Diffusion along the perivascular space as a potential biomarker for glioma grading and isocitrate dehydrogenase 1 mutation status prediction.

Background: The diffusion tensor image analysis along the perivascular space (DTI-ALPS) may have the potential to reflect glymphatic dysfunction in patients with glioma. The study aimed to determine the correlation of DTI-ALPS with glioma grade and isocitrate dehydrogenase 1 (IDH1) genotype and to then compare the ALPS index with other diffusion metrics. Methods: In this study, 81 patients with glioma and 31 healthy controls underwent magnetic resonance imaging (MRI) examination. The ALPS-index, fractional anisotropy (FA), mean diffusivity (MD), and mean kurtosis (MK) were calculated. Comparisons were made between the left and right hemispheres and between patients and controls. IDH1 status was compared after age adjustment. The diagnostic performance of each metric was assessed via receiver operating characteristic (ROC) analysis. Results: In patients with glioma, the ALPS-index of the hemisphere ipsilateral to glioma was significantly lower than that of the hemisphere contralateral to glioma (1.417±0.177 vs. 1.478±0.165; P=0.002), and the bilateral ALPS-index values in patients were significantly decreased compared with those in healthy controls. The ALPS-index was significantly higher in lower-grade gliomas (LrGGs) than that in glioblastomas (GBMs) (1.495±0.151 vs. 1.320±0.159; P<0.001) and was significantly lower in IDH1-wild-type LrGGs than in IDH1-mutant LrGGs (1.400±0.185 vs. 1.530±0.123; P=0.036). FA, MD, and MK also showed significant differences between LrGGs and GBMs and between IDH1-mutant and IDH1-wild-type LrGGs (P<0.05). Furthermore, the combination of the ALPS-index with FA, MD, or MK, exhibited superior discrimination ability compared to each metric used alone. The ALPS-index combined with MD had the highest area under the curve (AUC) of 0.854 as compared to that of 0.614-0.807 for a single metric in glioma grading, while for IDH1 mutation prediction, this combination had the highest AUC of 0.861 as compared to that of 0.707-0.778 for a single metric. Conclusions: The reduced ALPS-index may reflect tumor-induced glymphatic system impairment, and the ALPS-index may be able to complement conventional diffusion metrics in glioma grading and IDH1 genotyping.

Effects of intrathecal pemetrexed on the survival of patients with leptomeningeal metastasis from lung adenocarcinoma: a propensity score matching analysis.

PURPOSE: To explore the impact of intrathecal pemetrexed (IP) on the survival of lung adenocarcinoma (LUAC) patients with leptomeningeal metastasis (LM). METHODS: We analyzed patients with LUAC and LM who received systemic therapy after LM diagnosis at the Fujian Cancer Hospital between July 2018 and March 2022. Patients who underwent IP were assigned to the IP group; those without IP treatment were designated as the non-IP group. Propensity score matching (PSM) was performed between the two groups. RESULTS: 165 patients were enrolled: 83 and 82 in the IP and non-IP groups, respectively. After 1:1 PSM, we included 114 patients in the matched cohort. Median overall survival (OS) was 13.2 months (95% CI 10.8-15.6 months) in the IP group versus 10.1 months (95% CI 5.3-14.9 months) in the non-IP group (P = 0.488). Only Eastern Cooperative Oncology Group Performance Status (ECOG PS) was confirmed as an independent predictor for OS in the matched cohort (hazard ratio (HR) 2.03; P = 0.023). Multivariate competing-risks analysis showed that IP significantly correlated with central nervous system-related death (HR 0.31; P = 0.046). When stratified by ECOG PS, IP improved survival in patients with poor ECOG PS (PS = 2) (14.3 months vs. 1.6 months; P = 0.003). CONCLUSIONS: Intrathecal pemetrexed did not enhance OS for the entire LUAC patient with LM compared to non-intrathecal chemotherapy. However, it exhibited the potential to reduce the risk of central nervous system-related mortality and improve survival in patients with poor ECOG PS.

Split-Cas9-based targeted gene editing and nanobody-mediated proteolysis-targeting chimeras optogenetically coordinated regulation of Survivin to control the fate of cancer cells.

