Non-invasive diagnosis of liver fibrosis via MRI using targeted gadolinium-based nanoparticles.

INTRODUCTION: Accurate diagnosis of liver fibrosis is crucial for preventing cirrhosis and liver tumors. Liver fibrosis is driven by activated hepatic stellate cells (HSCs) with elevated CD44 expression. We developed hyaluronic acid (HA)-coated gadolinium-based nanoprobes to specifically target CD44 for diagnosing liver fibrosis using T1-weighted magnetic resonance imaging (MRI). MATERIALS AND METHODS: NaGdF4 nanoparticles (NPs) were synthesized via thermal decomposition and modified with polyethylene glycol (PEG) to obtain non-targeting NaGdF4@PEG NPs. These were subsequently coated with HA to target HSCs, resulting in liver fibrosis-targeting NaGdF4@PEG@HA nanoprobes. Characterization includedd transmission electron microscopy and X-ray diffraction. Cell viability was assessed using the Cell Counting Kit-8 (CCK-8). Internalization of NaGdF4@PEG@HA nanoprobes by mouse HSCs JS1 cells via ligand-receptor interaction was observed using flow cytometry and confocal laser scanning microscopy (CLSM). Liver fibrosis was induced in C57BL/6 mice using a methionine-choline deficient (MCD) diet. MRI performance and nanoprobe distribution in fibrotic and normal livers were analyzed using a GE Discovery 3.0T MR 750 scanner. RESULTS: NaGdF4@PEG@HA nanoprobes exhibited homogeneous morphology, low toxicity, and a high T1 relaxation rate (7.645 mM⁻¹s⁻¹). CLSM and flow cytometry demonstrated effective phagocytosis of NaGdF4@PEG@HA nanoprobes by JS1 cells compared to NaGdF4@PEG. MRI scans revealed higher T1 signals in fibrotic livers compared to normal livers after injection of NaGdF4@PEG@HA. NaGdF4@PEG@HA demonstrated higher targeting ability in fibrotic mice. CONCLUSIONS: NaGdF4@PEG@HA nanoprobes effectively target HSCs with high T1 relaxation rate, facilitating efficient MRI diagnosis of liver fibrosis.

Highly Graphitized Coal Tar Pitch-Derived Porous Carbon as High-Performance Lithium Storage Materials.

Because of its high specific capacity and superior rate performance, porous carbon is regarded as a potential anode material for lithium-ion batteries (LIBs). However, porous carbon materials with wide pore diameter distributions suffer from low structural stability and low electrical conductivity during the application process. During this study, the calcium carbonate nanoparticle template method is used to prepare coal tar pitch-derived porous carbon (CTP-X). The coal tar pitch-derived porous carbon has a well-developed macroporous-mesoporous-microporous hierarchical porous network structure, which provides abundant active sites for Li+ storage, significantly reduces polarization and charge transfer resistance, shortens the diffusion path and promotes the rapid transport of Li+. More specifically, the CTP-2 anode shows high charge capacity (496.9 mAh g-1 at 50 mA g-1), excellent rate performance (413.6 mAh g-1 even at 500 mA g-1), and high cycling stability (capacity retention rate of about 100 % after 1,000 cycles at 2 A g-1). The clean and eco-friendly large-scale utilization of coal tar pitch will facilitate the development of high-performance anodes in the field of LIBs.

Low Expression of GRIM-19 Correlates with Poor Prognosis in Patients with Upper Urinary Tract Urothelial Carcinoma.

