Weakened APC/C activity at mitotic exit drives cancer vulnerability to KIF18A inhibition.

The efficacy of current antimitotic cancer drugs is limited by toxicity in highly proliferative healthy tissues. A cancer-specific dependency on the microtubule motor protein KIF18A therefore makes it an attractive therapeutic target. Not all cancers require KIF18A, however, and the determinants underlying this distinction remain unclear. Here, we show that KIF18A inhibition drives a modest and widespread increase in spindle assembly checkpoint (SAC) signaling from kinetochores which can result in lethal mitotic delays. Whether cells arrest in mitosis depends on the robustness of the metaphase-to-anaphase transition, and cells predisposed with weak basal anaphase-promoting complex/cyclosome (APC/C) activity and/or persistent SAC signaling through metaphase are uniquely sensitive to KIF18A inhibition. KIF18A-dependent cancer cells exhibit hallmarks of this SAC:APC/C imbalance, including a long metaphase-to-anaphase transition, and slow mitosis overall. Together, our data reveal vulnerabilities in the cell division apparatus of cancer cells that can be exploited for therapeutic benefit.

Age, sex, and lung volume dependence of dissolved xenon-129 MRI gas exchange metrics.

PURPOSE: To characterize the dependence of Xe-MRI gas transfer metrics upon age, sex, and lung volume in a group of healthy volunteers. METHODS: Sixty-five subjects with no history of chronic lung disease were assessed with 129Xe-MRI using a four-echo 3D radial spectroscopic imaging sequence and a dose of xenon titrated according to subject height that was inhaled from a lung volume of functional residual capacity (FRC). Imaging was repeated in 34 subjects at total lung capacity (TLC). Regional maps of the fractions of dissolved xenon in red blood cells (RBC), membrane (M), and airspace (Gas) were acquired at an isotropic resolution of 2 cm, from which global averages of the ratios RBC:M, RBC:Gas, and M:Gas were computed. RESULTS: Data from 26 males and 36 females with a median age of 43 y (range: 20-69 y) were of sufficient quality to analyze. Age (p = 0.0006) and sex (p < 0.0001) were significant predictors for RBC:M, and a linear regression showed higher values and steeper decline in males: RBC:M(Males) = -0.00362 × Age + 0.60 (p = 0.01, R2 = 0.25); RBC:M(Females) = -0.00170 × Age + 0.44 (p = 0.02, R2 = 0.15). Similarly, age and sex were significant predictors for RBC:Gas but not for M:Gas. RBC:M, M:Gas and RBC:Gas were significantly lower at TLC than at FRC (plus inhaled volume), with an average 9%, 30% and 35% decrease, respectively. CONCLUSION: Expected age and sex dependence of pulmonary function concurs with 129Xe RBC:M imaging results, demonstrating that these variables must be considered when reporting Xe-MRI metrics. Xenon doses and breathing maneuvers should be controlled due to the strong dependence of Xe-MRI metrics upon lung volume.

Image Phenotyping of Preterm-Born Children Using Hyperpolarized 129Xe Lung Magnetic Resonance Imaging and Multiple-Breath Washout.

Rationale: Preterm birth is associated with low lung function in childhood, but little is known about the lung microstructure in childhood. Objectives: We assessed the differential associations between the historical diagnosis of bronchopulmonary dysplasia (BPD) and current lung function phenotypes on lung ventilation and microstructure in preterm-born children using hyperpolarized 129Xe ventilation and diffusion-weighted magnetic resonance imaging (MRI) and multiple-breath washout (MBW). Methods: Data were available from 63 children (aged 9-13 yr), including 44 born preterm (⩽34 weeks' gestation) and 19 term-born control subjects (⩾37 weeks' gestation). Preterm-born children were classified, using spirometry, as prematurity-associated obstructive lung disease (POLD; FEV1 < lower limit of normal [LLN] and FEV1/FVC < LLN), prematurity-associated preserved ratio of impaired spirometry (FEV1 < LLN and FEV1/FVC ⩾ LLN), preterm-(FEV1 ⩾ LLN) and term-born control subjects, and those with and without BPD. Ventilation heterogeneity metrics were derived from 129Xe ventilation MRI and SF6 MBW. Alveolar microstructural dimensions were derived from 129Xe diffusion-weighted MRI. Measurements and Main Results: 129Xe ventilation defect percentage and ventilation heterogeneity index were significantly increased in preterm-born children with POLD. In contrast, mean 129Xe apparent diffusion coefficient, 129Xe apparent diffusion coefficient interquartile range, and 129Xe mean alveolar dimension interquartile range were significantly increased in preterm-born children with BPD, suggesting changes of alveolar dimensions. MBW metrics were all significantly increased in the POLD group compared with preterm- and term-born control subjects. Linear regression confirmed the differential effects of obstructive disease on ventilation defects and BPD on lung microstructure. Conclusion: We show that ventilation abnormalities are associated with POLD, and BPD in infancy is associated with abnormal lung microstructure.

