Immune checkpoint inhibitors and anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors with or without transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma (CHANCE2201): a target trial emulation study.

Background: The role of transarterial chemoembolization (TACE) in the treatment of advanced hepatocellular carcinoma (HCC) is unconfirmed. This study aimed to assess the efficacy and safety of immune checkpoint inhibitors (ICIs) plus anti-vascular endothelial growth factor (anti-VEGF) antibody/tyrosine kinase inhibitors (TKIs) with or without TACE as first-line treatment for advanced HCC. Methods: This nationwide, multicenter, retrospective cohort study included advanced HCC patients receiving either TACE with ICIs plus anti-VEGF antibody/TKIs (TACE-ICI-VEGF) or only ICIs plus anti-VEGF antibody/TKIs (ICI-VEGF) from January 2018 to December 2022. The study design followed the target trial emulation framework with stabilized inverse probability of treatment weighting (sIPTW) to minimize biases. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and safety. The study is registered with ClinicalTrials.gov, NCT05332821. Findings: Among 1244 patients included in the analysis, 802 (64.5%) patients received TACE-ICI-VEGF treatment, and 442 (35.5%) patients received ICI-VEGF treatment. The median follow-up time was 21.1 months and 20.6 months, respectively. Post-application of sIPTW, baseline characteristics were well-balanced between the two groups. TACE-ICI-VEGF group exhibited a significantly improved median OS (22.6 months [95% CI: 21.2-23.9] vs 15.9 months [14.9-17.8]; P < 0.0001; adjusted hazard ratio [aHR] 0.63 [95% CI: 0.53-0.75]). Median PFS was also longer in TACE-ICI-VEGF group (9.9 months [9.1-10.6] vs 7.4 months [6.7-8.5]; P < 0.0001; aHR 0.74 [0.65-0.85]) per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. A higher ORR was observed in TACE-ICI-VEGF group, by either RECIST v1.1 or modified RECIST (41.2% vs 22.9%, P < 0.0001; 47.3% vs 29.7%, P < 0.0001). Grade ≥3 adverse events occurred in 178 patients (22.2%) in TACE-ICI-VEGF group and 80 patients (18.1%) in ICI-VEGF group. Interpretation: This multicenter study supports the use of TACE combined with ICIs and anti-VEGF antibody/TKIs as first-line treatment for advanced HCC, demonstrating an acceptable safety profile. Funding: National Natural Science Foundation of China, National Key Research and Development Program of China, Jiangsu Provincial Medical Innovation Center, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, and Nanjing Life Health Science and Technology Project.

Mechanisms of intermittent theta-burst stimulation attenuating nerve injury after ischemic reperfusion in rats through endoplasmic reticulum stress and ferroptosis.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) exerts neuroprotective effects early in cerebral ischemia/reperfusion (I/R) injury. Intermittent theta-brust stimulation (iTBS), a more time-efficient modality of rTMS, improves the efficiency without at least decreasing the efficacy of the therapy. iTBS elevates cortical excitability, and in recent years it has become increasingly common to apply iTBS to patients in the early post-IS period. However, little is known about the neuroprotective mechanisms of iTBS. Endoplasmic reticulum stress (ERS), and ferroptosis have been shown to be involved in the development of I/R injury. We aimed to investigate the potential regulatory mechanisms by which iTBS attenuates neurological injury after I/R in rats. METHODS: Rats were randomly divided into three groups: sham-operated group, MCAO/R group, and MCAO/R + iTBS group, and were stimulated with iTBS 36 h after undergoing middle cerebral artery occlusion (MCAO) or sham-operated. The expression of ERS, ferroptosis, and apoptosis-related markers was subsequently detected by western blot assays. We also investigated the mechanism by which iTBS attenuates nerve injury after ischemic reperfusion in rats by using the modified Neurological Severity Score (mNSS) and the balance beam test to measure nerve function. RESULTS: iTBS performed early in I/R injury attenuated the levels of ERS, ferroptosis, and apoptosis, and improved neurological function, including mNSS and balance beam experiments. It is suggested that this mode of stimulation reduces the cost per treatment by several times without compromising the efficacy of the treatment and could be a practical and less costly intervention.

Efficacy and safety of Wuhu oral liquid in treating acute soft tissue injuries: a multicenter, randomized, double-blind, double-dummy, parallel-controlled trial.