PURPOSE: This study aimed to clarify the expression of a gene associated with Retinoid- Interferon-Induced Mortality-19 (GRIM-19) in Upper Urinary Tract Urothelial Carcinoma (UUTUC) and its prognostic significance for UUTUC patients. MATERIALS AND METHODS: Immunohistochemical (IHC) staining was used to determine the GRIM-19 expression in 70 paired samples. Progression-Free Survival (PFS) and Cancer-Specific Survival (CSS) were assessed using the Kaplan-Meier method. The independent prognostic factors for PFS and CSS were analyzed by multivariable Cox regression models. RESULTS: IHC staining showed that GRIM-19 expression was significantly decreased in UUTUC, and its cellular location changed from being both cytoplasmic and nuclear to only cytoplasmic. Kaplan- Meier analysis revealed that the patients with tumors expressing low GRIM-19 had a significantly higher risk for tumor progression (P = 0.002) and cancer-specific mortality (P < 0.001) compared to those with high GRIM-19 levels. The Cox regression showed that both GRIM-19 expression (P = 0.025) and lymph node metastasis (LN) (P = 0.007) were independent predictors of progression in the muscle-invasive (MIC) subgroup. GRIM-19 expressions (entire cohort: P = 0.011; MIC subgroup: P = 0.025), LN (entire cohort: P = 0.019; MIC subgroup: P = 0.007), and progression (entire cohort: P < 0.001; MIC subgroup: P < 0.001) were independent predictors of cancer-specific survival. CONCLUSION: Low expression of GRIM-19 in patients with UUTUC had significantly shorter PFS or CSS compared to those with high GRIM-19-expressing tumors. High GRIM-19 expression was also strongly associated with longer PFS in MIC patients. It indicates that GRIM-19 might serve as a promising prognostic biomarker for UUTUC patients.

Berlin Green with tunable iron content as ultra-high rate host for efficient aqueous ammonium ion storage.

Prussian blue analogues (PBAs) are regarded as promising cathode materials for ammonium-ion batteries (AIBs) because of their low cost and superb theoretical capacity. However, its inherently poor conductivity and structural collapse can significantly limit the enhancement of rate property and cycling stability. In this work, Berlin Green (BG) electrode materials with similar wool-like clusters were constructed by direct precipitation method to accelerate the kinetic, which realizes outstanding cycling stability. Berlin Green with the appropriate amount of iron (BG-2) has a fast ion transport channel, enhanced structure stability, highly reversible insertion/extraction of NH4+, and fine electrochemical reaction activity. Benefiting from the unique architecture and component, the BG-2 electrode shows an excellent rate performance with a discharge/charge specific capacity of 60.1/59.3 mAh g-1 at 5 A g-1. Even at 5 A g-1, BG-2 exhibits remarkable cycling stability with an initial discharge capacity of 59.5 mAh g-1 and a capacity retention rate of approximately 76% after 30,000 cycles. The BG-2 reveals exceedingly good electrochemical reversibility during the process of NH4+ (de)insertion. BG materials indicate huge potential as a cathode material for the next generation of high-performance aqueous batteries.

Multi-task reconstruction network for synthetic diffusion kurtosis imaging: Predicting neoadjuvant chemoradiotherapy response in locally advanced rectal cancer.

PURPOSE: To assess the feasibility and clinical value of synthetic diffusion kurtosis imaging (DKI) generated from diffusion weighted imaging (DWI) through multi-task reconstruction network (MTR-Net) for tumor response prediction in patients with locally advanced rectal cancer (LARC). METHODS: In this retrospective study, 120 eligible patients with LARC were enrolled and randomly divided into training and testing datasets with a 7:3 ratio. The MTR-Net was developed for reconstructing Dapp and Kapp images from apparent diffusion coefficient (ADC) images. Tumor regions were manually segmented on both true and synthetic DKI images. The synthetic image quality and manual segmentation agreement were quantitatively assessed. The support vector machine (SVM) classifier was used to construct radiomics models based on the true and synthetic DKI images for pathological complete response (pCR) prediction. The prediction performance for the models was evaluated by the receiver operating characteristic (ROC) curve analysis. RESULTS: The mean squared error (MSE), peak signal-to-noise ratio (PSNR), and structural similarity index measure (SSIM) for tumor regions were 0.212, 24.278, and 0.853, respectively, for the synthetic Dapp images and 0.516, 24.883, and 0.804, respectively, for the synthetic Kapp images. The Dice similarity coefficient (DSC), positive predictive value (PPV), sensitivity (SEN), and Hausdorff distance (HD) for the manually segmented tumor regions were 0.786, 0.844, 0.755, and 0.582, respectively. For predicting pCR, the true and synthetic DKI-based radiomics models achieved area under the curve (AUC) values of 0.825 and 0.807 in the testing datasets, respectively. CONCLUSIONS: Generating synthetic DKI images from DWI images using MTR-Net is feasible, and the efficiency of synthetic DKI images in predicting pCR is comparable to that of true DKI images.