BACKGROUND: Precise regulation of partial critical proteins in cancer cells, such as anti-apoptotic proteins, is one of the crucial strategies for treating cancer and discovering related molecular mechanisms. Still, it is also challenging in actual research and practice. The widely used CRISPR/Cas9-based gene editing technology and proteolysis-targeting chimeras (PROTACs) have played an essential role in regulating gene expression and protein function in cells. However, the accuracy and controllability of their targeting remain necessary. METHODS: Construction of UMUC-3-EGFP stable transgenic cell lines using the Sleeping Beauty system, Flow cytometry, quantitative real-time PCR, western blot, fluorescence microplate reader and fluorescence inverted microscope analysis of EGFP intensity. Characterization of Survivin inhibition was done by using Annexin V-FITC/PI apoptosis, calcein/PI/DAPI cell viability/cytotoxicity assay, cloning formation assay and scratch assay. The cell-derived xenograft (CDX) model was constructed to assess the in vivo effects of reducing Survivin expression. RESULTS: Herein, we established a synergistic control platform that coordinated photoactivatable split-Cas9 targeted gene editing and light-induced protein degradation, on which the Survivin gene in the nucleus was controllably edited by blue light irradiation (named paCas9-Survivin) and simultaneously the Survivin protein in the cytoplasm was degraded precisely by a nanobody-mediated target (named paProtacL-Survivin). Meanwhile, in vitro experiments demonstrated that reducing Survivin expression could effectively promote apoptosis and decrease the proliferation and migration of bladder cancerous cells. Furthermore, the CDX model was constructed using UMUC-3 cell lines, results from animal studies indicated that both the paCas9-Survivin system and paProtacL-Survivin significantly inhibited tumour growth, with higher inhibition rates when combined. CONCLUSIONS: In short, the coordinated regulatory strategies and combinable technology platforms offer clear advantages in controllability and targeting, as well as an excellent reference value and universal applicability in controlling the fate of cancer cells through multi-level regulation of key intracellular factors.

Flavonoid Synthesis by Deinococcus sp. 43 Isolated from the Ginkgo Rhizosphere.

Flavonoids are crucial in physiological and pharmaceutical processes, especially the treatment of cancer and the prevention of cardiovascular and cerebrovascular diseases. Flavonoid-producing plants and fungi have been extensively reported, but bacteria have been much less investigated as a source of flavonoid production. Deinococcus sp. 43, a spherical flavonoid-producing bacteria from the Ginkgo rhizosphere, was reported in this study. First, the whole genome of Deinococcus sp. 43 was sequenced and a series of flavonoid anabolic genes were annotated. Simultaneously, High Performance Liquid Chromatography (HPLC) results showed that Deinococcus sp. 43 was capable of producing flavonoids, with a maximum quercetin output of 2.9 mg/L. Moreover, the relative expression of key genes involved in flavonoid synthesis was determined to test the completeness of the flavonoid anabolic pathway. The results of LC-MS analysis demonstrated that the flavonoids produced by Deinococcus sp. 43 were significantly different between intracellular and extracellular environments. The concentration of multiple glycosylated flavonoids was substantially higher in extracellular than intracellular environments, while the majority of flavonoids obtained in intracellular environments were hydroxylated multiple times. Lastly, the flavonoid biosynthetic pathway of Deinococcus sp. 43 was constructed based on the genomic analysis and the detected flavonoids. In conclusion, this study represents the first comprehensive characterization of the flavonoid-producing pathway of Deinococcus. The findings demonstrate that the strain has excellent potential as a genetically engineered strain for the industrial production of flavonoids.

Vegetable Oil-Peroxidation Product 'Hydroxynonenal' Causes Hepatocyte Injury and Steatosis via Hsp70.1 and BHMT Disorders in the Monkey Liver.

Hsp70.1 has a dual function as a chaperone protein and lysosomal stabilizer. In 2009, we reported that calpain-mediated cleavage of carbonylated Hsp70.1 causes neuronal death by inducing lysosomal rupture in the hippocampal CA1 neurons of monkeys after transient brain ischemia. Recently, we also reported that consecutive injections of the vegetable oil-peroxidation product 'hydroxynonenal' induce hepatocyte death via a similar cascade in monkeys. As Hsp70.1 is also related to fatty acid ß-oxidation in the liver, its deficiency causes fat accumulation. The genetic deletion of betaine-homocysteine S-methyltransferase (BHMT) was reported to perturb choline metabolism, inducing a decrease in phosphatidylcholine and resulting in hepatic steatosis. Here, focusing on Hsp70.1 and BHMT disorders, we studied the mechanisms of hepatocyte degeneration and steatosis. Monkey liver tissues with and without hydroxynonenal injections were compared using proteomics, immunoblotting, immunohistochemical, and electron microscopy-based analyses. Western blotting showed that neither Hsp70.1 nor BHMT were upregulated, but an increased cleavage was observed in both. Proteomics showed a marked downregulation of Hsp70.1, albeit a two-fold increase in the carbonylated BHMT. Hsp70.1 carbonylation was negligible, in contrast to the ischemic hippocampus, which was associated with ~10-fold increments. Although histologically, the control liver showed very little lipid deposition, numerous tiny lipid droplets were seen within and around the degenerating/dying hepatocytes in monkeys after the hydroxynonenal injections. Electron microscopy showed permeabilization/rupture of lysosomal membranes, dissolution of the mitochondria and rough ER membranes, and proliferation of abnormal peroxisomes. It is probable that the disruption of the rough ER caused impaired synthesis of the Hsp70.1 and BHMT proteins, while impairment of the mitochondria and peroxisomes contributed to the sustained generation of reactive oxygen species. In addition, hydroxynonenal-induced disorders facilitated degeneration and steatosis in the hepatocytes.

