Dihydroartemisinin modulated arachidonic acid metabolism and mitigated liver inflammation by inhibiting the activation of 5-LOX and COX-2.

Background: Dihydroartemisinin (DHA), a derivative of Artemisia annua, has been shown to possess anti-inflammatory properties. Besides, Yes-associated protein 1 (YAP1) plays a crucial role in maintaining liver homeostasis. Methods: This study used Yap1 Flox/Flox, Albumin-Cre mice with hepatocyte-specific Yap1 knockout (referred to as Yap1 LKO) and their control mice (Yap1 Flox/Flox, referred to as Yap1 Flox). The effect of Yap1 on lipid metabolism homeostasis was investigated through non-targeted metabolomic analysis of mouse liver. Subsequently, DHA was administered to Yap1 LKO mice to assess its potential as a treatment. Liver pathology was evaluated via H&E staining, and the levels of AST, ALT, and TG were quantified using biochemical assays. The contents of arachidonic acid (AA), prostaglandin E1 (PGE1), and leukotrienes (LT) in the liver were measured using ELISA, while the protein expressions of PLIN2, 5-lipoxygenase (5-LOX), and cyclooxygenase-2 (COX-2) were analyzed through IHC staining. Results: Hepatocyte-specific Yap1 knockout activated the AA metabolic pathway, resulting in increased elevated levels of AA, PGE1, and LT levels, along with inflammatory cytokine infiltration. DHA mitigated the elevation of metabolites such as PGE1 and LT caused by the AA metabolic pathway activation by down-regulating the levels of COX-2 and 5-LOX in the liver of Yap1 LKO mice. Moreover, it alleviated the accumulation of lipid vacuoles and reduced triglyceride (TG) and perilipin-2 (PLIN2) levels in the liver of Yap1 LKO mice. Conclusions: Excessively low YAP1 expression induces liver inflammation and disturbances in lipid metabolism, whereas DHA modulated AA metabolism and mitigated liver inflammation by inhibiting the activation of 5-LOX and COX-2.

Dihydroartemisinin breaks the immunosuppressive tumor niche during cisplatin treatment in Hepatocellular carcinoma.

OBJECTIVE: Hepatocellular carcinoma, characterized by high mortality rates, often exhibits limited responsiveness to conventional treatments such as surgery, radiotherapy, and chemotherapy. Therefore, identifying a sensitizer for cisplatin has become crucial. Dihydroartemisinin, known for its potent role of tumor treatment, arises as a prospective candidate for cisplatin sensitization in clinical settings. METHODS: A mouse model of liver tumor was established through chemical induction of DEN/TCPOBOP. Upon successful model establishment, ultrasound was employed to detect tumors, Hematoxylin and eosin staining was conducted for observation of liver tissue pathology, and ELISA was utilized to assess cytokine changes (IFN-γ, IL-2, IL-4, IL-10, TGF-ß, IL-1ß, CCL2, and CCL21) in peripheral blood, para-tumor tissues, and tumor tissues. The infiltration of CD8+T cells and macrophages in tumor tissue sections was detected by immunofluorescence. RESULTS: Dihydroartemisinin combined with cisplatin obviously restrained the growth of liver tumors in mice and improved the weight and spleen loss caused by cisplatin. Cisplatin treatment of liver tumor mice increased the content of CCL2 and the number of macrophages in tumor tissues and promoted the formation of an immunosuppressive microenvironment. The combination therapy decreased the content of TGF-ß in tumor tissues while increasing CCL2 levels in para-tumor tissues. Both combination therapy and cisplatin alone increased the number of CD8+T cells in tumor tissue, but there was no difference between them. CONCLUSION: Dihydroartemisinin combined with cisplatin obviously prevented the deterioration of liver tumor in hepatocellular carcinoma mice and improve the therapeutic effect of cisplatin by improving the immunosuppressive microenvironment induced by cisplatin. Our findings provide a theoretical basis for considering dihydroartemisinin as an adjuvant drug for cisplatin in the treatment of hepatocellular carcinoma in the future.

