IFIT3 mediates TBK1 phosphorylation to promote activation of pDCs and exacerbate systemic sclerosis in mice.

OBJECTIVE: To assess the impact of the IFIT3/TBK1 signalling pathway in activating plasmacytoid dendritic cells (pDCs) and its role in the development of SSc. METHODS: Utilized single-cell RNA sequencing (scRNA-seq) and high-throughput transcriptome RNA sequencing to reveal the differential abundance of pDCs and the role of the key gene IFIT3 in SSc. Conducted in vitro cell experiments to evaluate the effect of IFIT3/TBK1 signalling pathway intervention on pDC activation cytokine release and fibroblast function. Constructed an IFIT3-/- mouse model using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene editing to assess the potential benefits of intervening in the IFIT3/TBK1 signalling pathway on skin and lung fibrosis in the SSc mouse model. RESULTS: The IFIT3/TBK1 signalling pathway plays a crucial role in activating pDCs, with IFIT3 acting as an upstream regulator of TBK1. Intervention in the IFIT3/TBK1 signalling pathway can inhibit pDC activation cytokine release and impact fibroblast function. The IFIT3-/- mouse model shows potential benefits of targeting the IFIT3/TBK1 signalling pathway in reducing skin and lung fibrosis in the SSc mouse model. CONCLUSION: This study provides new insights into potential therapeutic targets for SSc, highlighting the critical role of the IFIT3/TBK1 signalling pathway in SSc development. HIGHLIGHTS: This study elucidates the pivotal role of plasmacytoid dendritic cells (pDCs) in systemic sclerosis (SSc). This study identified the key regulatory gene involved in systemic sclerosis (SSc) as IFIT3. This study has found that IFIT3 functions as an upstream regulatory factor, activating TBK1. This study provides Evidence of the regulatory effects of the IFIT3/TBK1 pathway on plasmacytoid dendritic cells (pDCs). This study validated the therapeutic potential using the IFIT3-/- mouse model.

Hydroxylamine hydrochloride-driven activation of NiFe2O4 for the degradation of phenol via peroxymonosulfate.

In this study, hydroxylamine hydrochloride (HA) was employed to enhance the activation of NiFe2O4 towards peroxymonosulfate (PMS) for the effective degradation of phenol. NiFe2O4 particles were synthesized via a simple hydrothermal method, followed by characterization of their surface morphology, and microstructure. Upon the addition of HA to the system of NiFe2O4/PMS, the degradation activity is significantly enhanced. The degradation efficiency of phenol reached 98.5% after 60 min using 0.6 g/L NiFe2O4, 3 mmol/L PMS, 2 mmol/L HA at pH 7, which increased by 4.76 times compared to the system without HA. The study further explored the activation mechanism of the NiFe2O4/HA/PMS system, revealing that HA significantly enhanced the conversion of Fe3+/Fe2+ and the leaching of metal ions, thereby accelerating the reaction rate. In addition, the NiFe2O4/HA/PMS system proved effective across a broad range of pH values. This study provides new insights and perspectives into enhancing peroxymonosulfate activation coupled with metal oxides catalysts through the use of reducing agents.

Abatacept versus tumor necrosis factor inhibitors on mortality and medical utilizations in the treatment of rheumatoid arthritis associated interstitial lung disease: a large-scale real-world retrospective cohort study.

Rheumatoid arthritis is a chronic inflammatory disease, and interstitial lung disease is one of the important extra-articular manifestations. There is limited evidence comparing abatacept (ABA) and tumor necrosis factor inhibitors (TNFi) regarding the risk of mortality among patients with rheumatoid arthritis associated interstitial lung disease (RA-ILD). The aim of this study is to investigate the risk of mortality in patients with RA-ILD treated with ABA compared to TNFi. This retrospective cohort study utilized TriNetX electronic health record database. We enrolled patients who were diagnosed with RA-ILD and had received a new prescription for either ABA or TNFi. Patients were categorized into two cohorts based on their initial prescription. The primary outcome was all-cause mortality, and secondary outcomes were healthcare utilizations, including hospitalization, critical care services, and mechanical ventilation. Subgroup analyses were performed on age, presence of anti-citrullinated peptide antibodies (ACPA), and cardiovascular risk. Among 34,388 RA-ILD patients, 895 were selected for each group (ABA and TNFi) following propensity score matching. The ABA group exhibited a higher all-cause mortality risk. (HR 1.296, 95% CI 1.006-1.671). Subgroup analysis showed a heightened risk of receiving mechanical ventilation in ABA-treated patients aged 18-64 years old (HR 1.853, 95% CI 1.002-3.426), and those with cardiovascular risk factors (HR 2.015, 95% CI 1.118-3.630). Another subgroup analysis indicated a higher risk of mortality among ABA-treated patients with positive-ACPA. (HR 4.138 95% CI 1.343-12.75). This real-world data research demonstrated a higher risk of all-cause mortality in RA-ILD patients treated with ABA compared to TNFi, particularly those aged 18-64 years, lacking cardiovascular risk factors, and positive-ACPA. ABA was associated with an increased risk of mechanical ventilation in patients aged 18-64 years and those with cardiovascular risk factors.

