Tumors cells with mismatch repair deficiency induce hyperactivation of pyroptosis resistant to cell membrane damage but are more sensitive to co-treatment of IFN-γ and TNF-α to PANoptosis.

Hypermutated neoantigens in cancers with DNA mismatch repair deficiency (dMMR) are prerequisites for favorable clinical responses to immune-checkpoint blockade (ICB) therapy. However, TMB is not significantly associated with favorable prognosis from Preclinical and clinical studies. It implies that except for TMB, other mechanisms should be needed to contribute to successful cancer immunotherapy. We found that the hyperactivation of PANoptotic effective molecules in dMMR tumor cells caused cell membrane damage, induced ESCRT-mediated membrane repair, and protected tumor cells from the damage caused by Triton X-100, while DNA mismatch repair proficient (pMMR) tumor cells were sensitive to Triton X-100 mediating cell membrane damage due to the lack of ESCRT-mediated membrane repair. There was hyperactivation of GSDMD, GSDME, and p-MLKL in dMMR tumor cells. Co-treatment of IFN-γ and TNF-α induced rapid death of dMMR tumor cells by inducing PANoptosis including pyroptosis, apoptosis, and no necrosis. pMMR tumor cells had defects in the PANoptosis pathway and were resistant to co-treatment of IFN-γ and TNF-α. In conclusion, we can activate immune cells to release IFN-γ and TNF-α to overcome resistance to ICB treatment.

Chemical Modifications to Enhance the Drug Properties of a VIP Receptor Antagonist (ANT) Peptide.

Antagonist peptides (ANTs) of vasoactive intestinal polypeptide receptors (VIP-Rs) are shown to enhance T cell activation and proliferation in vitro, as well as improving T cell-dependent anti-tumor response in acute myeloid leukemia (AML) murine models. However, peptide therapeutics often suffer from poor metabolic stability and exhibit a short half-life/fast elimination in vivo. In this study, we describe efforts to enhance the drug properties of ANTs via chemical modifications. The lead antagonist (ANT308) is derivatized with the following modifications: N-terminus acetylation, peptide stapling, and PEGylation. Acetylated ANT308 exhibits diminished T cell activation in vitro, indicating that N-terminus conservation is critical for antagonist activity. The replacement of residues 13 and 17 with cysteine to accommodate a chemical staple results in diminished survival using the modified peptide to treat mice with AML. However, the incorporation of the constraint increases survival and reduces tumor burden relative to its unstapled counterpart. Notably, PEGylation has a significant positive effect, with fewer doses of PEGylated ANT308 needed to achieve comparable overall survival and tumor burden in leukemic mice dosed with the parenteral ANT308 peptide, suggesting that polyethylene glycol (PEG) incorporation enhances longevity, and thus the antagonist activity of ANT308.

Thermal ablation with and without adjuvant systemic therapy: a nationwide multicenter observational cohort study of solitary colorectal liver metastases.

BACKGROUND: Thermal ablation is routinely used for solitary colorectal liver metastases (SCLM), but the added value of adjuvant systemic therapy in SCLM remains unclear. This study aimed to compare the long-term outcomes for SCLM treated by ablation alone (AB) versus ablation plus systemic therapy (AS). METHODS: This multicenter retrospective study using nationwide data from fourteen institutions between October 2010 and May 2023, 369 patients with initial SCLM smaller than 5 cm, no extrahepatic metastases, and colorectal cancer R0 resection treated by thermal ablation were included. The crude analysis was used to analyze eligible cases between the two groups. The propensity score matching (PSM) to control for potential confounders in each matched group. Subgroup analyses were performed to identify specific survival benefits. RESULTS: 61.2% (226/369) of eligible patients were treated with AS and 38.8% (143/369) with AB. During the median follow-up period of 8.8 years, 1-/3-/5-year DFS/OS rates did not differ between the two groups, when analyzed via PSM (P=0.52/0.08). Subgroup analysis revealed that AS was significantly associated with better OS than AB in patients with plasma CEA >5 ug/L (P=0.036), T (III-IV) category of primary cancer (P=0.034), or clinical risk score (1-2) (P=0.041). In each matched group, we did find a significant difference in drug-related adverse events (P<0.001) between AS group (24.1%, 28/116) and AB group (0.0%, 0/116). CONCLUSIONS: For patients with plasma CEA >5 ug/L, T (III-IV) category of primary cancer, or clinical risk score (1-2), thermal ablation plus systemic therapy appeared to be associated with improved overall survival. Thermal ablation was equally effective in disease-free survival for treating solitary colorectal liver metastasis, whether with or without adjuvant systemic therapy.