LncRNA CCAT1 participates in pancreatic ductal adenocarcinoma progression by forming a positive feedback loop with c-Myc.

Long noncoding RNAs (lncRNAs) play fundamental roles in cancer development; however, the underlying mechanisms for a large proportion of lncRNAs in pancreatic ductal adenocarcinoma (PDAC) have not been elucidated. The expression of colon cancer-associated transcript-1 (CCAT1) in PDAC specimens and cell lines was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The function of CCAT1 was examined in vitro and in vivo. The interactions among CCAT1, miR-24-3p and c-Myc were determined by bioinformatics analysis, RNA immunoprecipitation (RIP), dual-luciferase reporter assay, and rescue experiments. CCAT1 was significantly increased in PDAC, positively correlated with PDAC progression and predicted a worse prognosis. Furthermore, CCAT1 enhanced Adenosine triphosphate (ATP) production to facilitate PDAC cell proliferation, colony formation and motility in vitro and tumor growth in vivo. CCAT1 may serve as an miR-24-3p sponge, thereby counteracting its repression by c-Myc expression. Reciprocally, c-Myc may act as a transcription factor to alter CCAT1 expression by directly targeting its promoter region, thus forming a positive feedback loop with CCAT1. Collectively, these results demonstrate that a positive feedback loop of CCAT1/miR-24-3p/c-Myc is involved in PDAC development, which may serve as a biomarker and therapeutic target for PDAC.

The Prognostic and Immune Significance of CILP2 in Pan-Cancer and Its Relationship with the Progression of Pancreatic Cancer.

Cartilage intermediate layer protein 2 (CILP2) facilitates interactions between matrix components in cartilage and has emerged as a potential prognostic biomarker for cancer. This study aimed to investigate the function and mechanisms of CILP2 in pan-cancer. We evaluated the pan-cancer expression, methylation, and mutation data of CILP2 for its clinical prognostic value. Additionally, we explored the immunological characteristics of CILP2 in pan-cancer and then focused specifically on pancreatic ductal adenocarcinoma (PAAD). The subtype analysis of PAAD identified subtype-specific expression and immunological characteristics. Finally, in vitro and in vivo experiments assessed the impact of CILP2 on pancreatic cancer progression. CILP2 exhibited high expression in most malignancies, with significant heterogeneity in epigenetic modifications across multiple cancer types. The abnormal methylation and copy number variations in CILP2 were correlated with poor prognoses. Upregulated CILP2 was associated with TGFB/TGFBR1 and more malignant subtypes. CILP2 exhibited a negative correlation with immune checkpoints in PAAD, suggesting potential for immunotherapy. CILP2 activated the AKT pathway, and it increased proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) in pancreatic cancer. We demonstrated that CILP2 significantly contributes to pancreatic cancer progression. It serves as a prognostic biomarker and a potential target for immunotherapy.

Radiomics for predicting survival in patients with locally advanced rectal cancer: a systematic review and meta-analysis.

Background: Radiomics has recently received considerable research attention for providing potential prognostic biomarkers for locally advanced rectal cancer (LARC). We aimed to comprehensively evaluate the methodological quality and prognostic prediction value of radiomic studies for predicting survival outcomes in patients with LARC. Methods: The Cochrane, Embase, Medline, and Web of Science databases were searched. The radiomics quality score (RQS), Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) checklist, the Image Biomarkers Standardization Initiative (IBSI) guideline, and the Prediction Model Risk of Bias Assessment Tool were used to assess the quality of the selected studies. A further meta-analysis of hazard ratio (HR) regarding disease-free survival (DFS) and overall survival (OS) was performed. Results: Among the 358 studies reported, 15 studies were selected for our review. The mean RQS score was 7.73±4.61 (21.5% of the ideal score of 36). The overall TRIPOD adherence rate was 64.4% (251/390). Most of the included studies (60%) were assessed as having a high risk of bias (ROB) overall. The pooled estimates of the HRs were 3.14 [95% confidence interval (CI): 2.12-4.64, P<0.01] for DFS and 3.36 (95% CI: 1.74-6.49, P<0.01) for OS. Conclusions: Radiomics has potential to noninvasively predict outcome in patients with LARC. However, the overall methodological quality of radiomics studies was low, and the adherence to the TRIPOD statement was moderate. Future radiomics research should put a greater focus on enhancing the methodological quality and considering the influence of higher-order features on reproducibility in radiomics.