Human umbilical cord mesenchymal stem cells promoted tumor cell growth associated with increased interleukin-18 in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is experiencing a concerning rise in both incidence and mortality rates. Current therapeutic strategies are limited in their effectiveness, largely due to the complex causes of the disease and significant levels of drug resistance. Given the latest developments in human umbilical cord mesenchymal stem cells (hUC-MSCs) research, there is a debate over the continued use of stem cell transplantation for treating tumors. Consequently, this study seeks to explore the role of hUC-MSCs in the management of HCC. METHODS AND RESULTS: HUC-MSCs increased the number (10.75 ± 1.50) in the DEN/TCPOBOP-induced mice hepatoma model, compared with DMSO group (7.25 ± 1.71). Moreover, the liver index in hUC-MSCs group (0.21 ± 0.06) was greater than that in DMSO group (0.09 ± 0.01). Immunohistochemical (IHC) analysis revealed that while hUC-MSCs did not alter Foxp3 expression, they significantly stimulated Ki67 expression, indicative of increased tumor cellular proliferation. Additionally, immunofluorescence (IF) studies showed that hUC-MSCs increased CD8+ T cell counts without affecting macrophage numbers. Notably, granzyme B expression remained nearly undetectable. We observed that serum IL-18 levels were higher in the hUC-MSCs group (109.66 ± 0.38 pg/ml) compared to the DMSO group (91.14 ± 4.37 pg/ml). Conversely, IL-1ß levels decreased in the hUC-MSCs group (63.00 ± 0.53 pg/ml) relative to the DMSO group (97.38 ± 9.08 pg/ml). CONCLUSIONS: According to this study, hUC-MSCs promoted the growth of liver tumors. Therefore, we proposed that hUC-MSCs are not suitable for treating HCC, as they exhibit clinically prohibited abnormalities.

Research Progress of Warburg Effect in Hepatocellular Carcinoma.

The Warburg effect, also called aerobic glycolysis, refers to tumor cells that metabolize glucose through glycolysis even in the presence of oxygen. This rapid breakdown of glucose fuels the fast development, growth, and migration of tumor cells. Lactate, the final product of aerobic glycolysis, contributes to an acidic environment within the tumor, promoting the formation of an immunosuppressive microenvironment and accelerating tumor progression by impeding anti-tumor immunity. Numerous studies have confirmed the critical role of aerobic glycolysis in the occurrence and development of hepatocellular carcinoma by influencing tumor cells proliferation, invasion, metastasis, apoptosis, immune escape, angiogenesis, and more. Clinical trials have shown that inhibitors of rate-limiting enzymes in the glycolysis pathway can enhance the effectiveness of sorafenib, a targeted drug for hepatocellular carcinoma, by reducing drug resistance. Additionally, active components of traditional Chinese medicine and specific compound prescriptions are gaining attention for their potential to target and regulate aerobic glycolysis in hepatocellular carcinoma. Therefore, inhibiting the aerobic glycolysis pathway holds promise as a therapeutic strategy for treating liver tumors. This manuscript aims to review the role, research directions, and clinical studies of aerobic glycolysis in hepatocellular carcinoma.

Dihydroartemisinin breaks the positive feedback loop of YAP1 and GLUT1-mediated aerobic glycolysis to boost the CD8+ effector T cells in hepatocellular carcinoma.