Feasibility of myocardial blood flow quantification to detect flow-limited coronary artery disease with a one-day rest/stress continuous rapid imaging protocol on cardiac-dedicated cadmium zinc telluride single photon emission computed tomography.

BACKGROUND: It is clinically needed to explore a more efficient imaging protocol for single photon emission computed tomography (SPECT) myocardial blood flow (MBF) quantitation derived from cadmium zinc telluride (CZT) SPECT camera for the routine clinical utilization. METHODS: One hundred and twenty patients with matched clinical characteristics and angiographic findings who completed one-day rest/stress SPECT imaging with either the intermittently sequential imaging (ISI) protocol (two dynamic and two electrocardiography (ECG)-gated scans) or the continuous rapid imaging (CRI) protocol (two dynamic/ECG-gated scans) were included. MBF quantitation adopted residual activity correction (RAC) to correct for rest residual activity (RRA) in the stress dynamic SPECT scan for the detection of flow-limited coronary artery disease. RESULTS: The CRI protocol reduced about 6.2 times shorter than the ISI protocol (25.5 min vs 157.6 min), but slightly higher than the RRA (26.7% ± 3.6% vs 22.3% ± 4.9%). With RAC, both protocols demonstrated close stress MBF (2.18 ± 1.13 vs 2.05 ± 1.10, P > 0.05) and myocardial flow reserve (MFR) (2.42 ± 1.05 vs 2.48 ± 1.11, P > 0.05) to deliver comparable diagnostic performance (sensitivity = 82.1%-92.3%, specificity = 81.2%-91.2%). Myocardial perfusion and left ventricular function overall showed no significant difference (all P > 0.26). CONCLUSION: One-day rest/stress SPECT with the CRI protocol and rest RAC is feasible to warrant the diagnostic performance of MBF quantitation with a shortened examination time and enhanced patient comfort. Further evaluation on the impact of extracardiac activity to regional MBF and perfusion pattern is required. Additional evaluation is needed in a patient population that is typical of those referred for SPECT MPI, including those with known or suspected coronary microvascular disease.

Structural characterisation of deer sinew peptides as calcium carriers, their promotion of MC3T3-E1 cell proliferation and their effect on bone deposition in mice.

Deer sinew as a by-product has high collagen and nutritional value. This study focuses on its hydrolysate being used as a calcium carrier to develop functional foods. The chelation mechanism was analyzed by SEM, EDS, UV-vis, FTIR, and fluorescence spectroscopy and zeta potential analysis after using peptide-sequenced deer sinew peptides for chelation with calcium ions. The results showed that the chelation of deer sinew peptides with calcium ions occurs mainly at the O and N atoms of carboxyl, amino and amide bonds. In vitro and in vivo studies revealed that deer sinew peptide-calcium chelate (DSPs-Ca) promoted the proliferation of MC3T3-E1 cells without toxic side effects and increased the alkaline phosphatase activity. The DSPs-Ca group improved the bone microstructure induced by low calcium, as well as up-regulated the expression of genes responsible for calcium uptake in the kidneys, as evidenced by serum markers, bone sections, bone parameters, and gene expression analyses in low-calcium-fed mice. From the above, it can be concluded that DSPs-Ca is expected to be a calcium supplement food for promoting bone health.

A promising Artemisia capillaris Thunb. Leaf proteins with high nutrition, applicable function and excellent antioxidant activity.

The nutritional and functional properties of leaf proteins is a decisive factor for their use in food. This work was aimed to extract defatted Artemisia capillaris Thunb. (ACD) leaf proteins (ACLP), and assess ACLP nutritional quality, functional properties and in vitro antioxidant activity, as well characterize the structure. ACLP had a balanced amino acid profile and high bioavailability (protein digestibility corrected amino acid score (PDCAAS) 99.29 %). Solubility, foaming capacity and emulsifying ability of ACLP correlated positively with pH. Water and oil holding capacity were increased with temperature. Gel electrophoresis shown the protein molecular size was mainly ∼25 kDa, and random coil was the mainly secondary structure while ß-sheet was dominant regular conformation as indicated by circular dichroism (CD). ACLP performed in vitro antioxidant activity which was better after digestion. All data implied ACLP met the WHO/FAO protein quality expectations and had application potential in food.