Radiomics based on readout-segmented echo-planar imaging (RS-EPI) diffusion-weighted imaging (DWI) for prognostic risk stratification of patients with rectal cancer: a two-centre, machine learning study using the framework of predictive, preventive, and personalized medicine.

Background: Currently, the rate of recurrence or metastasis (ROM) remains high in rectal cancer (RC) patients treated with the standard regimen. The potential of diffusion-weighted imaging (DWI) in predicting ROM risk has been reported, but the efficacy is insufficient. Aims: This study investigated the potential of a new sequence called readout-segmented echo-planar imaging (RS-EPI) DWI in predicting the ROM risk of patients with RC using machine learning methods to achieve the principle of predictive, preventive, and personalized medicine (PPPM) application in RC treatment. Methods: A total of 195 RC patients from two centres who directly received total mesorectal excision were retrospectively enrolled in our study. Machine learning methods, including recursive feature elimination (RFE), the synthetic minority oversampling technique (SMOTE), and the support vector machine (SVM) classifier, were used to construct models based on clinical-pathological factors (clinical model), radiomic features from RS-EPI DWI (radiomics model), and their combination (merged model). The Harrell concordance index (C-index) and the area under the time-dependent receiver operating characteristic curve (AUC) were calculated to evaluate the predictive performance at 1 year, 3 years, and 5 years. Kaplan‒Meier analysis was performed to evaluate the ability to stratify patients according to the risk of ROM. Findings: The merged model performed well in predicting tumour ROM in patients with RC at 1 year, 3 years, and 5 years in both cohorts (AUC = 0.887/0.813/0.794; 0.819/0.795/0.783) and was significantly superior to the clinical model (AUC = 0.87 [95% CI: 0.80-0.93] vs. 0.71 [95% CI: 0.59-0.81], p = 0.009; C-index = 0.83 [95% CI: 0.76-0.90] vs. 0.68 [95% CI: 0.56-0.79], p = 0.002). It also had a significant ability to differentiate patients with a high and low risk of ROM (HR = 12.189 [95% CI: 4.976-29.853], p < 0.001; HR = 6.427 [95% CI: 2.265-13.036], p = 0.002). Conclusion: Our developed merged model based on RS-EPI DWI accurately predicted and effectively stratified patients with RC according to the ROM risk at an early stage with an individualized profile, which may be able to assist physicians in individualizing the treatment protocols and promote a meaningful paradigm shift in RC treatment from traditional reactive medicine to PPPM. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-022-00303-3.

Positive feedback regulation of lncRNA TPT1-AS1 and ITGB3 promotes cell growth and metastasis in pancreatic cancer.

Emerging evidence has indicated that long noncoding RNAs (lncRNAs) are potential biomarkers and play crucial roles in cancer development. However, the functions and underlying mechanisms of lncRNA TPT1-AS1 in pancreatic ductal adenocarcinoma (PDAC) remain elusive. RNAseq data of PDAC tissues and normal tissues were analyzed, and lncRNAs which were associated with PDAC prognosis were identified. The clinical relevance of TPT1-AS1 for PDAC patients was explored, and the effects of TPT1-AS1 in PDAC progression were investigated in vitro and in vivo. LncRNA TPT1-AS1 was highly expressed in PDAC, and high TPT1-AS1 levels predicted a poor prognosis. Moreover, functional experiments revealed that TPT1-AS1 promoted pancreatic cancer cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT) process in vitro and in vivo. Mechanistically, TPT1-AS1 functioned as an endogenous sponge for miR-30a-5p, which increased integrin ß3 (ITGB3) level in pancreatic cancer cells. Conversely, our data revealed that ITGB3 could activate the transcription factor signal transducer and activator of transcription 3 (STAT3), which in turn bound directly to the TPT1-AS1 promoter and affected the expression of TPT1-AS1, thus forming a positive feedback loop with TPT1-AS1. Taken together, our results uncovered a reciprocal loop of TPT1-AS1 and ITGB3 which contributed to pancreatic cancer growth and development, and indicated that TPT1-AS1 might serve as a novel potential diagnostic biomarker and therapeutic target for PDAC patients.