A comparison of free amino nitrogen and yeast-assimilable nitrogen measurement methods for use in alcoholic fermentation of whey.

The continued efficient use of whey as a fermentable substrate to produce alcoholic beverages will benefit from improving the measurement of key components relevant to the fermentability of whey. One component of fermentation that is not well studied in whey is the concentration of fermentable nitrogen, either as free amino nitrogen (FAN) or yeast-assimilable nitrogen (YAN). Fermentable nitrogen in media is essential for yeast cells to replicate. Insufficient concentrations of FAN or YAN to support the growing yeast population can result in sluggish or "stuck" fermentations. We evaluated 3 common methods of fermentable nitrogen determination and compared them for use in whey fermentation systems, based on ninhydrin, nitrogen by o-phthalaldehyde (NOPA), and formaldehyde pH (Sørensen titration) values. Each measurement method was evaluated independently using standard addition curves and compared for overall accuracy using paired t-tests (α = 0.05). Although the formaldehyde pH method showed high precision, it did not measure nitrogen accurately, as it overestimated YAN in whey by up to 6 times relative to other tests. The ninhydrin and NOPA methods both showed accuracy for fermentable nitrogen determination in whey based on analysis of standardized nitrogen sources. We concluded that either the ninhydrin FAN or NOPA YAN method may be used to determine the fermentable nitrogen content in whey. This is expected to improve the ability of producers to use whey as a fermentation medium.

A Dual-Channel Deep Learning Approach for Lung Cavity Estimation From Hyperpolarized Gas and Proton MRI.

BACKGROUND: Hyperpolarized gas MRI can quantify regional lung ventilation via biomarkers, including the ventilation defect percentage (VDP). VDP is computed from segmentations derived from spatially co-registered functional hyperpolarized gas and structural proton (1 H)-MRI. Although acquired at similar lung inflation levels, they are frequently misaligned, requiring a lung cavity estimation (LCE). Recently, single-channel, mono-modal deep learning (DL)-based methods have shown promise for pulmonary image segmentation problems. Multichannel, multimodal approaches may outperform single-channel alternatives. PURPOSE: We hypothesized that a DL-based dual-channel approach, leveraging both 1 H-MRI and Xenon-129-MRI (129 Xe-MRI), can generate LCEs more accurately than single-channel alternatives. STUDY TYPE: Retrospective. POPULATION: A total of 480 corresponding 1 H-MRI and 129 Xe-MRI scans from 26 healthy participants (median age [range]: 11 [8-71]; 50% females) and 289 patients with pulmonary pathologies (median age [range]: 47 [6-83]; 51% females) were split into training (422 scans [88%]; 257 participants [82%]) and testing (58 scans [12%]; 58 participants [18%]) sets. FIELD STRENGTH/SEQUENCE: 1.5-T, three-dimensional (3D) spoiled gradient-recalled 1 H-MRI and 3D steady-state free-precession 129 Xe-MRI. ASSESSMENT: We developed a multimodal DL approach, integrating 129 Xe-MRI and 1 H-MRI, in a dual-channel convolutional neural network. We compared this approach to single-channel alternatives using manually edited LCEs as a benchmark. We further assessed a fully automatic DL-based framework to calculate VDPs and compared it to manually generated VDPs. STATISTICAL TESTS: Friedman tests with post hoc Bonferroni correction for multiple comparisons compared single-channel and dual-channel DL approaches using Dice similarity coefficient (DSC), average boundary Hausdorff distance (average HD), and relative error (XOR) metrics. Bland-Altman analysis and paired t-tests compared manual and DL-generated VDPs. A P value < 0.05 was considered statistically significant. RESULTS: The dual-channel approach significantly outperformed single-channel approaches, achieving a median (range) DSC, average HD, and XOR of 0.967 (0.867-0.978), 1.68 mm (37.0-0.778), and 0.066 (0.246-0.045), respectively. DL-generated VDPs were statistically indistinguishable from manually generated VDPs (P = 0.710). DATA CONCLUSION: Our dual-channel approach generated LCEs, which could be integrated with ventilated lung segmentations to produce biomarkers such as the VDP without manual intervention. EVIDENCE LEVEL: 4. TECHNICAL EFFICACY: Stage 1.