Determination of viable myocardium through delayed enhancement cardiac magnetic resonance imaging combined with 18F-FDG PET myocardial perfusion/metabolic imaging before CABG.

PURPOSE: Study aims to investigate the consistency of delayed enhancement cardiac magnetic resonance imaging (DE-CMR) and 18F-FDG PET myocardial imaging in evaluating myocardial viability before CABG. METHODS: The study analyzed data from 100 patients who were examined with DE-CMR, PET imaging, and echocardiography before and after CABG. All subjects were followed up for 6-12 month post- CABG. RESULTS: DE-CMR and PET imaging have high consistency (90.1%; Kappa value = 0.71, p < 0.01) in determining myocardial viability. The degree of delayed enhancement was negatively correlated with the improvement in myocardial contractile function in this segment after revascularization (P < 0.001). The ratio of scarred myocardial segments and total DE score was significantly lower in the improvement group than non-improvement group. Multivariate regression identified that hibernating myocardium (OR = 1.229, 95%CI: 1.053-1.433, p = 0.009) was influencing factor of LVEF improvement after CABG. CONCLUSION: Both imaging techniques are consistent in evaluating myocardial viability. Detecting the number of hibernating myocardium by PET is also important to predict the left heart function improvement after CABG.

Targeting Erbin-mitochondria axis in platelets/megakaryocytes promotes B cell-mediated antitumor immunity.

The roles of platelets/megakaryocytes (MKs), the key components in the blood system, in the tumor microenvironment and antitumor immunity are unclear. In patients with colorectal cancer, the number of platelets was significantly increased in patients with metastasis, and Erbin expression was highly expressed in platelets from patients with metastases. Moreover, Erbin knockout in platelets/MKs suppressed lung metastasis in mice and promoted aggregations of platelets. Mechanistically, Erbin-deficient platelets have increasing mitochondrial oxidative phosphorylation and secrete lipid metabolites like acyl-carnitine (Acar) by abolishing interaction with prothrombotic protein ESAM. Notably, Acar enhanced the activity of mitochondrial electron transport chain complex and mitochondrial oxidative phosphorylation in B cells by acetylation of H3K27 epigenetically. Targeting Erbin in platelets/MKs by a nanovesicle system dramatically attenuated lung metastasis in mice in vivo. Our study identifies an Erbin-mitochondria axis in platelets/MKs, which suppresses B cell-mediated antitumor immunity, suggesting a new way for the treatment of metastasis.

Microwave ablation versus liver resection for primary intrahepatic cholangiocarcinoma within Milan criteria: a long-term multicenter cohort study.

Background: Ablation has been recommended by worldwide guidelines as first-line treatment for hepatocellular carcinoma (HCC), while evidence regarding its efficacy for primary intrahepatic cholangiocarcinoma (iCCA) is lacking. We aimed to study the efficacy of ablation in treating iCCA by comparing its prognosis with surgery. Methods: In this real-world multicenter cohort study from January 2009 to June 2022, 10,441 iCCA patients from ten tertiary hospitals were identified. Patients who underwent curative-intent microwave ablation (MWA) or liver resection (LR) for tumors within Milan criteria were included. One-to-many propensity score matching (PSM) at variable ratios (1:n ≤4) was used to balance baseline characteristics. Mediation analysis was applied to identify potential mediators of the survival difference. Findings: 944 patients were finally enrolled in this study, with 221 undergoing MWA and 723 undergoing LR. After PSM, 203 patients in the MWA group were matched with 588 patients in the LR group. The median follow-up time was 4.7 years. Compared with LR, MWA demonstrated similar overall survival (5-year 44.8% versus 40.4%; HR 0.96, 95% CI 0.71-1.29, P = .761). There was an improvement in the 5-year disease-free survival rate for MWA from 17.1% during the period of 2009-2016 to 37.3% during 2017-2022, becoming comparable to the 40.8% of LR (P = .129). The proportion of ablative margins ≥5 mm increased from 25% to 61% over the two periods, while this proportion of surgical margins was 62% and 77%, respectively. 34.5% of DFS disparity can be explained by the mediation effect of margins (P < .0001). Similar DFS was observed when both ablative and surgical margins exceeded 5 mm (HR 0.83, 95% CI 0.52-1.32, P = .41). Interpretation: MWA may be considered as a viable alternative to LR for iCCA within Milan criteria when an adequate margin can be obtained. Funding: National Natural Science Foundation of China.

