Evaluation of a continuous-time random-walk diffusion model for the differentiation of malignant and benign breast lesions and its association with Ki-67 expression.

The purpose of the current study was to evaluate the performance of a continuous-time random-walk (CTRW) diffusion model for differentiating malignant and benign breast lesions and to consider the potential association between CTRW parameters and the Ki-67 expression. Sixty-four patients (46.2 ± 11.4 years) with breast lesions (29 malignant and 35 benign) were evaluated with the CTRW model, intravoxel incoherent motion model, and diffusion-weighted imaging. Echo planar diffusion-weighted imaging was conducted using 13 b-values (0-3000 s/mm2 ). Three CTRW model parameters, including an anomalous diffusion coefficient Dm , and two parameters related to temporal and spatial diffusion heterogeneity, α and ß, respectively, were obtained, and had MRI b-values of 0-3000 s/mm2 . Receiver operating characteristic (ROC) analysis was conducted to determine the sensitivity, specificity, and diagnostic accuracy of CTRW parameters for differentiating malignant from benign breast lesions. In malignant breast lesions, the CTRW parameters Dm , α, and ß were significantly lower than the corresponding parameters of benign breast lesions. In the malignant breast lesion group, the CTRW parameter Dm was significantly lower in high Ki-67 expression than in low Ki-67 expression. In ROC analysis, the combination of CTRW parameters (Dm , α, ß) demonstrated the highest area under the curve value (0.985) and diagnostic accuracy (94.23%) in differentiating malignant and benign breast lesions. The CTRW model effectively differentiated malignant from benign breast lesions. The CTRW diffusion model offers a new way for noninvasive assessment of breast malignancy and better understanding of the proliferation of malignant lesions.

Phosphorylation of KRT8 (keratin 8) by excessive mechanical load-activated PKN (protein kinase N) impairs autophagosome initiation and contributes to disc degeneration.

Excessive mechanical load (overloading) is a well-documented pathogenetic factor for many mechano stress-induced pathologies, i.e. intervertebral disc degeneration (IDD). Under overloading, the balance between anabolism and catabolism within nucleus pulposus (NP) cells are badly thrown off, and NP cells undergo apoptosis. However, little is known about how the overloading is transduced to the NP cells and contributes to disc degeneration. The current study shows that conditional knockout of Krt8 (keratin 8) within NP aggravates load-induced IDD in vivo, and overexpression of Krt8 endows NP cells greater resistance to overloading-induced apoptosis and degeneration in vitro. Discovery-driven experiments shows that phosphorylation of KRT8 on Ser43 by overloading activated RHOA-PKN (protein kinase N) impedes trafficking of Golgi resident small GTPase RAB33B, suppresses the autophagosome initiation and contributes to IDD. Overexpression of Krt8 and knockdown of Pkn1 and Pkn2, at an early stage of IDD, ameliorates disc degeneration; yet only knockdown of Pkn1 and Pkn2, when treated at late stage of IDD, shows a therapeutic effect. This study validates a protective role of Krt8 during overloading-induced IDD and demonstrates that targeting overloading activation of PKNs could be a novel and effective approach to mechano stress-induced pathologies with a wider window of therapeutic opportunity.Abbreviations: AAV: adeno-associated virus; AF: anulus fibrosus; ANOVA: analysis of variance; ATG: autophagy related; BSA: bovine serum albumin; cDNA: complementary deoxyribonucleic acid; CEP: cartilaginous endplates; CHX: cycloheximide; cKO: conditional knockout; Cor: coronal plane; CT: computed tomography; Cy: coccygeal vertebra; D: aspartic acid; DEG: differentially expressed gene; DHI: disc height index; DIBA: dot immunobinding assay; dUTP: 2'-deoxyuridine 5'-triphosphate; ECM: extracellular matrix; EDTA: ethylene diamine tetraacetic acid; ER: endoplasmic reticulum; FBS: fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GPS: group-based prediction system; GSEA: gene set enrichment analysis; GTP: guanosine triphosphate; HE: hematoxylin-eosin; HRP: horseradish peroxidase; IDD: intervertebral disc degeneration; IF: immunofluorescence staining; IL1: interleukin 1; IVD: intervertebral disc; KEGG: Kyoto encyclopedia of genes and genomes; KRT8: keratin 8; KD: knockdown; KO: knockout; L: lumbar vertebra; LBP: low back pain; LC/MS: liquid chromatograph mass spectrometer; LSI: mouse lumbar instability model; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MMP3: matrix metallopeptidase 3; MRI: nuclear magnetic resonance imaging; NC: negative control; NP: nucleus pulposus; PBS: phosphate-buffered saline; PE: p-phycoerythrin; PFA: paraformaldehyde; PI: propidium iodide; PKN: protein kinase N; OE: overexpression; PTM: post translational modification; PVDF: polyvinylidene fluoride; qPCR: quantitative reverse-transcriptase polymerase chain reaction; RHOA: ras homolog family member A; RIPA: radio immunoprecipitation assay; RNA: ribonucleic acid; ROS: reactive oxygen species; RT: room temperature; TCM: rat tail compression-induced IDD model; TCS: mouse tail suturing compressive model; S: serine; Sag: sagittal plane; SD rats: Sprague-Dawley rats; shRNA: short hairpin RNA; siRNA: small interfering RNA; SOFG: safranin O-fast green; SQSTM1: sequestosome 1; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; VG/ml: viral genomes per milliliter; WCL: whole cell lysate.