Multicenter Standardization of Phase-Resolved Functional Lung MRI in Patients With Suspected Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: Detection of pulmonary perfusion defects is the recommended approach for diagnosing chronic thromboembolic pulmonary hypertension (CTEPH). This is currently achieved in a clinical setting using scintigraphy. Phase-resolved functional lung (PREFUL) magnetic resonance imaging (MRI) is an alternative technique for evaluating regional ventilation and perfusion without the use of ionizing radiation or contrast media. PURPOSE: To assess the feasibility and image quality of PREFUL-MRI in a multicenter setting in suspected CTEPH. STUDY TYPE: This is a prospective cohort sub-study. POPULATION: Forty-five patients (64 ± 16 years old) with suspected CTEPH from nine study centers. FIELD STRENGTH/SEQUENCE: 1.5 T and 3 T/2D spoiled gradient echo/bSSFP/T2 HASTE/3D MR angiography (TWIST). ASSESSMENT: Lung signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were compared between study centers with different MRI machines. The contrast between normally and poorly perfused lung areas was examined on PREFUL images. The perfusion defect percentage calculated using PREFUL-MRI (QDPPREFUL ) was compared to QDP from the established dynamic contrast-enhanced MRI technique (QDPDCE ). Furthermore, QDPPREFUL was compared between a patient subgroup with confirmed CTEPH or chronic thromboembolic disease (CTED) to other clinical subgroups. STATISTICAL TESTS: t-Test, one-way analysis of variance (ANOVA), Pearson's correlation. Significance level was 5%. RESULTS: Significant differences in lung SNR and CNR were present between study centers. However, PREFUL perfusion images showed a significant contrast between normally and poorly perfused lung areas (mean delta of normalized perfusion -4.2% SD 3.3) with no differences between study sites (ANOVA: P = 0.065). QDPPREFUL was significantly correlated with QDPDCE (r = 0.66), and was significantly higher in 18 patients with confirmed CTEPH or CTED (57.9 ± 12.2%) compared to subgroups with other causes of PH or with excluded PH (in total 27 patients with mean ± SD QDPPREFUL = 33.9 ± 17.2%). DATA CONCLUSION: PREFUL-MRI could be considered as a non-invasive method for imaging regional lung perfusion in multicenter studies. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 1.

Implementable Deep Learning for Multi-sequence Proton MRI Lung Segmentation: A Multi-center, Multi-vendor, and Multi-disease Study.

