B-Myb deficiency boosts bortezomib-induced immunogenic cell death in colorectal cancer.

B-Myb has received considerable attention for its critical tumorigenic function of supporting DNA repair. However, its modulatory effects on chemotherapy and immunotherapy have rarely been reported in colorectal cancer. Bortezomib (BTZ) is a novel compound with chemotherapeutic and immunotherapeutic effects, but it fails to work in colorectal cancer with high B-Myb expression. The present study was designed to investigate whether B-Myb deletion in colorectal cancer could potentiate the immune efficacy of BTZ against colorectal cancer and to clarify the underlying mechanism. Stable B-Myb knockdown was induced in colorectal cancer cells, which increased apoptosis of the cancer cells relative to the control group in vitro and in vivo. We found that BTZ exhibited more favourable efficacy in B-Myb-defective colorectal cancer cells and tumor-bearing mice. BTZ treatment led to differential expression of genes enriched in the p53 signaling pathway promoted more powerful downstream DNA damage, and arrested cell cycle in B-Myb-defective colorectal cancer. In contrast, recovery of B-Myb in B-Myb-defective colorectal cancer cells abated BTZ-related DNA damage, cell cycle arrest, and anticancer efficacy. Moreover, BTZ promoted DNA damage-associated enhancement of immunogenicity, as indicated by potentiated expression of HMGB1 and HSP90 in B-Myb-defective cells, thereby driving M1 polarization of macrophages. Collectively, B-Myb deletion in colorectal cancer facilitates the immunogenic death of cancer cells, thereby further promoting the immune efficacy of BTZ by amplifying DNA damage. The present work provides an effective molecular target for colorectal cancer immunotherapy with BTZ.

AURKB activates EMT through PI3K/AKT signaling axis to promote ICC progression.

Intrahepatic cholangiocarcinoma (ICC) is a fatal disease and the molecular mechanism of its progression remains unknown. Aurora Kinase B (AURKB) is a central regulator of chromosome separation and cytokinesis and is abnormally expressed in a variety of cancer cells. This research aimed to explore the effect of AURKB in occurrence and metastasis of ICC. We found that AURKB showed a progressive up-regulation pattern from normal bile duct tissue to ICC with high invasion. Our data showed that AURKB significantly promoted ICC cell proliferation, induced epithelial-mesenchymal transition (EMT), migration and invasion through gain- and loss- of function experiments. In vivo results consistently showed that AURKB up-regulation not only promoted tumor growth, but also promoted tumor metastasis. Importantly, we discovered that AURKB regulates the expressions of EMT-related genes via PI3K/AKT signaling axis. Herein, our results suggest that AURKB induced EMT through the activation of PI3K/AKT signaling pathway is critical to the progression of ICC, which may be a prospective therapeutic treatment for overcoming ICC metastasis and progression.

Up-regulation of ABCG2 by MYBL2 deletion drives Chlorin e6-mediated photodynamic therapy resistance in colorectal cancer.

OBJECTIVE: Photodynamic therapy (PDT) may be an effective therapeutic strategy for colorectal cancer at an early stage. However, malignant cells' resistance to photodynamic agents can lead to treatment failure. MYBL2 (B-Myb) is an oncogene in colorectal carcinogenesis and development, for which little research has focused on its effect on drug resistance. MATERIALS AND METHODS: In the present work, a colorectal cancer cell line with a stable knockdown of MYBL2 (ShB-Myb) was constructed first. Chlorin e6 (Ce6) was utilized to induced PDT. The anti-cancer efficacy was measured by CCK-8, PI staining, and Western blots. The drug uptake of Ce6 was assayed by flow cytometry and confocal microscopy. The ROS generation was detected by the CellROX probe. DDSB and DNA damage were assayed through comet experiment and Western blots. The over-expression of MYBL2 was conducted by MYBL2 plasmid. RESULTS: The findings indicated that the viability of ShB-Myb treated with Ce6-PDT was not decreased compared to control SW480 cells (ShNC), which were resistant to PDT. Further investigation revealed reduced photosensitizer enrichment and mitigated oxidative DNA damage in colorectal cancer cells with depressed MYBL2. It turned out that SW480 cells knocking down MYBL2 showed phosphorylation of NF-κB and led to up-regulation of ABCG2 expression thereupon. When MYBL2 was replenished back in MYBL2-deficient colorectal cancer cells, phosphorylation of NF-κB was blocked and ABCG2 expression up-regulation was suppressed. Additionally, replenishment of MYBL2 also increased the enrichment of Ce6 and the efficacy of PDT. CONCLUSION: In summary, MYBL2 absence in colorectal cancer contributes to drug resistance by activating NF-κB to up-regulate ABCG2 and thereby leading to photosensitizer Ce6 efflux. This study provides a novel theoretical basis and strategy for how to effectively improve the anti-tumor efficacy of PDT.