Background: Wuhu Oral Liquid (WHOL) is a modified preparation derived from the famous Wuhu Powder, which has a long history of use in treating traumatic injuries. This preparation has anti-inflammatory and analgesic properties and accelerates recovery following acute soft tissue injuries. Aims: To evaluate the efficacy and safety of WHOL in treating acute soft tissue injury associated with qi stagnation and blood stasis syndrome and to provide a basis for applying for the protection of varieties of Chinese medicine for WHOL. Methods: This study was a randomized, controlled, double-blind, multicenter clinical trial in which Fufang Shang Tong Capsule (FFSTC) was selected as the control drug. A total of 480 subjects with acute soft tissue injury associated with qi stagnation and blood stasis syndrome were randomly divided into a test and control group in a 3:1 ratio. The duration of drug treatment was 10 days. The primary outcome was Visual Analogue Scale (VAS) score for pain (including pain at rest and pain on activity). Secondary outcomes included the disappearance time of the pain at rest and on activity; the curative effect of TCM syndrome and improvement in the individual symptoms of TCM (swelling, ecchymosis, and dysfunction); and changes in C-reactive protein (CRP) and interleukin-6 (IL-6) levels. Safety was assessed using vital signs, laboratory examinations, electrocardiograms, and physical examinations. Results: Patient compliance was satisfactory in both groups (all between 80% and 120%). After 4 days of treatment, the WHOL group was superior to the FFSTC group in decreasing the VAS scores for pain at rest (-1.88 ± 1.13 vs. -1.60 ± 0.93, p < 0.05) and on activity (-2.16 ± 1.18 vs. -1.80 ± 1.07, p < 0.05). After 7 days of treatment, the WHOL group was superior to the FFSTC group in decreasing the VAS scores for pain on activity (-3.87 ± 1.60 vs. -3.35 ± 1.30, p < 0.01) and improving swelling (cure rate: 60.4% vs. 46.2%, p < 0.05; obvious effective rate: 60.7% vs. 47.0%, p < 0.05). After 10 days of treatment, the WHOL group was superior to the FFSTC group in decreasing the levels of CRP (-0.13 ± 2.85 vs. 0.25 ± 2.09, p < 0.05) and improving the TCM syndrome (cure rate: 44.1% vs. 30.8%, p < 0.05) and swelling (cure rate: 75.6% vs. 67.5%, p < 0.01; obvious effective rate: 75.6% vs. 68.4%, p < 0.05; effective rate: 77.0% vs. 71.8%, p < 0.05). The disappearance time of pain at rest was 8 days in both groups and 9 days on activity in both groups. In addition, there was no statistical difference between the incidence of adverse events (4.5% vs. 2.6%, p > 0.05) and adverse reactions (0.3% vs. 0%, p > 0.05) between the WHOL group and the FFSTC group. No serious adverse events occurred in either group, and no subjects were withdrawn because of adverse events. Conclusion: WHOL relieves the symptoms caused by acute soft tissue injury associated with qi stagnation and blood stasis syndrome more rapidly than FFSTC, and it is effective and safe in the treatment of acute soft tissue injury. Future studies still need a larger sample size to verify its efficacy and safety. Clinical Trial Registration: https:// www.chictr.org.cn/showproj.html?proj=149531, Identifier ChiCTR2200056411.

Transarterial chemoembolization with PD-(L)1 inhibitors plus molecular targeted therapies for hepatocellular carcinoma (CHANCE001).

There is considerable potential for integrating transarterial chemoembolization (TACE), programmed death-(ligand)1 (PD-[L]1) inhibitors, and molecular targeted treatments (MTT) in hepatocellular carcinoma (HCC). It is necessary to investigate the therapeutic efficacy and safety of TACE combined with PD-(L)1 inhibitors and MTT in real-world situations. In this nationwide, retrospective, cohort study, 826 HCC patients receiving either TACE plus PD-(L)1 blockades and MTT (combination group, n = 376) or TACE monotherapy (monotherapy group, n = 450) were included from January 2018 to May 2021. The primary endpoint was progression-free survival (PFS) according to modified RECIST. The secondary outcomes included overall survival (OS), objective response rate (ORR), and safety. We performed propensity score matching approaches to reduce bias between two groups. After matching, 228 pairs were included with a predominantly advanced disease population. Median PFS in combination group was 9.5 months (95% confidence interval [CI], 8.4-11.0) versus 8.0 months (95% CI, 6.6-9.5) (adjusted hazard ratio [HR], 0.70, P = 0.002). OS and ORR were also significantly higher in combination group (median OS, 19.2 [16.1-27.3] vs. 15.7 months [13.0-20.2]; adjusted HR, 0.63, P = 0.001; ORR, 60.1% vs. 32.0%; P < 0.001). Grade 3/4 adverse events were observed at a rate of 15.8% and 7.5% in combination and monotherapy groups, respectively. Our results suggest that TACE plus PD-(L)1 blockades and MTT could significantly improve PFS, OS, and ORR versus TACE monotherapy for Chinese patients with predominantly advanced HCC in real-world practice, with an acceptable safety profile.