Aerobic glycolysis is a hallmark of hepatocellular carcinoma (HCC). Dihydroartemisinin (DHA) exhibits antitumor activity towards liver cancer. Our previous studies have shown that DHA inhibits the Warburg effect in HCC cells. However, the mechanism still needs to be clarified. Our study aimed to elucidate the interaction between YAP1 and GLUT1-mediated aerobic glycolysis in HCC cells and focused on the underlying mechanisms of DHA inhibiting aerobic glycolysis in HCC cells. In this study, we confirmed that inhibition of YAP1 expression lowers GLUT1-mediated aerobic glycolysis in HCC cells and enhances the activity of CD8+T cells in the tumor niche. Then, we found that DHA was bound to cellular YAP1 in HCC cells. YAP1 knockdown inhibited GLUT1-mediated aerobic glycolysis, whereas YAP1 overexpression promoted GLUT1-mediated aerobic glycolysis in HCC cells. Notably, liver-specific Yap1 knockout by AAV8-TBG-Cre suppressed HIF-1α and GLUT1 expression in tumors but not para-tumors in DEN/TCPOBOP-induced HCC mice. Even more crucial is that YAP1 forms a positive feedback loop with GLUT1-mediated aerobic glycolysis, which is associated with HIF-1α in HCC cells. Finally, DHA reduced GLUT1-aerobic glycolysis in HCC cells through YAP1 and prevented the binding of YAP1 and HIF-1α. Collectively, our study revealed the mechanism of DHA inhibiting glycolysis in HCC cells from a perspective of a positive feedback loop involving YAP1 and GLUT1 mediated-aerobic glycolysis and provided a feasible therapeutic strategy for targeting enhanced aerobic glycolysis in HCC.

Lycium barbarum L. Balanced intestinal flora with YAP1/FXR activation in drug-induced liver injury.

Drug-induced liver injury (DILI) is a common and severe adverse drug reaction that can result in acute liver failure. Previously, we have shown that Lycium barbarum L. (wolfberry) ameliorated liver damage in acetaminophen (APAP)-induced DILI. Nevertheless, the mechanism needs further clarification. Herein, we utilized APAP-induced DILI mice to investigate how wolfberry impacts the gut-liver axis to mitigate liver damage. We showed that the abundance of Akkermansia muciniphila (A. muciniphila) was decreased, and intestinal microbiota was disrupted, while the expression levels of YAP1 and FXR-mediated CYP7A1 were reduced in the liver of DILI mice. Furthermore, wolfberry increased the abundance of A. muciniphila and the number of goblet cells in the intestines, while decreasing AST, ALT, and total bile acids (TBA) levels in the serum. Interestingly, A. muciniphila promoted YAP1 and FXR expression in hepatocytes, leading to the inhibition of CYP7A1 expression and a decrease in TBA content. Notably, wolfberry did not exert the beneficial effects mentioned above after the removal of intestinal bacteria by antibiotics (ATB)-containing water. Additionally, Yap1 knockout downregulated FXR expression and enhanced CYP7A1 expression in the liver of hepatocyte-specific Yap1 knockout mice. Therefore, wolfberry stimulated YAP1/FXR activation and reduced CYP7A1 expression by promoting the balance of intestinal microbiota, thereby suppressing the overproduction of bile acids.

Research on radiotherapy related genes and prognostic target identification of rectal cancer based on multi-omics.

BACKGROUND: Radiosensitivity of rectal cancer is related to the radiotherapy efficacy and prognosis of patients with rectal cancer, and the genes and molecular mechanisms related to radiosensitivity of rectal cancer have not been clarified. We explored the radiosensitivity related genes of rectal cancer at a multi omics level. METHODS: mRNA expression data and rectum adenocarcinoma (READ) data were obtained from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus Database (GEO) (GSE150082, GSE60331, GSE46862, GSE46862). Differentially expressed genes between radiotherapy sensitive group and radiotherapy insensitive group were screened. GO analysis and KEGG pathway analysis were performed for differentially expressed genes. Among the differentially expressed genes, five core genes associated with rectal cancer prognosis were selected using random survival forest analysis. For these five core genes, drug sensitivity analysis, immune cell infiltration analysis, TISIDB database immune gene correlation analysis, GSEA enrichment analysis, construction of Nomogram prediction model, transcriptional regulatory network analysis, and qRT-PCR validation was performed on human rectal adenocarcinoma tissue. RESULTS: We found that 600 up-regulated genes and 553 down-regulated genes were significantly different between radiotherapy sensitive group and radiotherapy insensitive group in rectal cancer. Five key genes, TOP2A, MATR3, APOL6, JOSD1, and HOXC6, were finally screened by random survival forest analysis. These five key genes were associated with different immune cell infiltration, immune-related genes, and chemosensitivity. A comprehensive transcriptional regulatory network was constructed based on these five core genes. qRT-PCR revealed that MATR3 expression was different in rectal cancer tissues and adjacent non-cancerous tissues, while APOL6, HOXC6, JOSD1, and TOP2A expression was not different. CONCLUSION: Five radiosensitivity-related genes related to the prognosis of rectal cancer: TOP2A, MATR3, APOL6, JOSD1, HOXC6, are involved in multiple processes such as immune cell infiltration, immune-related genes, chemosensitivity, signaling pathways and transcriptional regulatory networks and may be potential biomarkers for radiotherapy of rectal cancer.