Evaluation of product conceptual design based on Pythagorean fuzzy set under big data environment.

The concept design evaluation phase of the new product launch is extremely important. However, current evaluation information relies mainly on the a priori knowledge of decision makers and is subjective and ambiguous. For this reason, a conceptual design solution decision model based on Pythagorean fuzzy sets in a big data environment is proposed. Firstly, we use the ability of big data to mine and analyze information to construct a new standard for product concept design evaluation in the big data environment. Secondly, the Pythagorean fuzzy set (PFS), Analytic Hierarchy Process (AHP), and Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) are integrated into a decision model. AHP, extended by the Pythagorean fuzzy set, is used to determine the weights of new conceptual design criteria in a big data environment. The Pythagorean fuzzy TOPSIS is used to prioritize alternative conceptual design solutions. The feasibility of the approach is proven with a practical case, the generalizability of the method is confirmed with two descriptive digital cases, and the reliability, validity, and superiority of the process are demonstrated with sensitivity analysis, comparative analysis, and computational complexity analysis.

The sarcopenia index is an effective predictor for malnutrition in patients with liver cirrhosis.

AIM: Reliable and valid predictors of malnutrition in patients with cirrhosis remain scarce, especially easily accessible blood indicators. Thus, this study aimed to investigate the validity of the sarcopenia index (serum creatinine/serum cystatin C × 100) as a tool in assessing the nutritional status of patients with cirrhosis. METHODS: This prospective cohort study included 109 patients with cirrhosis who were hospitalised in Renmin Hospital of Wuhan University from August 2020 to June 2021. Malnutrition was diagnosed by the Global Leadership Initiative on Malnutrition criteria. Multivariable logistic regression was used to examine the relationship between sarcopenia index and malnutrition. The area under the receiver operating characteristic curve was used to evaluate the diagnostic performance of sarcopenia index. By contrast, we evaluated the subjective global assessment and traditional nutrition-related indicators. RESULTS: Of the 109 included patients, 71 (65.1%) were diagnosed with malnutrition. The sarcopenia index was significantly lower in malnourished patients (56.39 ± 15.23) compared with well-nourished patients (74.95 ± 13.18, p < 0.001). In addition, the sarcopenia index was independently correlated with malnutrition (p < 0.001). The sarcopenia index was a good tool to predict malnutrition (area under curve = 0.833), which performed better than the subjective global assessment (area under curve = 0.782) and cholinesterase (area under curve = 0.812). A low sarcopenia index indicated longer hospital stay and higher risk of 90-day re-hospitalisation. CONCLUSION: Malnutrition is highly prevalent in this population. The sarcopenia index seems to be a good predictor in nutritional assessment of patients with cirrhosis.

Corrigendum to "System Analysis of ROS-Related Genes in the Prognosis, Immune Infiltration, and Drug Sensitivity in Hepatocellular Carcinoma".

[This corrects the article DOI: 10.1155/2021/6485871.].

System Analysis of ROS-Related Genes in the Prognosis, Immune Infiltration, and Drug Sensitivity in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is an aggressive malignant tumor with a poor prognosis. Reactive oxygen species (ROS) play an important role in tumors; however, the role of ROS-related genes is still unclear in HCC. Therefore, we analyzed the role of ROS-related genes in HCC via bioinformatics methods. Firstly, a prognosis model was constructed using LASSO Cox regression and multivariate analyses. We also investigated the potential function of the ROS-related genes and the correlation with immune infiltration, tumor stemness, and drug sensitivity. ICGC database was used for validation. Secondly, we further analyzed the role of 11 ROS-related genes in HCC. As a member of ROS gene family, the role of STK25 has remained unclear in HCC. We explored the biological function of STK25 using in vitro experiments. The present study was the first to construct a ROS-related prognostic model in HCC. The correlation of ROS-related genes with immune infiltration, tumor stemness, and drug sensitivity was dissected. Furthermore, we demonstrated that STK25 knockdown could increase the proliferation, migration, and invasion capacity of HCC cells.