Drip Fertigation Increases Maize Grain Yield by Affecting Phenology, Grain Filling Process, Biomass Accumulation and Translocation: A 4-Year Field Trial.

Drip fertigation (DF) is a widely used technology to increase grain yield with water and fertilizer conservation. However, the mechanism of high grain yield (GY) under DF is still unclear. Here, a four-year field experiment assessed the impacts of four treatments (i.e., conventional irrigation and nitrogen application, CK; drip irrigation with conventional nitrogen fertilization, DI; split-nitrogen fertigation with conventional irrigation, SF; and drip fertigation, DF) on maize phenology, leaf photosynthetic rates, grain filling processes, plant biomass, and GY. The results showed that DF significantly increased maize GY by affecting phenology, grain filling traits, aboveground biomass (BIO) accumulation, and translocation. Specifically, DF significantly increased leaf chlorophyll content, which enhanced leaf photosynthetic rates, and together with an increase of leaf area index, promoted BIO accumulation. As a result, the BIO at the silking stage of DF increased by 29.5%, transported biomass increased by 109.2% (1.2 t ha-1), and the accumulation of BIO after silking increased by 23.1% (1.7 t ha-1) compared with CK. Meanwhile, DF prolonged grain filling days, significantly increased the grain weight of 100 kernels, and promoted GY increase. Compared with CK, the four-year averaged GY and BIO increased by 34.3% and 26.8% under DF; a 29.7%, 46.1%, and 24.2% GY increase and a 30.7%, 39.5%, and 29.9% BIO increase were contributed by irrigation, nitrogen, and coupling effects of irrigation and nitrogen, respectively. These results reveal the high yield mechanism of drip-fertigated maize, and are of important significance for promoting the application of drip fertigation.

Purification and Structural Analyses of Sulfated Polysaccharides from Low-Value Sea Cucumber Stichopus naso and Anticoagulant Activities of Its Oligosaccharides.

Three polysaccharides (SnNG, SnFS and SnFG) were purified from the body wall of Stichopus naso. The physicochemical properties, including monosaccharide composition, molecular weight, sulfate content, and optical rotation, were analyzed, confirming that SnFS and SnFG are sulfated polysaccharides commonly found in sea cucumbers. The highly regular structure {3)-L-Fuc2S-(α1,}n of SnFS was determined via a detailed NMR analysis of its oxidative degradation product. By employing ß-elimination depolymerization of SnFG, tri-, penta-, octa-, hendeca-, tetradeca-, and heptadeca-saccharides were obtained from the low-molecular-weight product. Their well-defined structures confirmed that SnFG possessed the backbone of {D-GalNAc4S6S-ß(1,4)-D-GlcA}, and each GlcA residue was branched with Fuc2S4S. SnFS and SnFG are both structurally the simplest version of natural fucan sulfate and fucosylated glycosaminoglycan, facilitating the application of low-value sea cucumbers S. naso. Bioactivity assays showed that SnFG and its derived oligosaccharides exhibited potent anticoagulation and intrinsic factor Xase (iXase) inhibition. Moreover, a comparative analysis with the series of oligosaccharides solely branched with Fuc3S4S showed that in oligosaccharides with lower degrees of polymerization, such as octasaccharides, Fuc2S4S led to a greater increase in APTT prolongation and iXase inhibition. As the degree of polymerization increases, the influence from the sulfation pattern diminishes, until it is overshadowed by the effects of molecular weight.

Monitoring of Chlorophyll Content of Potato in Northern Shaanxi Based on Different Spectral Parameters.