Computational Dissection of the Role of Trp305 in the Regulation of the Death-Associated Protein Kinase-Calmodulin Interaction.

Death-associated protein kinase 1 (DAPK1), as a calcium/calmodulin (CaM) regulated serine/threonine kinase, functions in apoptotic and autophagy pathways and represents an interesting drug target for inflammatory bowel disease and Alzheimer's disease. The crystal structure of the DAPK1 catalytic domain and the autoregulatory domain (ARD) in complex with CaM provides an understanding of CaM-dependent regulation of DAPK1 activity. However, the molecular basis of how distinct Trp305 (W305Y and W305D) mutations in the ARD modulate different DAPK1 activities remains unknown. Here, we performed multiple, µs-length molecular dynamics (MD) simulations of the DAPK1-CaM complex in three different (wild-type, W305Y, and W305D) states. MD simulations showed that the overall structural complex did not change significantly in the wild-type and W305Y systems, but underwent obvious conformational alteration in the W305D system. Dynamical cross-correlation and principal component analyses revealed that the W305D mutation enhanced the anti-correlated motions between the DAPK1 and CaM and sampled a broader distribution of conformational space relative to the wild-type and W305Y systems. Structural and energetical analyses further exhibited that CaM binding was unfavored in response to the W305D mutation, resulting in the decreased binding of CaM to the W305D mutant. Furthermore, the hydrogen bonds and salt bridges responsible for the loss of CaM binding on the interface of the DAPK1-CaM complex were identified in the W305D mutant. This result may provide insights into the key role of Trp305 in the regulation of CaM-mediated DAPK1 activity.

Efficacy and safety of transarterial chemoembolization combining sorafenib with or without immune checkpoint inhibitors in previously treated patients with advanced hepatocellular carcinoma: A propensity score matching analysis.

Purpose: To compare the efficacy and safety of transarterial chemoembolization (TACE) plus sorafenib and immune checkpoint inhibitors (T+S+ICIs) and TACE plus sorafenib (T+S) when treating patients with advanced hepatocellular carcinoma (HCC) who have previously received locoregional treatment. Materials and methods: A retrospective analysis was performed on the patients with Barcelona Clinic Liver Cancer (BCLC) stage C HCC from May 2019 to December 2020. These patients were treated with locoregional therapy and showed radiographic progression after the treatment. Patients received either T+S+ICIs or T+S. The outcomes, including disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety, were compared. The propensity score matching (PSM) methodology was used to reduce the influence of confounding factors on the outcomes. Results: Forty-three patients were included in the T+S group and 33 in the T+S+ICI group. After PSM (n = 29 in each group), patients who received T+S+ICIs had a higher DCR (82.8% vs. 58.6%, p = 0.043), longer median PFS (6.9 vs. 3.8 months, p = 0.003), and longer median OS (12.3 vs. 6.3 months, p = 0.008) than those who underwent T+S. Eastern Cooperative Oncology Group performance status was an independent predictor of PFS, and age was an independent predictor of OS. The incidence of treatment-related adverse events in T+S+ICIs was well controlled. Conclusions: Compared with TACE combined with sorafenib, TACE combined with sorafenib plus ICIs is a potentially safe and effective treatment regimen for patients with advanced HCC who previously received locoregional treatment.

Efficacy and Safety of Drug-Eluting Beads Transarterial Chemoembolization Combining Immune Checkpoint Inhibitors in Unresectable Intrahepatic Cholangiocarcinoma: A Propensity Score Matching Analysis.

