Melatonin inhibits EMT and PD‐L1 expression through the ERK1/2/FOSL1 pathway and regulates anti‐tumor immunity in HNSCC

Melatonin is an endogenous hormone with various biological functions and possesses anti‐tumor properties in multiple malignancies. Immune evasion is one of the most important hallmarks of head and neck squamous cell carcinoma (HNSCC) and is closely related to tumor progression. However, as an immune modulator under physiological conditions, the roles of melatonin in tumor immunity in HNSCC remains unclear. In this study, we found that the endogenous melatonin levels in patients with HNSCC were lower than those in patients with benign tumors in head and neck. Importantly, lower melatonin levels were related to lymph node metastasis among patients with HNSCC. Moreover, melatonin significantly suppressed programmed death‐ligand 1 (PD‐L1) expression and inhibited epithelial–mesenchymal transition (EMT) of HNSCC through the ERK1/2/FOSL1 pathway in vitro and in vivo. In SCC7/C3H syngeneic mouse models, anti‐programmed death‐1 (PD‐1) antibody combined with melatonin significantly inhibited tumor growth and modulated anti‐tumor immunity by increasing CD8⁺ T cell infiltration and decreasing the regulatory T cell (Treg) proportion in the tumor microenvironment. Taken together, melatonin inhibited EMT and downregulated PD‐L1 expression in HNSCC through the ERK1/2/FOSL1 pathway and exerted synergistic effects with anti‐PD‐1 antibody in vivo, which could provide promising strategies for HNSCC treatment.     

IL-1 receptor-associated kinase 1 participates in the modulation of the NLRP3 inflammasome by tumor-associated macrophages in hepatocellular carcinoma

BackgroundHepatocellular carcinomas (HCCs) occur frequently in the digestive system and are associated with high mortality. This current study examined the regulatory relationship between interleukin (IL)-1 receptor-associated kinase 1 (IRAK1), NLR family pyrin domain-containing 3 (NLRP3) inflammasomes, and tumor-associated macrophages (TAMs) in the growth and metastasis of HCC.MethodsThe expression of IRAK1 and NLRP3 was assessed in tissues and cells via quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. Immunohistology was performed to detect the macrophage markers CD68, CD163, and CD168 in tumor tissues. Small interfering (si)RNA targeting IRAK1 (si-IRAK1) was designed to silence IRAK1 expression. Following si-IRAK1 transfection and/or co-culture with TAMs, HCC cell viability, proliferation, migration, and invasion, as well as the expression of NLRP3 and pro-inflammatory cytokines IL-1 β, IL-18, and monocyte chemotactic protein 1 (MCP-1) were assessed.ResultsHCC tissues showed elevated expression of IRAK1 and NLRP3, as well as increased expression of the macrophage markers CD68, CD163, and CD168, compared to adjacent healthy tissues. Silencing of IRAK1 expression in HepG2 and Huh7 cells resulted in suppression of cell proliferation, migration, and invasion, and also reduced expression of NLRP3 and the pro-inflammatory cytokines IL-1β, IL-18, and MCP-1. Moreover, TAMs promoted HepG2 and Huh7 cell proliferation, migration, and invasion, and elevated the expression of NLRP3, IL-1β, IL-18, and MCP-1. Furthermore, IRAK1 silencing reversed the effects of TAMs on HepG2 and Huh7 cells.ConclusionsThe expression of IRAK1 was associated with HCC growth and metastasis, as well as NLRP3 inflammasome activation. The ability of TAMs to promote HCC growth and metastasis may be activated by NLRP3 inflammasomes and regulated by IRAK1.     

UBE2C promotes the progression of pancreatic cancer and glycolytic activity via EGFR stabilization-mediated PI3K-Akt pathway activation

BackgroundPancreatic cancer (PC) is among the most prevalent and deadliest endocrine tumors, yet the mechanisms governing its pathogenesis remain to be fully clarified. While ubiquitin-conjugating enzyme E2C (UBE2C) has been identified as an important oncogene in several cancers, its importance in PC has yet to be established.MethodsUBE2C expression in PC tumor samples and cell lines was examined via quantitative real-time polymerase chain reaction (qRT-PCR), while appropriate commercial kits were used to assess lactate production, ATP generation, and the uptake of glucose.ResultsUBE2C was found to be upregulated in PC patient tumors and correlated with poorer survival outcomes. In PC cell lines, the silencing of this gene suppressed the malignant activity of cells, thus supporting its identification as an oncogene in this cancer type. Mechanistically, UBE2C was found to promote enhanced matrix metalloproteinase (MMP) protein expression via activating the PI3K-Akt pathway. Moreover, it was found to bind to the epidermal growth factor receptor (EGFR), stabilizing it and driving additional PI3K-Akt pathway activation. UBE2C knockdown in PC cells impaired their uptake of glucose and their ability to produce lactate and ATP.ConclusionsIn conclusion, the results of this study support a role for UBE2C as a driver of metastatic PC progression owing to its ability to bind to EGFR and to induce signaling via the PI3K-Akt pathway.     