Leaf chlorophyll content (LCC) is an important physiological index to evaluate the photosynthetic capacity and growth health of crops. In this investigation, the focus was placed on the chlorophyll content per unit of leaf area (LCCA) and the chlorophyll content per unit of fresh weight (LCCW) during the tuber formation phase of potatoes in Northern Shaanxi. Ground-based hyperspectral data were acquired for this purpose to formulate the vegetation index. The correlation coefficient method was used to obtain the "trilateral" parameters with the best correlation between potato LCCA and LCCW, empirical vegetation index, any two-band vegetation index constructed after 0-2 fractional differential transformation (step size 0.5), and the parameters with the highest correlation among the three spectral parameters, which were divided into four combinations as model inputs. The prediction models of potato LCCA and LCCW were constructed using the support vector machine (SVM), random forest (RF) and back propagation neural network (BPNN) algorithms. The results showed that, compared with the "trilateral" parameter and the empirical vegetation index, the spectral index constructed by the hyperspectral reflectance after differential transformation had a stronger correlation with potato LCCA and LCCW. Compared with no treatment, the correlation between spectral index and potato LCC and the prediction accuracy of the model showed a trend of decreasing after initial growth with the increase in differential order. The highest correlation index after 0-2 order differential treatment is DI, and the maximum correlation coefficients are 0.787, 0.798, 0.792, 0.788 and 0.756, respectively. The maximum value of the spectral index correlation coefficient after each order differential treatment corresponds to the red edge or near-infrared band. A comprehensive comparison shows that in the LCCA and LCCW estimation models, the RF model has the highest accuracy when combination 3 is used as the input variable. Therefore, it is more recommended to use the LCCA to estimate the chlorophyll content of crop leaves in the agricultural practices of the potato industry. The results of this study can enhance the scientific understanding and accurate simulation of potato canopy spectral information, provide a theoretical basis for the remote sensing inversion of crop growth, and promote the development of modern precision agriculture.

Pegmolesatide for the treatment of anemia in patients undergoing dialysis: a randomized clinical trial.

Background: Pegmolesatide, a synthetic peptide-based erythropoietin (EPO) receptor agonist, is being evaluated as an alternative to epoetin alfa for treating anemia of chronic kidney disease (CKD) in Chinese dialysis patients. There is a critical need for a long-acting, cost-effective erythropoiesis-stimulating agent that does not produce EPO antibodies. Methods: A randomized, open-label, active-comparator, non-inferiority phase three trial was conducted at 43 dialysis centers in China between May 17th, 2019, and March 28th, 2022. Eligible patients aged 18-70 years were randomly assigned (2:1) to receive pegmolesatide once every four weeks or epoetin alfa one to three times per week, with doses adjusted to maintain a hemoglobin level between 10.0 and 12.0 g/dL. The primary efficacy endpoint was the mean change in hemoglobin level from baseline to the efficacy evaluation period in the per-protocol set (PPS) population. Non-inferiority of pegmolesatide to epoetin alfa was established if the lower limit of the two-sided 95% confidence interval for the between-group difference was ≥ -1.0 g/dL. Safety assessment included adverse events and potential anaphylaxis reactions. This trial is registered at ClinicalTrials.gov, NCT03902691. Findings: Three hundreds and seventy-two patients were randomly assigned to the pegmolesatide group (248 patients) or the epoetin alfa group (124 patients). A total of 347 patients (233 in the pegmolesatide group and 114 in the epoetin alfa group) were included in the PPS population. In the PPS, the mean change (standard deviation, SD) in hemoglobin level from baseline to the efficacy evaluation period was 0.07 (0.92) g/dL in the pegmolesatide group and -0.22 (0.97) g/dL in the epoetin alfa group. The between-group difference was 0.29 g/dL (95% confidence interval: 0.11-0.47), verifying non-inferiority of pegmolesatide to epoetin alfa. Adverse events occurred in 231 (94%) participants in the pegmolesatide group and in 110 (89%) in the epoetin alfa group. Hypertension was the most common treatment-related adverse event. No fatal cases of anaphylaxis or hypotension were reported. Interpretation: Monthly subcutaneously injection of pegmolesatide was as effective and safe as conventional epoetin alfa administrated one to three times a week in treating anemia in Chinese dialysis patients. Funding: The study was supported by Hansoh Medical Development Group.

Mitochondrial Lon protease promotes CD4+ T cell activation by activating the cGAS-STING-TBK1 axis in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease in which autoreactive CD4+ T cells play an essential role. We extracted CD4+ T cells from SLE-prone Fcgr2b-/- mice to elaborate the mechanism of mitochondrial Lon protease in CD4+ T cell activation in SLE. Transcriptome sequencing was performed in SLE-prone Fcgr2b-/- mice, and the stimulator of interferon gene (STING) related to SLE was obtained. It was demonstrated that STING expression was elevated in CD4+ T cells in SLE-prone Fcgr2b-/- mice. The downstream genes and pathways of STING were predicted by GO and KEGG approaches. The data indicated that STING regulated IFN signaling to promote CD4+ T cell activation in SLE-prone Fcgr2b-/- mice. Next, the interaction of cGAS, STING, TBK1, and IFN-I was verified by Co-IP assay. Moreover, the roles of cGAS, STING, and TBK1 in activating CD4+ T cells from SLE-prone Fcgr2b-/- mice were evaluated using gain- or loss-of-function experiments. Mechanistically, cGAS upregulated the IFN-I signaling pathway by directly interacting with STING and TBK1, contributing to CD4+ T cell activation. Besides, cytosolic mtDNA could activate CD4+ T cell activation in SLE-prone Fcgr2b-/- mice by upregulating the cGAS-STING-TBK1 axis. The function of mitochondrial Lon protease in oxidative damage and mtDNA release in CD4+ T cells of SLE-prone Fcgr2b-/- mice were explored. Mitochondrial Lon protease enhanced mtDNA release into the cytoplasm under oxidative stress. Collectively, our work indicates that mitochondrial Lon protease enhances CD4+ T cell activation by inducing mtDNA leakage and offers new candidate targets for developing diagnostic and therapeutic strategies.