Age-Dependent Female Survival Advantage in Hepatocellular Carcinoma: A Multicenter Cohort Study.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) has a higher incidence in males, but the association of sex with survival remains controversial. This study aimed to examine the effect of sex on HCC survival and its association with age. METHODS: Among 33,238 patients with HCC from 12 Chinese tertiary hospitals, 4175 patients who underwent curative-intent hepatectomy or ablation were analyzed. Cancer-specific survival (CSS) was analyzed using Cox regression and Kaplan-Meier methods. Two propensity score methods and multiple mediation analysis were applied to mitigate confounding. To explore the effect of estrogen, a candidate sex-specific factor that changes with age, female participants' history of estrogen use, and survival were analyzed. RESULTS: There were 3321 males and 854 females included. A sex-related disparity of CSS was present and showed a typical age-dependent pattern: a female survival advantage over males appeared at the perimenopausal age of 45 to 54 years (hazard risk [HR], 0.77; 5-year CSS, 85.7% vs 70.6%; P = .018), peaked at the early postmenopausal age of 55 to 59 years (HR, 0.57; 5-year CSS, 89.8% vs 73.5%; P = .015), and was not present in the premenopausal (<45 y) and late postmenopausal groups (≥60 y). Consistent patterns were observed in patients after either ablation or hepatectomy. These results were sustained with propensity score analyses. Confounding or mediation effects accounted for only 19.5% of sex survival disparity. Female estrogen users had significantly longer CSS than nonusers (HR, 0.74; 5-year CSS, 79.6% vs 72.5%; P = .038). CONCLUSIONS: A female survival advantage in HCC depends on age, and this may be associated with age-dependent, sex-specific factors.

Contrast Enhancement Ultrasound Improves Diagnostic Accuracy for Thyroid Nodules: A Prospective Multicenter Study.

Objective: To evaluate potential improvements in the diagnosis of thyroid nodules when conventional ultrasound (US) is combined with contrast-enhanced US (CEUS). Methods: We recruited 515 participants with 323 malignant and 192 benign nodules, who underwent both US and CEUS examinations at 8 different medical centers in China between October 2020 and October 2021. We assessed the malignancy of thyroid nodules in US using the American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TIRADS). Diagnostic criteria for US and US + CEUS were developed by investigators based on evaluations of sonographic features. Using multivariate logistic regression and receiver operating characteristic (ROC) analysis, we compared diagnostic performance between the 2 methods based on criteria identified by investigators and via statistical models. Results: On the basis of diagnostic criteria identified by investigators, we measured statistically significant differences in area under the curve (AUC) values between ACR TIRADS (0.83) and CEUS TIRADS (0.87; P < .001). On the basis of diagnostic regression models, we found statistically significant differences in AUC values between US (0.76) and US + CEUS (0.84; P = .001). Models based on US + CEUS outperformed those based on US alone (Akaike information criterion of 347.7 and significant improvement in integrated discrimination). These results were confirmed by similar analyses applied to a validation cohort. Conclusion: The accuracy of conventional US for differentiating between benign and malignant thyroid nodules can be improved by combining this approach with CEUS.

Palmatine Protects PC12 Cells and Mice from Aß25-35-Induced Oxidative Stress and Neuroinflammation via the Nrf2/HO-1 Pathway.

Alzheimer's disease is a common degenerative disease which has a great impact on people's daily lives, but there is still a certain market gap in the drug research about it. Palmatine, one of the main components of Huangteng, the rattan stem of Fibraurea recisa Pierre (Menispermaceae), has potential in the treatment of Alzheimer's disease. The aim of this study was to evaluate the neuroprotective effect of palmatine on amyloid beta protein 25-35-induced rat pheochromocytoma cells and AD mice and to investigate its mechanism of action. CCK8 assays, ELISA, the Morris water maze assay, fluorescent probes, calcein/PI staining, immunofluorescent staining and Western blot analysis were used. The experimental results show that palmatine can increase the survival rate of Aß25-35-induced PC12 cells and mouse hippocampal neurons, reduce apoptosis, reduce the content of TNF-α, IL-1ß, IL-6, GSH, SOD, MDA and ROS, improve the learning and memory ability of AD mice, inhibit the expression of Keap-1 and Bax, and promote the expression of Nrf2, HO-1 and Bcl-2. We conclude that palmatine can ameliorate oxidative stress and neuroinflammation produced by Aß25-35-induced PC12 cells and mice by modulating the Nrf2/HO-1 pathway. In conclusion, our results suggest that palmatine may have a potential therapeutic effect on AD and could be further investigated as a promising therapeutic agent for AD. It provides a theoretical basis for the development of related drugs.

