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.

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.

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.

Tumor Size at Magnetic Resonance Imaging Association With Lymph Node Metastasis and Lymphovascular Space Invasion in Resectable Cervical Cancer: A Multicenter Evaluation of Surgical Specimens.

OBJECTIVE: To determine whether gross tumor volume (GTV) and the maximum diameter of resectable cervical cancer at magnetic resonance imaging (MRI) could predict lymph node metastasis (LNM) and lymphovascular space invasion (LVSI). MATERIALS AND METHODS: A total of 315 consecutive patients with cervical cancer were retrospectively identified. Gross tumor volume and the maximum diameter of tumor were evaluated on MRI. Univariate and multivariate logistic regression analyses were performed to determine whether tumor size could predict LNM and LVSI. Cutoffs of GTV, maximum diameter, and the International Federation of Gynecology and Obstetrics (FIGO) classification of tumor were first investigated in 255 patients (group A) and then validated in an independent cohort of 60 patients (group B) using area under the receiver operating characteristic curve (AUC) analysis for predicting the presence of LNM and LVSI. RESULTS: Univariate analysis showed that GTV and the maximum diameter of tumor could predict LNM and LVSI (all P < 0.0001). Multivariate analyses indicated GTV as an independent risk factor of LNM and LVSI (all P < 0.0001). In group A, GTV, the maximum diameter, and the FIGO stage could identify LNM (AUC, 0.813, 0.741, and 0.69, respectively) and LVSI (AUC, 0.806, 0.751, and 0.684, respectively). In group B, GTV, the maximum diameter, and the FIGO stage could help identify LNM (AUC, 0.902, 0.825, and 0.759, respectively) and LVSI (AUC, 0.771, 0.748, and 0.700, respectively). CONCLUSIONS: Gross tumor volume and the maximum diameter of resectable cervical cancer at MRI demonstrated capability in predicting LNM and LVSI, which were more accurate than FIGO stage.

[Quality Control and Biological Assessment of Automated Synthesized 3'-deoxy-3'-¹8F-fluorothymidine using CFN-MPS-200 Module].

OBJECTIVES: To synthesize 3'-deoxy-3'-¹8F-fluorotyhymidine)(¹8F-FLT) using CFN-MPS-200 automatic synthesis module, and evaluate its distribution in Wistar rats. METHODS: We used 3-N-Boc-5!d-O-dimethoxytrityl-3!d-O-nosyl-thymidine (Boc-FLT)-percursor as raw material to synthesize ¹8F-FLT without residual solvents. Its radiochemical purity was confirmed with radio-HPLC and thin layer chromatography (TLC). Normal Wistar rats were injected with 18 F-FLT and underwent PET scanning. RESULTS: The entire preparation procedure took about 60 min, which resulted in a radio chemical yield of (24±5)% (after attenuation correction, n =20) and radiochemical purity of over 99%, with 1.11×108 Bq/mL specific activity. The ¹8F-FLT solution was colorless and had a pH value between 7.0-8.0. ¹8F-FLT was mainly concentrated in the kidney, bladder, liver, bone marrow and Liver of normal Wistar rats. CONCLUSION: Automated synthesis of ¹8F-FLT using CFN-MPS-200 is a stable method, with high yield, safety without solvent, and acceptable quality.

Diagnostic Accuracy of MRI for Assessment of T Category and Circumferential Resection Margin Involvement in Patients With Rectal Cancer: A Meta-Analysis.

BACKGROUND: The prognosis of rectal cancer is directly related to the stage of the tumor at diagnosis. Accurate preoperative staging is essential for selecting patients to receive optimal treatment. OBJECTIVE: The purpose of this study was to evaluate the diagnostic performance of MRI in tumor staging and circumferential resection margin involvement in rectal cancer. DATA SOURCES: A systematic literature search was performed in MEDLINE, EMBASE, PubMed, Cochrane Database of Systematic Reviews, and Web of Science database. STUDY SELECTION: Original articles from 2000 to 2016 on the diagnostic performance of MRI in the staging of rectal cancer and/or assessment of mesorectal fascia status were eligible. MAIN OUTCOME MEASURES: Pooled diagnostic statistics including sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were calculated for invasion of muscularis propria, perirectal tissue, and adjacent organs and for circumferential resection margin involvement through bivariate random-effects modeling. Summary receiver operating characteristic curves were fitted, and areas under summary receiver operating characteristic curves were counted to evaluate the diagnostic performance of MRI for each outcome. RESULTS: Thirty-five studies were eligible for this meta-analysis. Preoperative MRI revealed the highest sensitivity of 0.97 (95% CI, 0.96-0.98) and specificity of 0.97 (95% CI, 0.96-0.98) for muscularis propria invasion and adjacent organ invasion. Areas under summary receiver operating characteristic curves indicated good diagnostic accuracy for each outcome, with the highest of 0.9515 for the assessment of adjacent organ invasion. Significant heterogeneity existed among studies. There was no notable publication bias for each outcome. LIMITATIONS: This meta-analysis revealed relatively high diagnostic accuracy for preoperative MRI, although significant heterogeneity existed. Therefore, exploration should be focused on standardized interpretation criteria and optimal MRI protocols for future studies. CONCLUSIONS: MRI showed relatively high diagnostic accuracy for preoperative T staging and circumferential resection margin assessment and should be reliable for clinical decision making.

