Functional gas exchange measures on 129Xe MRI and spectroscopy are associated with age, sex, and BMI in healthy subjects.

Introduction: Hyperpolarized 129Xe MRI and spectroscopy is a rapidly growing technique for assessing lung function, with applications in a wide range of obstructive, restrictive, and pulmonary vascular disease. However, normal variations in 129Xe measures of gas exchange across healthy subjects are not well characterized, presenting an obstacle to differentiating disease processes from the consequences of expected physiological heterogeneity. Here, we use multivariate models to evaluate the role of age, sex, and BMI in a range of commonly used 129Xe measures of gas exchange. Materials and methods: Healthy subjects (N = 40, 16F, age 44.3 ± 17.8 yrs., min-max 22-87 years) with no history of cardiopulmonary disease underwent 129Xe gas exchange MRI and spectroscopy. We used multivariate linear models to assess the associations of age, sex, and body mass index (BMI) with the RBC:Membrane (RBC:M), membrane to gas (Mem:Gas), and red blood cell to gas (RBC:Gas) ratios, as well as measurements of RBC oscillation amplitude and RBC chemical shift. Results: Age, sex, and BMI were all significant covariates in the RBC:M model. Each additional 10 years of age was associated with a 0.05 decrease in RBC:M (p < 0.001), each additional 10 points of BMI was associated with a decrease of 0.07 (p = 0.02), and males were associated with a 0.17 higher RBC:M than females (p < 0.001). For Mem:Gas, male sex was associated with a decrease and BMI was associated with an increase. For RBC:Gas, age was associated with a decrease and male sex was associated with an increase. RBC oscillation amplitude increased with age and RBC chemical shift was not associated with any of the three covariates. Discussion: 129Xe MRI and spectroscopy measurements in healthy subjects, particularly the widely used RBC:M measurement, exhibit heterogeneity associated in part with variations in subject age, sex, and BMI. Elucidating the contributions of these and other factors to 129Xe gas exchange measurements is a critical component for differentiating disease processes from expected variation in healthy subjects. Notably, the Mem:Gas and RBC chemical shift appear to be stable with aging, suggesting that unexplained deviations in these metrics may be signs of underlying abnormalities.

Quantifying Regional Radiation-Induced Lung Injury in Patients Using Hyperpolarized 129Xe Gas Exchange Magnetic Resonance Imaging.

PURPOSE: Radiation-induced lung injury has been shown to alter regional ventilation and perfusion in the lung. However, changes in regional pulmonary gas exchange have not previously been measured. METHODS AND MATERIALS: Ten patients receiving conventional radiation therapy (RT) for lung cancer underwent pre-RT and 3-month post-RT magnetic resonance imaging (MRI) using an established hyperpolarized 129Xe gas exchange technique to map lung function. Four patients underwent an additional 8-month post-RT MRI. The MR signal from inhaled xenon was measured in the following 3 pulmonary compartments: the lung airspaces, the alveolar membrane tissue, and the pulmonary capillaries (interacting with red blood cells [RBCs]). Thoracic 1H MRI scans were acquired, and deformable registration was used to transfer 129Xe functional maps to the RT planning computed tomography scan. The RT-associated changes in ventilation, membrane uptake, and RBC transfer were computed as a function of regional lung dose (equivalent dose in 2-Gy fractions). Pearson correlations and t tests were used to determine statistical significance, and weighted sum of squares linear regression subsequently characterized the dose dependence of each functional component. The pulmonary function testing metrics of forced vital capacity and diffusing capacity for carbon monoxide were also acquired at each time point. RESULTS: Compared with pre-RT baseline, 3-month post-RT ventilation decreased by an average of -0.24 ± 0.05%/Gy (ρ = -0.88; P < .001), membrane uptake increased by 0.69 ± 0.14%/Gy (ρ = 0.94; P < .001), and RBC transfer decreased by -0.41 ± 0.06%/Gy (ρ = -0.92; P < .001). Membrane uptake maintained a strong positive correlation with regional dose at 8 months post-RT, demonstrating an increase of 0.73 ± 0.11%/Gy (ρ = 0.92; P = .006). Changes in membrane uptake and RBC transfer appeared greater in magnitude (%/Gy) for individuals with low heterogeneity in their baseline lung function. An increase in whole-lung membrane uptake showed moderate correlation with decreases in forced vital capacity (ρ = -0.50; P = .17) and diffusing capacity for carbon monoxide (ρ = -0.44; P = .23), with neither correlation reaching statistical significance. CONCLUSIONS: Hyperpolarized 129Xe MRI measured and quantified regional, RT-associated, dose-dependent changes in pulmonary gas exchange. This tool could enable future work to improve our understanding and management of radiation-induced lung injury.