Microwave ablation versus radiofrequency ablation for patients with primary and secondary hyperparathyroidism: a meta-analysis.

OBJECTIVE: Thermal ablation, including microwave ablation (MWA) and radiofrequency ablation (RFA), has been recommended for the treatment of primary hyperparathyroidism (PHPT) and refractory secondary hyperparathyroidism (SHPT). This meta-analysis was conducted to evaluate the efficacy and safety of MWA and RFA in patients with PHPT and refractory SHPT. METHODS: Databases including PubMed, EMbase, the Cochrane Library, CNKI (China National Knowledge Infrastructure), and Wanfang were searched from inception to December 5, 2022. Eligible studies comparing MWA and RFA for PHPT and refractory SHPT were included. Data were analyzed using Review Manager software, version 5.3. RESULTS: Five studies were included in the meta-analysis. Two were retrospective cohort studies, and three were RCTs. Overall, 294 patients were included in the MWA group, and 194 patients were included in the RFA group. Compared with RFA for refractory SHPT, MWA had a shorter operation time for a single lesion (P < 0.01) and a higher complete ablation rate for a single lesion ≥ 15 mm (P < 0.01) but did not show a difference in the complete ablation rate for a single lesion < 15 mm (P > 0.05). There were no significant differences between MWA and RFA for refractory SHPT concerning parathyroid hormone (P > 0.05), calcium (P > 0.05), and phosphorus levels (P > 0.05) within 12 months after ablation, except that calcium (P < 0.01) and phosphorus levels (P = 0.02) in the RFA group were lower than those in the MWA group at one month after ablation. There was no significant difference between MWA and RFA concerning the cure rate of PHPT (P > 0.05). There were no significant differences between MWA and RFA for PHPT and refractory SHPT concerning the complications of hoarseness (P > 0.05) and hypocalcaemia (P > 0.05). CONCLUSION: MWA had a shorter operation time for single lesions and a higher complete ablation rate for large lesions in patients with refractory SHPT. However, there was no significant difference in efficacy and safety between MWA and RFA in cases of both PHPT and refractory SHPT. Both MWA and RFA are effective treatment methods for PHPT and refractory SHPT.

Dynamic variation of Paris polyphylla root-associated microbiome assembly with planting years.

MAIN CONCLUSION: P. polyphylla selectively enriches beneficial microorganisms to help their growth. Paris polyphylla (P. polyphylla) is an important perennial plant for Chinese traditional medicine. Uncovering the interaction between P. polyphylla and the related microorganisms would help to utilize and cultivate P. polyphylla. However, studies focusing on P. polyphylla and related microbes are scarce, especially on the assembly mechanisms and dynamics of the P. polyphylla microbiome. High-throughput sequencing of the 16S rRNA genes was implemented to investigate the diversity, community assembly process and molecular ecological network of the bacterial communities in three root compartments (bulk soil, rhizosphere, and root endosphere) across three years. Our results demonstrated that the composition and assembly process of the microbial community in different compartments varied greatly and were strongly affected by planting years. Bacterial diversity was reduced from bulk soils to rhizosphere soils to root endosphere and varied over time. Microorganisms benefit to plants was selectively enriched in P. polyphylla roots as was its core microbiome, including Pseudomonas, Rhizobium, Steroidobacter, Sphingobium and Agrobacterium. The network's complexity and the proportion of stochasticity in the community assembly process increased. Besides, nitrogen metabolism, carbon metabolism, phosphonate and phosphinate metabolism genes in bulk soils increased over time. These findings suggest that P. polyphylla exerts a selective effect to enrich the beneficial microorganisms and proves the sequential increasing selection pressure with P. polyphylla growth. Our work adds to the understanding of the dynamic processes of plant-associated microbial community assembly, guides the selection and application timing of P. polyphylla-associated microbial inoculants and is vital for sustainable agriculture.