BACKGROUND: Recently, deep learning via convolutional neural networks (CNNs) has largely superseded conventional methods for proton (1 H)-MRI lung segmentation. However, previous deep learning studies have utilized single-center data and limited acquisition parameters. PURPOSE: Develop a generalizable CNN for lung segmentation in 1 H-MRI, robust to pathology, acquisition protocol, vendor, and center. STUDY TYPE: Retrospective. POPULATION: A total of 809 1 H-MRI scans from 258 participants with various pulmonary pathologies (median age (range): 57 (6-85); 42% females) and 31 healthy participants (median age (range): 34 (23-76); 34% females) that were split into training (593 scans (74%); 157 participants (55%)), testing (50 scans (6%); 50 participants (17%)) and external validation (164 scans (20%); 82 participants (28%)) sets. FIELD STRENGTH/SEQUENCE: 1.5-T and 3-T/3D spoiled-gradient recalled and ultrashort echo-time 1 H-MRI. ASSESSMENT: 2D and 3D CNNs, trained on single-center, multi-sequence data, and the conventional spatial fuzzy c-means (SFCM) method were compared to manually delineated expert segmentations. Each method was validated on external data originating from several centers. Dice similarity coefficient (DSC), average boundary Hausdorff distance (Average HD), and relative error (XOR) metrics to assess segmentation performance. STATISTICAL TESTS: Kruskal-Wallis tests assessed significances of differences between acquisitions in the testing set. Friedman tests with post hoc multiple comparisons assessed differences between the 2D CNN, 3D CNN, and SFCM. Bland-Altman analyses assessed agreement with manually derived lung volumes. A P value of <0.05 was considered statistically significant. RESULTS: The 3D CNN significantly outperformed its 2D analog and SFCM, yielding a median (range) DSC of 0.961 (0.880-0.987), Average HD of 1.63 mm (0.65-5.45) and XOR of 0.079 (0.025-0.240) on the testing set and a DSC of 0.973 (0.866-0.987), Average HD of 1.11 mm (0.47-8.13) and XOR of 0.054 (0.026-0.255) on external validation data. DATA CONCLUSION: The 3D CNN generated accurate 1 H-MRI lung segmentations on a heterogenous dataset, demonstrating robustness to disease pathology, sequence, vendor, and center. EVIDENCE LEVEL: 4. TECHNICAL EFFICACY: Stage 1.

Integrated Cardiopulmonary MRI Assessment of Pulmonary Hypertension.

Pulmonary hypertension (PH) is a heterogeneous condition that can affect the lung parenchyma, pulmonary vasculature, and cardiac chambers. Accurate diagnosis often requires multiple complex assessments of the cardiac and pulmonary systems. MRI is able to comprehensively assess cardiac structure and function, as well as lung parenchymal, pulmonary vascular, and functional lung changes. Therefore, MRI has the potential to provide an integrated functional and structural assessment of the cardiopulmonary system in a single exam. Cardiac MRI is used in the assessment of PH in most large PH centers, whereas lung MRI is an emerging technique in patients with PH. This article reviews the current literature on cardiopulmonary MRI in PH, including cine MRI, black-blood imaging, late gadolinium enhancement, T1 mapping, myocardial strain analysis, contrast-enhanced perfusion imaging and contrast-enhanced MR angiography, and hyperpolarized gas functional lung imaging. This article also highlights recent developments in this field and areas of interest for future research including cardiac MRI-based diagnostic models, machine learning in cardiac MRI, oxygen-enhanced 1 H imaging, contrast-free 1 H perfusion and ventilation imaging, contrast-free angiography and UTE imaging. EVIDENCE LEVEL: 5 TECHNICAL EFFICACY: Stage 3.

Acute extracorporeal shockwave lithotripsy for ureteric stones - 7-years' experience from a busy district general hospital.

OBJECTIVES: To demonstrate the efficacy and cost-effectiveness of acute extracorporeal shockwave lithotripsy (ESWL) for ureteric stones we present our experience of ESWL in 530 ureteric stone cases, in the largest UK series we are aware of to date. ESWL is underutilised in ureteric stone management. The Getting It Right First Time (GIRFT) report showed just four units nationally treated >10% of acute ureteric stones with ESWL. Despite guideline recommendations as a first-line treatment option, few large volume studies have been published. PATIENTS AND METHODS: Retrospective review of prospectively collected data between December 2012 and February 2020 was performed. Data relating to patient demographics, stone characteristics, skin-to-stone distance, and treatment failure were collected. Cost analysis was conducted by the Trust's surgical financial manager. Multivariable analyses were performed to assess for predictors of ESWL success. RESULTS: A success rate of 68% (95% confidence interval 64%-72%) at 6 weeks was observed (n = 530). The median (interquartile range) number of treatment sessions was 2 (1, 2). Stone diameter was observed to be a predictor of ESWL success. The small number of stones treated of >13 mm or >1250 HU had an ~50% chance of successful treatment. Acute ureteric ESWL was less costly than acute ureterorenoscopy, consistent with findings from previous NHS studies. CONCLUSION: Acute ESWL is a safe, reliable, and financially viable treatment option for a wider spectrum of patients than reflected in international guidelines based on our large, heterogenous series. In the coronavirus disease 2019 (COVID-19) era, with theatre access reduced and concerns over aerosol generating procedures, acute ESWL remains an attractive first-line treatment option.