Targeting YAP1 to improve the efficacy of immune checkpoint inhibitors in liver cancer: mechanism and strategy.

Liver cancer is the third leading of tumor death, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Immune checkpoint inhibitors (ICIs) are yielding much for sufferers to hope for patients, but only some patients with advanced liver tumor respond. Recent research showed that tumor microenvironment (TME) is critical for the effectiveness of ICIs in advanced liver tumor. Meanwhile, metabolic reprogramming of liver tumor leads to immunosuppression in TME. These suggest that regulating the abnormal metabolism of liver tumor cells and firing up TME to turn "cold tumor" into "hot tumor" are potential strategies to improve the therapeutic effect of ICIs in liver tumor. Previous studies have found that YAP1 is a potential target to improve the efficacy of anti-PD-1 in HCC. Here, we review that YAP1 promotes immunosuppression of TME, mainly due to the overstimulation of cytokines in TME by YAP1. Subsequently, we studied the effects of YAP1 on metabolic reprogramming in liver tumor cells, including glycolysis, gluconeogenesis, lipid metabolism, arachidonic acid metabolism, and amino acid metabolism. Lastly, we summarized the existing drugs targeting YAP1 in the treatment of liver tumor, including some medicines from natural sources, which have the potential to improve the efficacy of ICIs in the treatment of liver tumor. This review contributed to the application of targeted YAP1 for combined therapy with ICIs in liver tumor patients.

Optimized quantitative mapping of cardiopulmonary oscillations using hyperpolarized 129 Xe gas exchange MRI: Digital phantoms and clinical evaluation in CTEPH.

PURPOSE: The interaction between 129 Xe atoms and pulmonary capillary red blood cells provides cardiogenic signal oscillations that display sensitivity to precapillary and postcapillary pulmonary hypertension. Recently, such oscillations have been spatially mapped, but little is known about optimal reconstruction or sensitivity to artifacts. In this study, we use digital phantom simulations to specifically optimize keyhole reconstruction for oscillation imaging. We then use this optimized method to re-establish healthy reference values and quantitatively evaluate microvascular flow changes in patients with chronic thromboembolic pulmonary hypertension (CTEPH) before and after pulmonary thromboendarterectomy (PTE). METHODS: A six-zone digital lung phantom was designed to investigate the effects of radial views, key radius, and SNR. One-point Dixon 129 Xe gas exchange MRI images were acquired in a healthy cohort (n = 17) to generate a reference distribution and thresholds for mapping red blood cell oscillations. These thresholds were applied to 10 CTEPH participants, with 6 rescanned following PTE. RESULTS: For undersampled acquisitions, a key radius of 0.14 k max $$ 0.14{k}_{\mathrm{max}} $$ was found to optimally resolve oscillation defects while minimizing excessive heterogeneity. CTEPH participants at baseline showed higher oscillation defect + low (32 ± 14%) compared with healthy volunteers (18 ± 12%, p < 0.001). For those scanned both before and after PTE, oscillation defect + low decreased from 37 ± 13% to 23 ± 14% (p = 0.03). CONCLUSIONS: Digital phantom simulations have informed an optimized keyhole reconstruction technique for gas exchange images acquired with standard 1-point Dixon parameters. Our proposed methodology enables more robust quantitative mapping of cardiogenic oscillations, potentially facilitating effective regional quantification of microvascular flow impairment in patients with pulmonary vascular diseases such as CTEPH.

Establishing a hemoglobin adjustment for 129 Xe gas exchange MRI and MRS.

PURPOSE: 129 Xe MRI and MRS signals from airspaces, membrane tissues (M), and red blood cells (RBCs) provide measurements of pulmonary gas exchange. However, 129 Xe MRI/MRS studies have yet to account for hemoglobin concentration (Hb), which is expected to affect the uptake of 129 Xe in the membrane and RBC compartments. We propose a framework to adjust the membrane and RBC signals for Hb and use this to assess sex-specific differences in RBC/M and establish a Hb-adjusted healthy reference range for the RBC/M ratio. METHODS: We combined the 1D model of xenon gas exchange (MOXE) with the principle of TR-flip angle equivalence to establish scaling factors that normalize the dissolved-phase signals with respect to a standard H b 0 $$ H{b}^0 $$ (14 g/dL). 129 Xe MRI/MRS data from a healthy, young cohort (n = 18, age = 25.0 ± $$ \pm $$ 3.4 years) were used to validate this model and assess the impact of Hb adjustment on M/gas and RBC/gas images and RBC/M. RESULTS: Adjusting for Hb caused RBC/M to change by up to 20% in healthy individuals with normal Hb and had marked impacts on M/gas and RBC/gas distributions in 3D gas-exchange maps. RBC/M was higher in males than females both before and after Hb adjustment (p < 0.001). After Hb adjustment, the healthy reference value for RBC/M for a consortium-recommended acquisition of TR = 15 ms and flip = 20° was 0.589 ± $$ \pm $$ 0.083 (mean ± $$ \pm $$ SD). CONCLUSION: MOXE provides a useful framework for evaluating the Hb dependence of the membrane and RBC signals. This work indicates that adjusting for Hb is essential for accurately assessing 129 Xe gas-exchange MRI/MRS metrics.

