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.

Wolfberry, Yam, and Chrysanthemum polysaccharides increased intestinal Akkermansia muciniphila abundance and hepatic YAP1 expression to alleviate DILI.

Drug-induced liver injury (DILI) is frequently induced by high dose of acetaminophen (APAP) and is concomitant with disturbances of gut flora. Akkermansia muciniphila is beneficial for the repair of liver injury. Lycium barbarum polysaccharide, yam polysaccharide, and chrysanthemum polysaccharide all have anti-inflammatory and antioxidation effects. The objective of this study is to investigate the potential of lycium barbarum polysaccharide, yam polysaccharide, and chrysanthemum polysaccharide (LYC) in improving DILI by increasing the abundance of A. muciniphila. Initially, screening for the optimal concentrations of wolfberry, yam, and chrysanthemum (WYC) or LYC to promote A. muciniphila proliferation in vitro and validated in antibiotic (ATB)-treated KM mice. Subsequently, APAP-induced DILI model in BALB/c mice were constructed to examine the treatment effects of LYC. Our findings indicate that the optimal concentration ratio of WYC was 2:3:2, and LYC was 1:1:1. WYC increased A. muciniphila proliferation in vitro and in ATB-treated mice under this ratio. Meanwhile, LYC increased A. muciniphila abundance in vitro and the combination LYC with A. muciniphila promoted the proliferation of A. muciniphila in ATB-treated mice. The overdose of APAP resulted in the impairment of the intestinal barrier function and subsequent leakage of lipopolysaccharide (LPS). Moreover, LYC increased A. muciniphila abundance, reduced intestinal inflammation and permeability, and upregulated the expression of the tight junction protein zonula occludens protein 1 (ZO-1) and occludin contents in the gut. Lastly, LYC inhibited LPS leakage and upregulated hepatic YAP1 expression, ultimately leading to the repair of DILI.

Wolfberry enhanced the abundance of Akkermansia muciniphila by YAP1 in mice with acetaminophen-induced liver injury.

Drug-induced liver injury (DILI) by acetaminophen (APAP) was one of the most challenging liver diseases. Wolfberry (Lycium barbarum L.), a traditional Chinese medicinal material and food supplement, has a potential effect on increasing the abundance of Akkermansia muciniphila (A. muciniphila) in mice colons. However, the effect and mechanism of wolfberry remain unclear in APAP-induced DILI. In this study, wolfberry promoted the proliferation of activated-A. muciniphila in vitro and in vivo. For the first time, we detected that the activated-A. muciniphila but not the killed-A. muciniphila increased the expression level of Yes-associated protein 1 (YAP1) in the liver and alleviated liver injury in APAP-induced DILI mice. Mechanically, A. muciniphila improved the intestinal mucosal barrier and reduced lipopolysaccharide (LPS) content in the liver, leading to the increased expression level of YAP1. Furthermore, wolfberry increased the A. muciniphila abundance in the colon and YAP1 expression in the liver from APAP-induced DILI mice, which promoted the recovery of APAP-induced liver injury. Meanwhile, wolfberry combination with A. muciniphila synergistically increased AKK abundance and YAP1 expression in the liver. Our research provides an innovative strategy to improve DILI.

Human umbilical cord mesenchymal stem cells promoted tumor cell growth associated with increased interleukin-18 in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is experiencing a concerning rise in both incidence and mortality rates. Current therapeutic strategies are limited in their effectiveness, largely due to the complex causes of the disease and significant levels of drug resistance. Given the latest developments in human umbilical cord mesenchymal stem cells (hUC-MSCs) research, there is a debate over the continued use of stem cell transplantation for treating tumors. Consequently, this study seeks to explore the role of hUC-MSCs in the management of HCC. METHODS AND RESULTS: HUC-MSCs increased the number (10.75 ± 1.50) in the DEN/TCPOBOP-induced mice hepatoma model, compared with DMSO group (7.25 ± 1.71). Moreover, the liver index in hUC-MSCs group (0.21 ± 0.06) was greater than that in DMSO group (0.09 ± 0.01). Immunohistochemical (IHC) analysis revealed that while hUC-MSCs did not alter Foxp3 expression, they significantly stimulated Ki67 expression, indicative of increased tumor cellular proliferation. Additionally, immunofluorescence (IF) studies showed that hUC-MSCs increased CD8+ T cell counts without affecting macrophage numbers. Notably, granzyme B expression remained nearly undetectable. We observed that serum IL-18 levels were higher in the hUC-MSCs group (109.66 ± 0.38 pg/ml) compared to the DMSO group (91.14 ± 4.37 pg/ml). Conversely, IL-1ß levels decreased in the hUC-MSCs group (63.00 ± 0.53 pg/ml) relative to the DMSO group (97.38 ± 9.08 pg/ml). CONCLUSIONS: According to this study, hUC-MSCs promoted the growth of liver tumors. Therefore, we proposed that hUC-MSCs are not suitable for treating HCC, as they exhibit clinically prohibited abnormalities.