Comparison of the safety and prognosis of sequential regorafenib after sorafenib and lenvatinib treatment failure in patients with unresectable hepatocellular carcinoma: a retrospective cohort study

BackgroundThere is lack of studies on sequential regorafenib after sorafenib and lenvatinib treatment failure in patients with unresectable hepatocellular carcinoma (HCC). This study was to explore the safety and prognosis of sequential regorafenib after sorafenib and lenvatinib failure in HCC patients.MethodsThis study was a retrospective, real-world study that included 50 HCC patients who received sequential regrafinib after sorafenib and lenvatinib failure. The safety and prognosis of two groups were compared.ResultsThe incidence of all grade and III/IV adverse events were 68% and 24%. According to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 and modified (m) RECIST standards, the objective response rates (ORRs) after receiving regorafenib were 14.0% and 22.0%, respectively. The disease control rates (DCRs) were 62.0% and 60.0%, respectively. Based on different first-line targeted drugs, 50 patients were divided into sorafenib (n=22) and lenvatinib group (n=28). There was no differences between two groups except age and bilirubin. And there was no differences in other treatments before or after regorafenib. The baseline between two groups was basically same and had good comparability. There was no difference in incidence of all grade and III/IV adverse events, ORR and DCR between two groups (P>0.05). On long-term prognosis, total overall survival (TOS) in sorafenib and lenvatinib group were 23.0 (95% CI: 15.1–30.9) vs. 29.7 (95% CI: 21.4–38.1) months. The difference was statistically significant (P=0.041). Besides, regorafenib overall survival (ROS) in sorafenib and lenvatinib group were 11.7 (95% CI: 7.1–16.3) vs. 15.9 (95% CI: 8.3–23.5) months. The difference was statistically significant ( P=0.045). The regorafenib progression-free survival (RPFS) was 5.6 (95% CI: 1.9–9.2) vs. 8.0 (95% CI: 5.1–10.9) months in sorafenib and lenvatinib group, respectively, and difference was not statistically significant (P=0.380).ConclusionsRegorafenib is an effective drug for second-line treatment of HCC, with fewer severe adverse events, ORR and DCR was 14–22% and 62–60%, respectively. Both TOS and ROS in lenvatinib group were better than those in sorafenib group. For HCC patients whose first-line targeted drug is lenvatinib, it is safe and effective to accept regorafenib after disease progresses.     

CONSORT-Characteristics and metabolic phenotype of gut microbiota in NAFLD patients

Patients with nonalcoholic fatty liver disease (NAFLD) have symptoms of a gut microbiota disorder with abnormal amino acid and glycolipid metabolism. This study was designed to analyze the characteristics of gut microbiota in patients with NAFLD, predict the gut microbiota phenotype, explore its role in the diagnosis of NAFLD, and establish its significance in disease progression.The characteristics of the gut microbiota in NAFLD patients (n = 28, 45.8 ± 14.2 years, male/female = 18/10) and healthy subjects (n = 20, 49.6 ± 4.8 years, male/female = 14/6) during March–May 2020 were analyzed using 16S rRNA sequencing technology and the phenotypes with large differences were predicted using the Tax4Fun method. The metabolites in the fecal samples of the patients were analyzed using mass spectrometry, and their correlation with different microorganisms was examined. The accuracy of the gut microbiota in diagnosing NAFLD was investigated by receiver operating characteristic curve analysis.We found that the microbial diversity and Bacteroides/Firmicutes (BF) ratio changed significantly (P < .05) in the feces of NAFLD patients. Phenotypic prediction showed that there were significant differences in the phenotypes of amino acid, glucose, and lipid metabolism of gut microbiota in the NAFLD group (P < .05). receiver operating characteristic curve analysis revealed that combination of Bacteroides and the BF ratio resulted in 88% and 100% sensitivity and specificity, respectively, when used for NAFLD diagnosis. Metabolomics and bioinformatics analysis revealed changes in the metabolism of nicotinate, nicotinamide, and pyrimidine; signaling pathways of calcium and oxytocin; pancreatic secretion with metabolites such as uracil, xanthine, and biliverdin; and enzymes such as xanthine dehydrogenase and xanthine oxidase (P < .05).Therefore, the phenotypic changes may be a potential marker for NAFLD and we considered that a combined analysis of Bacteroides and BF ratio had good diagnostic accuracy for NAFLD.     