Systematic in situ hydration neutron reflectometry study on Nafion thin films.

Reported herein is a neutron reflectometry (NR) study on hydrated Nafion thin films (∼30 nm) on a silicon substrate with native oxide. The Nafion morphology is investigated systematically across the whole relative humidity range using both H2O and D2O vapours to enable a comparative study. By utilising this systematic approach two key results have been obtained. The first is that by leveraging the strong positive scattering signal from the D2O vapour, a complete and systematic water adsorption isotherm (Type II) for a Nafion thin film is produced. Utilising the slight negative scattering signal of the H2O enabled the quantification of the hydration dependent evolution of the formation of Nafion/water lamellae near the substrate surface. The number of lamellae layers increases continuously with hydration, and does not form abruptly. We also report the effects of swelling on the thin films across the relative humidity ranges. The work reported should prove useful in quantifying other hydration dependent properties of Nafion thin films such as conductivity and understanding Nafion/semiconductor based devices, as well as showcasing a NR methodology for other hydrophilic polymers.

Quantification of pulmonary perfusion in idiopathic pulmonary fibrosis with first pass dynamic contrast-enhanced perfusion MRI.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a fatal disease of lung scarring. Many patients later develop raised pulmonary vascular pressures, sometimes disproportionate to the interstitial disease. Previous therapeutic approaches that have targeted pulmonary vascular changes have not demonstrated clinical efficacy, and quantitative assessment of regional pulmonary vascular involvement using perfusion imaging may provide a biomarker for further therapeutic insights. METHODS: We studied 23 participants with IPF, using dynamic contrast-enhanced MRI (DCE-MRI) and pulmonary function tests, including forced vital capacity (FVC), transfer factor (TLCO) and coefficient (KCO) of the lungs for carbon monoxide. DCE-MRI parametric maps were generated including the full width at half maximum (FWHM) of the bolus transit time through the lungs. Key metrics used were mean (FWHMmean) and heterogeneity (FWHMIQR). Nineteen participants returned at 6 months for repeat assessment. RESULTS: Spearman correlation coefficients were identified between TLCO and FWHMIQR (r=-0.46; p=0.026), KCO and FWHMmean (r=-0.42; p=0.047) and KCO and FWHMIQR (r=-0.51; p=0.013) at baseline. No statistically significant correlations were seen between FVC and DCE-MRI metrics. Follow-up at 6 months demonstrated statistically significant decline in FVC (p=0.040) and KCO (p=0.014), with an increase in FWHMmean (p=0.040), but no significant changes in TLCO (p=0.090) nor FWHMIQR (p=0.821). CONCLUSIONS: DCE-MRI first pass perfusion demonstrates correlations with existing physiological gas exchange metrics, suggesting that capillary perfusion deficit (as well as impaired interstitial diffusion) may contribute to gas exchange limitation in IPF. FWHMmean showed a significant increase over a 6-month period and has potential as a quantitative biomarker of pulmonary vascular disease progression in IPF.

Repeatability and sensitivity to change of non-invasive end points in PAH: the RESPIRE study.

End points that are repeatable and sensitive to change are important in pulmonary arterial hypertension (PAH) for clinical practice and trials of new therapies. In 42 patients with PAH, test-retest repeatability was assessed using the intraclass correlation coefficient and treatment effect size using Cohen's d statistic. Intraclass correlation coefficients demonstrated excellent repeatability for MRI, 6 min walk test and log to base 10 N-terminal pro-brain natriuretic peptide (log10NT-proBNP). The treatment effect size for MRI-derived right ventricular ejection fraction was large (Cohen's d 0.81), whereas the effect size for the 6 min walk test (Cohen's d 0.22) and log10NT-proBNP (Cohen's d 0.20) were fair. This study supports further evaluation of MRI as a non-invasive end point for clinical assessment and PAH therapy trials.Trial registration number NCT03841344.

MR properties of 19 F C3 F8 gas in the lungs of healthy volunteers: T 2 ∗ and apparent diffusion coefficient at 1.5T and T 2 ∗ at 3T.

