ± 2.5mm). The differences in ITV D95% between the treatment plan and avgCBCT calculations were 4.3 ± 3.0% and -0.5 ± 4.6%, between treatment plan and 4DCBCT plans, respectively, while the ITV V100% coverages were 99.0 ± 1.9% and 93.1 ± 8.0% for avgCBCT and 4DCBCT, respectively. CONCLUSION: There is great potential for 4DCBCT to evaluate the extent of tumor motion before treatment, but image quality challenges the clinician to consistently delineate lung target volumes

Commissioning, clinical implementation, and initial experience with a new brain tumor treatment package on a low-field MR-linac

To evaluate the image quality, dosimetric properties, setup reproducibility, and planar cine motion detection of a high-resolution brain coil and integrated stereotactic brain immobilization system that constitute a new brain treatment package (BTP) on a low-field magnetic resonance imaging (MRI) linear accelerator (MR-linac). Image quality of the high-resolution brain coil was evaluated with the 17 cm diameter spherical phantom and the American College of Radiology (ACR) Large MRI Phantom. Patient imaging studies approved by the institutional review board (IRB) assisted in selecting image acquisition parameters. Radiographic and dosimetric evaluation of the high-resolution brain coil and the associated immobilization devices was performed using dose calculations and ion chamber measurements. End-to-end testing was performed simulating a cranial lesion in a phantom. Inter-fraction setup variability and motion detection tests were evaluated on four healthy volunteers. Inter-fraction variability was assessed based on three repeat setups for each volunteer. Motion detection was evaluated using three-plane (axial, coronal, and sagittal) MR-cine imaging sessions, where volunteers were asked to perform a set of specific motions. The images were post-processed and evaluated using an in-house program. Contrast resolution of the high-resolution brain coil is superior to the head/neck and torso coils. The BTP receiver coils have an average HU value of 525 HU. The most significant radiation attenuation (3.14%) of the BTP, occurs through the lateral portion of the overlay board where the high-precision lateral-profile mask clips attach to the overlay. The greatest inter-fraction setup variability occurred in the pitch (average 1.08 degree) and translationally in the superior/inferior direction (average 4.88 mm). Three plane cine imaging with the BTP was able to detect large and small motions. Small voluntary motions, sub-millimeter in magnitude (maximum 0.9 mm), from motion of external limbs were detected. Imaging tests, inter-fraction setup variability, attenuation, and end-to-end measurements were quantified and performed for the BTP. Results demonstrate better contrast resolution and low contrast detectability that allows for better visualization of soft tissue anatomical changes relative to head/neck and torso coil systems

YAP/TAZ deficiency reprograms macrophage phenotype and improves infarct healing and cardiac function after myocardial infarction

Adverse cardiac remodeling after myocardial infarction (MI) causes structural and functional changes in the heart leading to heart failure. The initial post-MI pro-inflammatory response followed by reparative or anti-inflammatory response is essential for minimizing the myocardial damage, healing, and scar formation. Bone marrow-derived macrophages (BMDMs) are recruited to the injured myocardium and are essential for cardiac repair as they can adopt both pro-inflammatory or reparative phenotypes to modulate inflammatory and reparative responses, respectively. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the key mediators of the Hippo signaling pathway and are essential for cardiac regeneration and repair. However, their functions in macrophage polarization and post-MI inflammation, remodeling, and healing are not well established. Here, we demonstrate that expression of YAP and TAZ is increased in macrophages undergoing pro-inflammatory or reparative phenotype changes. Genetic deletion of YAP/TAZ leads to impaired pro-inflammatory and enhanced reparative response. Consistently, YAP activation enhanced pro-inflammatory and impaired reparative response. We show that YAP/TAZ promote pro-inflammatory response by increasing interleukin 6 (IL6) expression and impede reparative response by decreasing Arginase-I (Arg1) expression through interaction with the histone deacetylase 3 (HDAC3)-nuclear receptor corepressor 1 (NCoR1) repressor complex. These changes in macrophages polarization due to YAP/TAZ deletion results in reduced fibrosis, hypertrophy, and increased angiogenesis, leading to improved cardiac function after MI. Also, YAP activation augmented MI-induced cardiac fibrosis and remodeling. In summary, we identify YAP/TAZ as important regulators of macrophage-mediated pro-inflammatory or reparative responses post-MI