Purpose: To assess the effectiveness and safety of drug-eluting beads transarterial chemoembolization plus immune checkpoint inhibitors (DEB-TACE+ICIs) versus chemotherapy (gemcitabine+cisplatin) for patients with unresectable intrahepatic cholangiocarcinoma (iCCA). Materials and Methods: This retrospective study included unresectable iCCA patients treated with DEB-TACE+ICIs or chemotherapy between May, 2019 and August, 2021. The differences in tumor responses, progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs) were compared between the 2 groups. Patient baseline characteristics, PFS, and OS were compared among 2 groups before and after propensity score-matching (PSM). Factors affecting PFS and OS were analyzed by Cox's proportional hazards regression model. Results: The study included 49 patients with unresectable iCCA patients, 20 in the DEB-TACE+ICIs group and 29 in the chemotherapy group. PSM analysis created 20 pairs of patients in 2 groups. The patients in the DEB-TACE+ICIs group had a higher objective response rate (55.0% vs. 20.0%, P=0.022), higher PFS (median, 7.2 vs. 5.7 months, P=0.036), and higher OS (median, 13.2 vs. 7.6 months, P=0.015) than those in the chemotherapy group. Multivariate analyses suggested that chemotherapy, tumor size >5cm, and multiple tumors were the independent risk factors for PFS and OS. The incidence of TRAEs was similar between the 2 groups. Conclusion: Compared to chemotherapy, DEB-TACE plus ICIs improved survival and was well-tolerated in patients with unresectable iCCA.

Predictive Value of Preoperative Neutrophil-to-Lymphocyte Ratio in Patients with Hepatocellular Carcinoma after Transarterial Chemoembolization Combined With Radiofrequency Ablation.

PURPOSE: To determine the predictive value of preoperative inflammatory markers in hepatocellular carcinoma (HCC) prognosis after transarterial chemoembolization (TACE) combined with radiofrequency ablation (RFA). MATERIALS AND METHODS: A total of 161 patients with HCC who underwent TACE combined with RFA were enrolled in this retrospective study. Receiver operating characteristic (ROC) curve analysis was used to decide the cutoff value of the neutrophil-to-lymphocyte ratio (NLR), the lymphocyte-to-monocyte ratio (LMR), the platelet-to-lymphocyte ratio (PLR), and the prognostic nutritional index (PNI). The relationship between preoperative NLR, LMR, PLR, PNI, and survival outcomes was analyzed using Kaplan-Meier curves and multivariate Cox regression analyses. RESULTS: The cutoff value of NLR for the best discrimination of HCC prognosis was 2.95. The median recurrence-free survival (RFS) of the low NLR (≤2.95) group was longer than that of the high NLR (>2.95) group (29 months vs. 20 months, p = 0.013). The median overall survival (OS) of the low NLR group was longer than that of the high NLR group (60 months vs. 38 months, p = 0.006). Multivariate analysis showed that the tumor size (≤3 cm vs. >3cm), tumor number (single vs. multiple), and NLR (≤2.95 vs. >2.95) were independent predictors of the PFS and OS. LMR, PLR, and PNI did not have any prognostic significance. CONCLUSION: NLR was confirmed as an independent predictive biomarker for hepatocellular carcinoma prognosis after TACE combined with RFA.

Analysis of the Electrophoretic Profiles of Prion Protein in Carcinous and Pericarcinous Lysates of Six Different Types of Cancers.

OBJECTIVE: To find the different electrophoretic profiles of prion protein in carcinous and individual pericarcinous tissues in lysates of gastric, colon, liver, lung, thyroid, and laryngeal cancers. METHODS: Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot were used to test the amounts and electrophoretic patterns of total PrP and the tolerance of PK (protease K) digestion among six various cancer tissue types. RESULTS: A mass of PrP signals with a large molecular weight were identified in the homogenates of peripheral tissues. The amounts and electrophoretic patterns of total PrP did not differ significantly between carcinous and pericarcinous tissues. PrPs in all types of the tested cancer samples were PK sensitive but showed diversity in the tolerance of PK digestion among various tissue types. CONCLUSIONS: The study revealed that the included electrophoretic patterns of carcinous and pericarcinous tissues were almost similar. Unlike PrP-specific immunohistochemical assay, evaluation of PrP electrophoretic patterns in the peripheral organs and tissues by Western blot does not reflect tumor malignancy.

Radiomic features of axillary lymph nodes based on pharmacokinetic modeling DCE-MRI allow preoperative diagnosis of their metastatic status in breast cancer.