Wolfberry, Yam, and Chrysanthemum polysaccharides increased intestinal Akkermansia muciniphila abundance and hepatic YAP1 expression to alleviate DILI.

Drug-induced liver injury (DILI) is frequently induced by high dose of acetaminophen (APAP) and is concomitant with disturbances of gut flora. Akkermansia muciniphila is beneficial for the repair of liver injury. Lycium barbarum polysaccharide, yam polysaccharide, and chrysanthemum polysaccharide all have anti-inflammatory and antioxidation effects. The objective of this study is to investigate the potential of lycium barbarum polysaccharide, yam polysaccharide, and chrysanthemum polysaccharide (LYC) in improving DILI by increasing the abundance of A. muciniphila. Initially, screening for the optimal concentrations of wolfberry, yam, and chrysanthemum (WYC) or LYC to promote A. muciniphila proliferation in vitro and validated in antibiotic (ATB)-treated KM mice. Subsequently, APAP-induced DILI model in BALB/c mice were constructed to examine the treatment effects of LYC. Our findings indicate that the optimal concentration ratio of WYC was 2:3:2, and LYC was 1:1:1. WYC increased A. muciniphila proliferation in vitro and in ATB-treated mice under this ratio. Meanwhile, LYC increased A. muciniphila abundance in vitro and the combination LYC with A. muciniphila promoted the proliferation of A. muciniphila in ATB-treated mice. The overdose of APAP resulted in the impairment of the intestinal barrier function and subsequent leakage of lipopolysaccharide (LPS). Moreover, LYC increased A. muciniphila abundance, reduced intestinal inflammation and permeability, and upregulated the expression of the tight junction protein zonula occludens protein 1 (ZO-1) and occludin contents in the gut. Lastly, LYC inhibited LPS leakage and upregulated hepatic YAP1 expression, ultimately leading to the repair of DILI.

Correlation between Preoperative Platelet Count/(Lymphocyte Count × Prealbumin Count) Ratio and the Prognosis of Patients with Gastric Cancer Undergoing Radical Operation.