Efficacy and Safety of CMAB008 Compared with Innovator Infliximab in Patients with Moderate-to-Severe Rheumatoid Arthritis Receiving Concomitant Methotrexate: A Randomized, Double-blind, Multi-center, Phase III Non-inferiority Study.

OBJECTIVES: The aim of this work is to verify the non-inferior efficacy and safety of CMAB008 compared with innovator infliximab in rheumatoid arthritis patients combined with methotrexate. METHODS: We conducted a randomized, double-blinded, parallel, positive control design, multicenter study, with a stable dose of methotrexate. Patients were enrolled randomly with a ratio of 1:1 to receive intravenously CMAB008 3 mg/kg or innovator infliximab 3 mg/kg at weeks 0, 2, 6, 14, 22 and 30. The primary efficacy endpoint was American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 30. The non-inferiority was established if the lower limit of the one-sided 97.5% confidence interval (CI) for the difference was more than - 15% and the equivalence was established if the two-sided 95% CI was within ± 15% in an exploratory equivalence analysis. The secondary endpoints included other efficacy assessment parameters, as well as immunogenicity, safety, and pharmacokinetics. RESULTS: In the full analysis population (FAS), 110 (57.6%) of 191 patients in the CMAB008 group and 120 (62.2%) of 193 patients in the innovator infliximab group reached the primary outcome of ACR20 at week 30. The differences of the rates were - 4.6% and the lower limit of one-sided 97.5% confidence interval was - 14.29%, not less than the lower limit of the non-inferiority margin (- 15%); so CMAB008 was non-inferior to innovator infliximab. Further, CMAB008 was equivalent to innovator infliximab both in FAS (difference - 4.6%, 95% CI - 14.29% to 5.12%) and PPS (difference - 3.3%, 95% CI - 13.18% to 6.62%). The efficacy, safety, immunogenicity, and pharmacokinetics are highly similar between CMAB008 and innovator infliximab. CONCLUSIONS: Non-inferior efficacy of CMAB008 to innovator infliximab is illustrated with similar early and lasting therapeutic effects, and the equivalence is further demonstrated. CMAB008 is well tolerated and has semblable safety compared with the innovator infliximab. TRIAL REGISTRATION NUMBER: NCT03478111.

A Reliable and Repeatable Model for Predicting Microvascular Invasion in Patients With Hepatocellular Carcinoma.

RATIONALE AND OBJECTIVES: The reproducibility of imaging models for predicting microvascular invasion (MVI) in patients with hepatocellular carcinoma (HCC) remains questionable due to inconsistent interpretation of image signs. Our aim was to screen for high-consensus MRI features to develop a repeatable model for predicting MVI. MATERIALS AND METHODS: We included 219 patients with HCC who underwent surgical resection, and patients were divided into a training cohort (n = 145) and a validation cohort (n = 74). Morphological characteristics, signal features on hepatobiliary phases, and dynamic enhancement patterns were qualitatively interobserver evaluated. Interobserver agreement was assessed using Cohen's κ for selecting features with high interobserver agreement. Risk factors that were significant in stepwise multivariate analysis and that could be measured with good interobserver agreement were used to construct a predictive model, which was assessed in the validation cohort. The diagnostic performance of the model was evaluated based on area under the receiver operating characteristic curve (AUC). RESULTS: Multivariate analysis identified nonsmooth tumor margin, absence of radiologic capsule, and intratumoral artery as independent risk factors of MVI. These MRI-based features showed good or nearly perfect interobserver agreement between radiologists (κ > 0.6). The predictive model predicted MVI well in the training (AUC 0.734) and validation cohorts (AUC 0.759) and fitted well to calibration curves. CONCLUSION: MRI features included nonsmooth tumor margin, absence of radiologic capsule, and intratumoral artery that can be assessed with high interobserver agreement can predict MVI in HCC patients. The predictive model described here may be useful to radiologists, regardless of experience level.

Breast Magnetic Resonance Imaging Can Predict Ki67 Discordance Between Core Needle Biopsy and Surgical Samples.