Noninvasive Evaluation of the Notch Signaling Pathway via Radiomic Signatures Based on Multiparametric MRI in Association With Biological Functions of Patients With Glioma: A Multi-institutional Study.

BACKGROUND: Noninvasive determination of Notch signaling is important for prognostic evaluation and therapeutic intervention in glioma. PURPOSE: To predict Notch signaling using multiparametric (mp) MRI radiomics and correlate with biological characteristics in gliomas. STUDY TYPE: Retrospective. POPULATION: A total of 63 patients for model construction and 47 patients from two public databases for external testing. FIELD STRENGTH/SEQUENCE: A 1.5 T and 3.0 T, T1-weighted imaging (T1WI), T2WI, T2 fluid attenuated inversion recovery (FLAIR), contrast-enhanced (CE)-T1WI. ASSESSMENT: Radiomic features were extracted from CE-T1WI, T1WI, T2WI, and T2FLAIR and imaging signatures were selected using a least absolute shrinkage and selection operator. Diagnostic performance was compared between single modality and a combined mpMRI radiomics model. A radiomic-clinical nomogram was constructed incorporating the mpMRI radiomic signature and Karnofsky Performance score. The performance was validated in the test set. The radiomic signatures were correlated with immunohistochemistry (IHC) analysis of downstream Notch pathway components. STATISTICAL TESTS: Receiver operating characteristic curve, decision curve analysis (DCA), Pearson correlation, and Hosmer-Lemeshow test. A P value < 0.05 was considered statistically significant. RESULTS: The radiomic signature derived from the combination of all sequences numerically showed highest area under the curve (AUC) in both training and external test sets (AUCs of 0.857 and 0.823). The radiomics nomogram that incorporated the mpMRI radiomic signature and KPS status resulted in AUCs of 0.891 and 0.859 in the training and test sets. The calibration curves showed good agreement between prediction and observation in both sets (P= 0.279 and 0.170, respectively). DCA confirmed the clinical usefulness of the nomogram. IHC identified Notch pathway inactivation and the expression levels of Hes1 correlated with higher combined radiomic scores (r = -0.711) in Notch1 mutant tumors. DATA CONCLUSION: The mpMRI-based radiomics nomogram may reflect the intratumor heterogeneity associated with downstream biofunction that predicts Notch signaling in a noninvasive manner. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Alterations in Hepatocellular Carcinoma-Specific Immune Responses Following Hepatitis C Virus Elimination by Direct-Acting Antivirals.

Direct-acting antivirals (DAAs) have recently revolutionized the eradication of chronic hepatitis C virus (HCV) infection. However, the effects of DAAs on the development of hepatocellular carcinoma (HCC) remain unknown. Therefore, the present study aimed to investigate immune responses to HCC influenced by DAAs in HCV-infected patients and elucidate the underlying mechanisms. We compared immune responses to 19 different HCC-related tumor-associated antigen (TAA)-derived peptides and host immune cell profiles before and 24 weeks after a treatment with DAAs in 47 HLA-A24-positive patients. The relationships between the different immune responses and phenotypic changes in immune cells were also examined. The treatment with DAAs induced four types of immune responses to TAAs and markedly altered host immune cell profiles. Prominently, reductions in the frequencies of PD-1+CD4+ and PD-1+CD8+ T cells by DAAs were associated with enhanced immune responses to TAAs. The HCV F protein was identified as contributing to the increased frequency of PD-1+ T cells, which may be decreased after eradication by DAAs. DAAs altered the immune responses of patients to HCC by decreasing the frequency of PD-1-expressing CD4+ and CD8+ T cells.

Hydroxynonenal Causes Hepatocyte Death by Disrupting Lysosomal Integrity in Nonalcoholic Steatohepatitis.