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.

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.

Bias field correction in hyperpolarized 129 Xe ventilation MRI using templates derived by RF-depolarization mapping.

PURPOSE: To correct for RF inhomogeneity for in vivo 129 Xe ventilation MRI using flip-angle mapping enabled by randomized 3D radial acquisitions. To extend this RF-depolarization mapping approach to create a flip-angle map template applicable to arbitrary acquisition strategies, and to compare these approaches to conventional bias field correction. METHODS: RF-depolarization mapping was evaluated first in digital simulations and then in 51 subjects who had undergone radial 129 Xe ventilation MRI in the supine position at 3T (views = 3600; samples/view = 128; TR/TE = 4.5/0.45 ms; flip angle = 1.5; FOV = 40 cm). The images were corrected using newly developed RF-depolarization and templated-based methods and the resulting quantitative ventilation metrics (mean, coefficient of variation, and gradient) were compared to those resulting from N4ITK correction. RESULTS: RF-depolarization and template-based mapping methods yielded a pattern of RF-inhomogeneity consistent with the expected variation based on coil architecture. The resulting corrected images were visually similar, but meaningfully distinct from those generated using standard N4ITK correction. The N4ITK algorithm eliminated the physiologically expected anterior-posterior gradient (-0.04 ± 1.56%/cm, P < 0.001). These 2 newly introduced methods of RF-depolarization and template correction retained the physiologically expected anterior-posterior ventilation gradient in healthy subjects (2.77 ± 2.09%/cm and 2.01 ± 2.73%/cm, respectively). CONCLUSIONS: Randomized 3D 129 Xe MRI ventilation acquisitions can inherently be corrected for bias field, and this technique can be extended to create flip angle templates capable of correcting images from a given coil regardless of acquisition strategy. These methods may be more favorable than the de facto standard N4ITK because they can remove undesirable heterogeneity caused by RF effects while retaining results from known physiology.

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.

Static Balance in Participants with Temporomandibular Joint Disc Displacement without Reduction Versus Healthy Participants: A Cross-Sectional Study.

BACKGROUND There is no consensus on the association between body posture and temporomandibular disorders (TMDs). This study aimed to assess differences in static balance between healthy participants and patients with temporomandibular joint disc displacement without reduction. MATERIAL AND METHODS Sixteen patients with temporomandibular joint disc displacement without reduction and 14 healthy participants were included. Static balance tests were performed in the rest and "cotton rolls" (participants biting 2 cotton rolls with their upper and lower teeth) mandibular positions. The mean body's center of gravity (COG) sway velocity was tested in each mandibular position on a firm surface with and without eyes open and on a foam surface with and without eyes open. RESULTS The COG sway velocity did not differ between the TMD and healthy groups regarding mandibular position or testing condition (P>0.05). However, in the control group, the COG sway velocity in the mandibular rest position was significantly higher than that in the "cotton rolls" mandibular position when standing on a foam surface with the eyes closed (P=0.024). In the TMD group, there was no difference in the COG sway velocity between the 2 mandible positions under any condition (P>0.05). CONCLUSIONS This study provides new evidence for static balance alterations in patients with temporomandibular joint disc displacement without reduction. Further studies are needed to investigate postural control changes in patients with arthrogenous TMDs. This study was registered in the Chinese Clinical Trial Registry (no. ChiCTR1800018369).

Biological mechanisms of growth performance and meat quality in porcine muscle tissue.

Growth performance and meat quality are important traits for pig production. The aim of the present study was to investigate the molecular mechanisms underlying growth performance and meat quality, and to identify novel target molecules for predicting the growth performance and meat quality. The differentially expressed genes (DEGs) in Diannan small ears pigs (DSP) and Landrace pigs (LP) were assessed by RNA-sequencing analyzing technology. A total of 339 DEGs were obtained between DSP and LP. 146 DEGs were upregulated in LP compared with DSP and 193 DEGs were upregulated in DSP compared with LP. The DEGs were significantly enriched in 26 GO and 3 KEGG pathways. The protein-protein interaction (PPI) network with 201 nodes and 382 edges was constructed and 5 modules were extracted from the entire network. The identified upregulated expression of genes involved in glycolysis and myogenesis as well as extracellular matrix may be associated with fast body and muscle deposition rates in LP. Increased expression of genes involved in PPAR signaling pathway and fatty acid metabolism as well as oxidative phosphate processes could be related to the intramuscular fat deposition and meat quality in DSP. The present study may provide an improved understanding of the growth performance and meat quality.