BACKGROUND: Disagreement in assessments of Ki67 expression based on core-needle biopsy and matched surgical samples complicates decisions in the treatment of breast cancer. PURPOSE: To examine whether preoperative breast MRI could be useful in predicting Ki67 discordance between core-needle biopsy and surgical samples. STUDY TYPE: Retrospective. POPULATION: Three hundred and sixty-five breast cancer patients with MRI scans and having both core-needle biopsy and surgical samples from 2017 to 2019. FIELD STRENGTH/SEQUENCE: 3.0 T, T2-weighted iterative decomposition of water and fat with echo asymmetry and least squares estimation sequence, diffusion-weighted sequence using b-values 0/1000, dynamic contrast enhanced image by volume imaged breast assessme NT. ASSESSMENT: We collected clinicopathologic variables and preoperative MRI features (tumor size, lesion type, shape of mass, spiculated margin, internal enhancement, peri-tumoral edema, intra-tumoral necrosis, multifocal/multicentric, apparent diffusion coefficient [ADC] minimum, ADC mean, ADC maximum, ADC difference). STATISTICAL TESTS: K-means clustering, multivariable logistic regression, receiver operating characteristic curve. RESULTS: Sixty-one patients showed Ki67 discordance and 304 patients show Ki67 concordance according to our definition using K-means clustering. Multivariable regression analysis showed that the following parameters were independently associated with Ki67 discordance: peri-tumoral edema, odds ratio (OR) 2.662, 95% confidence interval (CI) 1.432-4.948; ADCmin ≤ 0.829 × 10-3  mm2 /sec, OR 2.180, 95% CI 1.075-4.418; and ADCdiff > 0.317 × 10-3  mm2 /sec, OR 3.365, 95% CI 1.698-6.669. This multivariable model resulted in an AUC of 0.758 (95% CI 0.711-0.802) with sensitivity and specificity being 0.803 and 0.621, respectively. CONCLUSION: Presence of peri-tumoral edema, smaller ADCmin and greater ADCdiff in preoperative breast MRI may indicate high risk of Ki67 discordance between core-needle biopsy and surgical samples. For patients with these MRI-based risk factors, clinicians should not rely on Ki67 assessment only from core-needle biopsy.

Comparison of the efficacy and safety of the adalimumab biosimilar TQ-Z2301 and adalimumab for the treatment of Chinese patients with active ankylosing spondylitis: a multi-center, randomized, double-blind, phase III clinical trial.

OBJECTIVE: To assess the clinical equivalence of TQ-Z2301, a biosimilar of adalimumab, to the reference adalimumab in the treatment of Chinese patients with active ankylosing spondylitis. METHODS: This multicenter, randomized, double-blind, positive-controlled phase III clinical trial was conducted in 19 centers across China. Chinese adults with active ankylosing spondylitis despite being treated with non-steroidal anti-inflammatory drugs for ≥ 4 weeks were randomized in a 1:1 ratio to subcutaneously receive 40 mg of TQ-Z2301 or adalimumab every other week for 24 weeks. The primary endpoint was the percentage of patients who achieved at least 20% improvement according to the Assessment of Spondyloarthritis International Society criteria (ASAS20) at week 24. The equivalence was established if the 90% CI for RR of ASAS20 between two groups at week 24 fell within (0.80, 1.25). Secondary endpoints included efficacy measures of disease activity, spinal mobility, physical function and quality of life, immunogenicity, and pharmacokinetic parameters. Safety analysis was done for all patients who received at least one study drug. RESULTS: A total of 380 patients were enrolled in the study between September 2018 and October 2019, including 188 in the TQ-Z2301 group and 192 in the adalimumab group. In the full analysis population, the ASAS20 response rate at week 24 was 86.70% in the TQ-Z2301 group, and 80.73% in the adalimumab group, the RR of ASAS20 for TQ-Z2301 versus adalimumab was 1.074, 90% CI (0.997, 1.157), fell within the predefined equivalence boundary (0.80, 1.25). Except for the SF-36 at week 12, there was no statistical difference between the two groups for all the secondary endpoints (P>0.05). The incidence of adverse events group was 82.45% in the TQ-Z2301, and 83.85% in the adalimumab group, the safety profile of the two groups was similar. The profiles of immunogenicity and pharmacokinetics were also similar between the two groups. CONCLUSION: TQ-Z2301 is equivalent to adalimumab for the treatment of Chinese patients with active ankylosing spondylitis. The safety, immunogenicity, and pharmacokinetic characteristics of both drugs are similar. TRIAL REGISTRATION: The study (CTR20181863) was registered in the Chinese Clinical Trial Registry on 19 October 2018. Key Points • TQ-Z2301 showed the equivalence of efficacy compared with the reference adalimumab for the treatment of Chinese patients with active ankylosing spondylitis. • The safety, immunogenicity, and pharmacokinetics profiles of TQZ-2301 were similar to those of the reference adalimumab.

Ultrasound and magnetic resonance imaging of cyclic arginine glycine aspartic acid-gadopentetic acid-polylactic acid in human breast cancer by targeting αvß3 in xenograft-bearing nude mice.