US Risk Stratification System for Follicular Thyroid Neoplasms.

Background Preoperative assessment of follicular thyroid neoplasms is challenging using the current US risk stratification systems (RSSs) that are applicable to papillary thyroid neoplasms. Purpose To develop a US feature-based RSS for differentiating between follicular thyroid adenoma (FTA) and follicular thyroid carcinoma (FTC) in biopsy-proven follicular neoplasm and compare it with existing RSSs. Materials and Methods This retrospective multicenter study included consecutive adult patients who underwent conventional US and received a final diagnosis of follicular thyroid neoplasm from seven centers between January 2018 and December 2022. US images from a pretraining data set were used to improve readers' understanding of the US characteristics of the FTC and FTA. Univariable and multivariable logistic regression analyses were used to assess the association of qualitative US features with FTC in a training data set. Features with P < .05 were used to construct a prediction model (follicular tumor model, referred to as F model) and RSS for follicular neoplasms using the Thyroid Imaging Reporting and Data System (TI-RADS). Area under the receiver operating characteristic curve (AUC) was compared between follicular TI-RADS (hereafter, F-TI-RADS) and existing RSS (American College of Radiology [ACR] TI-RADS, Korean Society of Thyroid Radiology and Korean Society of Radiology TI-RADS [hereafter, referred to as K-TI-RADS], and Chinese TI-RADS [hereafter, referred to as C-TI-RADS]) in a validation data set. Results The pretraining, training, and validation data sets included 30 (mean age, 47.6 years ± 16.0 [SD]; 16 male patients; FTCs, 30 of 60 [50.0%]), 703 (mean age, 47.9 years ± 14.5; 530 female patients; FTCs, 188 of 703 [26.7%]), and 155 (mean age, 49.9 years ± 13.3 [SD]; 155 female patients; FTCs, 43 of 155 [27.7%]) patients. In the validation data set, the F-TI-RADS showed improved performance for differentiating between FTA and FTC (AUC, 0.81; 95% CI: 0.71, 0.86) compared with ACR TI-RADS (AUC, 0.74; 95% CI: 0.66, 0.80; P = .02), K-TI-RADS (AUC, 0.69; 95% CI: 0.61, 0.76; P = .002), and C-TI-RADS (AUC, 0.68; 95% CI: 0.60, 0.75; P = .002). Conclusion F-TI-RADS outperformed existing RSSs for differentiating between FTC and FTA. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Baumgarten in this issue.

ZDHHC9: a promising therapeutic target for triple-negative breast cancer through immune modulation and immune checkpoint blockade resistance.

BACKGROUND: Triple-negative breast cancer (TNBC) is a subtype of breast cancer with limited treatment options and poor prognosis. This study aimed to identify potential therapeutic targets based on the expression profiles of differentially expressed genes (DEGs) in TNBC. METHODS: The Limma package was used to identify DEGs in TCGA and GEO datasets. Immunohistochemical (IHC) analysis and western blotting were used to determine the expression of ZDHHC9 in TNBC tissues. Flow cytometry assay and tissue immunofluorescence analysis were used to detect infiltration of multiple immune cells in tumor tissue at different levels of ZDHHC9 expression. RESULTS: ZDHHC9 was identified as a key factor associated with resistance to ICB therapy through weighted gene co-expression network analysis (WGCNA) and single-cell RNA sequencing (scRNA-seq). Subsequently, immunohistochemical (IHC) analysis and western blotting verified that ZDHHC9 expression was elevated in TNBC cancer tissues and that elevated expression of ZDHHC9 was associated with the poor survival of patients with TNBC. Analysis of data from several public datasets revealed that patients with high ZDHHC9 expression had an increased proportion of Ki-67 + breast cancer cells and tended to be basal-like breast cancer. In addition, in vitro and in vivo experiments demonstrated that high expression of ZDHHC9 significantly predicted the efficacy and responsiveness of immunotherapy in TNBC. CONCLUSION: These findings suggest that ZDHHC9 is a valuable marker for guiding the classification, diagnosis and prognosis of TNBC and developing specific targeted therapies.