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.

Pharmacokinetics-based identification of pseudoaldosterogenic compounds originating from Glycyrrhiza uralensis roots (Gancao) after dosing LianhuaQingwen capsule.

LianhuaQingwen capsule, prepared from an herbal combination, is officially recommended as treatment for COVID-19 in China. Of the serial pharmacokinetic investigations we designed to facilitate identifying LianhuaQingwen compounds that are likely to be therapeutically important, the current investigation focused on the component Glycyrrhiza uralensis roots (Gancao). Besides its function in COVID-19 treatment, Gancao is able to induce pseudoaldosteronism by inhibiting renal 11ß-HSD2. Systemic and colon-luminal exposure to Gancao compounds were characterized in volunteers receiving LianhuaQingwen and by in vitro metabolism studies. Access of Gancao compounds to 11ß-HSD2 was characterized using human/rat, in vitro transport, and plasma protein binding studies, while 11ß-HSD2 inhibition was assessed using human kidney microsomes. LianhuaQingwen contained a total of 41 Gancao constituents (0.01-8.56 µmol/day). Although glycyrrhizin (1), licorice saponin G2 (2), and liquiritin/liquiritin apioside (21/22) were the major Gancao constituents in LianhuaQingwen, their poor intestinal absorption and access to colonic microbiota resulted in significant levels of their respective deglycosylated metabolites glycyrrhetic acid (8), 24-hydroxyglycyrrhetic acid (M2D; a new Gancao metabolite), and liquiritigenin (27) in human plasma and feces after dosing. These circulating metabolites were glucuronized/sulfated in the liver and then excreted into bile. Hepatic oxidation of 8 also yielded M2D. Circulating 8 and M2D, having good membrane permeability, could access (via passive tubular reabsorption) and inhibit renal 11ß-HSD2. Collectively, 1 and 2 were metabolically activated to the pseudoaldosterogenic compounds 8 and M2D. This investigation, together with such investigations of other components, has implications for precisely defining therapeutic benefit of LianhuaQingwen and conditions for its safe use.

Congenital muscular dystrophies in China.

Congenital muscular dystrophies (CMDs) are clinically and genetically heterogeneous conditions. We launched a nationwide study to determine the frequency of CMD in the Chinese population and assess the status of diagnosis and disease management for CMD in China. Cases were chosen from databases in 34 tertiary academic hospitals from 29 first-level administrative divisions (provinces, municipalities, autonomous regions, and special administrative regions), and medical records were reviewed to confirm the diagnoses. The study included 409 patients, of those patients who consented to genetic testing (n = 340), mutations were identified in 286 of them. The most common forms identified were LAMA2-related CMD (36.4%), followed by COL6-related CMD (23.2%) and α-dystroglycanopathy (21.0%). The forms of CMD related to mutations in LMNA and SEPN1 were less frequent (12.5% and 2.4%, respectively). We also recorded a significant difference in the diagnostic capabilities and disease management of CMD, with this being relatively backward in research centers from less developed regions. We provide, for the first time, comprehensive epidemiologic information of CMD in a large cohort of Chinese people. To our knowledge, this is the largest sample size of its kind so far highlighting the prevalence of CMD in China.

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.

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.

Dihydroartemisinin breaks the positive feedback loop of YAP1 and GLUT1-mediated aerobic glycolysis to boost the CD8+ effector T cells in hepatocellular carcinoma.

Aerobic glycolysis is a hallmark of hepatocellular carcinoma (HCC). Dihydroartemisinin (DHA) exhibits antitumor activity towards liver cancer. Our previous studies have shown that DHA inhibits the Warburg effect in HCC cells. However, the mechanism still needs to be clarified. Our study aimed to elucidate the interaction between YAP1 and GLUT1-mediated aerobic glycolysis in HCC cells and focused on the underlying mechanisms of DHA inhibiting aerobic glycolysis in HCC cells. In this study, we confirmed that inhibition of YAP1 expression lowers GLUT1-mediated aerobic glycolysis in HCC cells and enhances the activity of CD8+T cells in the tumor niche. Then, we found that DHA was bound to cellular YAP1 in HCC cells. YAP1 knockdown inhibited GLUT1-mediated aerobic glycolysis, whereas YAP1 overexpression promoted GLUT1-mediated aerobic glycolysis in HCC cells. Notably, liver-specific Yap1 knockout by AAV8-TBG-Cre suppressed HIF-1α and GLUT1 expression in tumors but not para-tumors in DEN/TCPOBOP-induced HCC mice. Even more crucial is that YAP1 forms a positive feedback loop with GLUT1-mediated aerobic glycolysis, which is associated with HIF-1α in HCC cells. Finally, DHA reduced GLUT1-aerobic glycolysis in HCC cells through YAP1 and prevented the binding of YAP1 and HIF-1α. Collectively, our study revealed the mechanism of DHA inhibiting glycolysis in HCC cells from a perspective of a positive feedback loop involving YAP1 and GLUT1 mediated-aerobic glycolysis and provided a feasible therapeutic strategy for targeting enhanced aerobic glycolysis in HCC.

