Search

Rationale: The role of MUC5B mucin expression in IPF pathogenesis is unknown. Bleomycin-exposed rodent models do not exhibit sustained fibrosis or airway remodeling. Unlike mice, ferrets have human-like distribution of MUC5B expressing cell types and natively express the risk-conferring variant that induces high MUC5B expression in humans. We hypothesized that ferrets would consequently exhibit aberrant repair to propagate fibrosis similar to human IPF., Methods: Bleomycin (5U/kg) or saline-control was micro-sprayed intratracheally then wild-type ferrets were evaluated through 22 wks. Clinical phenotype was assessed with lung function. Fibrosis was assessed with µCT imaging and comparative histology with Ashcroft scoring. Airway remodeling was assessed with histology and quantitative immunofluorescence., Results: Bleomycin ferrets exhibited sustained restrictive physiology including decreased inspiratory capacity, decreased compliance, and shifted Pressure-Volume loops through 22 wks. Volumetric µCT analysis revealed increased opacification of the lung bleomycin-ferrets. Histology showed extensive fibrotic injury that matured over time and MUC5B-positive cystic structures in the distal lung suggestive of honeycombing. Bleomycin ferrets had increased proportion of small airways that were double-positive for CCSP and alpha-tubulin compared to controls, indicating an aberrant 'proximalization' repair phenotype. Notably, this aberrant repair was associated with extent of fibrotic injury at the airway level., Conclusions: Bleomycin-exposed ferrets exhibit sustained fibrosis through 22 wks and have pathologic features of IPF not found in rodents. Ferrets exhibited proximalization of the distal airways and other pathologic features characteristic of human IPF. MUC5B expression through native cell types may play a key role in promoting airway remodeling and lung injury in IPF.

Background: Understanding the characteristics of multiparametric MRI (mpMRI) in patients from different racial/ethnic backgrounds is important for reducing the observed gaps in clinical outcomes., Purpose: To investigate the diagnostic performance of mpMRI and quantitative MRI parameters of prostate cancer (PCa) in African American (AA) and matched White (W) men., Study Type: Retrospective., Subjects: One hundred twenty-nine patients (43 AA, 86 W) with histologically proven PCa who underwent mpMRI before radical prostatectomy., Field Strength/sequence: 3.0 T, T2-weighted turbo spin echo imaging, a single-shot spin-echo EPI sequence diffusion-weighted imaging, and a gradient echo sequence dynamic contrast-enhanced MRI with an ultrafast 3D spoiled gradient-echo sequence., Assessment: The diagnostic performance of mpMRI in AA and W men was assessed using detection rates (DRs) and positive predictive values (PPVs) in zones defined by the PI-RADS v2.1 prostate sector map. Quantitative MRI parameters, including K trans and v e of clinically significant (cs) PCa (Gleason score ≥ 7) tumors were compared between AA and W sub-cohorts after matching age, prostate-specific antigen (PSA), and prostate volume., Statistical Tests: Weighted Pearson's chi-square and Mann-Whitney U tests with a statistically significant level of 0.05 were used to examine differences in DR and PPV and to compare parameters between AA and matched W men, respectively., Results: A total number of 264 PCa lesions were identified in the study cohort. The PPVs in the peripheral zone (PZ) and posterior prostate of mpMRI for csPCa lesions were significantly higher in AA men than in matched W men (87.8% vs. 68.1% in PZ, and 89.3% vs. 69.6% in posterior prostate). The K trans of index csPCa lesions in AA men was significantly higher than in W men (0.25 ± 0.12 vs. 0.20 ± 0.08 min -1 ; P < 0.01)., Data Conclusion: This study demonstrated race-related differences in the diagnostic performances and quantitative MRI measures of csPCa that were not reflected in age, PSA, and prostate volume., Evidence Level: 3 TECHNICAL EFFICACY: Stage 2., (© 2024 International Society for Magnetic Resonance in Medicine.)

Purpose: This study aimed to investigate if a deep learning model trained with a single institution's data has comparable accuracy to that trained with multi-institutional data for segmenting kidney and cyst regions in magnetic resonance (MR) images of patients affected by autosomal dominant polycystic kidney disease (ADPKD)., Methods: We used TensorFlow with a Keras custom UNet on 2D slices of 756 MRI images of kidneys with ADPKD obtained from four institutions in the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) study. The ground truth was determined via a manual plus global thresholding method. Five models were trained with 80 % of all institutional data (n = 604) and each institutional data (n = 232, 172, 148, or 52), respectively, and validated with 10 % and tested on an unseen 10 % of the data. The model's performance was evaluated using the Dice Similarity Coefficient (DSC)., Results: The DSCs by the model trained with all institutional data ranged from 0.92 to 0.95 for kidney image segmentation, only 1-2 % higher than those by the models trained with single institutional data (0.90-0.93).In cyst segmentation, however, the DSCs by the model trained with all institutional data ranged from 0.83 to 0.89, which were 2-20 % higher than those by the models trained with single institutional data (0.66-0.86)., Conclusion: The UNet performance, when trained with a single institutional dataset, exhibited similar accuracy to the model trained on a multi-institutional dataset. Segmentation accuracy increases with models trained on larger sample sizes, especially in more complex cyst segmentation., Competing Interests: Declaration of competing interest M. M. reports grants and consulting fees outside the submitted work from Otsuka Pharmaceuticals, Sanofi, Palladio Biosciences, Reata, Natera, Chinook Therapeutics, Goldilocks Therapeutics, and Carraway Therapeutics., (Copyright © 2023. Published by Elsevier Inc.)

Background: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder that causes uncontrolled kidney cyst growth, leading to kidney volume enlargement and renal function loss over time. Total kidney volume (TKV) and cyst burdens have been used as prognostic imaging biomarkers for ADPKD., Objective: This study aimed to evaluate nnUNet for automatic kidney and cyst segmentation in T2-weighted (T2W) MRI images of ADPKD patients., Methods: 756 kidney images were retrieved from 95 patients in the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort (95 patients × 2 kidneys × 4 follow-up scans). The nnUNet model was trained, validated, and tested on 604, 76, and 76 images, respectively. In contrast, all images of each patient were exclusively assigned to either the training, validation, or test sets to minimize evaluation bias. The kidney and cyst regions defined using a semi-automatic method were employed as ground truth. The model performance was assessed using the Dice Similarity Coefficient (DSC), the intersection over union (IoU) score, and the Hausdorff distance (HD)., Results: The test DSC values were 0.96±0.01 (mean±SD) and 0.90±0.05 for kidney and cysts, respectively. Similarly, the IoU scores were 0.91± 0.09 and 0.81±0.06, and the HD values were 12.49±8.71 mm and 12.04±10.41 mm, respectively, for kidney and cyst segmentation., Conclusion: The nnUNet model is a reliable tool to automatically determine kidney and cyst volumes in T2W MRI images for ADPKD prognosis and therapy monitoring., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: A power injector is typically employed to deliver a contrast agent to a subject (e.g., humans, animals, phantoms) during MRI, but it is costly and cannot inject more than one subject at a time. Conventional syringe pumps housing multiple syringes are typically non-MRI compatible and, thus, should be placed outside the MRI room., Purpose: To develop the prototype of a cost-effective, easy-to-use, reliable syringe pump that could be deployed inside a clinical MRI bore and operated on during a scan., Methods: The MRI-compatible syringe pump (MSP) was designed using Solidworks 3D modeling software and fabricated using a Raise3D Pro2 Printer. The MSP was designed to infuse up to three syringes simultaneously. The injection speed was mainly controlled with different gear sets in the escapement unit and further adjusted by changing the effective hairspring length via a pinch pin. The MSP was evaluated with three gear sets (gear ratios: 0.20:1, 0.56:1, and 1.09:1) and 10 different effective hairspring lengths at each gear ratio. A video was recorded while operating MSP at each injection speed to calculate the volume injection rate of a 5-mL syringe (mL/s). The MSP was operated five times repeatedly at each injection speed, and the mean and standard deviation of the volume injection rate were calculated., Results: The volume injection rates produced by three gear ratios (0.20:1, 0.56:1, and 1.09:1) were 0.209 ± 0.003 mL/s, 0.411 ± 0.002 mL/s, and 0.625 ± 0.006 mL/s, respectively, at the full hairspring length. The injection rates of gear set 1 (gear ratio: 0.20:1) decreased from 0.273 ± 0.001 mL/s to 0.245 ± 0.001 mL/s with a decrement of 0.003 mL/s for 10 different effective hairspring lengths (r = 0.997, p < 0.001). The injection rates of gear set 2 (gear ratio: 0.56:1) decreased from 0.519 ± 0.003 mL/s to 0.469 ± 0.003 mL/s with a decrement of 0.006 mL/s (r = 0.987, p < 0.001), and that of gear set 3 (gear ratio: 1.09:1) decreased from 0.779 ± 0.012 mL/s to 0.709 ± 0.005 mL/s with a decrement of 0.007 mL/s (r = 0.963, p < 0.001). The coefficient of variation in the injection rate measurement was 0.727 ± 0.346%., Conclusions: The MSP is a portable device that can reliably deliver a liquid agent to multiple subjects inside a clinical MRI bore during a scan., (© 2023 American Association of Physicists in Medicine.)

