Differentiation between small hepatocellular carcinoma (<3 cm) and benign hepatocellular lesions in patients with Budd-Chiari syndrome: the role of multiparametric MR imaging

ObjectiveTo investigate the value of multiparametric MR imaging to differentiate between small hepatocellular carcinoma (s-HCC) versus benign liver lesions in patients with Budd-Chiari syndrome.Methods12 patients with benign hepatocellular lesions and 32 patients with small (&lt;3 cm) HCCs were assessed. MRI images were reviewed by two radiologists blinded to the patient background information; lesion T1 and T2 signal intensities and ADC values were compared with the background liver. Enhancement of lesion relative to hepatic parenchyma [(T1Enh-T1liver)/T1liver] in the arterial, venous, and delayed phases was also compared between the two groups. A multivariable logistic model was developed using these categorical measures; the predictive value of the model was tested using the Area Under the Receiver operating characteristic (AU-ROC) curve for logistic models. P-values &lt;0.05 were considered statistically significant.ResultsThere were consistent differences in T1lesion/T1liver, and T2lesion/T2liver, and ADClesion/ADCliver between benign hepatocellular lesions versus the sHCC group (p&lt;0.001, p&lt;0.001, p = 0.045, respectively). Lesion-to-background liver enhancement in the portal venous and delayed phases was different between the benign lesions versus sHCC (p=0.001). ROC analysis for the logistic model that included the T1 ratio, T2 ratio, and portal venous enhancement ratio demonstrated excellent discriminatory power with the area under the curve of 0.94.ConclusionMultiparametric MR imaging is a useful method to help differentiate benign liver lesions from sHCC in patients with Budd-Chiari syndrome

Evaluating protein cross-linking as a therapeutic strategy to stabilize SOD1 variants in a mouse model of familial ALS

Mutations in the gene encoding Cu-Zn superoxide dismutase 1 (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS) cases. A shared effect of these mutations is that SOD1, which is normally a stable dimer, dissociates into toxic monomers that seed toxic aggregates. Considerable research effort has been devoted to developing compounds that stabilize the dimer of fALS SOD1 variants, but unfortunately, this has not yet resulted in a treatment. We hypothesized that cyclic thiosulfinate cross-linkers, which selectively target a rare, 2 cysteine-containing motif, can stabilize fALS-causing SOD1 variants in vivo. We created a library of chemically diverse cyclic thiosulfinates and determined structure-cross-linking-activity relationships. A pre-lead compound, “S-XL6,” was selected based upon its cross-linking rate and drug-like properties. Co-crystallographic structure clearly establishes the binding of S-XL6 at Cys 111 bridging the monomers and stabilizing the SOD1 dimer. Biophysical studies reveal that the degree of stabilization afforded by S-XL6 (up to 24°C) is unprecedented for fALS, and to our knowledge, for any protein target of any kinetic stabilizer. Gene silencing and protein degrading therapeutic approaches require careful dose titration to balance the benefit of diminished fALS SOD1 expression with the toxic loss-of-enzymatic function. We show that S-XL6 does not share this liability because it rescues the activity of fALS SOD1 variants. No pharmacological agent has been proven to bind to SOD1 in vivo. Here, using a fALS mouse model, we demonstrate oral bioavailability; rapid engagement of SOD1G93A by S-XL6 that increases SOD1G93A’s in vivo half-life; and that S-XL6 crosses the blood–brain barrier. S-XL6 demonstrated a degree of selectivity by avoiding off-target binding to plasma proteins. Taken together, our results indicate that cyclic thiosulfinate-mediated SOD1 stabilization should receive further attention as a potential therapeutic approach for fALS

The Additive Value of Radiomics Features Extracted from Baseline MR Images to the Barcelona Clinic Liver Cancer (BCLC) Staging System in Predicting Transplant-Free Survival in Patients with Hepatocellular Carcinoma: A Single-Center Retrospective Analysis

Background: To study the additive value of radiomics features to the BCLC staging system in clustering HCC patients. Methods: A total of 266 patients with HCC were included in this retrospective study. All patients had undergone baseline MR imaging, and 95 radiomics features were extracted from 3D segmentations representative of lesions on the venous phase and apparent diffusion coefficient maps. A random forest algorithm was utilized to extract the most relevant features to transplant-free survival. The selected features were used alongside BCLC staging to construct Kaplan–Meier curves. Results: Out of 95 extracted features, the three most relevant features were incorporated into random forest classifiers. The Integrated Brier score of the prediction error curve was 0.135, 0.072, and 0.048 for the BCLC, radiomics, and combined models, respectively. The mean area under the receiver operating curve (ROC curve) over time for the three models was 81.1%, 77.3%, and 56.2% for the combined radiomics and BCLC models, respectively. Conclusions: Radiomics features outperformed the BCLC staging system in determining prognosis in HCC patients. The addition of a radiomics classifier increased the classification capability of the BCLC model. Texture analysis features could be considered as possible biomarkers in predicting transplant-free survival in HCC patients

The Additive Value of Radiomics Features Extracted from Baseline MR Images to the Barcelona Clinic Liver Cancer (BCLC) Staging System in Predicting Transplant-Free Survival in Patients with Hepatocellular Carcinoma: A Single-Center Retrospective Analysis