A let-7 KRAS rs712 polymorphism increases colorectal cancer risk.

Growing evidence has indicated that polymorphism present in the miRNA binding site of target gene can alter the ability of miRNAs to bind its target gene and modulate the development and progression of cancer. We aimed to investigate the association between let-7 KRAS rs712 polymorphism and the risk of colorectal cancer (CRC). The let-7 KRAS rs712 was analyzed in a case-control study, including 339 CRC patients and 313 age- and sex-matched controls; the relationship between the polymorphism and the clinicopathological features of CRC was also examined. Individuals carrying the let-7 KRAS rs712 TT genotype and T allele had an increased risk of developing CRC (TT vs. GG, adjusted OR = 2.18; 95% CI, 1.00-4.77; T vs. G, adjusted OR = 1.50; 95% CI, 1.15-1.96). Stratified analyses revealed that CRC patients with the let-7 KRAS rs712 TT genotype were more likely to have clinical stage III or IV disease (OR = 3.29, 95% CI, 1.32-8.20) and distant metastasis (OR = 4.70, 95% CI, 1.81-12.25). These findings provide evidence that the let-7 KRAS rs712 polymorphism may play crucial roles in the etiology of CRC.

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.

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.

Biomechanical comparison of gourd-shaped LCP versus LCP for fixation of comminuted tibial shaft fracture.

The purpose of this study was to compare monotonic biomechanical properties of gourd-shaped LCP fixation with LCP fixation of human tibial shaft in gap fracture mode. Twenty paired fresh cadaveric human tibias were randomly divided into 4 groups (5 pairs each): (1) axial loading single cycle to failure testing, (2) torsion single cycle to failure testing, (3) 4-point bending single cycle to failure testing, and (4) dynamic 4-point bending testing. A 7-hole 4.5 mm gourd-shaped LCP was secured on the anteromedial surface of 1 randomly selected bone from each pair, respectively, using 6 locking screws in the 1st, 2nd, 3rd, 5th, 6th and 7th hole with the middle hole unfilled and just located at the mid-diaphysis of the tibia. A 7-hole 4.5 mm LCP was secured on the other bone with the same method. Standard AO/ASIF techniques were used. After fixation finished, a 10 mm gap in the mid-diaphysis of tibia was created, centrally located at the unfilled hole. The axial, torsional, and bending stiffness and failure strengths were calculated from the collected data in static testings and statistically compared using paired Student's t-test. The 4-point bending fatigue lives of the two constructs were calculated from the dynamic testing data and also statistically compared using paired Student's t-test. Failure modes were recorded and visually analyzed. P<0.05 was considered significant. Results showed that the axial, torsional and bending stiffness of gourd-shaped LCP construct was greater (4%, 19%, 12%, respectively, P<0.05) than that of the LCP construct, and the axial, torsional and bending failure strengths of gourd-shaped LCP construct were stronger (10%, 46%, 29%, respectively, P<0.05) than those of the LCP construct. Both constructs failed as a result of plate plastic torsional deformation. After axial loading and 4-point bending testings, LCP failed in term of an obvious deformation of bent apex just at the unfilled plate hole, while the gourd-shaped LCP failed in term of a deformation of bent arc between the 3rd and 5th holes, which indicated a more consistent stress distribution on gourd-shaped LCP. Fatigue life of gourd-shaped LCP construct was significantly greater than LCP construct (153 836±2 228 vs. 132 471±6 460 cycles, P<0.01). All constructs failed as a result of fracture of the plate through the compression hole of the unfilled combination screw hole. The biomechanical testing showed that gourd-shaped LCP can provide greater stiffness and strength, and longer fatigue life than LCP. The gourd-shaped LCP may be more advantageous mechanically and may reduce the plate breakage rate clinically.

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.

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.

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.

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.

The association between MLH1 -93 G>A polymorphism of DNA mismatch repair and cancer susceptibility: a meta-analysis.

