The value of computed tomography perfusion deficit volumes in acute isolated brainstem infarction.

Purpose: Diagnosis of acute isolated brainstem infarction is challenging owing to non-specific, variable symptoms, and the effectiveness of non-contrast computed tomography (NCCT) is poor owing to limited spatial resolution and artifacts. Computed tomography perfusion (CTP) imaging parameters are significantly associated with functional outcomes in posterior circulation acute ischemic stroke; however, the role of CTP in isolated brainstem infarction remains unclear. We aimed to determine the value of CTP imaging parameters in predicting functional outcomes for affected patients. Methods: In total, 116 consecutive patients with isolated pontine/midbrain hypoperfusion who underwent CTP and follow-up by magnetic resonance imaging (MRI) between January 2018 and March 2022, were retrospectively analyzed. Perfusion deficit volumes on all maps, and the final infarction volume (FIV) on MRI were quantified. "Good" functional outcome was defined as a 90-day modified Rankin Scale score of 0 and 1. Statistical analysis included uni- and multivariate regression analyses, binary logistic regressions, and receiver operating characteristics (ROC) analyses. Results: In total, 113 patients had confirmed isolated pontine/midbrain infarction on follow-up MRI. Onset-to-scan time, visibility of ischemic lesions on NCCT, the baseline National Institutes of Health Stroke Scale (NIHSS) score, and perfusion deficit volumes on all CTP maps were significantly associated with FIV (p < 0.05). In a multivariate linear regression model, adjusted for age, sex, NIHSS score, onset-to-scan time, and visibility of NCCT, perfusion deficit volumes remained significantly associated with FIV. In binary logistic regression analyses, perfusion deficit volumes on all CTP maps remained independent predictors of a good functional outcome. In ROC analyses, the cerebral blood flow deficit volume showed a slightly higher discriminatory value with the largest area under the curve being 0.683 [(95% CI, 0.587-0.780), p = 0.001]. Conclusion: Perfusion deficit volumes of CTP imaging could reflect the FIV and contain prognostic information on functional outcomes in patients with acute isolated brainstem infarction.

The use of SNAP and T1-weighted VISTA in cervical artery dissection.

BACKGROUND AND PURPOSE: Some cervical artery dissection (CAD) can't be easily confirmed by commonly used angiography techniques in clinical practice. We aimed to compare the abilities of the vessel wall magnetic resonance imaging (MRI) techniques including simultaneous noncontrast angiography and intraplaque hemorrhage (SNAP) sequence and T1-weighted volumetric isotropic turbo spin echo acquisition (T1-w VISTA) sequence alone for evaluating CAD. MATERIALS AND METHODS: From July 2017 to October 2020, 59 patients underwent MRI examinations including SNAP and T1-w VISTA sequences for cervical artery pathologies. SNAP and T1-w VISTA images were retrospectively and independently reviewed to evaluate their diagnostic performances of CAD by using the final diagnosis as the reference standard which was established by clinical history, physical examination, and all available images. The agreement between T1-w VISTA and SNAP in the identification of the imaging features of CAD, including intramural hematoma (IMH), intimal flap, and double lumen, were compared. The IMH-wall contrasts by T1-w VISTA and SNAP were also compared. RESULTS: CAD was confirmed in 43 of the 59 patients. T1-w VISTA and SNAP showed the same diagnostic performance, and their consistencies with the final diagnosis were good (κ = 0.776, p < 0.001). The sensitivity and specificity in CAD diagnosis were 0.978 and 0.750 for T1-w VISTA and SNAP. The IMH, intimal flap, and double lumen observed on SNAP were also determined by T1-w VISTA (κ = 1.000, p < 0.001 for all). The SNAP sequence showed higher IMH-wall contrast than T1-w VISTA (7.34 ± 4.56 vs. 3.12 ± 1.17, p < 0.001). CONCLUSIONS: SNAP and T1-w VISTA sequences had the same performance in CAD diagnosis, thus they were both recommended. In addition, SNAP showed better IMH-wall contrast than T1-w VISTA.