Extraction, Purification, and Structural Characterization of Polysaccharides from Sanghuangporus vaninii with Anti-Inflammatory Activity.

In order to obtain homogeneous Sanghuangporus vaninii polysaccharides with antioxidant and anti-inflammatory activities, a response surface method (RSM) was used to compare the polysaccharide extraction rate of hot water extraction and ultrasonic-assisted extraction from Sanghuangporus vaninii. The optimal conditions for ultrasonic-assisted extraction were determined as follows: an extraction temperature of 60 °C, an extraction time of 60 min, a solid-liquid ratio of 40 g/mL, and an ultrasonic power of 70 W. An SVP (Sanghuangporus vaninii polysaccharides) extraction rate of 1.41% was achieved. Five homogeneous monosaccharides were obtained by gradient ethanol precipitation with diethylaminoethyl-cellulose (DEAE) and SephadexG-100 separation and purification. The five polysaccharides were characterized by high performance liquid chromatography, the ultraviolet spectrum, the Fourier transform infrared spectrum, TG (thermogravimetric analysis), the Zeta potential, and SEM (scanning electron microscopy). The five polysaccharides had certain levels of antioxidant activity in vitro. In addition, we the investigated the anti-inflammatory effects of polysaccharides derived from Sanghuangporus vaninii on lipopolysaccharide (LPS)-induced RAW 264.7 cells and Kupffer cells. Further, we found that SVP-60 significantly inhibited the levels of pro-inflammatory cytokines, such as interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α in lipopolysaccharide (LPS)-induced RAW 264.7 cells and promoted the level of the anti-inflammatory cytokine IL-10 in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Our study provides theoretical support for the potential application of Sanghuangporus vaninii in the field of antioxidant and anti-inflammatory activities in vitro.

Lipotoxicity-polarised macrophage-derived exosomes regulate mitochondrial fitness through Miro1-mediated mitophagy inhibition and contribute to type 2 diabetes development in mice.

AIMS/HYPOTHESIS: Insulin resistance is a major pathophysiological defect in type 2 diabetes and obesity. Numerous experimental and clinical studies have provided evidence that sustained lipotoxicity-induced mitophagy deficiency can exacerbate insulin resistance, leading to a vicious cycle between mitophagy dysfunction and insulin resistance, and thereby the onset of type 2 diabetes. Emerging evidence suggests that exosomes (Exos) from M2 macrophages play an essential role in modulating metabolic homeostasis. However, how macrophages are affected by lipotoxicity and the role of lipotoxicity in promoting macrophage activation to the M1 state have not been determined. The objective of this study was to determine whether M1 macrophage-derived Exos polarised by lipopolysaccharide (LPS) + palmitic acid (PA)-induced lipotoxicity contribute to metabolic homeostasis and impact the development of insulin resistance in type 2 diabetes. METHODS: Lipotoxicity-polarised macrophage-derived M1 Exos were isolated from bone marrow (C57BL/6J mouse)-derived macrophages treated with LPS+PA. Exos were characterised by transmission electron microscopy, nanoparticle tracking analysis and western blotting. Flow cytometry, H&E staining, quantitative real-time PCR, immunofluorescence, glucose uptake and output assays, confocal microscopy imaging, western blotting, GTTs and ITTs were conducted to investigate tissue inflammation, mitochondrial function and insulin resistance in vitro and in vivo. The roles of miR-27-3p and its target gene Miro1 (also known as Rhot1, encoding mitochondrial rho GTPase 1) and relevant pathways were predicted and assessed in vitro and in vivo using specific miRNA mimic, miRNA inhibitor, miRNA antagomir and siRNA. RESULTS: miR-27-3p was highly expressed in M1 Exos and functioned as a Miro1-inactivating miRNA through the miR-27-3p-Miro1 axis, leading to mitochondria fission rather than fusion as well as mitophagy impairment, resulting in NOD-like receptor 3 inflammatory activation and development of insulin resistance both in vivo and in vitro. Inactivation of miR-27-3p induced by M1 Exos prevented type 2 diabetes development in high-fat-diet-fed mice. CONCLUSIONS/INTERPRETATION: These findings suggest that the miR-27-3p-Miro1 axis, as a novel regulatory mechanism for mitophagy, could be considered as a new therapeutic target for lipotoxicity-related type 2 diabetes disease development.