Nonswelling injectable chitosan hydrogel via UV crosslinking induced hydrophobic effect for minimally invasive tissue engineering.

Injectable chitosan hydrogels exhibit excellent biological properties for application in biomedical engineering, however most of these hydrogels have limited applicability because "Swelling" can induce volume expansion of conventional hydrogels implanted in the body damages the surrounding tissues. Here, we report a new "Nonswelling" pentenyl chitosan (PTL-CS) hydrogel via N‒acylation reaction to graft an UV crosslinkable short hydrophobic alkyl chain (n‒pentenyl groups). The incorporated pentenyl groups can be crosslinked by UV irradiation to form hydrophobic chains via combination termination, which generate strong hydrophobic effect to extrude the excess water in hydrogel, resulting in a "Nonswelling" state at biological temperature. Furthermore, the PTL-CS solution showed no cytotoxicity in vitro and minimally invasive treatment in vivo demonstrated the PTL-CS hydrogel no adverse effects in a rat model. The nonswelling injectable and UV crosslinkable chitosan hydrogel hold potential applications in smart biomaterials and biological engineering as well as providing a new natural hydrogel in minimally invasive tissue engineering..

Engineered Bacterial Bioreactor for Tumor Therapy via Fenton-Like Reaction with Localized H2 O2 Generation.

Synthetic biology based on bacteria has been displayed in antitumor therapy and shown good performance. In this study, an engineered bacterium Escherichia coli MG1655 is designed with NDH-2 enzyme (respiratory chain enzyme II) overexpression (Ec-pE), which can colonize in tumor regions and increase localized H2 O2 generation. Following from this, magnetic Fe3 O4 nanoparticles are covalently linked to bacteria to act as a catalyst for a Fenton-like reaction, which converts H2 O2 to toxic hydroxyl radicals (•OH) for tumor therapy. In this constructed bioreactor, the Fenton-like reaction occurs with sustainably synthesized H2 O2 produced by engineered bacteria, and severe tumor apoptosis is induced via the produced toxic •OH. These results show that this bioreactor can achieve effective tumor colonization, and realize a self-supplied therapeutic Fenton-like reaction without additional H2 O2 provision.

Construction and Characterization of Phthalocyanine-Loaded Particles of Curdlan and Their Photosensitivity.

To optimize the physicochemical properties of phthalocyanine (PC), we examined its behavior in particles of triple helix glucan curdlan (CUR). CUR was denatured and renatured in DMSO, in the presence of PC. Infrared spectroscopy and transmission electron microscopy (TEM) showed that PC and CUR formed an inclusion complex, in which PC was trapped inside CUR molecules. This redshifted the absorption peak of PC, which would improve its usefulness as a photosensitizer, because infrared light can penetrate more deeply into human tissues. The conductivity of the solution of CUR-PC was higher than the conductivities of either a CUR solution or a PC dispersion, indicating that CUR-PC is more water soluble than PC. In addition, CUR-PC was highly stable in water. Thus, the use of CUR as a carrier of PC improves several of its physical properties. PC is used as a photosensitizer for killing cancer cells, but its use is hampered by its low solubility. Further, its absorption range limits its use to a depth of 1⁻3 mm in tissues. CUR-PC, with its high solubility and infrared absorption peak, was highly effective as a photosensitizer. It killed 84% of HeLa cells under 15 min of long wavelength radiation and had little cytotoxicity in the absence of light. These results demonstrate that CUR-PC has promise as a photosensitizer, as well as provide theoretical support for a wide range of applications for PC and CUR.

Nitrogen source and mineral optimization enhance D: -xylose conversion to ethanol by the yeast Pichia stipitis NRRL Y-7124.