Effective early detection shows the potential to reduce breast cancer mortality. This study aimed to establish a targeted contrast agent for Magnetic Resonance Imaging (MRI)/ultrasound dual-modality molecular radiography for breast cancer. The cyclic arginine-glycine-aspartate-gadopentetic acid-polylactic acid (cRGD and Gd-DTPA) coated by multi-functional blank poly (lactic-co-glycolic acid) (PLGA) nanoparticles) was successfully constructed by chemical synthesis method with high stability. The safety of cRGD-Gd-DTPA-PLGA was demonstrated in vitro and in vivo, and their affinity to breast cancer cells was revealed. Moreover, MRI/ultrasound dual-modality molecular radiography in vitro showed that as the concentration of contrast agent increased, the echo enhancement and signal intensity of MRI imaging were also elevated. The mouse models of human breast cancer also indicated significant target enhancements of cRGD-Gd-DTPA-PLGA magnetic nanoparticles in the mouse tumor. Thus, cRGD-Gd-DTPA-PLGA magnetic nanoparticles were suggested as qualified MRI/ultrasound dual-modality molecular radiography contrast agent. We further explored the targeting mechanism of cRGD-Gd-DTPA-PLGA in breast cancer. The results showed that αvß3 was highly expressed in breast cancer tissues, and cRGD-Gd-DTPA-PLGA used for MRI/ultrasound dual-modality molecular radiography by targeting αvß3. Additionally, we found that the signal-to-noise ratio of MRI was positively correlated with microvessel density (MVD). The cRGD-Gd-DTPA-PLGA dynamicly and quantitatively monitored breast cancer by monitoring the state of neovascularization. In conclusion, in the present study, we successfully constructed the cRGD-Gd-DTPA-PLGA magnetic nanoparticles for MRI/ultrasound dual-modality molecular radiography. The cRGD-Gd-DTPA-PLGA showed potential in early detection and diagnosis of metastasis, and dynamic evaluation of the efficacy of molecular targeted therapy of integrin αvß3.

A functional liver imaging score for preoperative prediction of liver failure after hepatocellular carcinoma resection.

OBJECTIVES: Posthepatectomy liver failure (PHLF) is a challenging complication after resection to treat hepatocellular carcinoma (HCC), and it is associated with high mortality. Preoperative prediction of PHLF may improve patient subsequent and reduce such mortality. This study examined whether a functional liver imaging score (FLIS) based on preoperative gadoxetic acid-enhanced magnetic resonance imaging (MRI) could predict PHLF. MATERIALS AND METHODS: The study included 502 patients who underwent preoperative gadoxetic acid-enhanced MRI, followed by HCC resection. Significant preoperative predictors of PHLF were identified using logistic regression analysis. The ability of FLIS to predict PHLF was evaluated using receiver operating characteristic curves, and its predictive power was compared to that of the model for end-stage liver disease (MELD) score, albumin-bilirubin (ALBI) score, and indocyanine green 15-min retention rate (ICG-R15). RESULTS: In multivariate analysis, PHLF was independently associated with FLIS (OR 0.452, 95% CI 0.361 to 0.568, p < 0.001) and major resection (OR 1.898, 95% CI 1.057 to 3.408, p = 0.032). FLIS was associated with a higher area under the receiver operating characteristic curve (0.752) than the MELD score (0.557), ALBI score (0.609), or ICG-R15 (0.605) (all p < 0.05). Patients with FLIS ≤ 4 who underwent major resection were at 9.4-fold higher risk of PHLF than patients with lower FLIS who underwent minor resection. CONCLUSION: FLIS is an independent predictor of PHLF, and it may perform better than the MELD score, ALBI score, and ICG-R15 clearance. We propose treating elevated FLIS and major resection as risk factors for PHLF. KEY POINTS: • A functional liver imaging score can independently predict posthepatectomy liver failure in patients with HCC. • The score may predict such failure better than MELD and ALBI scores and ICG-R15. • Patients with scores ≤ 4 who undergo major hepatic resection may be at nearly tenfold higher risk of posthepatectomy liver failure.

Effect of Tacrolimus vs Intravenous Cyclophosphamide on Complete or Partial Response in Patients With Lupus Nephritis: A Randomized Clinical Trial.

