Citations

A simple, and yet robust, high pass filter is designed to remove non-linear background drift in fast scan cyclic voltammetry.

PurposeTo accurately model the beam delivery time (BDT) for a synchrotron‐based proton spot scanning system using experimentally determined beam parameters.MethodsA model to simulate the proton spot delivery sequences was constructed, and BDT was calculated by summing times for layer switch, spot switch, and spot delivery. Test plans were designed to isolate and quantify the relevant beam parameters in the operation cycle of the proton beam therapy delivery system. These parameters included the layer switch time, magnet preparation and verification time, average beam scanning speeds in x‐ and y‐directions, proton spill rate, and maximum charge and maximum extraction time for each spill. The experimentally determined parameters, as well as the nominal values initially provided by the vendor, served as inputs to the model to predict BDTs for 602 clinical proton beam deliveries. The calculated BDTs (TBDT) were compared with the BDTs recorded in the treatment delivery log files (TLog): ∆t = TLog−TBDT.ResultsThe experimentally determined average layer switch time for all 97 energies was 1.91 s (ranging from 1.9 to 2.0 s for beam energies from 71.3 to 228.8 MeV), average magnet preparation and verification time was 1.93 ms, the average scanning speeds were 5.9 m/s in x‐direction and 19.3 m/s in y‐direction, the proton spill rate was 8.7 MU/s, and the maximum proton charge available for one acceleration is 2.0 ± 0.4 nC. Some of the measured parameters differed from the nominal values provided by the vendor. The calculated BDTs using experimentally determined parameters matched the recorded BDTs of 602 beam deliveries (∆t = −0.49 ± 1.44 s), which were significantly more accurate than BDTs calculated using nominal timing parameters (∆t = −7.48 ± 6.97 s).ConclusionsAn accurate model for BDT prediction was achieved by using the experimentally determined proton beam therapy delivery parameters, which may be useful in modeling the interplay effect and patient throughput. The model may provide guidance on how to effectively reduce BDT and may be used to identifying deteriorating machine performance.

Delivery of biomolecules to the correct subcellular locales is critical for proper physiological function. To that end, we have previously determined that type I and II transforming growth factor beta (TGF-β) receptors (TβRI and TβRII, respectively) localize to the basolateral domain in polarized epithelia. While TβRII targeting was shown to be regulated by sequences between amino acids 529 and 538, the analogous region(s) within TβRI is unknown. To address that question, sequential cytoplasmic TβRI truncations and point mutations identified a targeting motif between residues 158 and 163 (VxxEED) required for basolateral TβRI expression. Further studies documented that receptor internalization, down-regulation, direct recycling, or Smad signaling were unaffected by motif mutations that caused TβRI mislocalization. However, inclusion of amino acids 148–217 containing the targeting motif was able to direct basolateral expression of the apically sorted nerve growth factor receptor (NGFR, p75; extracellular and transmembrane regions) in a dominant manner. Finally, coexpression of apically targeted type I and type II TGF-β receptors mediated Smad3 signaling from the apical membrane of polarized epithelial cells. These findings demonstrate that the absence of apical TGF-β signaling in normal epithelia is primarily a reflection of domain-specific receptor expression and not an inability to couple with the signaling machinery.

Tumours arising from mesenchymal tissue components such as vascular, fibrous and adipose tissue can manifest in the liver. Although histopathology is often necessary for definitive diagnosis, many of these lesions exhibit characteristic imaging features. The radiologist plays an important role in suggesting the diagnosis, which can direct appropriate immunohistochemical staining at histology. The aim of this review is to present clinical and imaging findings of a spectrum of mesenchymal liver tumours such as haemangioma, epithelioid haemangioendothelioma, lipoma, PEComa, angiosarcoma, inflammatory myofibroblastic tumour, solitary fibrous tumour, leiomyoma, leiomyosarcoma, Kaposi sarcoma, mesenchymal hamartoma, undifferentiated embryonal sarcoma, rhabdomyosarcoma and hepatic metastases. Knowledge of the characteristic features of these tumours will aid in guiding the radiologic diagnosis and appropriate patient management.

Abstract Malignant primary brain tumors represent one of the most common causes of cancer death in the world. Grade IV gliomas (glioblastoma multiform, GBM) are routinely resistant to current chemoradiationchemo radiation therapy with a median progression-free and overall survival for glioblastoma following current chemoradiation of ~7 and 15 months, respectively. While TGF-β functions as a growth inhibitor for most normal cell types, many tumors (including GBMs) have lost this inhibitory response and TGF-β now functions to promote tumor progression and/or dissemination. As aberrant TGF-β signaling is often considered a hallmark of high-grade gliomas, we examined whether inhibition of specific components would impact the malignant phenotype of glioblastoma. The primary mediators of TGF-β action are the Smad proteins (R-Smads), Smad2 and Smad3. Following receptor activation and R-Smad phosphorylation, they translocate to the nucleus to modulate gene expression. Since we previously determined that a cell penetrating peptide conjugate of the HIV TAT protein fused to a 30 amino acid sequence from sorting nexin 9 (SNX9) prevented Smad3, but not Smad2, nuclear import and target gene expression in models of organ fibrosis, we further investigated whether it might similarly impact aspects of GBM proliferation. To that end, twenty-one patient-derived xenografts (PDXs) were examined for their responsiveness to TGF-β. Of those, TGF-β stimulated migration and fibronectin expression in seven (33%), which was prevented by inhibiting Smad3 signaling with the TAT-SNX9 peptide but not a control peptide unable to block Smad3 action. These findings indicate that the TGB-b/Smad3 axis is a potentially important mediator of glioma cell invasion in a significant minority of GBM models. specifically targeting Smad3 might be effective in a subset of gliomas. This work was supported by Public Health Service grants GM-055816 and GM-054200 from the National Institutes of General Medical Sciences and P50 CA-108961 Developmental Pilot Award from the National Cancer Institute. Citation Format: Jeonghan Kang. Inhibition of Smad3 signaling with a TAT fusion peptide prevented TGF-β-induced fibronectin expression and cell migration in malignant gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 354. doi:10.1158/1538-7445.AM2017-354

Significance Deposition of amyloid-β (Aβ) peptide in the form of parenchymal plaques and Aβ accumulation in the walls of cerebral vessels as cerebral amyloid angiopathy (CAA) are pathological hallmarks of Alzheimer’s disease (AD). The clusterin ( CLU ) gene, which confers AD risk, is associated with amyloid deposition. Here we show that loss of CLU promotes cerebrovascular CAA, yet significantly reduces the amount of parenchymal plaques by altering perivascular drainage of Aβ in the APP/PS1 mouse model of AD. The absence of CLU in these mice is associated with a lower number of hemorrhages and a decrease in inflammation. These results suggest that CLU functions as a major Aβ chaperone to maintain Aβ solubility along interstitial fluid drainage pathways and prevent CAA formation.