Dihydroartemisinin inhibited interleukin-18 expression by decreasing YAP1 in hepatocellular carcinoma cells.

BACKGROUND: Yes-associated protein 1 (YAP1) is highly expressed in liver cancer and has been used as an independent prognostic marker for hepatocellular carcinoma (HCC), while inhibition of YAP1 slows down the progression of HCC. Interleukin-18 (IL-18) also tends to be highly expressed in liver cancer. Previous research has proved that dihydroartemisinin (DHA) plays an important role in HCC treatment by reducing YAP1 expression. However, the relationship between YAP1 and IL-18 has not been reported in HCC, especially during DHA therapy. OBJECTIVE: The purpose of this study was to clarify the relationship between YAP1 and IL-18 in HCC cells, and to explicit the role of IL-18 in the treatment of HCC by DHA. METHODS AND RESULTS: We found that YAP1 and IL-18 were highly expressed in patients with hepatocellular carcinoma by bioinformatics analysis. Moreover, YAP1 was positively correlated with IL18 in liver cancer. YAP1 and IL18 correlated with immune cell infiltration, notably T cell exhaustion. YAP1 knockdown decreased IL-18 expression, while YAP1 overexpression increased the IL-18 expression in HCC cells. DHA reduced IL-18 expression through YAP1 in HCC cells. Further, DHA reduced the growth of Hepa1-6 cells subcutaneous xenograft tumors by inhibiting the expression of YAP1 and IL-18. However, DHA improved IL-18 in serum and adjacent tissues from DEN/TCPOBOP-induced liver tumor model in C57BL/6 mice. CONCLUSION: YAP1 was positively correlated with IL-18 in HCC. DHA reduced the expression of IL-18 by inhibiting YAP1 and plays a role in the treatment of HCC. Our study suggested that IL-18 is a potential target for the treatment of HCC, and DHA is a promising drug for HCC therapy. DATA AVAILABILITY: The dataset that supports the findings of this study is available from the corresponding author upon reasonable request.

Dihydroartemisinin increased the abundance of Akkermansia muciniphila by YAP1 depression that sensitizes hepatocellular carcinoma to anti-PD-1 immunotherapy.

The effect of anti-programmed cell death 1 (anti-PD-1) immunotherapy is limited in patients with hepatocellular carcinoma (HCC). Yes-associated protein 1 (YAP1) expression increased in liver tumor cells in early HCC, and Akkermansia muciniphila abundance decreased in the colon. The response to anti-PD-1 treatment is associated with A. muciniphila abundance in many tumors. However, the interaction between A. muciniphila abundance and YAP1 expression remains unclear in HCC. Here, anti-PD-1 treatment decreased A. muciniphila abundance in the colon, but increased YAP1 expression in the tumor cells by mice with liver tumors in situ. Mechanistically, hepatocyte-specific Yap1 knockout (Yap1LKO) maintained bile acid homeostasis in the liver, resulting in an increased abundance of A. muciniphila in the colon. Yap1 knockout enhanced anti-PD-1 efficacy. Therefore, YAP1 inhibition is a potential target for increasing A. muciniphila abundance to promote anti-PD-1 efficacy in liver tumors. Dihydroartemisinin (DHA), acting as YAP1 inhibitor, increased A. muciniphila abundance to sensitize anti-PD-1 therapy. A. muciniphila by gavage increased the number and activation of CD8+ T cells in liver tumor niches during DHA treatment or combination with anti-PD-1. Our findings suggested that the combination anti-PD-1 with DHA is an effective strategy for liver tumor treatment.

YAP1 suppression inhibits autophagy and improves the efficacy of anti-PD-1 immunotherapy in hepatocellular carcinoma.