Purpose: To investigate whether the early perfusion change in hepatocellular carcinoma (HCC) predicts the long-term therapeutic response to atezolizumab plus bevacizumab., Methods: We retrospectively selected 19 subjects (median age: 62 years, 4 females, and 15 males) having advanced HCC and treated with atezolizumab alone (n = 3) or in combination with bevacizumab (n = 16). The 4-phased CT or MRI imaging was performed for each subject before and at 9 ± 2 and 21 ± 5 weeks after therapy initiation. The tumor-to-liver signal ratio in the arterial phase was used to estimate the tumor perfusion. The change in tumor perfusion from the baseline to the 1st follow-up exam was correlated with the tumor response evaluated using mRECIST at the 2nd follow-up exam. The difference between favorably responding and non-responding groups was statistically analyzed using one-way ANOVA., Results: The mean tumor long axis in the baseline image was 59 ± 47 mm. The HCC perfusion changes were -26 ± 18% for complete (or partial) response (CR/PR, n = 8), -24 ± 12% for stable disease (SD, n = 8), and 9 ± 13% for progressive disease (PD, n = 3). The HCC perfusion change of the CR/PR groups was significantly lower than that of the PD group (p = 0.0040). The HCC perfusion changes between the SD and PD groups were also significantly different (p = 0.0135). The sensitivity and specificity of the early perfusion change to predict the long-term progression of the disease were 100 and 94%, respectively., Conclusion: The early change in HCC perfusion may predict the long-term therapeutic response to atezolizumab plus bevacizumab, promoting personalized treatment for HCC patients., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Organoarsenicals, such as lewisite and related chloroarsine, diphenylchloroarsine (DPCA), are chemical warfare agents developed during World War I. Stockpiles in Eastern Europe remain a threat to humans. The well-documented effects of cutaneous exposure to these organoarsenicals include skin blisters, painful burns, and life-threatening conditions such as acute respiratory distress syndrome. In survivors, long-term effects such as the development of respiratory ailments are reported for the organoarsenical sulfur mustard; however, no long-term pulmonary effects are documented for lewisite and DPCA. No animal models exist to explore the relationship between skin exposure to vesicants and constrictive bronchiolitis. We developed and characterized a mouse model to study the long-term effects of cutaneous exposure on the lungs after exposure to a sublethal dose of organoarsenicals. We exposed mice to lewisite, DPCA, or a less toxic surrogate organoarsenic chemical, phenyl arsine oxide, on the skin. The surviving mice were followed for 20 weeks after skin exposure to arsenicals. Lung microcomputed tomography, lung function, and histology demonstrated increased airway resistance, increased thickness of the smooth muscle layer, increased collagen deposition in the subepithelium, and peribronchial lymphocyte infiltration in mice exposed to arsenical on skin.

Measurement of total kidney volume (TKV) using magnetic resonance imaging (MRI) is a valuable approach for monitoring disease progression in autosomal dominant polycystic kidney disease (PKD) and is becoming more common in preclinical studies using animal models. Manual contouring of kidney MRI areas [i.e., manual method (MM)] is a conventional, but time-consuming, way to determine TKV. We developed a template-based semiautomatic image segmentation method (SAM) and validated it in three commonly used PKD models: Cys1 cpk/cpk mice, Pkd1 RC/RC mice, and Pkhd1 pck/pck rats ( n = 10 per model). We compared SAM-based TKV with that obtained by clinical alternatives including the ellipsoid formula-based method (EM) using three kidney dimensions, the longest kidney length method (LM), and MM, which is considered the gold standard. Both SAM and EM presented high accuracy in TKV assessment in Cys1 cpk/cpk mice [interclass correlation coefficient (ICC) ≥ 0.94]. SAM was superior to EM and LM in Pkd1 RC/RC mice (ICC = 0.87, 0.74, and <0.10 for SAM, EM, and LM, respectively) and Pkhd1 pck/pck rats (ICC = 0.59, <0.10, and <0.10, respectively). Also, SAM outperformed EM in processing time in Cys1 cpk/cpk mice (3.6 ± 0.6 vs. 4.4 ± 0.7 min/kidney) and Pkd1 RC/RC mice (3.1 ± 0.4 vs. 7.1 ± 2.6 min/kidney, both P < 0.001) but not in Pkhd1 PCK/PCK rats (3.7 ± 0.8 vs. 3.2 ± 0.5 min/kidney). LM was the fastest (∼1 min) but correlated most poorly with MM-based TKV in all studied models. Processing times by MM were longer for Cys1 cpk/cpk mice, Pkd1 RC/RC mice, and Pkhd1 pck.pck rats (66.1 ± 7.3, 38.3 ± 7.5, and 29.2 ± 3.5 min). In summary, SAM is a fast and accurate method to determine TKV in mouse and rat PKD models. NEW & NOTEWORTHY Total kidney volume (TKV) is a valuable readout in preclinical studies for autosomal dominant and autosomal recessive polycystic kidney diseases (ADPKD and ARPKD). Since conventional TKV assessment by manual contouring of kidney areas in all images is time-consuming, we developed a template-based semiautomatic image segmentation method (SAM) and validated it in three commonly used ADPKD and ARPKD models. SAM-based TKV measurements were fast, highly reproducible, and accurate across mouse and rat ARPKD and ADPKD models.

The coronavirus disease (COVID-19) pandemic, caused by SARS-CoV-2 coronavirus, is devastatingly impacting human health. A prominent component of COVID-19 is the infection and destruction of the ciliated respiratory cells, which perpetuates dissemination and disrupts protective mucociliary transport (MCT) function, an innate defense of the respiratory tract. Thus, drugs that augment MCT could improve the barrier function of the airway epithelium and reduce viral replication and, ultimately, COVID-19 outcomes. We tested five agents known to increase MCT through distinct mechanisms for activity against SARS-CoV-2 infection using a model of human respiratory epithelial cells terminally differentiated in an air/liquid interphase. Three of the five mucoactive compounds tested showed significant inhibitory activity against SARS-CoV-2 replication. An archetype mucoactive agent, ARINA-1, blocked viral replication and therefore epithelial cell injury; thus, it was further studied using biochemical, genetic, and biophysical methods to ascertain the mechanism of action via the improvement of MCT. ARINA-1 antiviral activity was dependent on enhancing the MCT cellular response, since terminal differentiation, intact ciliary expression, and motion were required for ARINA-1-mediated anti-SARS-CoV2 protection. Ultimately, we showed that the improvement of cilia movement was caused by ARINA-1-mediated regulation of the redox state of the intracellular environment, which benefited MCT. Our study indicates that intact MCT reduces SARS-CoV-2 infection, and its pharmacologic activation may be effective as an anti-COVID-19 treatment.

Substantial clinical evidence supports the notion that ciliary function in the airways is important in COVID-19 pathogenesis. Although ciliary damage has been observed in both in vitro and in vivo models, the extent or nature of impairment of mucociliary transport (MCT) in in vivo models remains unknown. We hypothesize that SARS-CoV-2 infection results in MCT deficiency in the airways of golden Syrian hamsters that precedes pathological injury in lung parenchyma. Micro-optical coherence tomography was used to quantitate functional changes in the MCT apparatus. Both genomic and subgenomic viral RNA pathological and physiological changes were monitored in parallel. We show that SARS-CoV-2 infection caused a 67% decrease in MCT rate as early as 2 days postinfection (dpi) in hamsters, principally due to 79% diminished airway coverage of motile cilia. Correlating quantitation of physiological, virological, and pathological changes reveals steadily descending infection from the upper airways to lower airways to lung parenchyma within 7 dpi. Our results indicate that functional deficits of the MCT apparatus are a key aspect of COVID-19 pathogenesis, may extend viral retention, and could pose a risk factor for secondary infection. Clinically, monitoring abnormal ciliated cell function may indicate disease progression. Therapies directed toward the MCT apparatus deserve further investigation.