Emerging Mechanisms and Targeted Therapy of Ferroptosis in Neurological Diseases and Neuro-oncology.

Ferroptosis is a novel type of cell death characterized by iron-dependent lipid peroxidation that involves a variety of biological processes, such as iron metabolism, lipid metabolism, and oxidative stress. A growing body of research suggests that ferroptosis is associated with cancer and neurodegenerative diseases, such as glioblastoma, Alzheimer's disease, Parkinson's disease, and stroke. Building on these findings, we can selectively induce ferroptosis for the treatment of certain cancers, or we can treat neurodegenerative diseases by inhibiting ferroptosis. This review summarizes the relevant advances in ferroptosis, the regulatory mechanisms of ferroptosis, the participation of ferroptosis in brain tumors and neurodegenerative diseases, and the corresponding drug therapies to provide new potential targets for its treatment.

Erratum: Selective targeting of the TLR4 co-receptor, MD2, prevents colon cancer growth and lung metastasis: Erratum.

[This corrects the article DOI: 10.7150/ijbs.39098.].

Radiomic Feature-Based Nomogram: A Novel Technique to Predict EGFR-Activating Mutations for EGFR Tyrosin Kinase Inhibitor Therapy.

OBJECTIVES: To develop and validate a radiomic feature-based nomogram for preoperative discriminating the epidermal growth factor receptor (EGFR) activating mutation from wild-type EGFR in non-small cell lung cancer (NSCLC) patients. MATERIAL: A group of 301 NSCLC patients were retrospectively reviewed. The EGFR mutation status was determined by ARMS PCR analysis. All patients underwent nonenhanced CT before surgery. Radiomic features were extracted (GE healthcare). The maximum relevance minimum redundancy (mRMR) and LASSO, were used to select features. We incorporated the independent clinical features into the radiomic feature model and formed a joint model (i.e., the radiomic feature-based nomogram). The performance of the joint model was compared with that of the other two models. RESULTS: In total, 396 radiomic features were extracted. A radiomic signature model comprising 9 selected features was established for discriminating patients with EGFR-activating mutations from wild-type EGFR. The radiomic score (Radscore) in the two groups was significantly different between patients with wild-type EGFR and EGFR-activating mutations (training cohort: P<0.0001; validation cohort: P=0.0061). Five clinical features were retained and contributed as the clinical feature model. Compared to the radiomic feature model alone, the nomogram incorporating the clinical features and Radscore exhibited improved sensitivity and discrimination for predicting EGFR-activating mutations (sensitivity: training cohort: 0.84, validation cohort: 0.76; AUC: training cohort: 0.81, validation cohort: 0.75). Decision curve analysis demonstrated that the nomogram was clinically useful and surpassed traditional clinical and radiomic features. CONCLUSIONS: The joint model showed favorable performance in the individualized, noninvasive prediction of EGFR-activating mutations in NSCLC patients.

Triptonide Modulates MAPK Signaling Pathways and Exerts Anticancer Effects via ER Stress-Mediated Apoptosis Induction in Human Osteosarcoma Cells.

BACKGROUND: Osteosarcoma (OS) is the most common primary malignancy arise from bone and is one of the causes of cancer-related deaths. Triptonide (TN), a diterpenoid epoxide presented in Tripterygium wilfordii, is shown to possess a broad spectrum of biological properties. METHODS: In this study, we investigate the growth inhibitory effect of TN against human OS cells and its underlying molecular mechanism of action. RESULTS: Findings of our in vitro study revealed that TN exhibited a dose-dependent cytotoxic effect in MG63 and U-2OS cells. ROS-mediated cytotoxic effect was achieved in OS cells treated with TN which was reversed upon NAC treatment. Significantly, increased expression of PERK, p-EIF2, GRP78, ATF4 and CHOP in TN-treated OS cells unfolds the molecular mechanism of TN targets ER stress-mediated apoptosis. Modulation of ERK MAPK pathway was also observed as evidenced by the increased phosphorylation of ERK (p-ERK) and p-p38 in TN-treated OS cells. CONCLUSION: Altogether, the outcome of the study for the first time revealed that TN exhibited its potential chemotherapeutic effects through ROS-mediated ER stress-induced apoptosis via p38 and ERK MAPK signaling pathways.