SIRT5-related desuccinylation modification of AIFM1 protects against compression-induced intervertebral disc degeneration by regulating mitochondrial homeostasis.

Mitochondrial dysfunction plays a major role in the development of intervertebral disc degeneration (IDD). Sirtuin 5 (SIRT5) participates in the maintenance of mitochondrial homeostasis through its desuccinylase activity. However, it is still unclear whether succinylation or SIRT5 is involved in the impairment of mitochondria and development of IDD induced by excessive mechanical stress. Our 4D label-free quantitative proteomic results showed decreased expression of the desuccinylase SIRT5 in rat nucleus pulposus (NP) tissues under mechanical loading. Overexpression of Sirt5 effectively alleviated, whereas knockdown of Sirt5 aggravated, the apoptosis and dysfunction of NP cells under mechanical stress, consistent with the more severe IDD phenotype of Sirt5 KO mice than wild-type mice that underwent lumbar spine instability (LSI) surgery. Moreover, immunoprecipitation-coupled mass spectrometry (IP-MS) results suggested that AIFM1 was a downstream target of SIRT5, which was verified by a Co-IP assay. We further demonstrated that reduced SIRT5 expression resulted in the increased succinylation of AIFM1, which in turn abolished the interaction between AIFM1 and CHCHD4 and thus led to the reduced electron transfer chain (ETC) complex subunits in NP cells. Reduced ETC complex subunits resulted in mitochondrial dysfunction and the subsequent occurrence of IDD under mechanical stress. Finally, we validated the efficacy of treatments targeting disrupted mitochondrial protein importation by upregulating SIRT5 expression or methylene blue (MB) administration in the compression-induced rat IDD model. In conclusion, our study provides new insights into the occurrence and development of IDD and offers promising therapeutic approaches for IDD.

Value of Intravoxel Incoherent Motion (IVIM) Imaging for Differentiation between Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma.

Efficient noninvasive imaging techniques in the differentiation of intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are very important because of their different management and prognosis. Our purpose was to evaluate the difference of parameters extracted from intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) between the two groups and their performance for the differentiation, as well as the significance of perfusion information. IVIM studies (9 b-values) in 41 patients with either ICC or HCC were reviewed retrospectively by two observers. Diffusion coefficient (D), pseudodiffusion coefficient (D∗), perfusion fraction (f), ADC, and the mean percentage of parenchymal enhancement (MPPE) at 30 s after contrast-enhancement were calculated and compared between ICC and HCC. The relationship between D∗, f values, and MPPE was evaluated by Spearman's correlation test. The diagnostic efficacy of all parameters was analyzed by the receiver operating characteristic (ROC) curve. Interobserver and intraobserver agreements were analyzed. The parameters (D and ADC) of ICC were distinctly higher than those of HCC; whereas the parameters (f and MPPE of arterial phase) were distinctly lower (all false discovery rate [FDR]-corrected P < 0.05). The metric D∗ value of ICC was slightly higher than that of HCC (71.44 vs 69.41) with FDR-corrected P > 0.05. Moreover, the value of parameter D was significantly lower than that of ADC (FDR-corrected P < 0.05). The parameters (D and f values) extracted from IVIM showed excellent diagnostic efficiency in the identification, and the diagnostic efficiency of D value was significantly higher than that of the ADC. There were positive correlations between perfusion-related parameters (D∗, f values) and MPPE. Interobserver and intraobserver agreements were excellent or perfect in measurements of all parameters. Parameters derived from IVIM were valuable for distinguishing ICC and HCC. Moreover, the D value showed better diagnostic efficiency for the differential diagnosis than monoexponential fitting-derived ADC value. Meanwhile, the significant correlation between perfusion-related parameters and MPPE demonstrates that specific IVIM metrics may serve as a noninvasive indicator for the vascular perfusion information of ICC and HCC.