Rationale: The majority of chronic obstructive pulmonary disease (COPD) patients have chronic bronchitis, for which specific therapies are unavailable. Acquired cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction is observed in chronic bronchitis, but has not been proven in a controlled animal model with airway disease. Furthermore, the potential of CFTR as a therapeutic target has not been tested in vivo, given limitations to rodent models of COPD. Ferrets exhibit cystic fibrosis-related lung pathology when CFTR is absent and COPD with bronchitis following cigarette smoke exposure., Objectives: To evaluate CFTR dysfunction induced by smoking and test its pharmacological reversal by a novel CFTR potentiator, GLPG2196, in a ferret model of COPD with chronic bronchitis., Methods: Ferrets were exposed for 6 months to cigarette smoke to induce COPD and chronic bronchitis and then treated with enteral GLPG2196 once daily for 1 month. Electrophysiological measurements of ion transport and CFTR function, assessment of mucociliary function by one-micron optical coherence tomography imaging and particle-tracking microrheology, microcomputed tomography imaging, histopathological analysis and quantification of CFTR protein and mRNA expression were used to evaluate mechanistic and pathophysiological changes., Measurements and Main Results: Following cigarette smoke exposure, ferrets exhibited CFTR dysfunction, increased mucus viscosity, delayed mucociliary clearance, airway wall thickening and airway epithelial hypertrophy. In COPD ferrets, GLPG2196 treatment reversed CFTR dysfunction, increased mucus transport by decreasing mucus viscosity, and reduced bronchial wall thickening and airway epithelial hypertrophy., Conclusions: The pharmacologic reversal of acquired CFTR dysfunction is beneficial against pathological features of chronic bronchitis in a COPD ferret model., Competing Interests: Conflict of interest: S.M. Rowe has received consulting fees from Abbvie related to the design and conduct of clinical trials in cystic fibrosis. M. Borgonovi and K. Conrath are employees of Galapagos. All other authors declare no competing interests., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Purpose: To develop a disposable point-of-care portable perfusion phantom (DP4) and validate its clinical utility in a multi-institutional setting for quantitative dynamic contrast-enhanced magnetic resonance imaging (qDCE-MRI)., Methods: The DP4 phantom was designed for single-use and imaged concurrently with a human subject so that the phantom data can be utilized as the reference to detect errors in qDCE-MRI measurement of human tissues. The change of contrast-agent concentration in the phantom was measured using liquid chromatography-mass spectrometry. The repeatability of the contrast enhancement curve (CEC) was assessed with five phantoms in a single MRI scanner. Five healthy human subjects were recruited to evaluate the reproducibility of qDCE-MRI measurements. Each subject was imaged concurrently with the DP4 phantom at two institutes using three 3T MRI scanners from three different vendors. Pharmacokinetic (PK) parameters in the regions of liver, spleen, pancreas, and paravertebral muscle were calculated based on the Tofts model (TM), extended Tofts model (ETM), and shutter speed model (SSM). The reproducibility of each PK parameter over three measurements was evaluated with the intraclass correlation coefficient (ICC) and compared before and after DP4-based error correction., Results: The contrast-agent concentration in the DP4 phantom was linearly increased over 10 min (0.17 mM/min, measurement accuracy: 96%) after injecting gadoteridol (100 mM) at a constant rate (0.24 ml/s, 4 ml). The repeatability of the CEC within the phantom was 0.997 when assessed by the ICC. The reproducibility of the volume transfer constant, K trans , was the highest of the PK parameters regardless of the PK models. The ICCs of K trans in the TM, ETM, and SSM before DP4-based error correction were 0.34, 0.39, and 0.72, respectively, while those increased to 0.93, 0.98, and 0.86, respectively, after correction., Conclusions: The DP4 phantom is reliable, portable, and capable of significantly improving the reproducibility of qDCE-MRI measurements., (© 2021 American Association of Physicists in Medicine.)

Providing sufficient testing capacities and accurate results in a time-efficient way are essential to prevent the spread and lower the curve of a health crisis, such as the COVID-19 pandemic. In line with recent research investigating how simulation-based models and tools could contribute to mitigating the impact of COVID-19, a discrete event simulation model is developed to design optimal saliva-based COVID-19 testing stations performing sensitive, non-invasive, and rapid-result RT-qPCR tests processing. This model aims to determine the adequate number of machines and operators required, as well as their allocation at different workstations, according to the resources available and the rate of samples to be tested per day. The model has been built and experienced using actual data and processes implemented on-campus at the University of Illinois at Urbana-Champaign, where an average of around 10,000 samples needed to be processed on a daily basis, representing at the end of August 2020 more than 2% of all the COVID-19 tests performed per day in the USA. It helped identify specific bottlenecks and associated areas of improvement in the process to save human resources and time. Practically, the overall approach, including the proposed modular discrete event simulation model, can easily be reused or modified to fit other contexts where local COVID-19 testing stations have to be implemented or optimized. It could notably support on-site managers and decision-makers in dimensioning testing stations by allocating the appropriate type and quantity of resources., Competing Interests: The authors have declared that no competing interests exist.

Despite the high morbidity and mortality among patients with extensive cutaneous burns in the intensive care unit due to the development of acute respiratory distress syndrome, effective therapeutics remain to be determined. This is primarily because the mechanisms leading to acute lung injury (ALI) in these patients remain unknown. We test the hypothesis that cutaneous chemical burns promote lung injury due to systemic activation of neutrophils, in particular, toxicity mediated by the deployment of neutrophil extracellular traps (NETs). We also demonstrate the potential benefit of a peptidyl arginine deiminase 4 (PAD4) inhibitor to prevent NETosis and to preserve microvascular endothelial barrier function, thus reducing the severity of ALI in mice. Our data demonstrated that phenylarsine oxide (PAO) treatment of neutrophils caused increased intracellular Ca2+-associated PAD4 activity. A dermal chemical burn by lewisite or PAO resulted in PAD4 activation, NETosis, and ALI. NETs disrupted the barrier function of endothelial cells in human lung microvascular endothelial cell spheroids. Citrullinated histone 3 alone caused ALI in mice. Pharmacologic or genetic abrogation of PAD4 inhibited lung injury following cutaneous chemical burns. Cutaneous burns by lewisite and PAO caused ALI by PAD4-mediated NETosis. PAD4 inhibitors may have potential as countermeasures to suppress detrimental lung injury after chemical burns.

Summary Statement: The present COVID-19 brief report addresses: (1) the problem of optimal design and resource allocation to mobile testing stations to ensure rapid results to the persons getting tested; (2) the proposed solution through a newly developed discrete event simulation model, experienced in on-campus saliva-based testing stations at the University of Illinois at Urbana-Champaign; and (3) the lessons learned on how 10,000 samples (from noninvasive polymerase chain reaction COVID-19 tests) can be processed per day on campus, as well as how the model could be reused or adapted to other contexts by site managers and decision makers., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Society for Simulation in Healthcare.)

Rationale and Objectives: The study goal was to test whether the improved accuracy in quantitative dynamic contrast-enhanced magnetic resonance imaging measurement using a point-of-care portable perfusion phantom (P4) leads to better stratification of prostate cancer grade., Materials and Methods: A prospective clinical study was conducted recruiting 44 patients scheduled for multi-parameter MRI prostate exams. All participants were imaged with the P4 placed under their pelvic regions. Tissue sampling was carried out for 25 patients at 22 ± 18 (mean ± SD) days after multi-parameter MRI. On histologic examination, a total of 31 lesions were confirmed as prostate cancer. Tumors were classified into low grade (n = 14), intermediate grade (n = 10), and high grade (n = 7). Tumor perfusion was assessed by volume transfer constant, K trans , before and after P4-based error correction, and the K trans of low, intermediate and high-grade tumors were statistically compared., Results: After P4-based error correction, the K trans of low, intermediate, and high-grade tumors were 0.109 ± 0.026 min -1 (95% CI: 0.0094 to 0.124 min -1 ), 0.163 ± 0.049 min -1 (95% CI: 0.129 to 0.198 min -1 ) and 0.356 ± 0.156 min -1 (95% CI: 0.215 to 0.495 min -1 ), respectively, with statistically significant difference among the groups (low vs intermediate: p = 0.002; intermediate vs high: p = 0.002; low vs high: p < 0.001). The sensitivity and specificity of K trans value, 0.14 min -1 , to detect the clinically significant prostate cancer were 88% and 93%, respectively, after P4 based error correction, but those before error correction were 88% and 86%, respectively., Conclusion: The P4 allows to reduce errors in quantitative dynamic contrast-enhanced magnetic resonance imaging measurement, enhancing accuracy in stratification of prostate cancer grade., (Copyright © 2020 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

While the COVID-19 pandemic has led to many disruptions in industrial value chains, the adoption of circular economy (CE) principles appears to be a commendable solution for more robust, resilient, and sustainable industrial supply chains. In this study, the standpoints and visions of two consecutive classes of engineering students - following the course "Circular Economy & Industrial Systems" at the Université Paris-Saclay - are given on how they value CE strategies to mitigate the impact of COVID-19 on industrial practices. Capturing and understanding the viewpoints of the engineers of tomorrow on such a pressing issue is key to train and provide them with the suitable methods and tools to build a more circular and sustainable society. At the end of their eight-week training class, including theoretical background on industrial ecology tools, workshops, and a hands-on project, part of the final exam included a one-hour essay in which the students had to argue their position on the following questions: (i) "Circular Economy as an answer to the COVID-19 crisis?" for the class of 2020, and (ii) "Circular Economy as an answer for green recovery and value chain resiliency in the COVID-19 context?" for the class of 2021. Interestingly, the evolution of viewpoints between the beginning of the COVID-19 crisis (exam conducted in May 2020 for the first class) and one year after (exam conducted in Mars 2021 for the second class) is discussed and illustrated. Also, the answers and insights provided by engineering students on these questions are positioned within the state-of-the-art literature on the topic. Last but not least, key recommendations and challenges on how CE could alleviate COVID-related disruptions and production shortages are synthesized in a SWOT (strengths, weaknesses, threats, and opportunities) diagram., (© 2021 The Author(s). Published by Elsevier B.V.)