ADAM15 correlates with prognosis, immune infiltration and apoptosis in hepatocellular carcinoma.

ADAM15 is highly expressed in malignant tumors and is correlated with tumor progression. However, the role of ADAM15 in hepatocellular carcinoma (HCC) remains unclear. In the study, our results indicated that ADAM15 was highly expressed in HCC tissues and cells compared with corresponding tissues and liver cells. Overexpression of ADAM15 was linked to poor prognosis, and was an independent risk factor for HCC prognosis. Besides, analysis of immune infiltration indicated that ADAM15 expression was related to tumor infiltrating lymphocytes based on the TIMER, TISIDB and GEPIA databases. Many immune checkpoint gene expression was associated with ADAM15 expression. Functional enrichment analyses indicated that apoptosis, cell adhesion was enriched. ADAM15 knockdown promoted apoptosis and suppressed proliferation, migration and invasion of liver cancer cells. The findings of western blot showed that ADAM15 knockdown reduced the expression of Bcl-2, Vimentin, N-Cadherin and Snail, and elevated the expression of Bax, E-cadherin and ZO-1. However, overexpression of ADAM15 had the opposite results. Collectively, our findings demonstrated that ADAM15 was connected with poor prognosis of HCC patients, and could be considered as a potential biomarker for the diagnosis and treatment of HCC.

Breast surgery for young women with early-stage breast cancer: Mastectomy or breast-conserving therapy?

ABSTRACT: Whether breast-conserving therapy (BCT) should be chosen as a local treatment for young women with early-stage breast cancer is controversial. This study compared the survival benefits of BCT or mastectomy in young women under 40 with early-stage breast cancer and further explored age-stratified outcomes. This study investigated whether there is a survival benefit when young women undergo BCT compared with mastectomy.The characteristics and prognosis of white women under 40 with stage I-II breast cancer from 1988 to 2016 were analyzed using the Surveillance, Epidemiology, and End Results (SEER) database. These women were either treated with BCT or mastectomy. The log-rank test of the Kaplan-Meier survival curve and Cox proportional risk regression model were used to analyze the data and survival. The analysis was stratified by age (18-35 and 36-40 years).A total of 23,810 breast cancer patients were included, of whom 44.9% received BCT and 55.1% underwent mastectomy, with a median follow-up of 116 months. Patients undergoing mastectomy had a higher tumor burden and younger age. By the end of the 20th century, the proportion of BCT had grown from nearly 35% to approximately 60%, and then gradually fell to 35% into the 21st century. Compared with the mastectomy group, the BCT group had improved breast cancer-specific survival (BCSS) (hazard ratio [HR] 0.917; 95% CI, 0.846-0.995, P = .037) and overall survival (OS) (HR 0.925; 95% CI, 0.859-0.997, P = .041). In stratified analysis according to the different ages, the survival benefit of BCT was more pronounced in the slightly older (36-40 years) group while there was no significant survival difference in the younger group (18-35 years).In young women with early-stage breast cancer, BCT showed survival benefits that were at least no worse than mastectomy, and these benefits were even better in the 36 to 40 years age group. Young age may not be a contraindication for BCT.

Inhibition of macrophage migration inhibitory factor prevents thyroid dysfunction in pregnant rats with acute pancreatitis.