Selective targeting of the TLR4 co-receptor, MD2, prevents colon cancer growth and lung metastasis.

Toll-like receptor (TLR) signaling is an emerging pathway in tumor cell invasion and metastasis. Myeloid differentiation protein-2 (MD2) contributes to ligand recognition and activation of TLRs in response to exogenous microbial insults or endogenous agents. We hypothesized that blocking MD2 using a specific inhibitor would prevent TLR4-mediated inflammatory responses and metastatic cancer growth. Here, we report that a MD2 inhibitor, L6H21, inhibited migration and invasion of LPS-activated colon cancer CT26.WT cells. These activities were accompanied by inhibition of nuclear factor-κB (NF-κB) activation, and thereby inhibition of the production of pro-inflammatory cytokines and adhesive molecules in colon cancer cells. Furthermore, L6H21 inhibited CT26.WT metastasis to the lung in BALB/c mice as well as suppressed colitis-induced colon cancer induced by azoxymethane/dextran sulfate sodium (AOM/DSS). Taken together, our results demonstrated that L6H21 suppressed tumor invasion and metastasis through blocking TLR4-MD2/NF-κB signaling axis. These findings reveal that inhibition of MD2 may be an important target for the development of colon cancer therapies.

Value of TSCT Features for Differentiating Preinvasive and Minimally Invasive Adenocarcinoma From Invasive Adenocarcinoma Presenting as Subsolid Nodules Smaller Than 3 cm.

BACKGROUND: To distinguish preinvasive (adenocarcinoma in situ/atypical adenomatous hyperplasia) and minimally invasive adenocarcinoma (MIA) from invasive adenocarcinoma (IA) appearing as solitary subsolid nodules (SSNs) less than 3 cm based on thin-section computed tomography (TSCT) features to guide therapeutic approaches. METHODS: A total of 154 lesions that were histopathologically confirmed to have pre/minimally invasive adenocarcinoma (hereafter pre/MIA) and IA presenting as part-solid nodules (PSNs) or pure ground-glass nodules (pGGNs) were retrospectively reviewed. The TSCT features, including diameter, area, CT value, shape, air bronchogram, margins, and location, were compared and assessed. Receiver operating characteristic analyses were conducted to determine the cut-off values for the qualitative variables and their diagnostic performances. RESULTS: Of 154 nodules, 89 IA, 53 MIA, eight adenocarcinoma in situ, and four atypical adenomatous hyperplasia lesions were found. Univariate and multivariate logistic regression of the pre/MIA and IA lesions were compared and analyzed among PSNs and pGGNs. Among pGGNs, a significant difference was found in the area (p = 0.004, odds ratio [OR] = 0.124, 95% confidence interval [CI] = 0.300-0.515) between the pre/MIA and IA groups. In PSNs, significant differences were found in the diameter (p = 0.001, OR = 0.171, 95% CI = 0.063-0.467) and CT value (p = 0.001, OR = 0.996, 95% CI = 0.993-0.998) between the pre/MIA and IA groups. According to the corresponding receiver operating characteristic curves, the optimal cut-off tumor area in pGGNs to differentiate pre/MIA from IA was 0.595 cm2. A higher CT value of the lesion (≥ -298.500 HU) and a larger diameter (≥1.450 cm) in PSNs were significantly associated with IA. CONCLUSION: Imaging features from TSCT contribute to distinguishing pre/MIA from IA in solitary subsolid nodules and may contribute to guide the clinical management of these lesions.

Visual targeted therapy of hepatic cancer using homing peptide modified calcium phosphate nanoparticles loading doxorubicin guided by T1 weighted MRI.