Aluminum nitride (AlN) thin films were grown using thermal atomic layer deposition in the temperature range of 175-350 °C. The thin films were deposited using trimethyl aluminum (TMA) and hydrazine (N 2 H 4 ) as a metal precursor and nitrogen source, respectively. Highly reactive N 2 H 4 , compared to its conventionally used counterpart, ammonia (NH 3 ), provides a higher growth per cycle (GPC), which is approximately 2.3 times higher at a deposition temperature of 300 °C and, also exhibits a low impurity concentration in as-deposited films. Low temperature AlN films deposited at 225 °C with a capping layer had an Al to N composition ratio of 1:1.1, a close to ideal composition ratio, with a low oxygen content (7.5%) while exhibiting a GPC of 0.16 nm/cycle. We suggest that N 2 H 4 as a replacement for NH 3 is a good alternative due to its stringent thermal budget.

The discovery of ferroelectricity in HfO 2 -based materials in 2011 provided new research directions and opportunities. In particular, for atomic layer deposited Hf 0.5 Zr 0.5 O 2 (HZO) films, it is possible to obtain homogenous thin films with satisfactory ferroelectric properties at a low thermal budget process. Based on experiment demonstrations over the past 10 years, it is well known that HZO films show excellent ferroelectricity when sandwiched between TiN top and bottom electrodes. This work reports a comprehensive study on the effect of TiN top and bottom electrodes on the ferroelectric properties of HZO thin films (10 nm). Investigations showed that during HZO crystallization, the TiN bottom electrode promoted ferroelectric phase formation (by oxygen scavenging) and the TiN top electrode inhibited non-ferroelectric phase formation (by stress-induced crystallization). In addition, it was confirmed that the TiN top and bottom electrodes acted as a barrier layer to hydrogen diffusion into the HZO thin film during annealing in a hydrogen-containing atmosphere. These features make the TiN electrodes a useful strategy for improving and preserving the ferroelectric properties of HZO thin films for next-generation memory applications.

Structural changes to airway morphology, such as increased bronchial wall thickness (BWT) and airway wall area, are cardinal features of chronic obstructive pulmonary disease (COPD). Ferrets are a recently established animal model uniquely exhibiting similar clinical and pathological characteristics of COPD as humans, including chronic bronchitis. Our objective was to develop a microcomputed tomography (µCT) method for evaluating structural changes to the airways in ferrets and assess whether the effects of smoking induce changes consistent with chronic bronchitis in humans. Ferrets were exposed to mainstream cigarette smoke or air control twice daily for 6 mo. µCT was conducted in vivo at 6 mo; a longitudinal cohort was imaged monthly. Manual measurements of BWT, luminal diameter (LD), and BWT-to-LD ratio (BWT/LD) were conducted and confirmed by a semiautomated algorithm. The square root of bronchial wall area (√WA) versus luminal perimeter was determined on an individual ferret basis. Smoke-exposed ferrets reproducibly demonstrated 34% increased BWT ( P < 0.001) along with increased LD and BWT/LD versus air controls. Regression indicated that the effect of smoking on BWT persisted despite controlling for covariates. Semiautomated measurements replicated findings. √WA for the theoretical median airway luminal perimeter of 4 mm (Pi4) was elevated 4.4% in smoke-exposed ferrets ( P = 0.015). Increased BWT and Pi4 developed steadily over time. µCT-based airway measurements in ferrets are feasible and reproducible. Smoke-exposed ferrets develop increased BWT and Pi4, changes similar to humans with chronic bronchitis. µCT can be used as a significant translational platform to measure dynamic airway morphological changes.

The mechanisms by which cigarette smoking impairs airway mucus clearance are not well understood. We recently established a ferret model of cigarette smoke-induced chronic obstructive pulmonary disease (COPD) exhibiting chronic bronchitis. We investigated the effects of cigarette smoke on mucociliary transport (MCT).Adult ferrets were exposed to cigarette smoke for 6 months, with in vivo mucociliary clearance measured by technetium-labelled DTPA retention. Excised tracheae were imaged with micro-optical coherence tomography. Mucus changes in primary human airway epithelial cells and ex vivo ferret airways were assessed by histology and particle tracking microrheology. Linear mixed models for repeated measures identified key determinants of MCT.Compared to air controls, cigarette smoke-exposed ferrets exhibited mucus hypersecretion, delayed mucociliary clearance (-89.0%, p<0.01) and impaired tracheal MCT (-29.4%, p<0.05). Cholinergic stimulus augmented airway surface liquid (ASL) depth (5.8±0.3 to 7.3±0.6 µm, p<0.0001) and restored MCT (6.8±0.8 to 12.9±1.2 mm·min -1 , p<0.0001). Mixed model analysis controlling for covariates indicated smoking exposure, mucus hydration (ASL) and ciliary beat frequency were important predictors of MCT. Ferret mucus was hyperviscous following smoke exposure in vivo or in vitro , and contributed to diminished MCT. Primary cells from smokers with and without COPD recapitulated these findings, which persisted despite the absence of continued smoke exposure.Cigarette smoke impairs MCT by inducing airway dehydration and increased mucus viscosity, and can be partially abrogated by cholinergic secretion of fluid secretion. These data elucidate the detrimental effects of cigarette smoke exposure on mucus clearance and suggest additional avenues for therapeutic intervention., Competing Interests: Conflict of interest: V.Y. Lin has nothing to disclose. Conflict of interest: N. Kaza has nothing to disclose. Conflict of interest: S.E. Birket has nothing to disclose. Conflict of interest: H. Kim has nothing to disclose. Conflict of interest: L.J. Edwards has nothing to disclose. Conflict of interest: J. LaFontaine has nothing to disclose. Conflict of interest: L. Liu has a patent “Method for functional investigation of respiratory airways and other ciliated tissues using µOCT” pending. Conflict of interest: M. Mazur has nothing to disclose. Conflict of interest: S.A. Byzek has nothing to disclose. Conflict of interest: J. Hanes is founder and owner of company stock (which is subject to certain rules and restrictions under Johns Hopkins University policy) of GrayBug Vision, Inc., and Kala Pharmaceuticals, Inc., outside the submitted work. Conflict of interest: G.J. Tearney has patents 14/240,938 and 12826303.5 pending. Conflict of interest: S.V. Raju has nothing to disclose. Conflict of interest: S.M. Rowe reports grants from Bayer, Forest Research Institute, AstraZeneca, N30/Nivalis, Novartis, Galapagos/AbbVie, Proteostasis, PTC Therapeutics and Eloxx, grants and personal fees for consultancy from Celtaxsys, personal fees for consultancy and advisory board work and in kind support for clinical trial work from Vertex Pharmaceuticals Incorporated, personal fees for consultancy from Bayer and Novartis, outside the submitted work; and has a patent “Use of OCT as a diagnostic modality for diseases of mucus clearance” issued., (Copyright ©ERS 2020.)

Though the synthesis of libraries of multicomponent metal oxide systems is prevalent using the combinatorial approach, the combinatorial approach has been rarely realized in studying simple metal oxides, especially applied to the atomic layer deposition (ALD) technique. In this literature, a novel combinatorial approach technique is utilized within an ALD grown simple metal oxide to synthesize a "spatially addressable combinatorial library". The two key factors in gradients were defined during the ALD process: (1) the process temperature and (2) a nonuniform flow of pulsed gases inside a cross-flow reactor. To validate the feasibility of our novel combinatorial approach, a case study of zinc oxide (ZnO), a simple metal oxide whose properties are well-known, is performed. Because of the induced gradient, the ZnO (002) crystallite size was found to gradually vary across a 100 mm wafer (∼10-20 nm) with a corresponding increase in the normalized Raman E 2 /A 1 peak intensity ratio. The findings agree well with the visible grain size observed from scanning electron microscope. The novel combinatorial approach provides a means of systematical interpretation of the combined effect of the two gradients, especially in the analysis of the microstructure of ZnO crystals. Moreover, the combinatorial library reveals that the process temperature, rather than the crystal size, plays the most significant role in determining the electrical conductivity of ZnO.