Objective: To clarify the relationship between preoperative platelet count/(lymphocyte count × prealbumin count) ratio (PLPR) and the prognosis of patients with gastric cancer undergoing a radical operation, combined with Tumor Node Metastasis (TNM) staging, a scoring system was established to guide clinical application. Methods: The clinical data of 238 patients receiving radical operations for gastric cancer were retrospectively analyzed. According to the area under the Receiver operating characteristic curve, the predictive value of the preoperative PLPR for the 5-year overall survival (OS) of gastric cancer was determined, and the best cut-off value of the ratio was corresponding to the maximum value of Yoden index. Chi-squared test was applied to analyze the correlation between the ratio and clinicopathological features. Kaplan-Meier curve was applied to analyze the influence of this ratio on 5-year OS. The Cox regression model was applied to analyze the hazards affecting the long-term survival of patients. The nomogram model was used to predict the long-term survival rate. Results: The optimal cut-off point of preoperative PLPR ratio was 7.46, and the patients were segmented into two sets: one set of ratio <7.46 and another set of ratio ≥7.46. The ratio was correlated with the size of the tumor, T stage, N stage, total stage, vascular cancer thrombus, and nerve invasion. In stage I-III patients, the prognosis was better in the low-ratio set than in the high-ratio set (P < 0.001), subgroup analysis indicated the prognosis was obviously better in the low-ratio set than in the high-ratio set in stage II and III patients (P < 0.05 and P < 0.001), but there was no difference in stage I patients (P > 0.05). Age, T stage, N stage, total TNM stage, tumor size, vascular tumor thrombus, nerve invasion, preoperative neutrophil count/lymphocyte count (NLR; reference value 3.68), preoperative PLPR (reference value 7.46), preoperative platelet count/lymphocyte count (PLR; reference value 159.56), and preoperative platelet count × NLR (SII; reference value 915.48) were related to patient prognosis (P < 0.05); meanwhile age, total TNM stage, preoperative PLPR (reference value 7.46), preoperative PLR (reference value 159.56), and preoperative SII (reference value 915.48) were independent hazards for prognosis (P < 0.05). Five independent risk factors were analyzed by nomogram model to predict the 5-year OS of patients who underwent a radical operation for carcinoma of the stomach. Conclusion: Preoperative PLPR ratio (reference value 7.46) is an independent risk factor for long-term prognosis in patients undergoing a radical operation for gastric cancer. The nomogram scoring system established by postoperative TNM staging combined with this ratio and age, PLR, and SII can better forecast the survival of patients who underwent radical operation for carcinoma of the stomach.

Dihydroartemisinin inhibited interleukin-18 expression by decreasing YAP1 in hepatocellular carcinoma cells.

BACKGROUND: Yes-associated protein 1 (YAP1) is highly expressed in liver cancer and has been used as an independent prognostic marker for hepatocellular carcinoma (HCC), while inhibition of YAP1 slows down the progression of HCC. Interleukin-18 (IL-18) also tends to be highly expressed in liver cancer. Previous research has proved that dihydroartemisinin (DHA) plays an important role in HCC treatment by reducing YAP1 expression. However, the relationship between YAP1 and IL-18 has not been reported in HCC, especially during DHA therapy. OBJECTIVE: The purpose of this study was to clarify the relationship between YAP1 and IL-18 in HCC cells, and to explicit the role of IL-18 in the treatment of HCC by DHA. METHODS AND RESULTS: We found that YAP1 and IL-18 were highly expressed in patients with hepatocellular carcinoma by bioinformatics analysis. Moreover, YAP1 was positively correlated with IL18 in liver cancer. YAP1 and IL18 correlated with immune cell infiltration, notably T cell exhaustion. YAP1 knockdown decreased IL-18 expression, while YAP1 overexpression increased the IL-18 expression in HCC cells. DHA reduced IL-18 expression through YAP1 in HCC cells. Further, DHA reduced the growth of Hepa1-6 cells subcutaneous xenograft tumors by inhibiting the expression of YAP1 and IL-18. However, DHA improved IL-18 in serum and adjacent tissues from DEN/TCPOBOP-induced liver tumor model in C57BL/6 mice. CONCLUSION: YAP1 was positively correlated with IL-18 in HCC. DHA reduced the expression of IL-18 by inhibiting YAP1 and plays a role in the treatment of HCC. Our study suggested that IL-18 is a potential target for the treatment of HCC, and DHA is a promising drug for HCC therapy. DATA AVAILABILITY: The dataset that supports the findings of this study is available from the corresponding author upon reasonable request.

Chemoradiotherapy with paclitaxel liposome plus cisplatin for locally advanced esophageal squamous cell carcinoma: A retrospective analysis.