Anti-PD-1 immunotherapy is a promising treatment for hepatocellular carcinoma (HCC), but some patients with HCC do not experience clinical benefits. Autophagy promotes tumor progression and participates in drug resistance. Previous studies have revealed that suppressing the expression level of Yes-associated protein 1 (YAP1) improves anti-PD-1 therapy efficacy. Therefore, the relationship between YAP1 expression and autophagy activity during anti-PD-1 treatment was investigated in this study. A positive correlation was found between the expression level of YAP1 and LC3B by analyzing The Cancer Genome Atlas (TCGA), UALCAN databases, and HCC tissue microarray. Meanwhile, YAP1 expression and autophagy constituted positive feedback, in which YAP1 inhibition decreased the autophagy activity in liver tumor cells by hepatocyte-specific Yap1 knockout mice. Further, anti-PD-1 treatment increased autophagy and YAP1 expression levels in the cancer tissues from DEN/TCPOBOP-induced liver cancer mice. Finally, Yap1 knockout suppressed autophagy and improved anti-PD-1 therapy efficacy in hepatocyte-specific Yap1 knockout mice with liver tumors. These results suggested that YAP1 suppression was sensitized to anti-PD-1 treatment and inhibited autophagy activity in liver tumor cells. YAP1 is a promising target for improving the efficacy of anti-PD-1 immunotherapy in HCC.

Dihydroartemisinin inhibited the Warburg effect through YAP1/SLC2A1 pathway in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) was the third most common cause of cancer death. But it has only limited therapeutic options, aggressive nature, and very low overall survival. Dihydroartemisinin (DHA), an anti-malarial drug approved by the Food and Drug Administration (FDA), inhibited cell growth in HCC. The Warburg effect was one of the ten new hallmarks of cancer. Solute carrier family 2 member 1 (SLC2A1) was a crucial carrier for glucose to enter target cells in the Warburg effect. Yes-associated transcriptional regulator 1 (YAP1), an effector molecule of the hippo pathway, played a crucial role in promoting the development of HCC. This study sought to determine the role of DHA in the SLC2A1 mediated Warburg effect in HCC. In this study, DHA inhibited the Warburg effect and SLC2A1 in HepG2215 cells and mice with liver tumors in situ. Meanwhile, DHA inhibited YAP1 expression by inhibiting YAP1 promoter binding protein GA binding protein transcription factor subunit beta 1 (GABPB1) and cAMP responsive element binding protein 1 (CREB1). Further, YAP1 knockdown/knockout reduced the Warburg effect and SLC2A1 expression by shYAP1-HepG2215 cells and Yap1LKO mice with liver tumors. Taken together, our data indicated that YAP1 knockdown/knockout reduced the SLC2A1 mediated Warburg effect by shYAP1-HepG2215 cells and Yap1LKO mice with liver tumors induced by DEN/TCPOBOP. DHA, as a potential YAP1 inhibitor, suppressed the SLC2A1 mediated Warburg effect in HCC.

Solute carrier family 2 members 1 and 2 as prognostic biomarkers in hepatocellular carcinoma associated with immune infiltration.

BACKGROUND: Metabolic reprogramming has been identified as a core hallmark of cancer. Solute carrier family 2 is a major glucose carrier family. It consists of 14 members, and we mainly study solute carrier family 2 member 1 (SLC2A1) and solute carrier family 2 member 2 (SLC2A2) here. SLC2A1, mainly existing in human erythrocytes, brain endothelial cells, and normal placenta, was found to be increased in hepatocellular carcinoma (HCC), while SLC2A2, the major transporter of the normal liver, was decreased in HCC. AIM: To identify if SLC2A1 and SLC2A2 were associated with immune infiltration in addition to participating in the metabolic reprogramming in HCC. METHODS: The expression levels of SLC2A1 and SLC2A2 were tested in HepG2 cells, HepG215 cells, and multiple databases. The clinical characteristics and survival data of SLC2A1 and SLC2A2 were examined by multiple databases. The correlation between SLC2A1 and SLC2A2 was analyzed by multiple databases. The functions and pathways in which SLC2A1, SLC2A2, and frequently altered neighbor genes were involved were discussed in String. Immune infiltration levels and immune marker genes associated with SLC2A1 and SLC2A2 were discussed from multiple databases. RESULTS: The expression level of SLC2A1 was up-regulated, but the expression level of SLC2A2 was down-regulated in HepG2 cells, HepG215 cells, and liver cancer patients. The expression levels of SLC2A1 and SLC2A2 were related to tumor volume, grade, and stage in HCC. Interestingly, the expression levels of SLC2A1 and SLC2A2 were negatively correlated. Further, high SLC2A1 expression and low SLC2A2 expression were linked to poor overall survival and relapse-free survival. SLC2A1, SLC2A2, and frequently altered neighbor genes played a major role in the occurrence and development of tumors. Notably, SLC2A1 was positively correlated with tumor immune infiltration, while SLC2A2 was negatively correlated with tumor immune infiltration. Particularly, SLC2A2 methylation was positively correlated with lymphocytes. CONCLUSION: SLC2A1 and SLC2A2 are independent therapeutic targets for HCC, and they are quintessential marker molecules for predicting and regulating the number and status of immune cells in HCC.