DNA mismatch repair, known as a fundamentally biological pathway, plays key roles in maintaining genomic stability, eliminating mismatch bases and preventing both mutagenesis in the short term and cancerogenesis in the long term. Polymorphisms of MLH1 in individuals may have an effect on the DNA repair capacity and therefore on cancer risk. Recently, emerging studies have been done to evaluate the association between MLH1 -93 G/A polymorphism and cancer risk in diverse populations. However, the results remain conflicting rather than conclusive. In this meta-analysis, we assessed reported studies of association between the MLH1 -93 G/A polymorphism and cancer risk including 13 691 cancer cases and 14 068 controls from 17 published studies. A borderline significant association between the MLH1 -93 G/A polymorphism and cancer risk was observed in overall analysis [heterozygote: odds ratio (OR) = 1.15; 95% confidence interval (CI) 1.05-1.26; homozygote: OR = 1.21; 95% CI, 1.04-1.40; dominant model: OR = 1.13; 95% CI 1.01-1.26; recessive model: OR = 1.21; 95% CI 1.07-1.35, respectively]. In subgroup analysis by ethnicity, significantly increased risks were found in Asian population and mixed population but not in Caucasian population. After stratified analysis according to the quality of literature, increased cancer risks were observed in the studies of lower quality but not in the studies of higher quality. Similarly, elevated cancer risks were observed in hospital-based studies but not in population-based studies. These findings showed no persuasive evidence that MLH1 -93 G/A polymorphism was associated with an increased risk of cancer. On the conservative standpoint, well-designed population-based studies with larger sample size in different ethnic groups should be performed to further confirm these results.

[Diagnostic and application value of 64-slice spiral CT scanning in preoperative staging of esophageal cancer].

OBJECTIVE: To investigate the diagnostic and application value of pre-operative 64-slice spiral CT evaluation in operation selection for esophagus cancer. METHODS: Multi-slice computed tomography (MSCT) was conducted in 50 patients with esophageal cancer before operation, using the work station for after-treatment to get CT virtual endoscopy (CTVE), multiplanar reconstruction (MRP), shaded surface display (SSD) and Raysum images, and combined with the transect images to record the preoperative MSCT staging and to predict the operation scheme, and compared with the postoperative pathological staging and the actual operational plan. RESULTS: The diagnostic sensitivity of MSCT for preoperative T staging was 100.0% (50/50), while the N staging was 80.0% (16/20). According to the MSCT prediction, the resection rate of esophageal cancer was 96.0% (48/50). Through the preoperative MSCT evaluation, the accuracy of CT-TNM stage was 90.0%, highly consistent with the pathological TNM stage (Kappa = 0.811, P < 0.05). CONCLUSIONS: MSCT can effectively display the shape, size and position of the tumor, determine the tumor invasion range, lymph node metastasis and distant metastasis, etc., make preoperative evaluation for esophagus cancer patients and provide evidence for clinicians to predict the operation scheme for esophagus cancer.

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.

[Relationship between urinary 1-hydroxypyrene level and peripheral blood lymphocyte chromosomal damage among coke oven workers].

OBJECTIVE: To investigate the relationship between the urinary 1-hydroxypyrene level and cytokinesis-block micronucleus in peripheral blood lymphocyte in coke oven workers. METHODS: One hundred and fifty-eight workers from a coke plant and 158 referents without occupational PAHs exposure were recruited in this study. Urnary level of 1-hydroxypyrene was measured by alkaline hydrolysis combined with high performance liquid chromatography as an internal exposure dose, and the chromosomal damage of peripheral blood lymphocyte were evaluated with cytokinesis-block micronucleus (CBMN) method. Personal information including occupational history, age, sex, smoking and alcohol drinking, was collected by questionnaire. RESULTS: The lymphocyte chromosomal damage level expressed as frequency of CBMN in coke oven workers was significantly higher than that of controls (3.32 ± 2.90 vs 0.57 ± 0.88, P < 0.01) after adjusting for sex, age, smoking and alcohol drinking, and correlation between urinary 1-hydroxypyrene concentrations and frequency of CBMN was found (Spearman Partial correlation coefficient = 0.28, P < 0.05) in coke oven workers. Three hundreds and sixteen subjects were divided into three groups by their urine 1-hydroxypyrene level (expressed as 0.11 ∼ 0.70, 0.71 ∼ 4.09 and 4.10 ∼ 24.74 µmol/mol Cr). After adjusting for age, sex, smoking and alcohol drinking by multiple nonparametric analysis of covariance, the frequency of CBMN in the groups of 0.71 ∼ 4.09 and 4.10 ∼ 24.74 µmol/mol C were 1.89 ± 2.37 and 3.29 ± 2.36, significantly higher than that in the group of 0 ∼ 0.70 µmol/mol Cr (0.56 ± 0.89). CONCLUSIONS: Under present PAHs exposure levels, the Cytokinesis-block micronucleus test could detect PAHs-induced genotoxicity in coke oven workers.

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.