PURPOSE: This single-center retrospective clinical study aimed to evaluate the efficacy and feasibility of chemoradiotherapy with paclitaxel liposome plus cisplatin for locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Patients with locally advanced ESCC treated with paclitaxel-liposome-based chemoradiotherapy between 2016 and 2019 were retrospectively analyzed. Overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan-Meier analysis. RESULTS: Thirty-nine patients with locally advanced ESCC were included in this study. The median follow-up time was 31.5 months. The median OS time was 38.3 (95% confidence interval [CI]: 32.1-45.1) months, and the 1-, 2-, and 3-year OS rates were 84.6%, 64.1%, and 56.2%, respectively. The median PFS time was 32.1 (95% CI: 25.4-39.0) months, and the 1-, 2-, and 3-year PFS rates were 71.8%, 43.6%, and 43.6%, respectively. The most common Grade IV toxicity was neutropenia (30.8%) followed by lymphopenia (20.5%). There were no cases of Grade III/IV radiation pneumonia, and four patients (10.3%) had Grade III/IV esophagitis. CONCLUSION: Chemoradiotherapy using paclitaxel liposome and cisplatin is a well-tolerated and effective treatment regimen for locally advanced ESCC.

Glucose-activatable insulin delivery with charge-conversional polyelectrolyte multilayers for diabetes care.

One of the most effective treatments for diabetes is to design a glucose-regulated insulin (INS) delivery system that could adjust the INS release time and rate to reduce diabetes-related complications. Here, mixed multiple layer-by-layer (mmLbL)-INS microspheres were developed for glucose-mediated INS release and an enhanced hypoglycemic effect for diabetes care. To achieve ultrafast glucose-activated INS release, glucose oxidase (GOx) was assembled with a positively charged polymer and modified on INS LbL. The mmLbL-INS microspheres were constructed with one, two, and four layers of the polyelectrolyte LbL assembly at a ratio of 1:1:1. Under hyperglycemia, GOx converts a change in the hyperglycemic environment to a pH stimulus, thus providing sufficient hydrogen ion. The accumulated hydrogen ion starts LbL charge shifting, and anionic polymers are converted to cationic polymers through hydrolytic cleavage of amine-functionalized side chains. The results of in vitro INS release suggested that glucose can modulate the mmLbL-INS microspheres in a pulsatile profile. In vivo studies validated that this formulation enhanced the hypoglycemic effect in STZ-induced diabetic rats within 2 h of subcutaneous administration and facilitated stabilization of blood glucose levels for up to 2 days. This glucose-activatable LbL microsphere system could serve as a powerful tool for constructing a precisely controlled release system.

Erythrocyte-mimicking subcutaneous platform with a laser-controlled treatment against diabetes.

Exogenous insulin (INS) is critical for managing diabetes. However, owing to its short in vivo half-life, frequent injection of INS is un-avoidable, which is both painful and inconvenient, compromising the quality of life. Herein, we developed a laser-regulated INS release system (INS-ICG@ER hydrogel) that allowed an on-demand release of INS from the subcutaneous INS reservoir by remote laser control without the frequent injection of INS. The amino acid hydrogel functions as a hydrogel 3D scaffold material, which offers increased subcutaneous stability of drug loaded erythrocytes (ER). This INS-ICG@ER hydrogel would release INS due to the elevated content of reactive oxygen species (ROS), generated by ICG under laser irritation. Conversely, the ROS would be scavenged without the laser irradiation and stopped the release of INS from INS-ICG@ER hydrogel. Furthermore, the release of INS from INS-ICG@ER hydrogel could be regulated by laser irradiation. The INS-ICG@ER hydrogels could control the hyperglycemia within 2 h in diabetic mice and maintained their normal blood glucose level (BGL) for up to 6 days with laser irradiation 30 min prior to meals avoiding the frequent injection of free INS. This delivery system is an effective method that offers a spatiotemporally controlled release of INS to control the glucose level in vivo.

Efficacy of Concurrent Chemoradiotherapy With S-1 vs Radiotherapy Alone for Older Patients With Esophageal Cancer: A Multicenter Randomized Phase 3 Clinical Trial.