OBJECTIVE: To study the feasibility of use of radiomic features extracted from axillary lymph nodes for diagnosis of their metastatic status in patients with breast cancer. MATERIALS AND METHODS: A total of 176 axillary lymph nodes of patients with breast cancer, consisting of 87 metastatic axillary lymph nodes (ALNM) and 89 negative axillary lymph nodes proven by surgery, were retrospectively reviewed from the database of our cancer center. For each selected axillary lymph node, 106 radiomic features based on preoperative pharmacokinetic modeling dynamic contrast enhanced magnetic resonance imaging (PK-DCE-MRI) and 5 conventional image features were obtained. The least absolute shrinkage and selection operator (LASSO) regression was used to select useful radiomic features. Logistic regression was used to develop diagnostic models for ALNM. Delong test was used to compare the diagnostic performance of different models. RESULTS: The 106 radiomic features were reduced to 4 ALNM diagnosis-related features by LASSO. Four diagnostic models including conventional model, pharmacokinetic model, radiomic model, and a combined model (integrating the Rad-score in the radiomic model with the conventional image features) were developed and validated. Delong test showed that the combined model had the best diagnostic performance: area under the curve (AUC), 0.972 (95% CI [0.947-0.997]) in the training cohort and 0.979 (95% CI [0.952-1]) in the validation cohort. The diagnostic performance of the combined model and the radiomic model were better than that of pharmacokinetic model and conventional model (P<0.05). CONCLUSION: Radiomic features extracted from PK-DCE-MRI images of axillary lymph nodes showed promising application for diagnosis of ALNM in patients with breast cancer.

Usefulness of preoperative coronary computed tomography angiography in high risk non-cardiovascular surgery old patients with unknown or suspected coronary artery disease.

BACKGROUND: Cumulative evidence has shown that the non-invasive modality of coronary computed tomography angiography (CCTA) has evolved as an alternative to invasive coronary angiography, which can be used to quantify plaque burden and stenosis and identify vulnerable plaque, assisting in diagnosis, prognosis and treatment. With the increasing elderly population, many patients scheduled for non-cardiovascular surgery may have concomitant coronary artery disease (CAD). The aim of this study was to investigate the usefulness of preoperative CCTA to rule out or detect significant CAD in this cohort of patients and the impact of CCTA results to clinical decision-making. METHODS: 841 older patients (age 69.5 ± 5.8 years, 74.6% males) with high risk non-cardiovascular surgery including 771 patients with unknown CAD and 70 patients with suspected CAD who underwent preoperative CCTA were retrospectively enrolled. Multivariate logistic regression analysis was performed to determine predictors of significant CAD and the event of cancelling scheduled surgery in patients with significant CAD. RESULTS: 677 (80.5%) patients had non-significant CAD and 164 (19.5%) patients had significant CAD. Single-, 2-, and 3- vessel disease was found in 103 (12.2%), 45 (5.4%) and 16 (1.9%) patients, respectively. Multivariate analysis demonstrated that positive ECG analysis and Agatston score were independently associated with significant CAD, and the optimal cutoff of Agatston score was 195.9. The event of cancelling scheduled surgery was increased consistently according to the severity of stenosis and number of obstructive major coronary artery. Multivariate analysis showed that the degree of stenosis was the only independent predictor for cancelling scheduled surgery. In addition, medication using at perioperative period increased consistently according to the severity of stenosis. CONCLUSIONS: In older patients referred for high risk non-cardiovascular surgery, preoperative CCTA was useful to rule out or detect significant CAD and subsequently influence patient disposal. However, it might be unnecessary for patients with negative ECG and low Agatston score. Trial registration Retrospectively registered.

Vesselplasty using the Mesh-Hold™ bone-filling container for the treatment of pathological vertebral fractures due to osteolytic metastases: A retrospective study.

PURPOSE: To evaluate the clinical benefits and complications of vesselplasty using the Mesh-Hold™ bone-filling container in the treatment of vertebral osteolytic fractures. METHODS: This was a retrospective study of patients with vertebral osteolytic pathological fractures treated by vesselplasty at Sichuan Cancer Hospital between 09/2014 and 01/2018. VAS1 (Visual analog scale) scores and ODI2 (Oswestry disability index) were recorded routinely 1 day preoperative, at 1 day, 1 month, 3 months, 6 months, and 1 year postoperation, and at the last follow-up. V13 (The of bone cement injection volume) and V24 (vertebral body osteolytic volume) were evaluated, and the R5 (ratio) of bone cement filling was obtained according to the V1/V2. RESULTS: Sixty-three patients were included (105 segments with osteolytic fractures). The amount of bone cement for each vertebra was 2.4-5.2 ml (3.1 ± 0.7 ml). The ratio (R) of bone cement filling was not related to pain relief or functional recovery (all P > 0.05).The VAS scores and ODI at different time points after surgery were decreased compared with before surgery (all P < 0.05). The bone cement leakage rate was 16.2 % (17/105). The follow-up was 4-30 months (mean of 13 ± 6 months). Thirty patients had died by the last follow-up, all from their cancer. CONCLUSIONS: The Mesh-Hold™ bone-filling container in the treatment of vertebral fractures induced by osteolytic metastases could reduce pain, improve function, and reduce the bone cement leakage rate in the process of vesselplasty.