PURPOSE: To measure the transverse relaxation time ( T 2 ∗ ) and apparent diffusion coefficient (ADC) of 19 F-C3 F8 gas in vivo in human lungs at 1.5T and 3T, and to determine the representative distribution of values of these parameters in a cohort of healthy volunteers. METHODS: Mapping of ADC at lung inflation levels of functional residual capacity (FRC) and total lung capacity (TLC) was performed with inhaled 19 F-C3 F8 (eight subjects) and 129 Xe (six subjects) at 1.5T. T 2 ∗ mapping with 19 F-C3 F8 was performed at 1.5T (at FRC and TLC) for 8 subjects and at 3T (at TLC for seven subjects). RESULTS: At both FRC and TLC, the 19 F-C3 F8 ADC was smaller than the free diffusion coefficient demonstrating airway microstructural diffusion restriction. From FRC to TLC, the mean ADC significantly increased from 1.56 mm2 /s to 1.83 mm2 /s (P = .0017) for 19 F-C3 F8, and from 2.49 mm2 /s to 3.38 mm2 /s (P = .0015) for 129 Xe. The posterior-to-anterior gradient in ADC for FRC versus TLC in the superior half of the lungs was measured as 0.0308 mm2 /s per cm versus 0.0168 mm2 /s per cm for 19 F-C3 F8 and 0.0871 mm2 /s per cm versus 0.0326 mm2 /s per cm for 129 Xe. A consistent distribution of 19 F-C3 F8 T 2 ∗ values was observed in the lungs, with low values observed near the diaphragm and large pulmonary vessels. The mean T 2 ∗ across volunteers was 4.48 ms at FRC and 5.33 ms at TLC for 1.5T, and 3.78 ms at TLC for 3T. CONCLUSION: In this feasibility study, values of physiologically relevant parameters of lung microstructure measurable by MRI ( T 2 ∗ , and ADC) were established for C3 F8 in vivo lung imaging in healthy volunteers.

Dissolved 129 Xe lung MRI with four-echo 3D radial spectroscopic imaging: Quantification of regional gas transfer in idiopathic pulmonary fibrosis.

PURPOSE: Imaging of the different resonances of dissolved hyperpolarized xenon-129 (129 Xe) in the lung is performed using a four-echo flyback 3D radial spectroscopic imaging technique and is evaluated in healthy volunteers (HV) and subjects with idiopathic pulmonary fibrosis (IPF). THEORY AND METHODS: 10 HV and 25 subjects with IPF underwent dissolved 129 Xe MRI at 1.5T. IPF subjects underwent same day pulmonary function tests to measure forced vital capacity and the diffusion capacity of the lung for carbon monoxide (DLCO ). A four-point echo time technique with k-space chemical-shift modeling of gas, dissolved 129 Xe in lung tissue/plasma (TP) and red blood cells (RBC) combined with a 3D radial trajectory was implemented within a 14-s breath-hold. RESULTS: Results show an excellent chemical shift separation of the dissolved 129 Xe compartments and gas contamination removal, confirmed by a strong agreement between average imaging and global spectroscopy RBC/TP ratio measurements. Subjects with IPF exhibited reduced imaging gas transfer when compared to HV. A significant increase of the amplitude of RBC signal cardiogenic oscillation was also observed. In IPF subjects, DLCO % predicted was significantly correlated with RBC/TP and RBC/GAS ratios and the correlations were stronger in the inferior and periphery sections of the lungs. CONCLUSION: Lung MRI of dissolved 129 Xe was performed with a four-echo spectroscopic imaging method. Subjects with IPF demonstrated reduced xenon imaging gas transfer and increased cardiogenic modulation of dissolved xenon signal in the RBCs when compared to HV.

The assessment of short and long term changes in lung function in CF using 129Xe MRI.