BACKGROUND & AIMS: The lipid oxidation is a key factor for damaging hepatocytes and causing cell death. However, the mechanisms underlying hepatocyte death and the role of the most popular lipid peroxidation product 4-hydroxy-2-nonenal (HNE) in nonalcoholic steatohepatitis (NASH) remains unclear. METHODS: We demonstrated using hepatoma cell lines, a NASH mouse model, HNE-treated monkeys, and biopsy specimens from patients with NASH that HNE induced hepatocyte death by disintegrating the lysosomal limiting membrane. RESULTS: The degree of HNE deposition in human NASH hepatocytes was more severe in cases with high lobular inflammation, ballooning, and fibrosis scores, and was associated with enlargement of the staining of lysosomes in hepatocytes. In in vitro experiments, HNE activated µ-calpain via G-protein coupled receptor (GPR) 120. The resultant rupture/permeabilization of the lysosomal limiting membrane induced the leakage of cathepsins from lysosomes and hepatocyte death. The blockade of G-protein coupled receptor 120 (GPR120) or µ-calpain expression suppressed lysosomal membrane damage and hepatocyte death by HNE. Alda-1, which activates aldehyde dehydrogenase 2 to degrade HNE, prevented HNE-induced hepatocyte death. Intravenous administration of HNE to monkeys for 6 months resulted in hepatocyte death by a mechanism similar to that of cultured cells. In addition, intraperitoneal administration of Alda-1 to choline-deficient, amino-acid defined treated mice for 8 weeks inhibited HNE deposition, decreased liver inflammation, and disrupted lysosomal membranes in hepatocytes, resulting in improvement of liver fibrosis. CONCLUSIONS: These results provide novel insights into the mechanism of hepatocyte death in NASH and will contribute to the development of new therapeutic strategies for NASH.

A Comparative Study Between Tumor Blood Vessels and Dynamic Contrast-enhanced MRI for Identifying Isocitrate Dehydrogenase Gene 1 (IDH1) Mutation Status in Glioma.

OBJECTIVE: Isocitrate dehydrogenase gene (IDH) mutations are associated with tumor angiogenesis and therefore play an important role in glioma management. This study compared the performance of tumor blood vessels counted from contrast-enhanced 3D brain volume (3D-BRAVO) sequence and dynamic contrast-enhanced (DCE) MRI in differentiating IDH1 status in gliomas. METHODS: Forty-four glioma patients [16 with IDH1 mutant-type (IDH1-MT), 28 with IDH1 wild-type (IDH1-WT)] were retrospectively analyzed. A blood vessel entering a tumor was defined as an intratumoral vessel; a blood vessel adjacent to the edge of a tumor was defined as a peritumoral vessel. Combined vessels were defined as the sum of the intratumoral and peritumoral vessels. DCE-derived metrics of tumor were normalized to the contralateral normal-appearing white matter. RESULTS: Intratumoral, peritumoral, and combined tumor blood vessels were all significantly different between IDH1-MT and IDH1-WT gliomas, and the range of area under curves (AUCs) was 0.816-0.855. For DCE-derived parameters, cerebral blood volume, cerebral blood flow, mean transit time, and volume transfer constant were significantly different between IDH1-MT and IDH1-WT gliomas, and the range of AUCs was 0.703-0.756. Combined vessels possessed the best performance for identifying IDH1 mutations in gliomas (AUC: 0.855, sensitivity: 0.857, specificity: 0.812, P<0.001). CONCLUSION: The number of tumor blood vessels has comparable diagnostic performance with DCE-derived parameters for differentiating IDH1 mutations and can serve as a potential imaging biomarker to reflect IDH1 mutations in gliomas.

A mathematical model to predict the probability of a successful pregnancy.

AIM: To develop a scoring system for the prediction of a successful pregnancy. METHODS: Data were collected prospectively from women diagnosed with pregnancy from January 1, 2015, to December 31, 2018. Pregnant days, hormone levels, and gestational sac diameters were recorded. Relationships among the pregnancy days, hormones, and gestational sac were analyzed by Spearman correlation analysis. A scoring system was established and stratified by the 5th, 50th, and 95th percentile of hormone levels and gestational sac diameters on different pregnancy days. Pregnancy outcomes were predicted by the scores using quadratic polynomial regression analyses. A portable desktop analyzer was developed and the performance was evaluated by receiver operating characteristic (ROC) curve. RESULTS: In 273 successful pregnancy cases, the length of gestational days was significantly correlated to beta-human chorionic gonadotropin (ß-hCG) (r = 0.74, p < 0.001) and E2 (r = 0.79, p < 0.001) levels, and the size of the gestational sac (r = 0.88, p < 0.001). Meanwhile, the size of gestational sac was positively correlated with ß-hCG (r = 0.93, p < 0.001) and E2 (r = 0.55, p < 0.001). For 273 delivery and 103 miscarriage cases included in this study, our scoring-based prediction model rendered an area under the ROC curve (AUC) of 0.86 with the sensitivity of 78.31% and the specificity of 80.83%. CONCLUSIONS: We successfully developed a scoring-based analyzer to evaluate the viability of embryos at different gestation stages and to predict the probability of a successful delivery, which would provide a reference for clinicians in postpregnancy management.

Monoexponential, biexponential and stretched exponential models of diffusion weighted magnetic resonance imaging in glioma in relation to histopathologic grade and Ki-67 labeling index using high B values.