Validation and evaluation of clinical prediction systems for first and repeated transarterial chemoembolization in unresectable hepatocellular carcinoma: A Chinese multicenter retrospective study.

BACKGROUND: The treatment outcome of transarterial chemoembolization (TACE) in unresectable hepatocellular carcinoma (HCC) varies greatly due to the clinical heterogeneity of the patients. Therefore, several prognostic systems have been proposed for risk stratification and candidate identification for first TACE and repeated TACE (re-TACE). AIM: To investigate the correlations between prognostic systems and radiological response, compare the predictive abilities, and integrate them in sequence for outcome prediction. METHODS: This nationwide multicenter retrospective cohort consisted of 1107 unresectable HCC patients in 15 Chinese tertiary hospitals from January 2010 to May 2016. The Hepatoma Arterial-embolization Prognostic (HAP) score system and its modified versions (mHAP, mHAP2 and mHAP3), as well as the six-and-twelve criteria were compared in terms of their correlations with radiological response and overall survival (OS) prediction for first TACE. The same analyses were conducted in 912 patients receiving re-TACE to evaluate the ART (assessment for re-treatment with TACE) and ABCR (alpha-fetoprotein, Barcelona Clinic Liver Cancer, Child-Pugh and Response) systems for post re-TACE survival (PRTS). RESULTS: All the prognostic systems were correlated with radiological response achieved by first TACE, and the six-and-twelve criteria exhibited the highest correlation (Spearman R = 0.39, P = 0.026) and consistency (Kappa = 0.14, P = 0.019), with optimal performance by area under the receiver operating characteristic curve of 0.71 [95% confidence interval (CI): 0.68-0.74]. With regard to the prediction of OS, the mHAP3 system identified patients with a favorable outcome with the highest concordance (C)-index of 0.60 (95%CI: 0.57-0.62) and the best area under the receiver operating characteristic curve at any time point during follow-up; whereas, PRTS was well-predicted by the ABCR system with a C-index of 0.61 (95%CI: 0.59-0.63), rather than ART. Finally, combining the mHAP3 and ABCR systems identified candidates suitable for TACE with an improved median PRTS of 36.6 mo, compared with non-candidates with a median PRTS of 20.0 mo (log-rank test P < 0.001). CONCLUSION: Radiological response to TACE is closely associated with tumor burden, but superior prognostic prediction could be achieved with the combination of mHAP3 and ABCR in patients with unresectable liver-confined HCC.

Differentiation between Luminal A and B Molecular Subtypes of Breast Cancer Using Pharmacokinetic Quantitative Parameters with Histogram and Texture Features on Preoperative Dynamic Contrast-Enhanced Magnetic Resonance Imaging.

OBJECTIVE: The aim of the present study was to use pharmacokinetic quantitative parameters with histogram and texture features on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to differentiate between the luminal A and luminal B molecular subtypes of breast cancer. METHODS: We retrospectively reviewed the data of 94 patients with histopathologically proven breast cancer. The pharmacokinetic quantitative parameters (Ktrans, Kep, and Ve) with their corresponding histogram and texture features based on preoperative DCE-MRI were obtained. The parameters were compared using the Mann-Whitney U-test between the luminal A and luminal B groups, the human epidermal growth factor receptor-2 (HER2)-positive luminal B and HER2-negative luminal B groups, and the lymph node metastasis (LNM)-positive and LNM-negative groups. Receiver operating characteristic curves were generated for parameters that presented significant between-group differences. RESULTS: The maximum values of Ktrans, Kep, and Ve, and the mean and 90th percentile values of Ve were significantly higher in the luminal B group than in the luminal A group. Among the texture features, only skewness of Ktrans significantly differed between the luminal A and B groups. All histogram features of Ktrans were higher in the HER2-positive luminal B group than in the HER2-negative luminal B group. However, no parameter differed between the LNM-positive and LNM-negative groups. CONCLUSION: Pharmacokinetic quantitative parameters with histogram and texture features obtained from DCE-MRI are associated with the molecular subtypes of breast cancer, and may serve as potential imaging biomarkers to differentiate between the luminal A and luminal B molecular subtypes.