INTRODUCTION: 129Xe ventilation MRI is sensitive to detect early CF lung disease and response to treatment. 129Xe-MRI could play a significant role in clinical trials and patient management. Here we present data on the repeatability of imaging measurements and their sensitivity to longitudinal change. METHODS: 29 children and adults with CF and a range of disease severity were assessed twice, a median [IQR] of 16.0 [14.4,19.5] months apart. Patients performed 129Xe-MRI, lung clearance index (LCI), body plethysmography and spirometry at both visits. Eleven patients repeated 129Xe-MRI in the same session to assess the within-visit repeatability. The ventilation defect percentage (VDP) was the primary metric calculated from 129Xe-MRI. RESULTS: At baseline, mean (sd) age=23.0 (11.1) years and FEV1 z-score=-2.2 (2.0). Median [IQR] VDP=9.5 [3.4,31.6]%, LCI=9.0 [7.7,13.7]. Within-visit and inter-visit repeatability of VDP was high. At 16 months there was no single trend of 129Xe-MRI disease progression. Visible 129Xe-MRI ventilation changes were common, which reflected changes in VDP. Based on the within-visit repeatability, a significant short-term change in VDP is >±1.6%. For longer-term follow up, changes in VDP of up to ±7.7% can be expected, or ±4.1% for patients with normal FEV1. No patient had a significant change in FEV1, however 59% had change in VDP >±1.6%. In patients with normal FEV1, there were significant changes in ventilation and in VDP. CONCLUSIONS: 129Xe-MRI is a highly effective method for assessing longitudinal lung disease in patients with CF. VDP has great potential as a sensitive clinical outcome measure of lung function and endpoint for clinical trials.

Single breath-held acquisition of coregistered 3D 129 Xe lung ventilation and anatomical proton images of the human lung with compressed sensing.

PURPOSE: To develop and assess a method for acquiring coregistered proton anatomical and hyperpolarized 129 Xe ventilation MR images of the lungs with compressed sensing (CS) in a single breath hold. METHODS: Retrospective CS simulations were performed on fully sampled ventilation images acquired from one healthy smoker to optimize reconstruction parameters. Prospective same-breath anatomical and ventilation images were also acquired in five ex-smokers with an acceleration factor of 3 for hyperpolarized 129 Xe images, and were compared to fully sampled images acquired during the same session. The following metrics were used to assess data fidelity: mean absolute error (MAE), root mean square error, and linear regression of the signal intensity between fully sampled and undersampled images. The effect of CS reconstruction on two quantitative imaging metrics routinely reported [percentage ventilated volume (%VV) and heterogeneity score] was also investigated. RESULTS: Retrospective simulations showed good agreement between fully sampled and CS-reconstructed (acceleration factor of 3) images with MAE (root mean square error) of 3.9% (4.5%). The prospective same-breath images showed a good match in ventilation distribution with an average R2 of 0.76 from signal intensity linear regression and a negligible systematic bias of +0.1% in %VV calculation. A bias of -1.8% in the heterogeneity score was obtained. CONCLUSION: With CS, high-quality 3D images of hyperpolarized 129 Xe ventilation (resolution 4.2 × 4.2 × 7.5 mm3 ) can be acquired with coregistered 1 H anatomical MRI in a 15-s breath hold. The accelerated acquisition time dispenses with the need for registration between separate breath-hold 129 Xe and 1 H MRI, enabling more accurate %VV calculation.

Targeted Therapy and Checkpoint Immunotherapy Combinations for the Treatment of Cancer.

Many advances in the treatment of cancer have been driven by the development of targeted therapies that inhibit oncogenic signaling pathways and tumor-associated angiogenesis, as well as by the recent development of therapies that activate a patient's immune system to unleash antitumor immunity. Some targeted therapies can have effects on host immune responses, in addition to their effects on tumor biology. These immune-modulating effects, such as increasing tumor antigenicity or promoting intratumoral T cell infiltration, provide a rationale for combining these targeted therapies with immunotherapies. Here, we discuss the immune-modulating effects of targeted therapies against the MAPK and VEGF signaling pathways, and how they may synergize with immunomodulatory antibodies that target PD1/PDL1 and CTLA4. We critically examine the rationale in support of these combinations in light of the current understanding of the underlying mechanisms of action of these therapies. We also discuss the available preclinical and clinical data for these combination approaches and their implications regarding mechanisms of action. Insights from these studies provide a framework for considering additional combinations of targeted therapies and immunotherapies for the treatment of cancer.

Volatile aroma composition of distillates produced from fermented sweet and acid whey.