PURPOSE: To explore the performance of various parameters obtained from monoexponential (Gaussian), biexponential and stretched exponential (non-Gaussian) models of Diffusion Weighted Magnetic Resonance Imaging in differentiating gliomas with correlation to histopathology and Ki-67 labeling index (LI). MATERIALS AND METHODS: This Institute Review Board approved retrospective study included 51 pathologically proven glioma patients (WHO Grade I, n = 1; Grade II, n = 19, Grade III, n = 12; Grade IV, n = 19), and immunohistochemistry for Ki-67 LI was obtained. The conventional Magnetic Resonance (MR) images and Diffusion Weighted (DW) images with 19 non-zero b values (0-4500 s/mm2) followed by contrast-enhanced MR images were obtained at 3T preoperatively. All images were processed with Advantage Workstation 4.5 (GE Medical Systems). Region of interest (ROI) in the solid part of the tumor was manually drawn along the border meticulously excluding areas of edema, cyst, hemorrhage, necrosis, and/or calcification, and the parameters: Apparent Diffusion Coefficient (ADC) of monoexponential; pure molecular diffusion coefficient (Dslow), pseudo-diffusion coefficient (Dfast), and perfusion fraction (f) of biexponential; Distributed Diffusion Coefficient (DDC), and heterogeneity index (α) of stretched exponential models were obtained. ROI of 50 mm2 in the contralateral normal appearing white matter (NAWM) was drawn for the internal control either on centrum semiovale or white matter of the frontal lobe. Analysis of reliability by Intra-class Correlation Coefficient (ICC); correlation with Ki-67 LI by Spearman's rank correlation; comparison between high grade glioma (HGG) and low grade glioma (LGG) by either Mann Whitney U test or Independent t-Test; comparison among Grade II, III and IV gliomas by one-way ANOVA with Bonferroni; and diagnostic performance by analysis of Area Under Receiver Operating Characteristic (ROC) Curve (AUC) were conducted. RESULTS: Highly significant differences were found between HGG and LGG for all the parameters (P < 0.001 for all). In differentiating HGG from LGG, AUC values were 0.955 for Ki-67 LI; 0.926 for α; 0.903 for Dslow; 0.897 for f; 0.863 for DDC; 0.852 for ADC; 0.820 for Dfast (P < 0.001 for all). The parameters ADC, Dslow, Dfast, f, DDC, and α showed moderate to good negative correlation with Ki-67 LI (P < 0.001 for all). The ICCs of all the parameters were found greater than 0.75 (P < 0.05 for all) suggesting good reliability of measurements. CONCLUSION: In comparison to ADC derived from monoexponential model, the parameters α and Dslow derived from stretched exponential, and biexponential models respectively can efficiently differentiate HGG from LGG with high diagnostic accuracy. Additionally, f and DDC derived from biexponential, and stretched exponential models respectively are also more useful in differentiating HGG from LGG in comparison to ADC.

Assessment of Isocitrate Dehydrogenase 1 Genotype and Cell Proliferation in Gliomas Using Multiple Diffusion Magnetic Resonance Imaging.

Objectives: To compare the efficacy of parameters from multiple diffusion magnetic resonance imaging (dMRI) for prediction of isocitrate dehydrogenase 1 (IDH1) genotype and assessment of cell proliferation in gliomas. Methods: Ninety-one patients with glioma underwent diffusion weighted imaging (DWI), multi-b-value DWI, and diffusion kurtosis imaging (DKI)/neurite orientation dispersion and density imaging (NODDI) on 3.0T MRI. Each parameter was compared between IDH1-mutant and IDH1 wild-type groups by Mann-Whitney U test in lower-grade gliomas (LrGGs) and glioblastomas (GBMs), respectively. Further, performance of each parameter was compared for glioma grading under the same IDH1 genotype. Spearman correlation coefficient between Ki-67 labeling index (LI) and each parameter was calculated. Results: The diagnostic performance was better achieved with apparent diffusion coefficient (ADC), slow ADC (D), fast ADC (D∗), perfusion fraction (f), distributed diffusion coefficient (DDC), heterogeneity index (α), mean diffusivity (MD), mean kurtosis (MK), and intracellular volume fraction (ICVF) for distinguishing IDH1 genotypes in LrGGs, with statistically insignificant AUC values from 0.750 to 0.817. In GBMs, no difference between the two groups was found. For IDH1-mutant group, all parameters, except for fractional anisotropy (FA) and D∗, significantly discriminated LrGGs from GBMs (P < 0.05). However, for IDH1 wild-type group, only ADC statistically discriminated the two (P = 0.048). In addition, MK has maximal correlation coefficient (r = 0.567, P < 0.001) with Ki-67 LI. Conclusion: dMRI-derived parameters are promising biomarkers for predicting IDH1 genotype in LrGGs, and MK has shown great potential in assessing glioma cell proliferation.