Nutrition-based strategies to optimize xylose to ethanol conversion by Pichia stipitis were identified in growing and stationary-phase cultures provided with a defined medium varied in nitrogen, vitamin, purine/pyrimidine, and mineral content via full or partial factorial designs. It is surprising to note that stationary-phase cultures were unable to ferment xylose (or glucose) to ethanol without the addition of a nitrogen source, such as amino acids. Ethanol accumulation increased with arginine, alanine, aspartic acid, glutamic acid, glycine, histidine, leucine, and tyrosine, but declined with isoleucine. Ethanol production from 150 g/l xylose was maximized (61+/-9 g/l) by providing C:N in the vicinity of approximately 57-126:1 and optimizing the combination of urea and amino acids to supply 40-80 % nitrogen from urea and 60-20 % from amino acids (casamino acids supplemented with tryptophan and cysteine). When either urea or amino acids were used as sole nitrogen source, ethanol accumulation dropped to 11 or 24 g/l, respectively, from the maximum of 46 g/l for the optimal nitrogen combination. The interaction of minerals with amino acids and/or urea was key to optimizing ethanol production by cells in both growing and stationary-phase cultures. In nongrowing cultures supplied with nitrogen as amino acids, ethanol concentration increased from 24 to 54 g/l with the addition of an optimized mineral supplement of Fe, Mn, Mg, Ca, Zn, and others.

27-Hydroxycholesterol inhibits neutral sphingomyelinase in cultured human endothelial cells.

To study the effect of 27-hydroxycholesterol (27OHC) on the catabolism of sphingomyelin, we cultured endothelial cells (ECs) from human umbilical veins with 27OHC, then measured activities of acid sphingomyelinase (ASMase) and neutral sphingomyelinase (NSMase) and sphingomyelin consumption by using [14C]sphingomyelin, and determined NSMase mRNA expressions by RT-PCR method. The results indicated that [14C]sphingomyelin accumulated in cells treated with 27OHC, and that the activities of both NSMase and ASMase were inhibited in ECs cultured with 27OHC. To further study the effect of 27OHC on NSMase, we used desipramine, an inhibitor of ASMase, to exclude the possible interference of ASMase's residual activity at neutral condition. Also, we observed the significant inhibition of NSMase activity by using glutathione, an inhibitor of NSMase, but found no further impact when 27OHC was added later. To determine whether the inhibition of NSMase activity was directly due to the effect of 27OHC, we exposed cell homogenate to 27OHC, and found no inhibitive effect of 27OHC on the activity of NSMase. All of our data confirmed that 27OHC had only an indirect inhibitive effect on NSMase. Our finding that no change of the NSMase mRNA expression by 27OHC indicated that the inhibitive effect of 27OHC on NSMase activity occurred at a post-transcriptional level. We suggest that an altered membrane fluidity caused by 27OHC could be involved in the inhibited activity of NSMase.

[Basic study of biodegradable controlled release chemotherapy].

This study sought to assess the biocompatibility of P(DA-SA)-Adriamycin, a new controlled-release chemotherapy system, in rabbit brain, and to examine its controlled release effect both in vitro and in vivo and its curative effects in vitro. The reaction of animal brain to the implanted P(DA-SA) or P(DA-SA)-Adriamycin was observed. The controlled-release profiles in phosphate buffer solutions and in rabbit brain were measured by UV spectrometry. Then, through flow cytometer, the rate of apoptosis in cultured glioma cells was tested. The reaction of rabbit brain to P(DA-SA) polymer was moderate and not significantly different from that to Gelfoam. The controlled-release rate of P(DA-SA)-Adriamycin in vitro and in vivo was stable and the duration of controlled-release of P(DA-SA)-Adriamycin spanned three weeks. The rate for apoptosis of glioma cells of P(DA-SA)-Adriamycin group was 69.9%, which was significantly higher than that of the control group. In conclusion, P (DA-SA)-Adriamycin controlled release chemotherapy system that bears curative effect has favorable controlled-release effect and good biocompatibility in rabbit brain. This system has potential value in treatment of malignant brain tumor.