Acute pancreatitis during pregnancy (APIP) rarely occurs but may lead to preterm delivery and be associated with high fetal mortality. Macrophage migration inhibitory factor (MIF) participates in various inflammatory diseases as a pro-inflammatory cytokine. In this study, we aimed to explore the effects of (S, R)-3-(4-hydroxyphenyl)-4, 5dihydro-5-isoxazole acetic methyl ester (ISO-1), an inhibitor of MIF, on maternal thyroid injury associated with APIP and its potential mechanisms in a pregnant rat model. APIP model was induced by retrograde injection of sodium taurocholate. ISO-1 was injected intraperitoneally 30 min before model establishment. The severity of pancreatitis was assessed by levels of tumor necrosis factor (TNF)­α, interleukin (IL)­1ß, IL-6 of maternal serum as well as histopathological score. Thyroid injury was determined by free triiodothyronine (FT3), free tetraiodothyronine (FT4) and thyroid histopathological score. Levels of MIF in maternal serum and the expression of MIF, CD68, CD3 and intercellular cell adhesion molecule-1 (ICAM-1) as well as oxidative stress status in maternal thyroid tissues were detected. Ultrastructure of maternal thyroid tissues was observed by transmission electron microscope. Thyroid injuries occurred in APIP and the lesions were attenuated with the pretreatment of ISO-1. Moreover, ISO-1 reduced the expression of MIF, attenuated the activations of CD68, CD3, ICAM-1 while improved oxidative stress status in maternal thyroid. Our research suggested a protective role of ISO-1 on thyroid injury and endocrine disorder during APIP, which may be associated with the inhibition of biological functions of MIF.

High-Fat Diet Aggravates Acute Pancreatitis via TLR4-Mediated Necroptosis and Inflammation in Rats.

High-fat diet (HFD) often increases oxidative stress and enhances inflammatory status in the body. Toll-like receptor 4 (TLR4) is widely expressed in the pancreatic tissues and plays an important role in pancreatitis. This study is aimed at investigating the effect of HFD on acute pancreatitis (AP) and the role of TLR4-mediated necroptosis and inflammation in this disease. Weight-matched rats were allocated for an 8-week feeding on the standard chow diet (SCD) or HFD, and then, the AP model was induced by infusion of 5% sodium taurocholate into the biliopancreatic duct. Rats were sacrificed at an indicated time point after modeling. Additionally, inhibition of TLR4 signaling by TAK-242 in HFD rats with AP was conducted in vivo. The results showed that the levels of serum free fatty acid (FFA) in HFD rats were higher than those in SCD rats. Moreover, HFD rats were more vulnerable to AP injury than SCD rats, as indicated by more serious pathological damage and much higher pancreatic malondialdehyde (MDA) and lipid peroxidation (LPO) levels as well as lower pancreatic superoxide dismutase (SOD) activities and reduced glutathione (GSH) contents and more intense infiltration of MPO-positive neutrophils and CD68-positive macrophages. In addition, HFD markedly increased the expressions of TLR4 and necroptosis marker (RIP3) and aggravated the activation of NF-κB p65 and the expression of TNF-α in the pancreas of AP rats at indicated time points. However, TLR4 inhibition significantly attenuated the structural and functional damage of the pancreas induced by AP in HFD rats, as indicated by improvement of the above indexes. Taken together, these findings suggest that HFD exacerbated the extent and severity of AP via oxidative stress, inflammatory response, and necroptosis. Inhibition of TLR4 signaling by TAK-242 alleviated oxidative stress and decreased inflammatory reaction and necroptosis, exerting a protective effect during AP in HFD rats.

Cervical vestibular evoked myogenic potential testing for assessment of vestibular functions in cochlear implant patients.

This study aims to investigate the vestibular function status of cochlear implant patients using cervical vestibular evoked myogenic potential (cVEMP) testing and estimate the effects of cochlear implants on vestibular function. The cVEMPs of 50 cochlear implant patients were measured preoperatively, and at one and six months postoperatively. Then, implanted ears and non-implanted ears were compared in terms of p13/n23 wave response rates, latency, amplitude and threshold. Preoperatively, the binaural cVEMP response rate was 92%, while the cVEMP response rates of implanted ears vs. non-implanted ears at postoperative one and six months were 24% vs. 80% and 52% vs. 82%, respectively. No significant difference between implanted and non-implanted ears was found preoperatively, in terms of latent period, amplitude, or threshold. However, significant changes were found in amplitude and threshold for implanted ears after the operation, but not in latency. No significant postoperative change was found in amplitude, latent period, or threshold for non-implanted ears. Significant differences between implanted and non-implanted ears were found in both amplitude and threshold. Cochlear implants affect vestibular function, especially saccular function, and reduce the cVEMP amplitude and threshold of implanted ears.