Application of Cluster Analysis of Time Evolution for Magnetic Resonance Imaging -Derived Oxygen Extraction Fraction Mapping: A Promising Strategy for the Genetic Profile Prediction and Grading of Glioma.

Background: The intratumoral heterogeneity of oxygen metabolism and angiogenesis are core hallmarks of glioma, unveiling that genetic aberrations associated with magnetic resonance imaging (MRI) phenotypes may aid in the diagnosis and treatment of glioma. Objective: To explore the predictability of MRI-based oxygen extraction fraction (OEF) mapping using cluster analysis of time evolution (CAT) for genetic profiling and glioma grading. Methods: Ninety-one patients with histopathologically confirmed glioma were examined with CAT for quantitative susceptibility mapping and quantitative blood oxygen level-dependent magnitude-based OEF mapping and dynamic contrast-enhanced (DCE) MRI. Imaging biomarkers, including oxygen metabolism (OEF) and angiogenesis [volume transfer constant, cerebral blood volume (CBV), and cerebral blood flow], were investigated to predict IDH mutation, O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status, receptor tyrosine kinase (RTK) subgroup, and differentiation of glioblastoma (GBM) vs. lower-grade glioma (LGG). The corresponding DNA sequencing was also obtained. Results were compared with DCE-MRI using receiver operating characteristic (ROC) analysis. Results: IDH1-mutated LGGs exhibited significantly lower OEF and hypoperfusion than IDH wild-type tumors (all p < 0.01). OEF and perfusion metrics showed a tendency toward higher values in MGMT unmethylated GBM, but only OEF retained significance (p = 0.01). Relative prevalence of RTK alterations was associated with increased OEF (p = 0.003) and perfusion values (p < 0.05). ROC analysis suggested OEF achieved best performance for IDH mutation detection [area under the curve (AUC) = 0.828]. None of the investigated parameters enabled prediction of MGMT status except OEF with a moderate AUC of 0.784. Predictive value for RTK subgroup was acceptable by using OEF (AUC = 0.764) and CBV (AUC = 0.754). OEF and perfusion metrics demonstrated excellent performance in glioma grading. Moreover, mutational landscape revealed hypoxia or angiogenesis-relevant gene signatures were associated with specific imaging phenotypes. Conclusion: CAT for MRI-based OEF mapping is a promising technology for oxygen measurement and along with perfusion MRI can predict genetic profiles and tumor grade in a non-invasive and clinically relevant manner. Clinical Impact: Physiological imaging provides an in vivo portrait of genetic alterations in glioma and offers a potential strategy for non-invasively selecting patients for individualized therapies.

Cannabidiol Effectively Promoted Cell Death in Bladder Cancer and the Improved Intravesical Adhesion Drugs Delivery Strategy Could Be Better Used for Treatment.

Cannabidiol (CBD), a primary bioactive phytocannabinoid extracted from hemp, is reported to possess potent anti-tumorigenic activity in multiple cancers. However, the effects of CBD on bladder cancer (BC) and the underlying molecular mechanisms are rarely reported. Here, several experiments proved that CBD promoted BC cells (T24, 5637, and UM-UC-3) death. For example, T24 cells were treated with 12 µM CBD for 48 h, flow cytometry analysis demonstrated that early and late apoptotic cells were accounted for by 49.91%, indicating CBD enhanced cell apoptosis ability. To deeper explore molecular mechanisms, the CBD-treated T24 cell transcriptome libraries were established. KEGG analysis implied that the significantly changed genes were enriched in the PI3K/Akt pathway. qRT-PCR and Western blot assays verified that CBD regulated BC cells growth and migration and induced apoptosis by inactivating the PI3K/Akt pathway. Meanwhile, the developed chitosan to wrap CBD-loaded PLGA nanoparticles can significantly enhance the adhesion of the material to the mouse bladder wall, and the binding efficiency of mucin to chitosan-PLGA nanoparticles reached 97.04% ± 1.90%. In summary, this work demonstrates that CBD may become a novel reliable anticancer drug and the developed intravesical adhesion system is expected to turn into a potential means of BC chemotherapy drug delivery.

T2-FLAIR, DWI and DKI radiomics satisfactorily predicts histological grade and Ki-67 proliferation index in gliomas.