Role of miR-199a-5p in osteoblast differentiation by targeting TET2.

OBJECTIVE: miR-199a-5p was increased during osteoblast differentiation, which may target and regulate TET2, a gene attracted a lot of attention in the osteoblast differentiation in the past few years. However, the role of miR-199a-5p in osteoblast differentiation by targeting TET2 is not established. METHODS: The correlation between miR-199a-5p and TET2 was verified through dual luciferase reporter assay, and their expressions in human bone marrow stromal cells (hBMSCs) during the osteoblast differentiation were detected. hBMSCs were transfected with TET2 siRNA, miR-199a-5p mimic or/and TET2 CRISPR activation plasmid., and then prepared for the induction of osteoblast differentiation, followed by alkaline phosphatase (ALP) and alizarin red staining, qRT-PCR and Western blotting. In vivo, ovariectomized (OVX) mice were injected with agomir-miR-199a-5p, antagomiR-199a-5p or/and TET2 siRNA to calculate the BMD and BV/TV ratio of mice, as well as to measure the expressions of osteogenesis-related genes in bone tissues. RESULTS: A gradual increase of miR-199a-5p was observed in hBMSCs during the induction of osteoblast differentiation, while TET2 expression was decreased. Besides, miR-199a-5p was reduced in the bone tissue of OVX mice, while TET2 was up-regulated. In addition, overexpression of miR-199a-5p and inhibition of TET2 augmented ALP activity in hBMSCs, with the enhanced calcification and the up-regulated expressions of Runx2, OSX and OCN, which also increased the quality of bone in OVX mice accompanying the enhancement BV/TV ratio, BMD and osteogenesis-related genes. CONCLUSION: MiR-199a-5p may promote the osteoblast differentiation and prevent OVX-induced osteoporosis by targeting TET2.

Non-invasive evaluation of renal structure and function of healthy individuals with multiparametric MRI: Effects of sex and age.

Clinically, when applying multiparametric magnetic resonance imaging (MRI) examinations in renal diseases, assessment of renal structure and function has to account for age- and sex-related effects. The aim of this study was to investigate the influence of age and sex on multiparametric MRI assessment of renal structure and function in healthy human beings. Studies on 33 healthy volunteers were performed using multiparametric MRI on a 3.0-Tesla MR scanner, including T1-weighted imaging, blood oxygen level-dependent MRI (BOLD MRI), diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI). Our results revealed that the mean renal cortical thickness (RCT), ratio of cortex to parenchyma (CPR), and cortical R2* values were higher in males than in females. The cortical R2* value was higher in older group than in younger group (18.57 ± 0.99 vs 17.53 ± 0.58, p = 0.001); there was no significant difference in medullary R2* between the older and younger groups (38.18 ± 2.96 vs 36.45 ± 2.47, p = 0.077). The parenchymal thickness (PT) and medullary fractional anisotropy (FA) were lower in older group than in younger group (1.547 ± 0.06 vs 1.604 ± 0.05, p = 0.005 and 0.343 ± 0.03 vs 0.371 ± 0.03, p = 0.016, respectively). Pearson's correlation analysis showed that PT and medullary FA were inversely related with age (r = -0.483, p = 0.004; r = -0.446, p = 0.009) while cortical R2* values was positively related (r = 0.511, p = 0.002, respectively). The medullary apparent diffusion coefficient (ADC) value had a significant association with PT (r = 0.359, p = 0.04). This study indicated that multiparametric renal MRI parameters are age and sex dependent.

Primary intracranial leiomyosarcoma in an immunocompetent patient: Case report with emphasis on imaging features.

RATIONALE: Primary intracranial leiomyosarcoma (LMS) is an extremely rare tumor in the central nervous system (CNS), and usually seen in immunocompromised individuals. Only a few cases of primary intracranial LMS have been documented in the literature and no study focused on their MRI findings. We reported a case of primary intracranial leiomyosarcoma in a immunocompetent patient and review its imaging features. PATIENT CONCERNS: A 20-year-old female was admitted to our hospital, complaining with nausea, weight loss and progressive headache in recent 2 years. DIAGNOSIS: The magnetic resonance imaging scan of the brain revealed a large well-defined extra-cerebral mass adherent to left temporal meninges. The mass was iso-intense on T1-weighted images (T1WI), lightly iso to hypointense on T2-weighted images (T2WI) and enhanced uniformly with contrast medium. The preoperative diagnosis is meningioma. INTERVENTIONS: A left craniotomy was performed for the complete resection of the mass. OUTCOMES: The lesion was diagnosed via surgical histopathology and immunochemistry as leiomyosarcoma. No evidence of recurrence and complications were found in the following 13 months. LESSIONS: Primary intracranial leiomyosarcoma which has some special MR imaging features should be considered in the differential diagnosis of intracranial tumor.