Background: To study the additive value of radiomics features to the BCLC staging system in clustering HCC patients. Methods: A total of 266 patients with HCC were included in this retrospective study. All patients had undergone baseline MR imaging, and 95 radiomics features were extracted from 3D segmentations representative of lesions on the venous phase and apparent diffusion coefficient maps. A random forest algorithm was utilized to extract the most relevant features to transplant-free survival. The selected features were used alongside BCLC staging to construct Kaplan&ndash;Meier curves. Results: Out of 95 extracted features, the three most relevant features were incorporated into random forest classifiers. The Integrated Brier score of the prediction error curve was 0.135, 0.072, and 0.048 for the BCLC, radiomics, and combined models, respectively. The mean area under the receiver operating curve (ROC curve) over time for the three models was 81.1%, 77.3%, and 56.2% for the combined radiomics and BCLC models, respectively. Conclusions: Radiomics features outperformed the BCLC staging system in determining prognosis in HCC patients. The addition of a radiomics classifier increased the classification capability of the BCLC model. Texture analysis features could be considered as possible biomarkers in predicting transplant-free survival in HCC patients

Evaluating protein cross-linking as a therapeutic strategy to stabilize SOD1 variants in a mouse model of familial ALS

Mutations in the gene encoding Cu-Zn superoxide dismutase 1 (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS) cases. A shared effect of these mutations is that SOD1, which is normally a stable dimer, dissociates into toxic monomers that seed toxic aggregates. Considerable research effort has been devoted to developing compounds that stabilize the dimer of fALS SOD1 variants, but unfortunately, this has not yet resulted in a treatment. We hypothesized that cyclic thiosulfinate cross-linkers, which selectively target a rare, 2 cysteine-containing motif, can stabilize fALS-causing SOD1 variants in vivo. We created a library of chemically diverse cyclic thiosulfinates and determined structure-cross-linking-activity relationships. A pre-lead compound, “S-XL6,” was selected based upon its cross-linking rate and drug-like properties. Co-crystallographic structure clearly establishes the binding of S-XL6 at Cys 111 bridging the monomers and stabilizing the SOD1 dimer. Biophysical studies reveal that the degree of stabilization afforded by S-XL6 (up to 24°C) is unprecedented for fALS, and to our knowledge, for any protein target of any kinetic stabilizer. Gene silencing and protein degrading therapeutic approaches require careful dose titration to balance the benefit of diminished fALS SOD1 expression with the toxic loss-of-enzymatic function. We show that S-XL6 does not share this liability because it rescues the activity of fALS SOD1 variants. No pharmacological agent has been proven to bind to SOD1 in vivo. Here, using a fALS mouse model, we demonstrate oral bioavailability; rapid engagement of SOD1G93A by S-XL6 that increases SOD1G93A\u27s in vivo half-life; and that S-XL6 crosses the blood-brain barrier. S-XL6 demonstrated a degree of selectivity by avoiding off-target binding to plasma proteins. Taken together, our results indicate that cyclic thiosulfinate-mediated SOD1 stabilization should receive further attention as a potential therapeutic approach for fALS

Evaluating protein cross-linking as a therapeutic strategy to stabilize SOD1 variants in a mouse model of familial ALS.

Mutations in the gene encoding Cu-Zn superoxide dismutase 1 (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS) cases. A shared effect of these mutations is that SOD1, which is normally a stable dimer, dissociates into toxic monomers that seed toxic aggregates. Considerable research effort has been devoted to developing compounds that stabilize the dimer of fALS SOD1 variants, but unfortunately, this has not yet resulted in a treatment. We hypothesized that cyclic thiosulfinate cross-linkers, which selectively target a rare, 2 cysteine-containing motif, can stabilize fALS-causing SOD1 variants in vivo. We created a library of chemically diverse cyclic thiosulfinates and determined structure-cross-linking-activity relationships. A pre-lead compound, "S-XL6," was selected based upon its cross-linking rate and drug-like properties. Co-crystallographic structure clearly establishes the binding of S-XL6 at Cys 111 bridging the monomers and stabilizing the SOD1 dimer. Biophysical studies reveal that the degree of stabilization afforded by S-XL6 (up to 24°C) is unprecedented for fALS, and to our knowledge, for any protein target of any kinetic stabilizer. Gene silencing and protein degrading therapeutic approaches require careful dose titration to balance the benefit of diminished fALS SOD1 expression with the toxic loss-of-enzymatic function. We show that S-XL6 does not share this liability because it rescues the activity of fALS SOD1 variants. No pharmacological agent has been proven to bind to SOD1 in vivo. Here, using a fALS mouse model, we demonstrate oral bioavailability; rapid engagement of SOD1G93A by S-XL6 that increases SOD1G93A's in vivo half-life; and that S-XL6 crosses the blood-brain barrier. S-XL6 demonstrated a degree of selectivity by avoiding off-target binding to plasma proteins. Taken together, our results indicate that cyclic thiosulfinate-mediated SOD1 stabilization should receive further attention as a potential therapeutic approach for fALS