Comparison of Billroth I, Billroth II, and Roux-en-Y Reconstruction After Totally Laparoscopic Distal Gastrectomy: A Randomized Controlled Study.

INTRODUCTION: This study aimed to explore the efficacy of delta-shaped Billroth I anastomosis in totally laparoscopic distal gastrectomy for digestive tract reconstruction, and provide clinical data for determining the most appropriate digestive tract reconstruction method after distal gastrectomy. METHODS: This was a prospective randomized controlled study. A total of 180 patients were randomly and prospectively selected from Renmin Hospital of Wuhan University by random number table. These patients were randomly divided into three groups: Billroth I group, Billroth II group, and Roux-en-Y (RY) group. RESULTS: There were significant differences in resection margin, blood nutrition, and the number of postoperative complications among these three groups (P < 0.05). Furthermore, the resection margin, blood nutrition status, and immunization of patients in these three groups were determined. Compared to the other groups, the RY group was better in terms of hematologic status, immunological index, and postoperative complications. CONCLUSION: Delta-shaped Billroth I anastomosis in totally laparoscopic distal gastrectomy for digestive tract reconstruction is simple and easy to perform, and has an advantage in postoperative gastrointestinal function recovery. RY reconstruction is superior to Billroth I and Billroth II in terms of postoperative complications.

Apocynin alleviates lung injury by suppressing NLRP3 inflammasome activation and NF-κB signaling in acute pancreatitis.

Mounting evidence has demonstrated that acute pancreatitis (AP) is one of the causes of multiple organ damage. NADPH (nicotinamide adenine dinucleotide phosphate) act as a substrate of NADPH oxidase (NOX) to generate reactive oxygen species (ROS), but the role NADPH oxidase signaling pathway plays in AP-induced acute lung injury remains unclear. Apocynin, an inhibitor of NOX, is highly effective in suppressing the production of ROS. Here, we used rat model of severe acute pancreatitis (SAP) to explore whether the NOX inhibitor apocynin produced protective effects in against SAP-induced lung injury via inhibition of inflammation and oxidation. We observed that apocynin significantly attenuated severe acute pancreatitis-induced increase of NOX2, NOX4 and ROS expressions in lung tissues. In addition, the phosphorylation and degradation of IκBα, and the nuclear localization of NF-κB p65 in SAP-induced lung injury were also inhibited after using apocynin. Simultaneously, down-regulation of NOX suppressed the levels of inflammasome proteins including NLRP3, ASC, pro-Caspase-1 and cleaved-Caspase-1 in the lung. Serum levels of TNF-α, interleukin (IL)-1ß and IL-6 were also reduced. Our findings suggest that beyond anti-oxidative effects, apocynin may also have anti-inflammatory effects by suppressing NLRP3 inflammasome activation and NF-κB signaling in acute pancreatitis. Therefore, apocynin may have therapeutic potential in the treatment of SAP and SAP-induced lung injury.

Correction to: Protective Effects of Calcitonin Gene-Related Peptide-Mediated p38 Mitogen-Activated Protein Kinase Pathway on Severe Acute Pancreatitis in Rats.

The original version of the article unfortunately contained errors in Materials and Methods section, Figure 3 and Figure 4.

4-Phenylbutyric Acid Attenuates Endoplasmic Reticulum Stress-Mediated Intestinal Epithelial Cell Apoptosis in Rats with Severe Acute Pancreatitis.

OBJECTIVES: The present study aimed to determine whether intestinal epithelial cell (IECs) apoptosis could be induced by endoplasmic reticulum stress (ERS) in severe acute pancreatitis (SAP), and the role of chemical chaperone 4-phenylbutyric acid (4-PBA) in SAP-associated intestinal barrier injury. METHODS: Twenty-four male Sprague Dawley rats were randomly divided into three groups: the sham operation group, the SAP group, and the SAP model plus 4-PBA treatment group (4-PBA group). A rat model of SAP was induced by retrograde injection of 5% sodium taurocholate (STC) into the biliopancreatic duct; in the 4-PBA group, 4-PBA was injected intraperitoneally at a dose of 50 mg/kg body weight for 3 days before modeling. RESULTS: The results indicated that 4-PBA attenuated the following: (1) pancreas and intestinal pathological injuries, (2) serum TNF-α, IL-1ß, and IL-6, (3) serum DAO level, serum endotoxin level, (4) the apoptosis of IECs, (5) ER stress markers (caspase-12, CHOP, GRP78, PERK, IRE1α, ATF6) and caspase-3 expression in intestinal. However, the serum AMY, LIPA levels, and the expression of caspase-9, caspase-8 were just slightly decreased. CONCLUSIONS: ERS may be considered a predominant pathway, which is involved in the apoptosis of IECs during SAP. Furthermore, 4-PBA protects IECs against apoptosis in STC-induced SAP by attenuating the severity of ERS.