Displaced proximal humerus fractures treated with ORIF via the deltoid interfascicular approach vs the deltopectoral approach: A prospective case-control study

Background:The purpose of this study was to evaluate the clinical outcomes and complications of displaced proximal humeral fractures treated with proximal humeral internal locking system (PHILOS) plate fixation via a deltoid interfascicular (DI) vs a deltopectoral (DP) approach.Methods:This prospective case-control study was conducted with patients admitted to our hospital from May 2015 to June 2018 who suffered from unilateral displaced proximal humerus fractures. Patients were treated with PHILOS plate fixation via a DI (DI group) or DP approach (DP group). The clinical outcomes and complication data were collected for comparison between the 2 groups. The patients were followed up at 3, 6, and 12 months; and every 6 months thereafter. The patients’ functional recoveries were evaluated according to the normalized Constant-Murley score, range of motion of the shoulder (flexion, abduction, external/internal rotation) and disabilities of the arm, shoulder and hand score.Results:A total of 77 patients, followed for an average of 15 ± 2.2months (range, 12–21), were enrolled (36 in DI group and 41 in DP group) for final analysis. No significant differences in age, sex, affected side, fracture type, injury mechanism or time from injury to operation were found between the 2 groups (all P > .05). The incision length, intra-operative blood loss, and duration of operation in the DI group were significantly less than those in the DP group, respectively (all P < .05). The functional outcomes assessed by the normalized Constant-Murley score and range of motion of flexion and internal rotation in the DI group were superior to those in the DP group at 3 and 6months after the operation (P < .05); however, no significant differences were observed at the 12-month and subsequent follow-ups (all P > .05). There was no significant difference in the range of shoulder external rotation and abduction during the postoperative follow-ups (P > .05). At the last follow-up, the mean disabilities of the arm, shoulder, and hand score was 14.0 (6.6) points in the DI group and 14.4 (6.9) points in the DP group (P = .793). Complications occurred in 1 patient in the DI group and 8 patients in the DP group (P = .049).Conclusion:The current study demonstrates that DI approach is a safe and effective alternative for the treatment displaced proximal humerus fractures. The DI approach rather than DP approach was recommended when lateral and posterior exposure of the proximal humerus is required, especially when fixed with PHILOS plate.     

Combined prognostic value of preoperative serum thyrotrophin and thyroid hormone concentration in papillary thyroid cancer

BackgroundA growing number of studies have found a close association between thyroid hormones and thyrotrophin (TSH), and they also have prognostic significance in some cancer types; this study aimed to investigate the prognostic value of free triiodothyronine (fT3), free thyroxine (fT4), fT3/fT4, TSH, and their combination in patients with papillary thyroid carcinoma (PTC).MethodsThis study retrospectively analyzed the relevant data of 726 newly diagnosed PTC patients. Both univariate and multivariate analyses were used to predict the recurrence rate, and a risk score was established. In addition, with the use of a random survival forest, a random forest (RF) score was constructed. After calculating the area under the curve (AUC), the diagnostic efficacy of risk score, RF score, and four indicators was compared.ResultsfT3, fT4, fT3/fT4, and TSH were strongly associated with some invasive clinicopathological features and postoperative recurrence. Patients with high expression of fT4 and TSH have a high risk of recurrence. By contrast, patients with high expression of fT3 and fT3/fT4 have a low risk of recurrence. At the same time, the combined use of various indicators is more helpful for establishing an accurate diagnosis. By comparison, we found that the RF score was better than the risk score in terms of predicting the recurrence of PTC.ConclusionThe diagnostic accuracy of a combination of fT3, fT4, fT3/fT4, and TSH can help improve our clinical estimate of the risk of recurrent PTC, thus allowing the development of a more effective treatment plan for patients.     