Outcomes Following Different Thermal Ablation Strategies in Patients with Unresectable Colorectal Liver Metastases.

Background For patients with unresectable colorectal liver metastases (CRLM), clinical guidelines recommend imaging-guided thermal ablation combined with systemic therapy. However, the optimal thermal ablation strategy remains unclear. Purpose To compare long-term outcomes between patients who underwent upfront ablation or delayed ablation for unresectable CRLM. Materials and Methods This retrospective study included patients with unresectable CRLM (three or fewer lesions; diameter, <3 cm) admitted to one of seven hospitals between October 2009 and December 2020. Upfront ablation was performed 2-4 weeks before the start of systemic therapy, and delayed ablation was performed 2-3 months after the start of systemic therapy. Propensity score matching was applied to adjust for differences in baseline variables between groups. Disease-free survival (DFS) was the primary outcome. Overall survival (OS), complications, and adverse events were secondary outcomes. Outcomes were compared between groups by using the log-rank test. Results In total, 255 patients who underwent delayed ablation (mean age, 57 years ± 11 [SD]; 184 men [72%]) and 103 patients who underwent upfront ablation (mean age, 56 years ± 12; 72 men [70%]) were included. After propensity score matching (n = 100 in both groups), the 5-year DFS for patients who underwent upfront ablation was better compared with patients who underwent delayed ablation (36% vs 21%; P = .02). For 5-year OS, no evidence of a difference was observed between ablation strategies (delayed ablation, 59% vs upfront ablation, 64%; P = .49). Additionally, no differences were observed between ablation strategies with respect to the rates of ablative complications (delayed ablation, 6% vs upfront ablation, 5%; P = .76) or drug-related adverse events (delayed and upfront ablation both 9%; P = .99). Conclusion In patients with relatively few (three or fewer) and small (<3 cm) unresectable CRLM, upfront thermal ablation combined with adjuvant systemic therapy led to better DFS compared with delayed ablation. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Georgiades in this issue.

Prognostic value of myocardial flow reserve measured with CZT cardiac-dedicated SPECT low-dose dynamic myocardial perfusion imaging in patients with INOCA.

BACKGROUND: Clinical use of dynamic myocardial perfusion imaging (D-MPI) of cadmium-zinc-telluride (CZT) cardiac-dedicated SPECT is growing, showing a higher application value than conventional SPECT. The prognostic value of ischemia in patients with non-obstructive coronary arteries (INOCA) remains an important challenge for investigation. The primary objective of this study was to investigate the prognostic value of myocardial flow reserve (MFR) measured with low-dose D-MPI of CZT cardiac-dedicated SPECT in the assessment of patients with INOCA. METHODS: Consecutive screening of patients with INOCA and obstructive coronary artery disease (OCAD) who had coronary angiography (CAG) data was performed within three months before or after D-MPI imaging. The patients who met the inclusion criteria were retrospectively analyzed and follow-up by telephone was performed. The enrolled patients were then divided into the INOCA and OCAD groups. INOCA was defined as signs and/or symptoms of myocardial ischemia but with < 50% epicardial stenosis. OCAD was defined as obstructive stenosis (≥ 50% stenosis) of epicardial coronary arteries or their major branches on the CAG. Medical treatments, Seattle Angina Questionnaire (SAQ) scores, and major adverse cardiac events (MACEs) were studied. The Kaplan-Meier survival curve, Log-rank test, and univariable COX regression analysis were used to evaluate the prognosis of patients and associated predictors, with P < 0.05 being considered statistically significant. RESULTS: A total of 303 patients (159 males and 144 females) were enrolled for the final analysis after excluding 24 patients who were lost to follow-up. The mean age of the included cases was 61.94 ± 8.59 years, of which 203 (67.0%) cases were OCAD and 100 (33.0%) cases were INOCA, respectively. The median follow-up was 16 months (14-21 months). Kaplan-Meier survival curves showed that the incidence of MACE was similar in the INOCA and OCAD groups (log-rank P = 0.2645), while those with reduced MFR showed a higher incidence of MACE than those with normal MFR (log-rank P = 0.0019). The subgroup analysis in the OCAD group revealed that 105 patients with reduced MFR had a higher incidence of MACE than those with normal MFR (log-rank P = 0.0226). The subgroup analysis in the INOCA group showed that 37 patients with reduced MFR had a higher incidence of MACE than those with normal MFR in the INOCA group (log-rank P = 0.0186). Univariable Cox regression analysis showed for every 1 unit increase in MFR, the risk of MACE for INOCA was reduced by 66.1% and that for OCAD by 64.2%. For each 1 mL·g-1·min-1 increase in LV-sMBF, the risk of MACE was reduced by 72.4% in INOCA patients and 63.6% in OCAD patients. CONCLUSIONS: MFR measured with low-dose D-MPI CZT SPECT provides incremental prognostic value in patients with INOCA. Patients with reduced MFR show an increased risk of MACE, increased symptom burdens, and impaired quality of life. INOCA patients with reduced MFR experienced higher rate of MACE than OCAD patients with normal MFR.