IMPORTANCE: Most older patients with esophageal cancer cannot complete the standard concurrent chemoradiotherapy (CCRT). An effective and tolerable chemoradiotherapy regimen for older patients is needed. OBJECTIVE: To evaluate the efficacy and toxic effects of CCRT with S-1 vs radiotherapy (RT) alone in older patients with esophageal cancer. DESIGN, SETTING, AND PARTICIPANTS: A randomized, open-label, phase 3 clinical trial was conducted at 23 Chinese centers between June 1, 2016, and August 31, 2018. The study enrolled 298 patients aged 70 to 85 years. Eligible participants had histologically confirmed esophageal cancer, stage IB to IVB disease based on the 6th edition of the American Joint Committee on Cancer (stage IVB: only metastasis to the supraclavicular/celiac lymph nodes) and an Eastern Cooperative Oncology Group performance status of 0 to 1. Data analysis was performed from August 1, 2020, to March 10, 2021. INTERVENTIONS: Patients were stratified according to age (<80 vs ≥80 years) and tumor length (<5 vs ≥5 cm) and randomly assigned (1:1) to receive either CCRT with S-1 or RT alone. MAIN OUTCOMES AND MEASURES: The primary end point was the 2-year overall survival rate using intention-to-treat analysis. RESULTS: Of the 298 patients enrolled, 180 (60.4%) were men. The median age was 77 (interquartile range, 74-79) years in the CCRT group and 77 (interquartile range, 74-80) years in the RT alone group. A total of 151 patients (50.7%) had stage III or IV disease. The CCRT group had a significantly higher complete response rate than the RT group (41.6% vs 26.8%; P = .007). Surviving patients had a median follow-up of 33.9 months (interquartile range: 28.5-38.2 months), and the CCRT group had a significantly higher 2-year overall survival rate (53.2% vs 35.8%; hazard ratio, 0.63; 95% CI, 0.47-0.85; P = .002). There were no significant differences in the incidence of grade 3 or higher toxic effects between the CCRT and RT groups except that grade 3 or higher leukopenia occurred in more patients in the CCRT group (9.5% vs 2.7%; P = .01). Treatment-related deaths were observed in 3 patients (2.0%) in the CCRT group and 4 patients (2.7%) in the RT group. CONCLUSIONS AND RELEVANCE: In this phase 3 randomized clinical trial, CCRT with S-1 was tolerable and provided significant benefits over RT alone in older patients with esophageal cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02813967.

Mechanism of hysteresis in shock wave reflection.

This paper reports on the mechanism of the hysteresis in the transition between regular and Mach shock wave reflections. We disclose that, for a given inflow Mach number, a stable reflection configuration should maintain the minimal dissipation. As the wedge angle varies, the set of the minimal dissipation points forms the valley lines in the dissipation landscape, and these valley lines compose the hysteresis loop. The saddle-nodes, intersections of the ridge line, and the valley lines are actually the transition points. Additionally, the predicted reflection configurations agree well with the experimental and numerical results, validating this theory.

Bi-enzymes treatments attenuate cognitive impairment associated with oxidative damage of heavy metals.

Oxidative stress has been implicated in the pathogenesis of cognitive impairment. Lead (Pb) is a common environmental toxicant and plays a vital role in oxidative stress activation. In this study, a superoxide dismutase (SOD) and catalase (CAT) containing poly (lactic-co-glycolic acid) (PLGA) meso-particles (PLGA@SOD-CAT) were prepared to attenuate cognitive impairment via inhibiting oxidative stress in rats. It was prepared using a double emulsion (water/oil/water phase) technique to minimize the hazardous effects of Pb burden on cognitive impairment. The meso-particles antagonized the Pb-induced cognitive impairments. Behaviour, serum biochemical parameters and biomarkers of oxidative stress in rats were evaluated after they were subjected to intravenous injection with lead nitrate and PLGA@SOD-CAT. Moreover, the potential protective mechanism of PLGA@SOD-CAT was determined. Notably, PLGA@SOD-CAT appreciably agented memory impairment caused by lead nitrate and it could significantly inhibit Pb-induced oxidative stress in the blood. Furthermore, a remarkable reversion effect of cognitive impairments, including escape latency, crossing platform times and time per cent during the platform quadrant, after PLGA@SOD-CAT administration were noted. Therefore, these results suggested that the bi-enzymes platform was a superior product in eliminating Pb-induced cognitive impairments through reducing expression of Pb-associated oxidative stress, and it could potentially be applied in detoxifying heavy metals in blood circulation.