Inhibition of macrophage migration inhibitory factor attenuates inflammation and fetal kidney injury in a rat model of acute pancreatitis in pregnancy.

Acute pancreatitis in pregnancy (APIP) is a severe disease during pregnancy that mostly occurs during the third trimester. It can lead to additional complications including preterm delivery and high fetal mortality. In this study, we investigated the protective effects of (S, R)-3-(4-hydroxyphenyl)-4, 5dihydro-5-isoxazole acetic methyl ester (ISO-1), an inhibitor of macrophage migration inhibitory factor (MIF), on fetal kidney injury associated with the maternal acute necrotizing pancreatitis (ANP) and its potential mechanisms in a rat model. The APIP rat model was induced by retrograde infusion of sodium taurocholate saline solution into biliopancreatic duct. ISO-1 was given by intraperitoneally injection 30 min before the model was induced. The levels of maternal serum amylase, lipase, tumor necrosis factor-α (TNF-α) and interleukins (IL)-1ß were measured. Maternal pancreas and fetal kidney injury were evaluated, and the expressions of MIF, phospho-p38MAPK (p-p38), nuclear factor-κB (NF-κB), TNF-α, IL-1ß in fetal kidneys were detected. The results showed that fetal rats exhibited obvious acute kidney injury during APIP, and pregnant rats pretreated with ISO-1 notably attenuated the lesions. ISO-1 also significantly reduced the expression of MIF and the activations of p38MAPK, NF-κB, as well as the levels of TNF-α and IL-1ß. These results indicated that ISO-1 could attenuate fetal kidney injury in pregnant rats with ANP by inhibiting MIF mediated p38MAPK/NF-κB signal pathways to reduce inflammatory response.

Protective Effects of Calcitonin Gene-Related Peptide-Mediated p38 Mitogen-Activated Protein Kinase Pathway on Severe Acute Pancreatitis in Rats.

BACKGROUND: Calcitonin gene-related peptide (CGRP) has antioxidant and anti-inflammatory activities on the pathological damage of acute pancreatitis. However, its molecular mechanism on severe acute pancreatitis (SAP) remains unknown. AIMS: To evaluate the influence of CGRP-mediated p38MAPK signaling pathway in rats with SAP. METHODS: SD rats were randomly divided into Sham group, SAP group, CGRP group (SAP rats injected with CGRP), SB203580 group (rats injected with p38MAPK pathway inhibitor SB203580), and CGRP8-37 group (SAP rats injected with CGRP8-37). Serum amylase and lipase activities were determined. Histopathological observations were evaluated, and the expression of inflammatory cytokines and oxidative stress-related indexes were measured. RESULTS: Compared with Sham group, SAP rats were increased in the activities of serum amylase and lipase, the pathologic assessment of pancreatic tissue, the levels of TNF-α, IL-1ß, IL-6, and IL-8, the content of MDA and MPO, and the expressions of CGRP, and p-p38MAPK protein, but they were decreased in SOD activity and GSH content. The above alterations were aggravated in the CGRP8-37 group when compared with SAP group. Besides, in comparison with SAP group, rats in the CGRP and SB203580 groups presented a reduction in the activities of serum amylase and lipase, the levels of inflammatory cytokines, the content of MDA and MPO, and the expressions of p-p38MAPK protein, while showed an elevation in SOD activity and GSH content. CONCLUSION: Pretreatment with CGRP alleviated oxidative stress and inflammatory response of SAP rats possibly by suppressing the activity of p38MAPK pathway, and thereby postponing the disease progression.