EphB6 deficiency in intestinal neurons promotes tumor growth in colorectal cancer by neurotransmitter GABA signaling.

EphB6 belongs to the receptor tyrosine kinase, whose low expression is associated with shorter survival of colorectal cancer (CRC) patients. But the role and mechanism of EphB6 in the progression of CRC need further study. In addition, EphB6 was mainly expressed in intestinal neurons. But how EphB6 is involved in functions of intestinal neurons has not been known. In our study, we constructed a mouse xenograft model of CRC by injecting CMT93 cells into the rectum of EphB6-deficient mice. We found that the deletion of EphB6 in mice promoted tumor growth of CMT93 cells in a xenograft model of CRC, which was independent of changes in the gut microbiota. Interestingly, inhibition of intestinal neurons by injecting botulinum toxin A into rectum of EphB6-deficient mice could eliminate the promotive effect of EphB6 deficiency on tumor growth in the xenograft model of CRC. Mechanically, the deletion of EphB6 in mice promoted the tumor growth in CRC by increasing GABA in the tumor microenvironment. Furthermore, EphB6 deficiency in mice increased the expression of synaptosomal-associated protein 25 in the intestinal myenteric plexus, which mediated the release of GABA. Our study concluded that EphB6 knockout in mice promotes tumor growth of CMT93 cells in a xenograft model of CRC by modulating GABA release. Our study found a new regulating mechanism of EphB6 on the tumor progression in CRC that is dependent on intestinal neurons.

Comparison of machine learning models and CEUS LI-RADS in differentiation of hepatic carcinoma and liver metastases in patients at risk of both hepatitis and extrahepatic malignancy.

BACKGROUND: CEUS LI-RADS (Contrast Enhanced Ultrasound Liver Imaging Reporting and Data System) has good diagnostic efficacy for differentiating hepatic carcinoma (HCC) from solid malignant tumors. However, it can be problematic in patients with both chronic hepatitis B and extrahepatic primary malignancy. We explored the diagnostic performance of LI-RADS criteria and CEUS-based machine learning (ML) models in such patients. METHODS: Consecutive patients with hepatitis and HCC or liver metastasis (LM) who were included in a multicenter liver cancer database between July 2017 and January 2022 were enrolled in this study. LI-RADS and enhancement features were assessed in a training cohort, and ML models were constructed using gradient boosting, random forest, and generalized linear models. The diagnostic performance of the ML models was compared with LI-RADS in a validation cohort of patients with both chronic hepatitis and extrahepatic malignancy. RESULTS: The mild washout time was adjusted to 54 s from 60 s, increasing accuracy from 76.8 to 79.4%. Through feature screening, washout type II, rim enhancement and unclear border were identified as the top three predictor variables. Using LI-RADS to differentiate HCC from LM, the sensitivity, specificity, and AUC were 68.2%, 88.6%, and 0.784, respectively. In comparison, the random forest and generalized linear model both showed significantly higher sensitivity and accuracy than LI-RADS (0.83 vs. 0.784; all P < 0.001). CONCLUSIONS: Compared with LI-RADS, the random forest and generalized linear model had higher accuracy for differentiating HCC from LM in patients with chronic hepatitis B and extrahepatic malignancy.