Research progress of gut microbiota in hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) is the sixth most common cancer and the fourth leading cause of cancer‐related death in the world. A number of challenges remain for the early detection and effective treatment of HCC. In recent years, microbiota have been proven to be associated with the development of HCC. Many studies have explored the pathogenesis, diagnostic marker, and therapeutic target potential of microbiota in hepatocellular carcinoma. Therefore, we aimed to introduce the research methods and achievements of gut microbiota in hepatocellular carcinoma and discuss the value of gut microbiota in the pathogenesis, diagnosis, and treatment of hepatocellular carcinoma.MethodsKeywords are used to search relevant articles which were mainly published from 2010 to 2021, and we further selected targeted articles and read the full text.ResultsGut microbiota involved in promoting the formation and development of hepatocellular carcinoma, and differential gut microbiota and microbial metabolites have the potential to be the biomarkers of hepatocellular carcinoma. Purposefully regulated gut microbiota can improve the prognosis of patients, which is expected to be used in hepatocellular carcinoma.ConclusionThe study of gut microbiota in hepatocellular carcinoma is definitely worthy of study. In‐depth and elaborate research design is crucial for the study of the mechanism of gut microbiota involved in hepatocellular carcinoma, which can provide new directions and targets for the diagnosis, treatment, and prognosis of hepatocellular carcinoma.     

Neoadjuvant chemotherapy endows CD9 with prognostic value that differs between tumor and stromal areas in patients with pancreatic cancer

BackgroundThe selective pressure imposed by chemotherapy creates a barrier to tumor eradication and an opportunity for metastasis and recurrence. As a newly discovered stemness marker of pancreatic ductal adenocarcinoma (PDAC), the impact of CD9 on tumor progression and patient''s prognosis remain controversial.MethodsA total of 179 and 211 PDAC patients who underwent surgical resection with or without neoadjuvant chemotherapy, respectively, were recruited for immunohistochemical analyses of CD9 expression in both tumor and stromal areas prior to statistical analyses to determine the prognostic impact and predictive accuracy of CD9.ResultsThe relationship between CD9 and prognostic indicators was not significant in the non‐neoadjuvant group. Nevertheless, CD9 expression in both tumor (T‐CD9) and stromal areas (S‐CD9) was significantly correlated with the clinicopathological features in the neoadjuvant group. High levels of T‐CD9 were significantly associated with worse OS (p = 0.005) and RFS (p = 0.007), while positive S‐CD9 showed the opposite results (OS: p = 0.024; RFS: p = 0.008). Cox regression analyses identified CD9 in both areas as an independent prognostic factor. The T&S‐CD9 risk‐level system was used to stratify patients with different survival levels. The combination of T&S‐CD9 risk level and TNM stage were accurate predictors of OS (C‐index: 0.676; AIC: 512.51) and RFS (C‐index: 0.680; AIC: 519.53). The calibration curve of the nomogram composed of the combined parameters showed excellent predictive consistency for 1‐year RFS. These results were verified using a validation cohort.ConclusionNeoadjuvant chemotherapy endows CD9 with a significant prognostic value that differs between tumor and stromal areas in patients with pancreatic cancer.     

High hemoglobin fluctuation was a protective factor for cardiovascular‐related death in peritoneal dialysis (PD) patients: A retrospective analysis of 232 patients with PD

ObjectivesThis study aimed to investigate the effect of hemoglobin (Hb) fluctuation after dialysis on the prognosis of cardiovascular‐related and all‐cause deaths in peritoneal dialysis (PD).MethodsAccording to the Hb fluctuation, patients were divided into low fluctuation group, moderate fluctuation group, and high fluctuation group, and then, the effects of Hb fluctuation after dialysis on the prognosis of cardiovascular‐related and all‐cause death in PD were analyzed by regression analysis.ResultsA total of 232 patients were selected in this study. Compared with the low Hb fluctuation group, the moderate and high fluctuation groups had lower body mass index (BMI), estimated glomerular filtration rate (eGFR), and baseline Hb, and the moderate fluctuation group had less erythropoietin (EPO) and dialysis dose. Compared with survivors, patients with cardiovascular‐related and all‐cause deaths had lower mean Hb and Hb fluctuation (all p < 0.05). Cox regression analysis showed that before and after adjusting for confounding factors, Hb fluctuation was still independently correlated with cardiovascular prognosis, and higher Hb fluctuation was still a protective factor for cardiovascular‐related death in the Hb‐substandard group, but there was no significant correlation between Hb fluctuation and all‐cause death. Multivariate linear regression analysis revealed that Hb fluctuation was positively correlated with Kt/V and EPO dosage, but negatively correlated with the baseline Hb.ConclusionHigh Hb fluctuation was a protective factor for cardiovascular‐related death in PD with substandard Hb. Compared with Hb fluctuation, correction of anemia timely and making Hb reaches the standard level had a greater impact on reducing cardiovascular‐related death in PD.