A Fatal Case of Acute Arsenic Poisoning.

This manuscript reported a case of fatal arsenic poisoning. A woman with schizophrenia took arsenic-containing "pills," which consisted of arsenic trioxide and realgar (arsenic (II) sulfide) and wrapped with gauze. The victim consumed 1.09 and 0.819 g arsenic on two occasions, respectively, with the interval between the two doses of 3 days. The woman died on the sixth day after the first dose without any treatment. In this case, pathological examination revealed fat degeneration of the liver rather than hepatomegaly, a rare finding in acute arsenic poisoning. Arsenic in tissue samples was measured, the total arsenic and inorganic arsenic in blood, liver, and gastric wall was 10.2 µg/mL (9.61 µg/mL), 23.1 µg/g (20.7 µg/g), and 32.3 µg/g (28.6 µg/g), respectively.

miR-145 protects the function of neuronal stem cells through targeting MAPK pathway in the treatment of cerebral ischemic stroke rat.

This study is designed to investigate the function of the miR-145 in the protection of neural stem cells (NSCs) through targeting mitogen-activated protein kinase (MAPK) pathway in the treatment of cerebral ischemic stroke rat. In our study, rat NSCs were selected and cultured in complete medium. The light microscopy was used to observe the morphology of NSCs at different times. The quantitative reverse transcriptase real-time polymerase chain reaction (qRT-PCR) was used to detect the miR-145 and other related mRNAs of the MARK pathway. The Western blotting was used to detect the activation of MAPK pathway and neuronal specific markers. The Immunofluorescence was used to detect the expression of the neuron-specific enolase. And the cell viability was detected by Cell Counting Kit (CCK)-8 assay. The flow cytometry was used to test the cell cycle and apoptosis. The ischemic stroke rat models were established and neural stem cell transplantation was performed. The neurological function score, balance beam experiment, and cortical Nissl staining were used to evaluate the postoperative neurological function in rats. The expression of miR-145, extracellular signal-regulated kinase (ERK), and p38 mRNA in rat NSCs increased in a time-dependent manner. Compared with the Blank group, the over-expression of miR-145 promoted the expression of related mRNA and protein of the MAPK pathway in NSCs, while the decreased expression of miR-145 suppressed the MAPK Pathways. Compared with the Blank group, over-expression of miR-145 in NSCs promoted the up-regulation of Cyclin D1, Nestin, neuron-specific enolase (NSE), and Glial fibrillary acidic protein (GFAP) proteins, enhanced the activity of NSCs, and promoted cell proliferation and differentiation, while inhibited the cell apoptosis and the Cleaved-caspase 3 expression. After treatment of NSCs in the SB203580 group, the Nestin, NSE, and GFAP were decreased; cell viability, proliferation and differentiation were inhibited, while Cleaved-caspase 3 protein and cell apoptosis rate increased. The results of animal experiments showed that compared with the Blank group, the walking ability and neurological impairment recovered rapidly in the rats after transplantation of NSCs with over-expression of miR-145, and more neurons were generated in the cortex. After the transplantation of SB203580-treated NSCs, the walking ability and neurological impairment of the rats were slower and the cortical neurons were less. We conclude that miR-145 protects the function of neuronal stem cells through targeting MAPK pathway in the treatment of cerebral ischemic stroke rat.

Primary squamous cell carcinoma of the pancreas with effective comprehensive treatment: A case report and literature review.

RATIONALE: Primary squamous cell carcinoma (SCC) of the pancreas is a rare entity since the pancreas lacks squamous cells. This condition is associated with a poor prognosis, and there is currently no optimal treatment strategy for it. PATIENT CONCERNS: A 64-year-old female patient with a complaint of epigastric pain for 3 months was referred to our hospital. DIAGNOSES: She was finally diagnosed with primary SCC of the pancreas with lymph node metastasis on the basis of radiological and pathological findings. INTERVENTIONS: She received chemoradiation along with targeted therapy and was provided with treatment response evaluation through PET/CT. OUTCOMES: She eventually died of tumor progression after 8 months. LESSONS: Primary SCC of the pancreas is associated with a poor prognosis. Comprehensive therapy and proper radiologic evaluation may facilitate prolonged survival of these patients.