Value of Magnetic Resonance Cholangiopancreatography in Santorinicele and Wirsungocele.

BACKGROUND: Former studies showed that magnetic resonance cholangiopancreatography (MRCP) is useful in diagnosing the presence of santorinicele; however, few studies have evaluated MRCP in diagnosing wirsungocele and the association between pancreatitis and santorinicele or wirsungocele. The purpose of the study was to explore the performance of MRCP in diagnosing santorinicele and wirsungocele and investigate the potential association among pancreatitis, pancreas divisum, and santorinicele or wirsungocele. METHODS: Sixty-five patients (mean age, 55.68 years; range, 11-82 years) with santorinicele or wirsungocele were included and sorted into two groups: the santorinicele group (n = 48) and the wirsungocele group (n = 17). All patients underwent MRCP. The images were evaluated for the appearance and size of santorinicele or wirsungocele. The diagnostic sensitivity of MRCP was assessed. Additionally, whether two groups are correlated with pancreas divisum or pancreatitis were investigated. RESULTS: The sensitivity of MRCP in detecting santorinicele and wirsungocele showed no difference (68.8% and 76.5%, respectively). The proportion of patients who developed pancreatitis in santorinicele and wirsungocele groups were 60.4% and 11.8%, respectively (p < 0.05). Pancreas divisum accounted for 77.1% and 11.8% of the patients in the santorinicele and wirsungocele groups, respectively (p < 0.05). Patients with santorinicele and pancreas divisum tended to be older when they acquired pancreatitis. CONCLUSION: MRCP could be an alternative imaging method to detect cystic dilation of the pancreatic duct. Pancreatitis is more common in patients with santorinicele than in those with wirsungocele. Moreover, santorinicele is more closely associated with pancreatitis than with pancreas divisum.

Diagnostic Performance of PET/CT Using 18F-FACBC in Prostate Cancer: A Meta-Analysis.

Background: Diagnostic performance of PET/CT using 18F-fluciclovine (18F-FACBC) in patients with prostate cancer (PCa) has been evaluated in only a few studies. There is no consensus on the diagnostic value of 18F-FACBC PET/CT in PCa recurrence or metastasis (except for bone metastasis), the primary diagnosis of the lesion. Hence, a meta-analysis was conducted to evaluate the performance of 18F-FACBC PET/CT. Methods: The literature published from June 2015 to June 2019 on using 18F-FACBC PET/CT for the diagnosis of PCa was retrieved from PubMed and EMBASE. Pooled sensitivity (Sen), specificity (Spe), positive and negative likelihood ratios (LR+ and LR-), area under the curve (AUC), and diagnostic odds ratio (DOR) of 18F-FACBC PET/CT in patients with PCa were calculated. An SROC map was made, and a meta-regression analysis was carried out. A Fagan plot and likelihood ratio dot plot were drawn. Sensitivity and funnel plot analysis were made. Meta-disc, Review Manager 5.3, and STATA 13 were used for the meta-analysis. Results: A total of nine articles met the strict criteria for diagnostic meta-analysis, which included 363 patients and 345 lesions. Pooled Sen, Spe, LR+, LR-, DOR were 0.88, 0.73, 3.3, 0.17, and 20, respectively. Lesions detected on the PET/CT image included primary lesions and metastases. For the lesion, the doctors considered the abnormal part as a lesion on the PET/CT image by their own experience and expertise, including primary lesions and metastases. For the patient, patients who participated in the trial can be diagnosed as PCa through 18F-FACBC. Conclusion: This study comprehensively evaluated the diagnostic value of 18F-FACBC PET/CT on PCa. Our analysis suggests that 18F-FACBC PET/CT is a valuable agent in diagnosing PCa. More studies are needed for further validation.