Dihydroartemisinin modulated arachidonic acid metabolism and mitigated liver inflammation by inhibiting the activation of 5-LOX and COX-2.

Background: Dihydroartemisinin (DHA), a derivative of Artemisia annua, has been shown to possess anti-inflammatory properties. Besides, Yes-associated protein 1 (YAP1) plays a crucial role in maintaining liver homeostasis. Methods: This study used Yap1 Flox/Flox, Albumin-Cre mice with hepatocyte-specific Yap1 knockout (referred to as Yap1 LKO) and their control mice (Yap1 Flox/Flox, referred to as Yap1 Flox). The effect of Yap1 on lipid metabolism homeostasis was investigated through non-targeted metabolomic analysis of mouse liver. Subsequently, DHA was administered to Yap1 LKO mice to assess its potential as a treatment. Liver pathology was evaluated via H&E staining, and the levels of AST, ALT, and TG were quantified using biochemical assays. The contents of arachidonic acid (AA), prostaglandin E1 (PGE1), and leukotrienes (LT) in the liver were measured using ELISA, while the protein expressions of PLIN2, 5-lipoxygenase (5-LOX), and cyclooxygenase-2 (COX-2) were analyzed through IHC staining. Results: Hepatocyte-specific Yap1 knockout activated the AA metabolic pathway, resulting in increased elevated levels of AA, PGE1, and LT levels, along with inflammatory cytokine infiltration. DHA mitigated the elevation of metabolites such as PGE1 and LT caused by the AA metabolic pathway activation by down-regulating the levels of COX-2 and 5-LOX in the liver of Yap1 LKO mice. Moreover, it alleviated the accumulation of lipid vacuoles and reduced triglyceride (TG) and perilipin-2 (PLIN2) levels in the liver of Yap1 LKO mice. Conclusions: Excessively low YAP1 expression induces liver inflammation and disturbances in lipid metabolism, whereas DHA modulated AA metabolism and mitigated liver inflammation by inhibiting the activation of 5-LOX and COX-2.

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.

Dihydroartemisinin breaks the immunosuppressive tumor niche during cisplatin treatment in Hepatocellular carcinoma.

OBJECTIVE: Hepatocellular carcinoma, characterized by high mortality rates, often exhibits limited responsiveness to conventional treatments such as surgery, radiotherapy, and chemotherapy. Therefore, identifying a sensitizer for cisplatin has become crucial. Dihydroartemisinin, known for its potent role of tumor treatment, arises as a prospective candidate for cisplatin sensitization in clinical settings. METHODS: A mouse model of liver tumor was established through chemical induction of DEN/TCPOBOP. Upon successful model establishment, ultrasound was employed to detect tumors, Hematoxylin and eosin staining was conducted for observation of liver tissue pathology, and ELISA was utilized to assess cytokine changes (IFN-γ, IL-2, IL-4, IL-10, TGF-ß, IL-1ß, CCL2, and CCL21) in peripheral blood, para-tumor tissues, and tumor tissues. The infiltration of CD8+T cells and macrophages in tumor tissue sections was detected by immunofluorescence. RESULTS: Dihydroartemisinin combined with cisplatin obviously restrained the growth of liver tumors in mice and improved the weight and spleen loss caused by cisplatin. Cisplatin treatment of liver tumor mice increased the content of CCL2 and the number of macrophages in tumor tissues and promoted the formation of an immunosuppressive microenvironment. The combination therapy decreased the content of TGF-ß in tumor tissues while increasing CCL2 levels in para-tumor tissues. Both combination therapy and cisplatin alone increased the number of CD8+T cells in tumor tissue, but there was no difference between them. CONCLUSION: Dihydroartemisinin combined with cisplatin obviously prevented the deterioration of liver tumor in hepatocellular carcinoma mice and improve the therapeutic effect of cisplatin by improving the immunosuppressive microenvironment induced by cisplatin. Our findings provide a theoretical basis for considering dihydroartemisinin as an adjuvant drug for cisplatin in the treatment of hepatocellular carcinoma in the future.

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.