Molecular Basis Underlying Hepatobiliary and Renal Excretion of Phenolic Acids of Salvia miltiorrhiza Roots (Danshen).

Phenolic acids are cardiovascular constituents (originating from the Chinese medicinal herb Salvia miltiorrhiza root/Danshen) of DanHong and many other Danshen-containing injections. Our earlier pharmacokinetic investigation of DanHong suggested that hepatic and/or renal uptake of the Danshen compounds was the crucial steps in their systemic elimination. This investigation was designed to survey the molecular basis underlying hepatobiliary and renal excretion of the Danshen compounds, i.e., protocatechuic acid, tanshinol, rosmarinic acid, salvianolic acid D, salvianolic acid A, lithospermic acid, and salvianolic acid B. A large battery of human hepatic and renal transporters were screened for transporting the Danshen compounds and then characterized for the uptake kinetics and also compared with associated rat transporters. The samples were analyzed by liquid chromatography/mass spectrometry. Because the Danshen phenolic acids are of poor or fairly good membrane permeability, their elimination via the liver or kidneys necessitates transporter-mediated hepatic or renal uptake from blood. Several human transporters were found to mediate hepatic and/or renal uptake of the Danshen compounds in a compound-molecular-mass-related manner. Lithospermic acid and salvianolic acid B (both >500 Da) underwent systemic elimination, initiated by organic anion-transporting polypeptide (OATP)1B1/OATP1B3-mediated hepatic uptake. Rosmarinic acid and salvianolic acids D (350-450 Da) underwent systemic elimination, initiated by OATP1B1/OATP1B3/organic anion transporter (OAT)2-mediated hepatic uptake and by OAT1/OAT2-mediated renal uptake. Protocatechuic acid and tanshinol (both <200 Da) underwent systemic elimination, initiated by OAT1/OAT2-mediated renal uptake and OAT2-mediated hepatic uptake. A similar scenario was observed with the rat orthologs. The investigation findings advance our understanding of the disposition of the Danshen phenolic acids and could facilitate pharmacokinetic research on other Danshen-containing injections.

Sex differences in the relationship of hip strength and functional performance to chronic ankle instability scores.

BACKGROUND: While decreased hip abductor strength, functional performance, and self-reported instability scores have all been shown in association with CAI, any sex difference in the relationship between these indicators is unclear. This study was to determine whether sex differences are present in the relationship between these indicators in individuals with CAI. METHODS: Thirty-two women and twenty-nine men with unilateral CAI took part. Hip abductor strength and functional performance were respectively assessed using a hand-held dynamometer and the figure-8-hop test. All 61 participants scored the Cumberland Ankle Instability Tool (CAIT) for self-reported ankle instability. Independent sample t-tests and correlation analysis were conducted. RESULTS: Normalized hip abductor strength and functional performance measures for females were lower than for males. The self-reported ankle instability CAIT score, where higher values represent less instability, was significantly and positively correlated with both normalized hip abductor strength (p = 0.003) and functional performance (p = 0.001) on the affected side in females, but not in males (p = 0.361 and p = 0.192 respectively). CONCLUSIONS: Sex differences were observed in that there were significant relationships between normalized hip abductor strength, functional performance, and CAIT scores in female CAI participants, but not males, suggesting that CAI evaluation and rehabilitation strategies should be sex-specific. HIGHLIGHTS: In females with CAI, hip abductor strength and functional performance showed significant relationships with self-reported instability scores. Correspondingly, in clinical practice with individuals with CAI, evaluation criteria may be formulated according to these observed sex differences. Sex differences should be factored into the evaluation and treatment of CAI individuals. Hip strength assessment should be employed with CAI individuals. Hip strengthening and functional hopping may be recommended for the rehabilitation of CAI, especially in female patients.

Utilizing flip angle/TR equivalence to reduce breath hold duration in hyperpolarized 129 Xe 1-point Dixon gas exchange imaging.