Physiological properties of tumors can be measured both in vivo and noninvasively by diffusion-weighted imaging and dynamic contrast-enhanced magnetic resonance imaging. Although these techniques have been used for more than two decades to study tumor diffusion, perfusion, and/or permeability, the methods and studies on how to reduce measurement error and bias in the derived imaging metrics is still lacking in the literature. This is of paramount importance because the objective is to translate these quantitative imaging biomarkers (QIBs) into clinical trials, and ultimately in clinical practice. Standardization of the image acquisition using appropriate phantoms is the first step from a technical performance standpoint. The next step is to assess whether the imaging metrics have clinical value and meet the requirements for being a QIB as defined by the Radiological Society of North America's Quantitative Imaging Biomarkers Alliance (QIBA). The goal and mission of QIBA and the National Cancer Institute Quantitative Imaging Network (QIN) initiatives are to provide technical performance standards (QIBA profiles) and QIN tools for producing reliable QIBs for use in the clinical imaging community. Some of QIBA's development of quantitative diffusion-weighted imaging and dynamic contrast-enhanced QIB profiles has been hampered by the lack of literature for repeatability and reproducibility of the derived QIBs. The available research on this topic is scant and is not in sync with improvements or upgrades in MRI technology over the years. This review focuses on the need for QIBs in oncology applications and emphasizes the importance of the assessment of their reproducibility and repeatability. Level of Evidence: 5 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2019;49:e101-e121., (© 2018 International Society for Magnetic Resonance in Medicine.)

Nanodiamonds hosting colour centres are a promising material platform for various quantum technologies. The fabrication of non-aggregated and uniformly-sized nanodiamonds with systematic integration of single quantum emitters has so far been lacking. Here, we present a top-down fabrication method to produce 30.0 ± 5.4 nm uniformly-sized single-crystal nanodiamonds by block copolymer self-assembled nanomask patterning together with directional and isotropic reactive ion etching. We show detected emission from bright single nitrogen vacancy centres hosted in the fabricated nanodiamonds. The lithographically precise patterning of large areas of diamond by self-assembled masks and their release into uniformly sized nanodiamonds open up new possibilities for quantum information processing and sensing.

Heterozygosity for human polycystic kidney and hepatic disease 1 ( PKHD1) mutations was recently associated with cystic liver disease and radiographic findings resembling medullary sponge kidney (MSK). However, the relevance of these associations has been tempered by a lack of cystic liver or renal disease in heterozygous mice carrying Pkhd1 gene trap or exon deletions. To determine whether heterozygosity for a smaller Pkhd1 defect can trigger cystic renal disease in mice, we generated and characterized mice with the predicted truncating Pkhd1 C642* mutation in a region corresponding to the middle of exon 20 cluster of five truncating human mutations (between PKHD1 G617fs and PKHD1 G644* ). Mouse heterozygotes or homozygotes for the Pkhd1 C642* mutation did not have noticeable liver or renal abnormalities on magnetic resonance images during their first weeks of life. However, when aged to ~1.5 yr, the Pkhd1 C642* heterozygotes developed prominent cystic liver changes; tissue analyses revealed biliary cysts and increased number of bile ducts without signs of congenital hepatic fibrosis-like portal field inflammation and fibrosis that was seen in Pkhd1 C642* homozygotes. Interestingly, aged female Pkhd1 C642* heterozygotes, as well as homozygotes, developed radiographic changes resembling MSK. However, these changes correspond to proximal tubule ectasia, not an MSK-associated collecting duct ectasia. In summary, by demonstrating that cystic liver and kidney abnormalities are triggered by heterozygosity for the Pkhd1 C642* mutation, we provide important validation for relevant human association studies. Together, these investigations indicate that PKHD1 mutation heterozygosity (predicted frequency 1 in 70 individuals) is an important underlying cause of cystic liver disorders and MSK-like manifestations in a human population.

Increasing interest in the development of alternative energy storage technologies has led to efforts being taken to improve the energy density of dielectric capacitors with high power density. However, dielectric polymer materials still have low energy densities because of their low dielectric constant, whereas Pb-based materials are limited by environmental issues and regulations. Here, the energy storage behaviors of atomic layer-deposited Hf 1- X Zr X O 2 ( X = 0-1) thin films (10 nm) and the phase transformation mechanism associated with an enhancement of their energy density are reported using unipolar pulse measurements. Based on electrical and material characterization, the energy density and energy efficiency are dependent on the Zr content, and stress-induced crystallization by the encapsulating Hf 1- X Zr X O 2 films with TiN top electrodes prior to annealing can enhance the energy density (up to 47 J/cm 3 at a small voltage value of 3.5 MV/cm) while minimizing energy loss even at low process temperatures (400 °C). This work will facilitate the realization of Hf 1- X Zr X O 2 -based capacitors for lead-free electrostatic energy storage applications.

Objectives: The aim of this study was to test the feasibility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with concurrent perfusion phantom for monitoring therapeutic response in patients with pancreatic ductal adenocarcinoma (PDAC)., Materials and Methods: A prospective pilot study was conducted with 8 patients (7 men and 1 woman) aged 46 to 78 years (mean age, 66 years). Participants had either locally advanced (n = 7) or metastatic (n = 1) PDAC, and had 2 DCE-MRI examinations: one before and one 8 ± 1 weeks after starting first-line chemotherapy. A small triplicate perfusion phantom was imaged with each patient, serving as an internal reference for accurate quantitative image analysis. Tumor perfusion was measured with K using extended Tofts model before and after phantom-based data correction. Results are presented as mean ± SD and 95% confidence intervals (CIs). Statistical difference was evaluated with 1-way analysis of variance., Results: Tumor-size change of responding group (n = 4) was -12% ± 4% at 8 weeks of therapy, while that of nonresponding group (n = 4) was 18% ± 15% (P = 0.0100). Before phantom-based data correction, the K change of responding tumors was 69% ± 23% (95% CI, 32% to 106%) at 8 weeks, whereas that of nonresponding tumors was -1% ± 41% (95% CI, -65% to 64%) (P = 0.0247). After correction, the data variation in each group was significantly reduced; the K change of responding tumors was 73% ± 6% (95% CI, 64% to 82%) compared with nonresponding tumors of -0% ± 5% (95% CI, -7% to 8%) (P < 0.0001)., Conclusions: Quantitative DCE-MRI measured the significant perfusion increase of PDAC tumors responding favorably to chemotherapy, with decreased variability after correction using a perfusion phantom.

Correlations between physical properties linking film quality with wet etch rate (WER), one of the leading figures of merit, in plasma-enhanced atomic layer deposition (PEALD) grown silicon nitride (SiN x ) films remain largely unresearched. Achieving a low WER of a SiN x film is especially significant in its use as an etch stopper for technology beyond 7 nm node semiconductor processing. Herein, we explore the correlation between the hydrogen concentration, hydrogen bonding states, bulk film density, residual impurity concentration, and the WERs of PEALD SiN x using Fourier transform infrared spectrometry, X-ray reflectivity, and spectroscopic ellipsometry, etc. PEALD SiN x films for this study were deposited using hexachlorodisilane and hollow cathode plasma source under a range of process temperatures (270-360 °C) and plasma gas compositions (N 2 /NH 3 or Ar/NH 3 ) to understand the influence of hydrogen concentration, hydrogen bonding states, bulk film density, and residual impurity concentration on the WER. Varying hydrogen concentration and differences in the hydrogen bonding states resulted in different bulk film densities and, accordingly, a variation in WER. We observe a linear relationship between hydrogen bonding concentration and WER as well as a reciprocal relationship between bulk film density and WER. Analogous to the PECVD SiN x processes, a reduction in hydrogen bonding concentration arises from either (1) thermal activation or (2) plasma excited species. However, unlike the case with silane (SiH 4 )-based PECVD SiN x , PEALD SiN x WERs are affected by residual impurities of Si precursors (i.e., chlorine impurity). Thus, possible wet etching mechanisms in HF in which the WER is affected by hydrogen bonding states or residual impurities are proposed. The shifts of amine basicity in SiN x due to different hydrogen bonding states and the changes in Si electrophilicity due to Cl impurity content are suggested as the main mechanisms that influence WER in the PEALD processes.