Effective treatment and real-time monitoring of hepatic cancer are essential. A multifunctional calcium phosphate nanoparticles loading chemotherapeutic agent doxorubicin and magnetic resonance imaging contrast agent diethylenetriaminepentaacetic acid gadolinium (A54-CaP/Gd-DTPA/DOX) was developed for visual targeted therapy of hepatic cancer via T1-weighted MRI in real-time. A54-CaP/Gd-DTPA/DOX exhibited a higher longitudinal relaxivity (6.02 mM-1 s-1) than commercial MR contrast agent Gd-DTPA (3.3765 mM-1 s-1). The DOX release from the nanoparticles exhibited a pH dependent behavior. The cellular uptake results showed that the internalization of A54-CaP/Gd-DTPA/DOX into BEL-7402 cells was1.9-fold faster than that of HepG2 cells via A54 binding. In vivo experiments presented that A54-CaP/Gd-DTPA/DOX had higher distribution and longer retention time in tumor tissue than CaP/Gd-DTPA/DOX and free DOX, and also displayed great antitumor efficacy (95.38% tumor inhibition rate) and lower toxicity. Furthermore, the Gd-DTPA entrapped in the nanoparticles could provide T1-weighted MRI for real-time monitoring the progress of tumor treatment.

Non-Small-Cell Lung Cancer: Feasibility of Intratumoral Radiofrequency Hyperthermia-enhanced Herpes Simplex Virus Thymidine Kinase Gene Therapy.

Purpose To validate the feasibility and efficacy of intratumoral radiofrequency hyperthermia (RFH)-enhanced herpes simplex virus (HSV) thymidine kinase (TK) and ganciclovir (GCV) (hereafter, HSV-TK/GCV) gene therapy for non-small-cell lung cancer (NSCLC). Materials and Methods This study was performed from November 11, 2015, to April 14, 2017, and included (a) in vitro experiments with human NSCLC cells to establish the proof of principle, (b) in vivo experiments using mice with subcutaneous NSCLC to further demonstrate the principle, and (c) in vivo experiments using rats with orthotopic NSCLC to validate the technical feasibility. Cells, nude mice, and nude rats were randomly divided into four groups (six animals per group): (a) combination therapy (HSV-TK/GCV combined with RFH), (b) RFH, (c) HSV-TK/GCV, and (d) phosphate-buffered saline. Data were analyzed by using the Dunnett t test or Kruskal-Wallis test. Results For in vitro experiments, the cell proliferation assay showed significantly diminished viable cells with combination therapy (mean, 0.56; 95% confidence interval [CI]: 0.44, 0.68) versus RFH (mean, 0.89; 95% CI: 0.82, 0.97), HSV-TK/GCV (mean, 0.71; 95% CI: 0.56, 0.86), and phosphate-buffered saline (mean, 1; 95% CI: 1, 1) (P < .05 for all). For in vivo experiments, optical imaging showed significantly decreased relative bioluminescence signal with combination therapy (mean, 0.71 [95% CI: 0.03, 1.39] in mice; 1.29 [95% CI: 0.51, 2.06] in rats) compared with RFH (mean, 2.66 [95% CI: 1.73, 3.59] in mice; 2.26 [95% CI: 1.51, 3.01] in rats), HSV-TK/GCV (mean, 1.37 [95% CI: 0.65, 2.08] in mice; 1.76 [95% CI: 1.20, 2.31] in rats), and phosphate-buffered saline (mean, 3.07 [95% CI: 2.50, 3.65] in mice; 2.94 [95% CI: 2.29, 3.58] in rats) (P < .001 for all). US showed that the smallest relative tumor volumes occurred with combination therapy (mean, 0.60; 95% CI: 0.15, 1.05) versus RFH (mean, 2.43; 95% CI: 1.80, 3.06), HSV-TK/GCV (mean, 1.32; 95% CI: 0.75, 1.89), and phosphate-buffered saline (mean, 2.56; 95% CI: 1.75, 3.38) (P < .05 for all) in the mouse subcutaneous model. Conclusion Intratumoral radiofrequency hyperthermia-enhanced herpes simplex virus thymidine kinase and ganciclovir gene therapy for non-small-cell lung cancer is feasible and can be guided by molecular imaging. © RSNA, 2018.