Lactose within whey can be fermented and distilled to produce a potable distilled spirit. The aim of this study was to determine if acid and sweet whey types can be fermented and distilled using similar processes and to investigate differences in volatile aroma compounds for the 2 distillates. Fermentation and distillation of the 2 whey types progressed in a similar manner, using Kluyveromyces marxianus for the initial fermentation and a glass still fitted with a Vigreux column for the subsequent distillation. Ethanol content of the wash (fermented whey) varied considerably following each fermentation and ranged from 1.2 and 2.0% (wt/wt) with no clear trend between acid and sweet whey samples. Volatile aroma compounds were extracted using headspace solid-phase microextraction and identified via gas chromatography-mass spectrometry. Acid and sweet whey distillates contained unique volatile aromatic compounds, and significant differences in compound peak areas were observed. These differences may have an effect upon the organoleptic qualities of spirits produced from whey; therefore, whey source may be an important factor when fermenting and distilling whey.

Patterns of regional lung physiology in cystic fibrosis using ventilation magnetic resonance imaging and multiple-breath washout.

Hyperpolarised helium-3 (3He) ventilation magnetic resonance imaging (MRI) and multiple-breath washout (MBW) are sensitive methods for detecting lung disease in cystic fibrosis (CF). We aimed to explore their relationship across a broad range of CF disease severity and patient age, as well as assess the effect of inhaled lung volume on ventilation distribution.32 children and adults with CF underwent MBW and 3He-MRI at a lung volume of end-inspiratory tidal volume (EIV T). In addition, 28 patients performed 3He-MRI at total lung capacity. 3He-MRI scans were quantitatively analysed for ventilation defect percentage (VDP), ventilation heterogeneity index (VHI) and the number and size of individual contiguous ventilation defects. From MBW, the lung clearance index, convection-dependent ventilation heterogeneity (Scond) and convection-diffusion-dependent ventilation heterogeneity (Sacin) were calculated.VDP and VHI at EIV T strongly correlated with lung clearance index (r=0.89 and r=0.88, respectively), Sacin (r=0.84 and r=0.82, respectively) and forced expiratory volume in 1 s (FEV1) (r=-0.79 and r=-0.78, respectively). Two distinct 3He-MRI patterns were highlighted: patients with abnormal FEV1 had significantly (p<0.001) larger, but fewer, contiguous defects than those with normal FEV1, who tended to have numerous small volume defects. These two MRI patterns were delineated by a VDP of ∼10%. At total lung capacity, when compared to EIV T, VDP and VHI reduced in all subjects (p<0.001), demonstrating improved ventilation distribution and regions of volume-reversible and nonreversible ventilation abnormalities.

Spatial fuzzy c-means thresholding for semiautomated calculation of percentage lung ventilated volume from hyperpolarized gas and 1 H MRI.

PURPOSE: To develop an image-processing pipeline for semiautomated (SA) and reproducible analysis of hyperpolarized gas lung ventilation and proton anatomical magnetic resonance imaging (MRI) scan pairs. To compare results from the software for total lung volume (TLV), ventilated volume (VV), and percentage lung ventilated volume (%VV) calculation to the current manual "basic" method and a K-means segmentation method. MATERIALS AND METHODS: Six patients were imaged with hyperpolarized 3 He and same-breath lung 1 H MRI at 1.5T and six other patients were scanned with hyperpolarized 129 Xe and separate-breath 1 H MRI. One expert observer and two users with experience in lung image segmentation carried out the image analysis. Spearman (R), Intraclass (ICC) correlations, Bland-Altman limits of agreement (LOA), and Dice Similarity Coefficients (DSC) between output lung volumes were calculated. RESULTS: When comparing values of %VV, agreement between observers improved using the SA method (mean; R = 0.984, ICC = 0.980, LOA = 7.5%) when compared to the basic method (mean; R = 0.863, ICC = 0.873, LOA = 14.2%) nonsignificantly (pR = 0.25, pICC = 0.25, and pLOA = 0.50 respectively). DSC of VV and TLV masks significantly improved (P < 0.01) using the SA method (mean; DSCVV = 0.973, DSCTLV = 0.980) when compared to the basic method (mean; DSCVV = 0.947, DSCTLV = 0.957). K-means systematically overestimated %VV when compared to both basic (mean overestimation = 5.0%) and SA methods (mean overestimation = 9.7%), and had poor agreement with the other methods (mean ICC; K-means vs. basic = 0.685, K-means vs. SA = 0.740). CONCLUSION: A semiautomated image processing software was developed that improves interobserver agreement and correlation of lung ventilation volume percentage when compared to the currently used basic method and provides more consistent segmentations than the K-means method. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:640-646.