Patients with triple negative breast cancer (TNBC) have no successful "targeted" treatment modality, which represents a priority for novel therapy strategies. Upregulated death receptor 5 (DR5) expression levels in breast cancer cells compared to normal cells enable TRA-8, a DR5 specific agonistic antibody, to specifically target malignant cells for apoptosis without inducing normal hepatocyte apoptosis. Drug resistance is a common obstacle in TRAIL-based therapy for TNBC. Calmodulin (CaM) is overexpressed in breast cancer. In this study, we characterized the novel function of CaM antagonist in enhancing TRA-8 induced cytotoxicity in TRA-8 resistant TNBC cells and its underlying molecular mechanisms. Results demonstrated that CaM antagonist(s) enhanced TRA-8 induced cytotoxicity in a concentration and time-dependent manner for TRA-8 resistant TNBC cells. CaM directly bound to DR5 in a Ca 2+ dependent manner, and CaM siRNA promoted DR5 recruitment of FADD and caspase-8 for DISC formation and TRA-8 activated caspase cleavage for apoptosis in TRA-8 resistant TNBC cells. CaM antagonist, trifluoperazine, enhanced TRA-8 activated DR5 oligomerization, DR5-mediated DISC formation, and TRA-8 activated caspase cleavage for apoptosis, and decreased anti-apoptotic pERK, pAKT, XIAP, and cIAP-1 expression in TRA-8 resistant TNBC cells. These results suggest that CaM could be a key regulator to mediate DR5-mediated apoptotic signaling, and suggests a potential strategy for using CaM antagonists to overcome drug resistance of TRAIL-based therapy for TRA-8 resistant TNBC., (© 2018 Wiley Periodicals, Inc.)

In this work, a novel chlorodisilane precursor, pentachlorodisilane (PCDS, HSi 2 Cl 5 ), was investigated for the growth of silicon nitride (SiN x ) via hollow cathode plasma-enhanced atomic layer deposition (PEALD). A well-defined self-limiting growth behavior was successfully demonstrated over the growth temperature range of 270-360 °C. At identical process conditions, PCDS not only demonstrated approximately >20% higher growth per cycle than that of a commercially available chlorodisilane precursor, hexachlorodisilane (Si 2 Cl 6 ), but also delivered a better or at least comparable film quality determined by characterizing the refractive index, wet etch rate, and density of the films. The composition of the SiN x films grown at 360 °C using PCDS, as determined by X-ray photoelectron spectroscopy, showed low O content (∼2 at. %) and Cl content (<1 at. %; below the detection limit). Fourier transform infrared spectroscopy spectra suggested that N-H bonds were the dominant hydrogen-containing bonds in the SiN x films without a significant amount of Si-H bonds originating from the precursor molecules. The possible surface reaction pathways of the PEALD SiN x using PCDS on the surface terminated with amine groups (-NH 2 and -NH-) are proposed. The PEALD SiN x films grown using PCDS also exhibited a leakage current density as low as 1-2 nA/cm 2 at 2 MV/cm and a breakdown electric field as high as ∼12 MV/cm.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis. There is a clinical need for effective, targeted therapy strategies that destroy both differentiated TNBC cells and TNBC cancer initiating cells (CICs), as the latter are implicated in the metastasis and recurrence of TNBC. Chondroitin sulfate proteoglycan 4 (CSPG4) is overexpressed on differentiated tumor cells and CICs obtained from TNBC patient specimens, suggesting that CSPG4 may be a clinically relevant target for the imaging and therapy of TNBC. The purpose of this study was to determine whether α-particle radioimmunotherapy (RIT) targeting TNBC cells using the CSPG4-specific monoclonal antibody (mAb) 225.28 as a carrier was effective at eliminating TNBC tumors in preclinical models. To this end, mAb 225.28 labeled with 212 Pb ( 212 Pb-225.28) as a source of α-particles for RIT was used for in vitro Scatchard assays and clonogenic survival assays with human TNBC cells (SUM159 and 2LMP) grown as adherent cells or non-adherent CIC-enriched mammospheres. Immune-deficient mice bearing orthotopic SUM159 or 2LMP xenografts were injected i.v. with the targeted (225.28) or irrelevant isotype-matched control (F3-C25) mAbs, labeled with 99m Tc, 125 I, or 212 Pb for in vivo imaging, biodistribution, or tumor growth inhibition studies. 212 Pb-225.28 bound to adherent SUM159 and 2LMP cells and to CICs from SUM159 and 2LMP mammospheres with a mean affinity of 0.5 nM. Nearly ten times more binding sites per cell were present on SUM159 cells and CICs compared with 2LMP cells. 212 Pb-225.28 was six to seven times more effective than 212 Pb-F3-C25 at inhibiting SUM159 cell and CIC clonogenic survival ( p < 0.05). Radiolabeled mAb 225.28 showed significantly higher uptake than radiolabeled mAb F3-C25 in SUM159 and 2LMP xenografts ( p < 0.05), and the uptake of 212 Pb-225.28 in TNBC xenografts was correlated with target epitope expression. 212 Pb-225.28 caused dose-dependent growth inhibition of SUM159 xenografts; 0.30 MBq 212 Pb-225.28 was significantly more effective than 0.33 MBq 212 Pb-F3-C25 at inhibiting tumor growth ( p < 0.01). These results suggest that CSPG4-specific 212 Pb-225.28 is a useful reagent for RIT of CSPG4-expressing tumors, including metastatic TNBC., Competing Interests: The authors declare no conflict of interest.

Introduction: We recently validated monoclonal antibody (mAb) 376.96 as an effective carrier for targeted α-particle radioimmunotherapy (RIT) with 212 Pb in ovarian cancer mouse models. In this study, we tested the binding of radiolabeled mAb 376.96 to human pancreatic ductal adenocarcinoma (PDAC) cells and localization in xenografts in immune-deficient mice and evaluated 212 Pb-labeled 376.96 ( 212 Pb-376.96) for PDAC therapy., Methods: In vitro Scatchard assays assessed the specific binding of 212 Pb-376.96 to human PDAC3 adherent differentiated cells and non-adherent cancer initiating cells (CICs) dissociated from tumorspheres. In vitro clonogenic assays were used to measure the proliferation of adherent PDAC3 cells and CIC-enriched tumorspheres treated with 212 Pb-376.96 or the irrelevant isotype-matched 212 Pb-F3-C25. Mice bearing patient derived pancreatic cancer Panc039 xenografts were i.v. injected with 0.17-0.70 MBq 212 Pb-376.96 or isotype control 212 Pb-F3-C25, and used for biodistribution and tumor growth inhibition studies. Mice bearing orthotopic PDAC3 xenografts were i.v. co-injected with 99m Tc-376.96 and 125 I-F3-C25 and used for biodistribution studies., Results: 212 Pb-376.96 specifically bound to PDAC3 adherent and dissociated tumorsphere CICs; K d values averaged 9.0 and 21.7 nM, respectively, with 10 4 -10 5  binding sites/cell. 212 Pb-376.96 inhibited the clonogenic survival of PDAC3 cells or CICs dissociated from tumorspheres 3-6 times more effectively than isotype-matched control 212 Pb-F3-C25. Panc039 s.c. tumors showed significantly higher uptake of 212 Pb-376.96 (14.0 ± 2.1% ID/g) compared to 212 Pb-F3-C25 (6.5 ± 0.9% ID/g, p < .001) at 24 h after dosing. Orthotopic PDAC3 tumors showed significantly higher uptake of 99m Tc-376.96 (6.4 ± 1.8% ID/g) compared to 125 I-F3-C25 (3.9 ± 0.9% ID/g, p < .05) at 24 h after dosing. Panc039 tumor growth was significantly inhibited by 212 Pb-376.96 compared to 212 Pb-F3-C25 or non-treated control tumors (p < .05)., Conclusion: Our results provide evidence for the efficacy of B7-H3 targeted RIT against preclinical models of pancreatic ductal adenocarcinoma (PDAC) and support future studies with 212 Pb-376.96 in combination with chemotherapy to potentiate efficacy against PDAC., (Copyright © 2018. Published by Elsevier Inc.)

DCE-MRI has been extensively used for diagnosis, prognosis and therapy monitoring of various diseases including cancer. However, it has been reported that the perfusion parameters measured by DCE-MRI largely vary across different research sites, preventing data comparison in multi-institutional clinical trials. Recently, novel perfusion phantoms have been developed to correct scanner-driven errors, enabling quality assurance of quantitative DCE-MRI measurement. However, the sources for the variability in quantitating perfusion parameters are not only MRI scanners but also software packages and imaging protocols set by the operators. In this manuscript, the various sources influencing the variability in quantitative DCE-MRI measurement are reviewed, and the proper solutions to minimize those are discussed.