Multiple mesodermal lineage differentiation of Apodemus sylvaticus embryonic stem cells in vitro

<p>Abstract</p> <p>Background</p> <p>Embryonic stem (ES) cells have attracted significant attention from researchers around the world because of their ability to undergo indefinite self-renewal and produce derivatives from the three cell lineages, which has enormous value in research and clinical applications. Until now, many ES cell lines of different mammals have been established and studied. In addition, recently, AS-ES1 cells derived from <it>Apodemus sylvaticus </it>were established and identified by our laboratory as a new mammalian ES cell line. Hence further research, in the application of AS-ES1 cells, is warranted.</p> <p>Results</p> <p>Herein we report the generation of multiple mesodermal AS-ES1 lineages via embryoid body (EB) formation by the hanging drop method and the addition of particular reagents and factors for induction at the stage of EB attachment. The AS-ES1 cells generated separately in vitro included: adipocytes, osteoblasts, chondrocytes and cardiomyocytes. Histochemical staining, immunofluorescent staining and RT-PCR were carried out to confirm the formation of multiple mesodermal lineage cells.</p> <p>Conclusions</p> <p>The appropriate reagents and culture milieu used in mesodermal differentiation of mouse ES cells also guide the differentiation of in vitro AS-ES1 cells into distinct mesoderm-derived cells. This study provides a better understanding of the characteristics of AS-ES1 cells, a new species ES cell line and promotes the use of Apodemus ES cells as a complement to mouse ES cells in future studies.</p

How does CBCT reconstruction algorithm impact on deformably mapped targets and accumulated dose distributions?

PURPOSE: We performed quantitative analysis of differences in deformable image registration (DIR) and deformable dose accumulation (DDA) computed on CBCT datasets reconstructed using the standard (Feldkamp-Davis-Kress: FDK_CBCT) and a novel iterative (iterative_CBCT) CBCT reconstruction algorithms. METHODS: Both FDK_CBCT and iterative_CBCT images were reconstructed for 323 fractions of treatment for 10 prostate cancer patients. Planning CT images were deformably registered to each CBCT image data set. After daily dose distributions were computed, they were mapped to planning CT to obtain deformed doses. Dosimetric and image registration results based CBCT images reconstructed by two algorithms were compared at three levels: (A) voxel doses over entire dose calculation volume, (B) clinical constraint results on targets and sensitive structures, and (C) contours propagated to CBCT images using DIR results based on three algorithms (SmartAdapt, Velocity, and Elastix) were compared with manually delineated contours as ground truth. RESULTS: (A) Average daily dose differences and average normalized DDA differences between FDK_CBCT and iterative_CBCT were ≤1 cGy. Maximum daily point dose differences increased from 0.22 ± 0.06 Gy (before the deformable dose mapping operation) to 1.33 ± 0.38 Gy after the deformable dose mapping. Maximum differences of normalized DDA per fraction were up to 0.80 Gy (0.42 ± 0.19 Gy). (B) Differences in target minimum doses were up to 8.31 Gy (-0.62 ± 4.60 Gy) and differences in critical structure doses were 0.70 ± 1.49 Gy. (C) For mapped prostate contours based on iterative_CBCT (relative to standard FDK_CBCT), dice similarity coefficient increased by 0.10 ± 0.09 (p \u3c 0.0001), mass center distances decreased by 2.5 ± 3.0 mm (p \u3c 0.00005), and Hausdorff distances decreased by 3.3 ± 4.4 mm (p \u3c 0.00015). CONCLUSIONS: The new iterative CBCT reconstruction algorithm leads to different mapped volumes of interest, deformed and cumulative doses than results based on conventional FDK_CBCT