MiR-155 and its functional variant rs767649 contribute to the susceptibility and survival of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) ranks the fourth common cancer and the third common cause of cancer mortality among Chinese population. The development of hepatocellular carcinoma (HCC) were confirmed to be involved in complex interactions between environmental and genetic factors. MicroRNAs (miRNAs) have been found to play an important role in tumorigenesis and metastasis. Emerging evidence suggested that upregulation of miR-155, one of the best characterized miRNAs, could serve as a promising marker for the diagnosis and prognosis of many cancers, except for HCC. In current we tested the hypothesis that functional variant rs767649 located in the flanking region of miR-155 gene contributes to the development and survival of HCC. We identified that functional variant rs767649 in miR-155 regulation region was associated with risk and survival of HCC. The minor allele of rs767649 was significantly associated with an increased risk of HCC (OR=1.23, 95% CI=1.11-1.36, P = 7.97x10-5). The genotype TT of rs767649 was significantly associated with a 1.94 fold poor survival of HCC (HR=1.94, 95% CI=1.01-3.79), while 1.15 fold for genotype AT (HR=1.15, 95% CI=1.06-1.25). Results showed that miR-155 was highly overexpressed in HCC tissues, compared with the adjacent normal tissues (P<0.001). The allele T contributes to higher expression of miR-155 in both the HCC tissues and the adjacent non-tumor tissues (P< 0.01). Our findings suggested that miR-155 and its functional variant rs767649 might contribute to the increased risk and poor prognosis of HCC, highlighting the importance of miR-155 in the prevention and prognosis of HCC.

Chemopreventive effect of chalcone derivative, L2H17, in colon cancer development.

BACKGROUND: Colon cancer is the third most commonly diagnosed cancer and the second leading cause of cancer mortality worldwide. Chalcone and its derivatives are reported to exhibit anti-cancer effects in several cancer cell lines, including colon cancer cells. In addition, chalcones have advantages such as poor interaction with DNA and low risk of mutagenesity. In our previous study, a group of chalcone derivatives were synthesized and exhibited strong anti-inflammatory activities. In this study, we evaluated the anti-cancer effects of the chalcone derivative, L2H17, in colon cancer cells. METHODS: The cytotoxicities of L2H17 on various colon cancer cell lines were investigated by MTT and clonogenic assay. Cell cycle and apoptosis analysis were performed to evaluate the molecular mechanism of L2H17-mediated inhibition of tumor growth. Also, scratch wound and matrigel invasion experiments were performed to estimate the cell migration and invasion after L2H17 treatment. Finally, we observed the anti-colon cancer effects of L2H17 in vivo. RESULTS: Our data show that compound L2H17 exhibited selective cytotoxic effect on colon cancer cells, via inducing G0/G1 cell cycle arrest and apoptosis in CT26.WT cells. Furthermore, L2H17 treatment decreased cell migration and invasion of CT26.WT cells. In addition, L2H17 possessed marked anti-tumor activity in vivo. The molecular mechanism of L2H17-mediated inhibition of tumor promotion and progression were function through inactivated NF-κB and Akt signaling pathways. CONCLUSIONS: All these findings show that L2H17 might be a potential growth inhibitory chalcones derivative for colon cancer cells.

Design, synthesis, and anticancer evaluation of long-chain alkoxylated mono-carbonyl analogues of curcumin.