This technical note describes how to modify a population-based arterial input function to incorporate variation among the individuals. In DCE-MRI, an arterial input function (AIF) is often distorted by pulsated inflow effect and noise. A population-based AIF (pAIF) has high signal-to-noise ratio (SNR), but cannot incorporate the individual variation. AIF variation is mainly induced by variation in cardiac output and blood volume of the individuals, which can be detected by the full width at half maximum (FWHM) during the first passage and the amplitude of AIF, respectively. Thus pAIF scaled in time and amplitude fitting to the individual AIF may serve as a high SNR AIF incorporating the individual variation. The proposed method was validated using DCE-MRI images of 18 prostate cancer patients. Root mean square error (RMSE) of pAIF from individual AIFs was 0.88±0.48mM (mean±SD), but it was reduced to 0.25±0.11mM after pAIF modification using the proposed method (p<0.0001)., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Interface engineering is considered the key to improving the device performance and stability of solar cells. In particular, TiO 2 nanostructures, when used as electron transporting layers (ETLs) in metal halide perovskite solar cells (PSCs), led to excellent power conversion efficiencies (PCEs) of over 20%. They effectively transferred charge carriers from the perovskite and suppressed charge recombination at the interfaces. However, the photocatalytic effect of TiO 2 on the perovskite can significantly degrade the device performance under ultraviolet illumination. Therefore, other classes of n-type metal oxides with a wide band gap should be developed to improve their photo-stability. Herein, we demonstrate the development of In 2 O 3 thin films by a solution process and their application as ETLs in PSCs and organic solar cells (OSCs). Pin hole-free In 2 O 3 ETLs obtained by the thermal decomposition of an In precursor thin film exhibit high conductivity (2.49 × 10 -4 S cm -1 ) and low surface roughness (7.33 nm). This leads to impressive PCEs of 14.63% and 3.03% for the PSC and the inverted OSC, respectively. Furthermore, the In 2 O 3 -PSC shows better photo-stability than the TiO 2 -PSC by virtue of the wider band gap of In 2 O 3 , which leads to a PCE retention of 74% and 46%, relative to the initial PCE values of the PSC and the inverted OSC, respectively.

Purpose: The aim of this study was to develop a portable perfusion phantom and validate its utility in quantitative dynamic contrast-enhanced magnetic resonance imaging of the abdomen., Methods: A portable perfusion phantom yielding a reproducible contrast enhancement curve (CEC) was developed. A phantom package including perfusion and static phantoms were imaged simultaneously with each of three healthy human volunteers in two different 3T MR scanners. Look-up tables correlating reference (known) contrast concentrations with measured ones were created using either the static or perfusion phantom. Contrast maps of image slices showing four organs (liver, spleen, pancreas, and paravertebral muscle) were generated before and after data correction using the look-up tables. The contrast concentrations at 4.5 min after dosing in each of the four organs were averaged for each volunteer. The mean contrast concentrations (4 organs × 3 volunteers = 12) were compared for the two scanners, and the intra-class correlation coefficient (ICC) was calculated. Also, the ICC of the mean K trans values between the two scanners was calculated before and after data correction., Results: The repeatability coefficient of CECs of perfusion phantom was higher than 0.997 in all measurements. The ICC of the tissue contrast concentrations between the two scanners was 0.693 before correction, but increased to 0.974 after correction using the look-up tables (LUTs) of perfusion phantom. However, the ICC was not increased after correction using static phantom (ICC: 0.617). Similarly, the ICC of the K trans values was 0.899 before correction, but increased to 0.996 after correction using perfusion phantom LUTs. The ICC of the K trans values, however, was not increased when static phantom LUTs were used (ICC: 0.866)., Conclusions: The perfusion phantom reduced variability in quantitating contrast concentration and K trans values of human abdominal tissues across different MR units, but static phantom did not. The perfusion phantom has the potential to facilitate multi-institutional clinical trials employing quantitative DCE-MRI to evaluate various abdominal malignancies., (© 2017 American Association of Physicists in Medicine.)

Activation of death receptor-5 (DR5) leads to the formation of death-inducing signaling complex (DISC) for apoptotic signaling. TRA-8, a DR5 specific agonistic antibody, has demonstrated significant cytotoxic activity in vitro and in vivo without inducing hepatotoxicity. Calmodulin (CaM) that is overexpressed in breast cancer plays a critical role in regulating DR5-mediated apoptosis. However, the mechanism of CaM in regulating DR5-mediated apoptotic signaling remains unknown. In this study, we characterized CaM binding to DR5-mediated DISC for apoptosis in TRA-8 sensitive breast cancer cell lines using co-immunoprecipitation, fluorescence microscopic imaging, caspase signaling analysis, and cell viability assay. Results show that upon DR5 activation, CaM was recruited into DR5-mediated DISC in a calcium dependent manner. CaM antagonist, trifluoperazine (TFP), inhibited CaM recruitment into the DISC and attenuated DISC formation. DR5 oligomerization is critical for DISC formation for apoptosis. TFP decreased TRA-8 activated DR5 oligomerization, which was consistent with TFP's effect on DR5-mediated DISC formation. TFP and Ca 2+ chelator, EGTA, impeded TRA-8-activated caspase-dependent apoptotic signaling, and TFP decreased TRA-8-induced cell cytotoxicity. These results demonstrated CaM binding to DR5-mediated DISC in a calcium dependent manner and may identify CaM as a key regulator of DR5-mediated DISC formation for apoptosis in breast cancer. J. Cell. Biochem. 118: 2285-2294, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

OBJECTIVE 17α-ethynylestradiol-3-sulfate (EE-3-SO 4 ) is a highly water-soluble synthetic estrogen that has an extended half-life (∼ 10 hours) over that of naturally occurring estrogen (∼ 10 minutes). In this study, EE-3-SO 4 was evaluated in a lateral fluid percussion-induced traumatic brain injury (TBI) model in rats. METHODS A total of 9 groups of Sprague-Dawley rats underwent craniectomy. Twenty-four hours later, lateral fluid percussion was applied to 6 groups of animals to induce TBI; the remaining 3 groups served as sham control groups. EE-3-SO 4 (1 mg/kg body weight in 0.4 ml/kg body weight) or saline (vehicle control) was injected intravenously 1 hour after TBI; saline was injected in all sham animals. One day after EE-3-SO 4 /saline injection, intracranial pressure (ICP), cerebral perfusion pressure (CPP), and partial brain oxygen pressure (PbtO 2 ) were measured in Groups 1-3 (2 TBI groups and 1 sham group), and brain edema, diffusion axonal injury, and cerebral glycolysis were assessed in Groups 4-6 using MRI T2 mapping, diffusion tensor imaging (DTI), and FDG-PET imaging, respectively. Four days after dosing, the open-field anxiety of animals was assessed in Groups 7-9 by measuring the duration that each animal spent in the center area of an open chamber during 4 minutes of monitoring. RESULTS EE-3-SO 4 significantly lowered ICP while raising CPP and PbtO 2 , compared with vehicle treatment in TBI-induced animals (p < 0.05). The mean size of cerebral edema of TBI animals treated with EE-3-SO 4 was 25 ± 3 mm 3 (mean ± SE), which was significantly smaller than that of vehicle-treated animals (67 ± 6 mm 3 , p < 0.001). Also, EE-3-SO 4 treatment significantly increased the fractional anisotropy of the white matter in the ipsilateral side (p = 0.003) and cerebral glycolysis (p = 0.014). The mean duration that EE-3-SO 4 -treated animals spent in the center area was 12 ± 2 seconds, which was significantly longer than that of vehicle-treated animals (4 ± 1 seconds; p = 0.008) but not different from that of sham animals (11 ± 3 seconds; p > 0.05). CONCLUSIONS These data support the clinical use of EE-3-SO 4 for early TBI treatment.