OBJECTIVE: To build highly predictive performance models for glioma stratification with radiomics features from non-invasive MRI. METHODS: T2-weighted fluid-attenuated inversion recovery (T2-FLAIR) imaging, diffusion-weighted MRI and diffusion kurtosis imaging were retrospectively collected for 139 glioma cases (2 with grade I, 67 with grade II, 36 with grade III and 34 with grade IV disease). Multi-parameter maps, including the apparent diffusion coefficient (ADC), mean diffusion coefficient (Dmean), fractional anisotropy (FA), and mean kurtosis (MK), were co-registered to T2-FLAIR, and 431 radiomics features for each were extracted within manually segmented tumour regions. Partial correlation analysis revealed correlations between radiomics features and glioma stratification factors (tumour grades and Ki-67 LI). Predictive models were built with adjusted-imbalanced logistic regression. RESULTS: MK radiomics features were more closely correlated with glioma stratification than other modalities analysed. The maximum R in MK was 0.52 for tumour grade and 0.56 for Ki-67 index (compared with 0.36 and 0.34 in FA, and 0.43 and 0.37 in ADC, and 0.48 and 0.42 in T2-FLAIR). The best predictive models for grade II vs. III, grade II vs. IV, low-grade vs. high-grade gliomas and positive vs. highly positive Ki-67 LI were obtained by combining multi-parameter MR radiomics features with AUCs of 0.858, 0.966, 0.853 and 0.870, respectively. However, for grade III vs. IV gliomas, the model obtained from MK radiomics features achieved the highest AUC (0.947), with excellent sensitivity and specificity. CONCLUSION: Compared with the other modalities, MK showed closer correlations with tumour grade and Ki-67 LI. Combined radiomics models integrating multi-parameter MRI allow for the generation of highly predictive models for glioma stratification.

Predicting cancer malignancy and proliferation in glioma patients: intra-subject inter-metabolite correlation analyses using MRI and MRSI contrast scans.

BACKGROUND: The non-invasive characterization of glioma metabolites would greatly assist the management of glioma patients in the clinical setting. This study investigated the applicability of intra-subject inter-metabolite correlation analyses for differentiating glioma malignancy and proliferation. METHODS: A total of 17 negative controls (NCs), 39 low-grade gliomas (LGGs) patients, and 25 high-grade gliomas (HGGs) subjects were included in this retrospective study. Amide proton transfer (APT) and magnetization transfer contrast (MTC) imaging contrasts, as well as total choline/total creatine (tCho/tCr) and total N-acetylaspartate/total creatine (tNAA/tCr) ratios quantified from magnetic resonance spectroscopic imaging (MRSI) were co-registered voxel-wise and used to produce three intra-subject inter-metabolite correlation coefficients (IMCCs), namely, RAPT vs . MTC, RAPT vs . tCho/tCr, and RMTC vs . tNAA/tCr. The correlation between the IMCCs and tumor grade and Ki-67 labeling index (LI) for tumor proliferation were explored. The differences in the IMCCs between the three groups were compared with one-way analysis of variance (ANOVA). Finally, regression analysis was used to build a combined model with multiple IMCCs to improve the diagnostic performance for tumor grades based on receiver operator characteristic curves. RESULTS: Compared with the NCs, gliomas showed stronger inter-metabolic correlations. RAPT vs . MTC was significantly different among the three groups (NC vs. LGGs vs. HGGs: -0.18±0.38 vs. -0.40±0.34 vs. -0.70±0.29, P<0.0001). No significant differences were detected in RMTC vs . tNAA/tCr among the three groups. RAPT vs . MTC and RAPT vs . tCho/tCr correlated significantly with tumor grade (R=-0.41, P=0.001 and R=0.448, P<0.001, respectively). However, only RAPT vs . MTC was mildly correlated with Ki-67 (R=-0.33, P=0.02). RAPT vs . MTC and RAPT vs . tCho/tCr achieved areas under the curve (AUCs) of 0.754 and 0.71, respectively, for differentiating NCs from gliomas; and 0.77 and 0.78, respectively, for differentiating LGGs from HGGs. The combined multi-IMCCs model improved the correlation with the Ki-67 LI (R=0.46, P=0.0008) and the tumor-grade stratification with AUC increased to 0.85 (sensitivity: 80.0%, specificity: 79.5%). CONCLUSIONS: This study demonstrated that glioma patients showed stronger inter-metabolite correlations than control subjects, and the IMCCs were significantly correlated with glioma grade and proliferation. The multi-IMCCs combined model further improved the performance of clinical diagnosis.