Curcumin is a nontoxic phenolic compound that modulates the activity of several cellular targets that have been linked with cancers and other chronic diseases. However, the efficacy of curcumin in the clinic has been limited by its poor bioavailability and rapid metabolism in vivo. We have previously reported the design and discovery of series of 5-carbon linker-containing mono-carbonyl analogues of curcumin (MACs) as anti-cancer agents. In continuation of our ongoing research, we designed and synthesized 37 novel long-chain alkoxylated MACs for anti-cancer evaluation here. The MTS assay was used to determine the cytotoxicity of compounds in gastrointestinal cancer cells. Compounds 5, 28, and 29 showed strongest inhibition against gastric cancer cell proliferation and were subjected to further analysis. The effects of 5, 28, and 29 on cell apoptosis were measured by flow cytometry. Expression levels of Bcl-2, cleaved poly ADP-ribose polymerase (PARP), and pro-caspase-3 were detected by western blotting. Compounds 5, 28, and 29 induced apoptosis in human gastric carcinoma cells, increased PARP cleavage, and decreased expression of Bcl-2 and pro-caspase-3 protein. We then showed that compound 28, which possessed the strongest activity among the test compounds in vitro, exhibited significant tumor inhibition in SGC7901-driven xenograft mouse model. Taken together, the novel compound 28 could be further explored as an effective anticancer agent for the treatment of human gastric cancer.

[Application values of 64-row computed tomographic angiography in diagnosing liver VX2 tumor in rabbits].

OBJECTIVE: To evaluate the diagnostic values of computed tomographic angiography (CTA) for liver VX2 tumor in rabbits. METHODS: A total of 40 New Zealand white rabbits were employed by implanting tumor fragment into left liver by computed tomography (CT)-guided percutaneous puncture. And successful modeling was established in 38 rabbits. Plain and three-phase enhanced CT scan and its CTA reconstruction were performed in different stages (14, 21 and 28 days) after tumor implantation, followed by digital subtraction angiography (DSA) via femoral artery and hepatic artery. Dynamic observations of tumor growth characteristics were recorded by plain and enhanced CT and comparing CTA and DSA images. And comparisons of CTA and DSA were made for identifying the origin, course and blood supply of transplanted tumors. RESULTS: (1) Multi-slice computed tomography (MSCT) could dynamically monitor the growth transfer characteristics. And all tumors became strengthened obviously in arterial phase and washed out in venous and delayed phases. (2) CTA showed that the feeding artery of transplanted tumor was hepatic artery. (3) No obvious differences existed in the display of feeding artery of transplanted tumor between CTA and DSA.However CTA was superior to DSA in displaying three-dimensional structure. CONCLUSION: Liver VX2 tumors are hypervascular in rabbits. CT enhanced scanning may dynamically monitor the growth patterns of tumors and CTA is a better method than DSA in visualizing the feeding arteries of tumors. Before and after interventions, CTA may replace DSA in evaluating liver VX2 tumors in rabbits.

[Surveillance and diagnostic values of ultrasound, computed tomography and magnetic resonance imaging follow-ups in malignant transformation of cirrhotic nodules].

OBJECTIVE: To explore the surveillance and diagnostic values of ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI) follow-ups in malignant transformation of cirrhotic nodules so as to improve the diagnostic accuracy of early hepatocellular carcinoma (HCC) with liver cirrhosis. METHODS: Retrospective analyses were conducted for US, CT and MRI features of 96 HCC patients confirmed by pathological examination or treatment. RESULTS: All patients (145 lesions) underwent US, CT, MRI examinations during follow-ups.US detected 62 lesions (42.6%) and 90 lesions on enhanced CT (62.1%) presented "fast-in fast-out" enhancement, pseudocapsule, progressive enlargement or increasing numbers in a short time. And 138 nodules on MRI (95.2%) manifested as decreased T1WI signal, increased T2WI and DWI signal, "nodule in nodule" on T2WI, fatty degeneration, change of enhancement patterns, pseudocapsule, progressive enlargement or increased number in a short time. CONCLUSION: MRI offers obvious advantages over CT and US (P < 0.05). US may serve as a routine follow-up mean for cirrhotic patients. Once lesions are found, enhanced CT and/or MRI should be performed for confirming a diagnosis. Cirrhotic patients without HCC should undergo MRI regularly to diagnose HCC earlier.