PURPOSE: To reduce scan duration in hyperpolarized 129 Xe 1-point Dixon gas exchange imaging by utilizing flip angle (FA)/TR equivalence. METHODS: Images were acquired in 12 subjects (n = 3 radiation therapy, n = 1 unexplained dyspnea, n = 8 healthy) using both standard (TR = 15 ms, FA = 20°, duration = 15 s, 998 projections) and "fast" (TR = 5.4 ms, FA = 12°, duration = 11.3 s, 2100 projections) acquisition parameters. For the fast acquisition, 3 image sets were reconstructed using subsets of 1900, 1500, and 1000 projections. From the resulting ventilation, tissue ("barrier"), and red blood cell (RBC) images, image metrics and biomarkers were compared to assess agreement between methods. RESULTS: Images acquired using both FA/TR settings had similar qualitative appearance. There were no significant differences in SNR, image mean, or image SD between images. Moreover, the percentage of the lungs in "defect", "normal", and "high" bins for each image (ventilation, RBC, barrier) was not significantly different among the acquisition types. After registration, comparison of 3D image metrics (Dice, volume similarity, average distance) agreed well between bins. Images using 1000 projections for reconstruction had no significant differences from images using all projections. CONCLUSION: Using flip angle/TR equivalence, hyperpolarized 129 Xe gas exchange images can be acquired via the 1-point Dixon technique in as little as 6 s, compared to ~15 s for previously reported parameter settings. The resulting images from this accelerated scan have no significant differences from the standard method in qualitative appearance or quantitative metrics.

Regional Gas Exchange Measured by 129 Xe Magnetic Resonance Imaging Before and After Combination Bronchodilators Treatment in Chronic Obstructive Pulmonary Disease.

BACKGROUND: Hyperpolarized 129 Xe magnetic resonance imaging (MRI) provides a non-invasive assessment of regional pulmonary gas exchange function. This technique has demonstrated that chronic obstructive pulmonary disease (COPD) patients exhibit ventilation defects, reduced interstitial barrier tissue uptake, and poor transfer to capillary red blood cells (RBCs). However, the behavior of these measurements following therapeutic intervention is unknown. PURPOSE: To characterize changes in 129 Xe gas transfer function following administration of an inhaled long-acting beta-agonist/long-acting muscarinic receptor antagonist (LABA/LAMA) bronchodilator. STUDY TYPE: Prospective. POPULATION: Seventeen COPD subjects (GOLD II/III classification per Global Initiative for Chronic Obstructive Lung Disease criteria) were imaged before and after 2 weeks of LABA/LAMA therapy. FIELD STRENGTH/SEQUENCES: Dedicated ventilation imaging used a multi-slice 2D gradient echo sequence. Three-dimensional images of ventilation, barrier uptake, and RBC transfer used an interleaved, radial, 1-point Dixon sequence. Imaging was acquired at 3 T. ASSESSMENT: 129 Xe measurements were quantified before and after LABA/LAMA treatment by ventilation defect + low percent (vendef + low ) and by barrier uptake and RBC transfer relative to a healthy reference population (bar%ref and RBC%ref ). Pulmonary function tests, including diffusing capacity of the lung for carbon monoxide (DLCO ), were also performed before and after treatment. STATISTICAL TESTS: Paired t-test, Pearson correlation coefficient (r). RESULTS: Baseline vendef + low was 57.8 ± 8.4%, bar%ref was 73.2 ± 19.6%, and RBC%ref was 36.5 ± 13.6%. Following treatment, vendef + low decreased to 52.5 ± 10.6% (P < 0.05), and improved in 14/17 (82.4%) of subjects. However, RBC%ref decreased in 10/17 (58.8%) of subjects. Baseline measurements of bar%ref and DLCO were correlated with the degree of post-treatment change in vendef + low (r = -0.49, P < 0.05 and r = -0.52, P < 0.05, respectively). CONCLUSION: LABA/LAMA therapy tended to preferentially improve ventilation in subjects whose 129 Xe barrier uptake and DLCO were relatively preserved. However, newly ventilated regions often revealed RBC transfer defects, an aspect of lung function opaque to spirometry. These microvasculature abnormalities must be accounted for when assessing the effects of LABA/LAMA therapy. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 4.

Secreted frizzled-related protein 3 was genetically and functionally associated with developmental dysplasia of the hip.

BACKGROUND: Developmental dysplasia of the hip (DDH) is the most common joint disease in child orthopedics. Secreted Frizzled-Related Protein 3 (FRZB) plays an important role in joint development. however, no direct association between FRZB and DDH has been demonstrated. METHODS: Analysis of genotype distribution and allele frequency for detected single nucleotide polymorphisms (SNP) of FRZB was performed. FRZB expression was assayed in DDH joint tissues. Further experiments to identify the chondrogenic properties of FRZB were conducted. Potential upstream miRNAs for FRZB were assayed in DDH. RESULTS: Significant difference in genotype distribution for rs3768842 (OR=1.46, P=0.0081) and rs2242040 (OR=0.65, P=0.0067) was found. DDH joint tissues showed significantly higher FRZB expression. FRZB demonstrated chondrogenic and anti-hypertrophic properties in vitro. FRZB modulated cell adhesion pathway and cell spreading by regulating integrins expressions. Upstream miRNAs regulating FRZB expression were identified in DDH synovial fluid. Experiments indicated that downregulated miRNA-454 caused FRZB upregulation in DDH joint. CONCLUSION: Dysregulated FRZB and its loci were associated with DDH. As a Wnt antagonist with chondrogenic properties, FRZB modulated cell adhesion pathway and cell spreading by regulating integrins expressions. FRZB in multiple DDH joint tissues might be mediated by the dysregulated miRNA expression profiles in the joint synovial fluid.