Introduction: Novel therapies that effectively kill both differentiated cancer cells and cancer initiating cells (CICs), which are implicated in causing chemotherapy-resistance and disease recurrence, are needed to reduce the morbidity and mortality of ovarian cancer. These studies used monoclonal antibody (mAb) 376.96, which recognizes a B7-H3 epitope expressed on ovarian cancer cells and CICs, as a carrier molecule for targeted α-particle radioimmunotherapy (RIT) in preclinical models of human ovarian cancer., Methods: mAb 376.96 was conjugated to the chelate 2-(4-isothiocyanotobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamoylmethyl)-cyclododecane (TCMC) and radiolabeled with 212 Pb, a source of α-particles. In vitro Scatchard assays determined the specific binding of 212 Pb-376.96 to adherent differentiated or non-adherent CIC-enriched ES-2 and A2780cp20 ovarian cancer cells. Adherent ovarian cancer cells and non-adherent CIC-enriched tumorspheres treated in vitro with 212 Pb-376.96 or the irrelevant isotype-matched 212 Pb-F3-C25 were assessed for clonogenic survival. Mice bearing i.p. ES-2 or A2780cp20 xenografts were injected i.p. with 0.17-0.70MBq 212 Pb-376.96 or 212 Pb-F3-C25 and were used for in vivo imaging, ex vivo biodistribution, and therapeutic survival studies., Results: 212 Pb-376.96 was obtained in high yield and purity (>98%); K d values ranged from 10.6-26.6nM for ovarian cancer cells, with 10 4 -10 5 binding sites/cell. 212 Pb-376.96 inhibited the clonogenic survival of ovarian cancer cells up to 40 times more effectively than isotype-matched control 212 Pb-F3-C25; combining 212 Pb-376.96 with carboplatin significantly decreased clonogenic survival compared to either agent alone. In vivo imaging and biodistribution analysis 24h after i.p. injection of 212 Pb-376.96 showed high peritoneal retention and tumor tissue accumulation (28.7% ID/g in ES-2 ascites, 73.1% ID/g in A2780cp20 tumors); normal tissues showed lower and comparable uptake for 212 Pb-376.96 and 212 Pb-F3-C25. Tumor-bearing mice treated with 212 Pb-376.96 alone or combined with carboplatin survived 2-3 times longer than mice treated with 212 Pb-F3-C25 or non-treated controls., Conclusion: These results support additional RIT studies with 212 Pb-376.96 for future evaluation in patients with ovarian cancer., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This work presents a novel barrier thin film based on an organic-inorganic nanolaminate, which consists of alternating nanolayers of self-assembled organic layers (SAOLs) and Al 2 O 3 . The SAOLs-Al 2 O 3 nanolaminated films were deposited using a combination of molecular layer deposition and atomic layer deposition techniques at 80 °C. Modulation of the relative thickness ratio of the SAOLs and Al 2 O 3 enabled control over the elastic modulus and stress in the films. Furthermore, the SAOLs-Al 2 O 3 thin film achieved a high degree of mechanical flexibility, excellent transmittance (>95%), and an ultralow water-vapor transmission rate (2.99 × 10 -7 g m -2 day -1 ), which represents one of the lowest permeability levels ever achieved by thin film encapsulation. On the basis of its outstanding barrier properties with high flexibility and transparency, the nanolaminated film was applied to a commercial OLEDs panel as a gas-diffusion barrier film. The results showed defect propagation could be significantly inhibited by incorporating the SAOLs layers, which enhanced the durability of the panel.

The goal of this study was to develop a semiautomatic segmentation technique of the abdominal aorta to determine the arterial input function (AIF). A total of 24 patients having therapy naïve abdominal cancers were imaged using DCE-MRI on a 3T MR scanner. DCE-MRI continued for 4.2 minutes with 2.1 seconds temporal resolution (120 acquisitions). Gadoteridol (0.1 mmol/kg) was infused intravenously at 30 seconds after starting DCE-MRI, and flushed with 20-ml saline (2 ml/s). Patients were instructed to hold breath after maximal inhalation, and repeat as needed to full inspiration. The location of the abdominal aorta was manually identified, but its segmentation and motion tracking were automatically implemented. AIFs determined in the aortic region with and without tracking motion were statistically compared. The aortic region was further segmented into multiple smaller regions, and the AIF change according to the size of the region of interest (ROI) was examined. The displacement of the abdominal aorta during DCE-MRI was 3.4±2.3 (mean±SD) mm. The root mean square error (RMSE) of AIF from the best fitting curve was 0.110±0.010 mM after motion correction, which was significantly smaller than that before motion correction (0.134±0.016 mM; p<0.001). The amplitude of AIF varied up to 15% according to the ROI size. However, when the radius of ROI was reduced more than 3 mm, the variation in AIF amplitude was less than 5%. Therefore the ROI having smaller radius than that of aorta will need to be used to determine a reliable AIF in abdominal DCE-MRI.

With the continued miniaturization of devices in the semiconductor industry, atomic layer deposition (ALD) of silicon nitride thin films (SiN x ) has attracted great interest due to the inherent benefits of this process compared to other silicon nitride thin film deposition techniques. These benefits include not only high conformality and atomic-scale thickness control, but also low deposition temperatures. Over the past 20 years, recognition of the remarkable features of SiN x ALD, reinforced by experimental and theoretical investigations of the underlying surface reaction mechanism, has contributed to the development and widespread use of ALD SiN x thin films in both laboratory studies and industrial applications. Such recognition has spurred ever-increasing opportunities for the applications of the SiN x ALD technique in various arenas. Nevertheless, this technique still faces a number of challenges, which should be addressed through a collaborative effort between academia and industry. It is expected that the SiN x ALD will be further perceived as an indispensable technique for scaling next-generation ultra-large-scale integration (ULSI) technology. In this review, the authors examine the current research progress, challenges and future prospects of the SiN x ALD technique.

Purpose: The aim of the study was to develop a reliable quantitative imaging biomarker from fluorescence microscopic imaging of TRA-8/death receptor 5 (DR5) oligomer to predict TRA-8 therapeutic efficacy in human breast and pancreatic cancer mouse models., Procedures: Two breast (2LMP, SUM159) and two pancreatic (MIA PaCa-2, PANC1) cancer cell lines were used. 10(5) cells per cell line were placed in a culture dish and treated with Cy5.5-labeled TRA-8 overnight in vitro. Three fluorescence microphotographs (×20) were acquired from randomly selected areas, and about 300 cells were analyzed per cell line. Two-dimensional (2D) fluorescence signal distribution of Cy5.5-TRA-8 on each cell was measured. Gaussian curve fitting to the distribution was determined by the least square regression method, and the coefficient of determination (R (2)) of the fitting was found. In addition, two features of the best fitting Gaussian curve such as peak amplitude and the volume under the curve (VUC) were retrieved. A novel image biomarker was extracted by correlating the combination of R (2) value, peak amplitude, and the VUC with the logarithmic values of the half maximal inhibitory concentrations (IC50) of TRA-8 for the four cell lines or the percentage of tumor growth inhibition (%TGI) at a week of TRA-8 treatment in animal models., Results: Cy5.5-TRA-8 binding to DR5 receptors resulted in an oligomer on each cell membrane, and its fluorescence signal distribution followed Gaussian curve. Peak amplitude of fluorescence signal in the oligomeric region, R (2) value of the Gaussian fitting, and the VUC in TRA-8-sensitive cells were significantly higher than those in resistant cells (p < 0.05). The novel imaging biomarker was significantly correlated with either log10(IC50) or %TGI (p < 0.001)., Conclusion: The imaging biomarker extracted from the cellular distribution pattern of Cy5.5-TRA-8 may serve as a predictive biomarker of TRA-8 therapy for cancer patients.

The study goal was to examine the relationship between nab-paclitaxel delivery and SPARC (secreted protein acidic and rich in cysteine) expression in pancreatic tumor xenografts and to determine the antistromal effect of nab-paclitaxel, which may affect tumor vascular perfusion. SPARC-positive and -negative mice bearing Panc02 tumor xenografts (n = 5-6/group) were injected with IRDye 800CW (IR800)-labeled nab-paclitaxel. After 24 hours, tumors were collected and stained with DL650-labeled anti-SPARC antibody, and the correlation between nab-paclitaxel and SPARC distributions was examined. Eight groups of mice bearing either Panc039 or Panc198 patient-derived xenografts (PDX; 4 groups/model, 5 animals/group) were untreated (served as control) or treated with gemcitabine (100 mg/kg body weight, i.p., twice per week), nab-paclitaxel (30 mg/kg body weight, i.v., for 5 consecutive days), and these agents in combination, respectively, for 3 weeks, and tumor volume and perfusion changes were assessed using T2-weighted MRI and dynamic contrast-enhanced (DCE) MRI, respectively. All tumors were collected and stained with Masson's Trichrome Stain, followed by a blinded comparative analysis of tumor stroma density. IR800-nab-paclitaxel was mainly distributed in tumor stromal tissue, but nab-paclitaxel and SPARC distributions were minimally correlated in either SPARC-positive or -negative animals. Nab-paclitaxel treatment neither decreased tumor stroma nor increased tumor vascular perfusion in either PDX model when compared with control groups. These data suggest that the specific tumor delivery of nab-paclitaxel is not directly related to SPARC expression, and nab-paclitaxel does not deplete tumor stroma in general. Mol Cancer Ther; 15(4); 680-8. ©2016 AACR., (©2016 American Association for Cancer Research.)