Importance: Lupus nephritis (LN) is typically treated with intravenous cyclophosphamide (IVCY), which is associated with serious adverse effects. Tacrolimus may be an alternative for initial treatment of LN; however, large-scale, randomized clinical studies of tacrolimus are lacking. Objective: To assess efficacy and safety of tacrolimus vs IVCY as an initial therapy for LN in China. Design, Setting, and Participants: This randomized (1:1), open-label, parallel-controlled, phase 3, noninferiority clinical trial recruited patients aged 18 to 60 years with systemic lupus erythematosus and LN class III, IV, V, III+V, or IV+V primarily from outpatient settings at 35 centers in China. Inclusion criteria included body mass index of 18.5 or greater to less than 27, 24-hour urine protein of 1.5 g or greater, and serum creatinine of less than 260 µmol/L. Of 505 patients screened, 191 failed screening (163 ineligible, 25 withdrawn consent, and 3 other reasons). Overall, 314 were randomized. The first patient was enrolled March 10, 2015, and the study finished September 13, 2018. The follow-up period was 24 weeks. Data were analyzed from December 2019 to March 2020. Interventions: Oral tacrolimus (target trough level, 4-10 ng/mL) or IVCY for 24 weeks plus prednisone. Main Outcomes and Measures: Complete or partial response rate at week 24 (prespecified). Results: A total of 314 patients were randomized (158 [50.3%] to tacrolimus and 156 [49.7%] to IVCY). Overall, 299 patients (95.2%) were treated (tacrolimus group, 157 [52.5%]; IVCY group, 142 [47.5%]). Baseline demographic and clinical characteristics were generally similar between groups (mean [SD] age, 34.2 [9.5] years; 262 [87.6%] female). Tacrolimus was found to be noninferior to IVCY for LN response at week 24. There was a complete or partial response rate of 83.0% (117 of 141 patients) in the tacrolimus group and 75.0% (93 of 124 patients) in the IVCY group (difference, 7.1%; 2-sided 95% CI, -2.7% to 16.9%; lower limit of 95% CI greater than -15%). At week 24, least-square mean change in Systemic Lupus Erythematosus Disease Activity Index score was -8.6 with tacrolimus and -6.4 with IVCY (difference, -2.2; 95% CI, -3.1 to -1.3). Changes in other immune parameters and kidney function were generally similar between groups. Serious treatment-emergent adverse events (TEAEs) were reported in 29 patients in the tacrolimus group (18.5%) and 35 patients in the IVCY group (24.6%). Most common serious study drug-related TEAEs were infections (14 [8.9%] and 23 [16.2%], respectively). Seven patients in each group withdrew due to AEs. Conclusions and Relevance: In this study, oral tacrolimus appeared noninferior to IVCY for initial therapy of active LN, with a more favorable safety profile than IVCY. Tacrolimus may be an alternative to IVCY as initial therapy for LN. Trial Registration: ClinicalTrials.gov Identifier: NCT02457221.

Glycogen synthase kinase 3 drives thymocyte egress by suppressing ß-catenin activation of Akt.

Molecular pathways controlling emigration of mature thymocytes from thymus to the periphery remain incompletely understood. Here, we show that T cell­specific ablation of glycogen synthase kinase 3 (GSK3) led to severely impaired thymic egress. In the absence of GSK3, ß-catenin accumulated in the cytoplasm, where it associated with and activated Akt, leading to phosphorylation and degradation of Foxo1 and downregulation of Klf2 and S1P1 expression, thereby preventing emigration of thymocytes. A cytoplasmic membrane-localized ß-catenin excluded from the nucleus promoted Akt activation, suggesting a new function of ß-catenin independent of its role as a transcriptional activator. Furthermore, genetic ablation of ß-catenin, retroviral expression of a dominant negative Akt mutant, and transgenic expression of a constitutively active Foxo1 restored emigration of GSK3-deficient thymocytes. Our findings establish an essential role for GSK3 in thymocyte egress and reveal a previously unidentified signaling function of ß-catenin in the cytoplasm.

Preoperative normalized iodine concentration derived from spectral CT is correlated with early recurrence of hepatocellular carcinoma after curative resection.

OBJECTIVES: To investigate whether normalized iodine concentration (NIC) correlates with tumor microvessel density and early recurrence in patients with HCC. MATERIALS AND METHODS: We included 71 patients with surgically resected single HCC in this prospective study who underwent preoperative spectral CT between November 2014 and June 2016. Two observers independently measured the NIC in the arterial phase (AP) and portal venous phase (PVP). The relationship between NIC and microvessel density was evaluated. Univariate and multivariate logistic regression was performed to evaluate independent predictors of early recurrence. RESULTS: Early recurrence occurred in 28 of 71 patients (39.4%) during the 2-year follow-up. NIC-AP positively correlated with microvessel density for the two observers (r = 0.593 and 0.527). Based on multivariate analysis, independent risk factors for early HCC recurrence were tumor size (odds ratio, 1.200; p = 0.043) and NIC-AP (odds ratio, 2.522; p = 0.005). For the two observers, areas under the receiver operating characteristic curve for predicting early HCC recurrence were 0.719 and 0.677. Early recurrence rates were significantly higher among patients with NIC-AP values higher than the optimal cutoff than among those with values below the cutoff. CONCLUSION: Normalized iodine concentration in the arterial phase from spectral CT reflects tumor-derived angiogenesis and is a potential predictive biomarker for early recurrence of hepatocellular carcinoma. KEY POINTS: • Normalized iodine concentration in the arterial phase positively correlated with microvessel density of hepatocellular carcinoma. • In the patients with hepatocellular carcinoma, tumor size and normalized iodine concentration in the arterial phase were independent risk factors for early hepatocellular carcinoma recurrence. • Early hepatocellular carcinoma recurrence rates were significantly higher when normalized iodine concentration in the arterial phase values was above the optimal cutoff.