Using hyperpolarized 129Xe gas-exchange MRI to model the regional airspace, membrane, and capillary contributions to diffusing capacity.

Hyperpolarized 129Xe MRI has emerged as a novel means to evaluate pulmonary function via 3D mapping of ventilation, interstitial barrier uptake, and RBC transfer. However, the physiological interpretation of these measurements has yet to be firmly established. Here, we propose a model that uses the three components of 129Xe gas-exchange MRI to estimate accessible alveolar volume (VA), membrane conductance, and capillary blood volume contributions to DLCO. 129Xe ventilated volume (VV) was related to VA by a scaling factor kV = 1.47 with 95% confidence interval [1.42, 1.52], relative 129Xe barrier uptake (normalized by the healthy reference value) was used to estimate the membrane-specific conductance coefficient kB = 10.6 [8.6, 13.6] mL/min/mmHg/L, whereas normalized RBC transfer was used to calculate the capillary blood volume-specific conductance coefficient kR = 13.6 [11.4, 16.7] mL/min/mmHg/L. In this way, the barrier and RBC transfer per unit volume determined the transfer coefficient KCO, which was then multiplied by image-estimated VA to obtain DLCO. The model was built on a cohort of 41 healthy subjects and 101 patients with pulmonary disorders. The resulting 129Xe-derived DLCO correlated strongly (R2 = 0.75, P < 0.001) with the measured values, a finding that was preserved within each individual disease cohort. The ability to use 129Xe MRI measures of ventilation, barrier uptake, and RBC transfer to estimate each of the underlying constituents of DLCO clarifies the interpretation of these images while enabling their use to monitor these aspects of gas exchange independently and regionally.NEW & NOTEWORTHY The diffusing capacity for carbon monoxide (DLCO) is perhaps one of the most comprehensive physiological measures used in pulmonary medicine. Here, we spatially resolve and estimate its key components-accessible alveolar volume, membrane, and capillary blood volume conductances-using hyperpolarized 129Xe MRI of ventilation, interstitial barrier uptake, and red blood cell transfer. This image-derived DLCO correlates strongly with measured values in 142 subjects with a broad range of pulmonary disorders.

Genetic variant of COL11A2 gene is functionally associated with developmental dysplasia of the hip in Chinese Han population.

OBJECTIVES: Developmental dysplasia of the hip (DDH) is a common skeletal disorder. This study was conducted to demonstrate the association between DDH and a polymorphism rs9277935 of COL11A2 gene. RESULTS: A significant difference in genotype distribution in a recessive model (TT+GT vs. GG) between two groups (P=0.017) was demonstrated. Analysis in female patients showed significantly greater frequency of minor allele G(0.49 vs. 0.43, p=0.024) and significantly higher distribution of GG genotype (p=0.006). DDH patients were found to have significantly lower COL11A2 expression than controls. Moreover, DDH patients with rs9277935 genotype TT have a significantly increased expression of COL11A2 than those with genotype GG. COL11A2 demonstrated chondrogenic properties in vitro. CONCLUSION: Polymorphism rs9277935 of gene COL11A2 is a functional variant regulating the expression and the chondrogenic properties of COL11A2 in DDH in Chinese Han population. METHODS: A case-control candidate gene association study was conducted in 945 patients (350 radiologically confirmed DDH patients and 595 healthy controls). Difference of COL11A2 expression in hip joint tissue was compared between the patients and the controls. Allelic difference in Col11a2 expression by rs9277935 was assessed with luciferase activity. Chondrogenic effects of Col11a2 signaling on BMSCs were also determined in vitro.

Multiple circulating saponins from intravenous ShenMai inhibit OATP1Bs in vitro: potential joint precipitants of drug interactions.

ShenMai, an intravenous injection prepared from steamed Panax ginseng roots (Hongshen) and Ophiopogon japonicus roots (Maidong), is used as an add-on therapy for coronary artery disease and cancer; saponins are its bioactive constituents. Since many saponins inhibit human organic anion-transporting polypeptides (OATP)1B, this investigation determined the inhibition potencies of circulating ShenMai saponins on the transporters and the joint potential of these compounds for ShenMai-drug interaction. Circulating saponins and their pharmacokinetics were characterized in rats receiving a 30-min infusion of ShenMai at 10 mL/kg. Inhibition of human OATP1B1/1B3 and rat Oatp1b2 by the individual saponins was investigated in vitro; the compounds' joint inhibition was also assessed in vitro and the data was processed using the Chou-Talalay method. Plasma protein binding was assessed by equilibrium dialysis. Altogether, 49 saponins in ShenMai were characterized and graded into: 10-100 µmol/day (compound doses from ShenMai; 7 compounds), 1-10 µmol/day (17 compounds), and <1 µmol/day (25 compounds, including Maidong ophiopogonins). After dosing, circulating saponins were protopanaxadiol-type ginsenosides Rb1, Rb2, Rc, Rd, Ra1, Rg3, Ra2, and Ra3, protopanaxatriol-type ginsenosides Rg1, Re, Rg2, and Rf, and ginsenoside Ro. The protopanaxadiol-type ginsenosides exhibited maximum plasma concentrations of 2.1-46.6 µmol/L, plasma unbound fractions of 0.4-1.0% and terminal half-lives of 15.6-28.5 h (ginsenoside Rg3, 1.9 h), while the other ginsenosides exhibited 0.1-7.7 µmol/L, 20.8-99.2%, and 0.2-0.5 h, respectively. The protopanaxadiol-type ginsenosides, ginsenosides without any sugar attachment at C-20 (except ginsenoside Rf), and ginsenoside Ro inhibited OATP1B3 more potently (IC50, 0.2-3.5 µmol/L) than the other ginsenosides (≥22.6 µmol/L). Inhibition of OATP1B1 by ginsenosides was less potent than OATP1B3 inhibition. Ginsenosides Rb1, Rb2, Rc, Rd, Ro, Ra1, Re, and Rg2 likely contribute the major part of OATP1B3-mediated ShenMai-drug interaction potential, in an additive and time-related manner.

[Clinical analysis of four patients with Schwartz-Jampel syndrome].

OBJECTIVE: To analyze the clinical manifestation, diagnosis and treatment of Schwartz-Jampel syndrome (SJS). METHOD: The clinical data, including demographic, laboratory tests (creatase, creatine kinase, etc.) and electromyography of 4 children with SJS were analyzed. RESULT: All the 4 patients were male. The age of onset was from 0.5 to 1.25 years (average 0.83 years). The onset of 4 patients was insidious, the age to see doctor was from 2.17 to 10 years (average 5.92 years), body height was less than the third percentile rank in the children of same age and gender, they presented with facial expression stiffness, microstomia, difficult in opening mouth, blepharophimosis, limbs stiffness and, so formed a characteristic phenotype. Investigations showed the creatase in serum increased, creatine kinase (CK): 229 - 1039 U/L (normal value < 200 U/L), Creatine Kinase MB (CK-MB): 30 - 45 U/L (normal value < 25 U/L), lactate dehydrogenase (LDH): 455 - 716 U/L (normal value < 240 U/L). General myotonia potential was found in electromyography, osteoarticular deformities in medical imaging, and muscle biopsy in 2 patients showed type I muscle fibers differed in size and were disproportionate. All the patients took oral vitamin B, and received rehabilitation training, 1 patient took carbamazepine for 1 month, blepharophimosis and limbs stiffness was improved. CONCLUSION: SJS is a rare autosomal recessive inherited disease. Clinical manifestations of SJS are characteristic facies, skeletal abnormalities, generous myotonia and short stature. Carbamazepine is effective for treatment.

[Anti-N-methyl-D-aspartate receptor encephalitis in seven children].

OBJECTIVE: To study the clinical and laboratory features and diagnosis of the patient with anti-N-methyl-D-aspartate receptor(NMDAR)encephalitis in children. METHOD: The data of clinical feature, laboratory findings, and radiological manifestation were reviewed and analyzed. RESULT: Of the 7 patients, 4 were female and 3 were male. The age of onset was from 6.6 to 15.5 years (average 9.5 years). The onset of 4 cases started with convulsion. Six cases had seizures which was difficult to control by antiepileptic drugs. All patients had psychiatric symptoms and speech disorder. Six cases had different levels of decreased consciousness and dyskinesias. 6 cases had autonomic nerve instability, and 7 cases developed sleep disorders. The results of MRI examination were normal in all patients. The EEG of most patients showed focal or diffuse slow waves. Six cases had oligoclonal bands. All cases were confirmed to have the disease by detection of anti-NMDA receptor antibodies. No tumor was detected in any of the patients. All patients received immunotherapy. CONCLUSION: Anti-NMDAR encephalitis is a severe but treatable disorder that frequently affects children and adolescents. Pediatric patients had clinical manifestations similar to those of adult patients. But children have a lower incidence of tumors and hypoventilation also occurs less frequently in children. Most of children had a good prognosis.