Changes in Apparent Diffusion Coefficient as Surrogate Marker for Changes in Ki-67 Index Due to Neoadjuvant Chemotherapy in Patients with Invasive Breast Cancer.

RATIONALE AND OBJECTIVES: To evaluate possible correlation between changes in apparent diffusion coefficient (ADC) and Ki-67 index as a result of neoadjuvant chemotherapy (NAC) in patients with invasive breast cancer. METHODS AND MATERIALS: Between February 2016 and October 2017, 87 patients with breast cancer underwent diffusion-weighted magnetic resonance imaging (b = 0 and 800 sec/mm2) before and after NAC. ADC and tumor diameter before and after NAC were compared to the Ki-67 index determined from biopsy or surgical specimens. RESULTS: Ki-67 index did not correlate significantly with ADC before NAC (p = 0.862) or afterwards (p = 0.292), nor did it correlate with tumor diameter before (p = 0.545) or afterwards (p = 0.478). However, change in ADC as a result of NAC correlated inversely with change in Ki-67 index (r = -0.326, p = 0.002). The percentage change in Ki-67 index did not correlate with the percentage change in ADC (p = 0.404). Similarly, the change in Ki-67 index or percentage change in that index did not correlate with the change in tumor diameter (p = 0.075) or percentage change in tumor diameter (p = 0.233). CONCLUSION: Comparison of pre- and post-NAC ADC can be used to estimate the change in Ki-67 index in patients with invasive breast cancer.

Value of Diffusion-Weighted Imaging Combined with Susceptibility-Weighted Imaging in Differentiating Benign from Malignant Parotid Gland Lesions.

BACKGROUND The aim of this study was to investigate the diagnostic value of diffusion-weighted imaging (DWI) in combination with susceptibility-weighted imaging (SWI) for differentiating benign parotid gland lesions from malignant ones. MATERIAL AND METHODS This retrospective study was approved by the Ethics Committee of our hospital. A total of 36 patients (26 benign cases and 10 malignant cases) were confirmed by surgical pathology. The apparent diffusion coefficient (ADC), normalized ADC (ADCNormalized), intratumoral susceptibility signals (ITSS), and morphological characteristics were analyzed with SPSS 19.0 software. RESULTS The mean ADC values of parotid gland lesions was not different between malignant and benign lesions (P=0.07), while the differences between ADCNormalized (P=0.026) and ITSS grading (P=0.014) were statistically significant. Logistic regression analysis identified use of ADCNormalized and ITSS as the only independent predictor of malignant lesions (odds ratio 0.038; 95% confidence interval 0.001~0.988; P=0.011) and (odds ratio 4.867; 95% confidence interval 1.442~16.423; P=0.049), respectively. The optimum threshold of the ADCNormalized values was -0.45%, ITSS grade was 2, the corresponding areas under the receiver operating characteristic curve (AUC) were 0.750 and 0.787 respectively, and the combination of the 2 was 0.846. CONCLUSIONS DWI integrated with SWI can significantly improve the diagnostic efficacy in distinguishing benign from malignant parotid lesions.

Identification of endothelial selectin as a potential prognostic marker in breast cancer.

Endothelial selectin (ELAM1 or CD62E) has been previously reported as being associated with the prognosis of multiple types of cancer. However, its prognostic value in breast cancer (BC) remains unclear. The aim of the present study was to investigate the prognostic value of ELAM1 mRNA expression in BC tissue. The prognostic value of ELAM1 mRNA was assessed in patients with BC using the Kaplan-Meier plotter (KM-plot) database. The KM-plot generated updated ELAM1 mRNA expression data and survival analysis from a total of 3,951 patients with BC, gathered from 35 datasets. Low expression of ELAM1 mRNA was correlated with a poorer overall survival in 1,402 patients with BC followed for 20 years [hazard ratio (HR), 0.71; 95% confidence interval (CI), 0.57-0.88; log-rank P=0.0016]. Low expression of ELAM1 was also correlated with poorer relapse-free survival (HR, 0.69; 95% CI, 0.62-0.77; log-rank P=2.2e-11) in 3,951 patients and poorer distant metastasis-free survival (HR, 0.79; 95% CI, 0.65-0.96; log-rank P=0.02) in 1,746 patients with BC followed for 20 years. Results from the Metabolic gEne RApid visualizer database indicated that ELAM1 mRNA expression was elevated in normal tissue. The results of the present study suggest that ELAM1 mRNA is a potential prognostic and metastatic marker in patients with BC.