Ultrasensitive all-fiber inline Fabry-Perot strain sensors for aerodynamic measurements in hypersonic flows.

This work proposes an ultrasensitive, temperature-insensitive, all-fiber inline Fabry-Perot (FP) strain sensor for aerodynamic coefficients measurements of a hypervelocity ballistic correlation model 2 in a Φ1 hypersonic wind tunnel. The FP sensors fabricated using 157 nm laser micromachining system are structurally simple, small-sized, and high-temperature resistance. 16 FP sensors are installed on a six-force balance, which is mounted inside the model, to sense the aerodynamic forces and moments of the model, and then the model's aerodynamic coefficients are calculated based on aerodynamic theory according to the test data. A new temperature-compensated method is proposed to improve measurement accuracy of aerodynamic coefficients via eliminating temperature-induced measurement errors. Experimental results show, at high temperatures, the FP sensors based on the balance (FP balance) exhibits a high-repeatability precision of the aerodynamic coefficients measurement of less than 1%, and match well with the results of the traditional method using foil-resistive strain sensors. This enhanced-sensitivity FP sensor is currently the most promising alternative to foil-resistive strain sensors for aerodynamic tests among kinds of fiber-optic strain sensors to the best of our knowledge. The FP balance satisfies the requirements of practical application of aerodynamic characteristic tests, and opens up another test system of the field.

Hypersonic Aerodynamic Force Balance Using Micromachined All-Fiber Fabry⁻Pérot Interferometric Strain Gauges.

This paper presents high-sensitivity, micromachined all-fiber Fabry-Pérot interferometric (FFPI) strain gauges and their integration in a force balance for hypersonic aerodynamic measurements. The FFPI strain gauge has a short Fabry-Pérot cavity fabricated using an excimer laser etching process, and the deformation of the cavity is detected by a white-light optical phase demodulator. A three-component force balance, using the proposed FFPI gauges as sensing elements, was fabricated, calibrated, and experimentally evaluated. To reduce thermal output of the balance, a simple and effective self-temperature compensation solution, without external temperature sensors, is proposed and examined through both oven heating and wind tunnel runs. As a result of this approach, researchers are able to use the balance continuously throughout a wide range of temperatures. During preliminary testing in a hypersonic wind tunnel with a free stream Mach number of 12, the measurement accuracies of the balance were clearly improved after applying the temperature self-compensation.

Hypersonic force measurements using internal balance based on optical micromachined Fabry-Perot interferometry.

Force measurements using wind tunnel balance are necessary for determining a variety of aerodynamic performance parameters, while the harsh environment in hypersonic flows requires that the measurement instrument should be reliable and robust, in against strong electromagnetic interference, high vacuum, or metal (oxide) dusts. In this paper, we demonstrated a three-component internal balance for hypersonic aerodynamic force measurements, using novel optical micromachined Fabry-Perot interferometric (FPI) strain gauges as sensing elements. The FPI gauges were fabricated using Micro-Opto-Electro-Mechanical Systems (MOEMS) surface and bulk fabrication techniques. High-reflectivity coatings are used to form a high-finesse Fabry-Perot cavity, which benefits a high resolution. Antireflective and passivation coatings are used to reduce unwanted interferences. The FPI strain gauge based balance has been calibrated and evaluated in a Mach 5 hypersonic flow. The results are compared with the traditional technique using the foil resistive strain gauge balance, indicating that the proposed balance based on the MOEMS FPI strain gauge is reliable and robust and is potentially suitable for the hypersonic wind tunnel harsh environment.

Fenofibrate enhances radiosensitivity of esophageal squamous cell carcinoma by suppressing hypoxia-inducible factor-1α expression.

Radiation therapy is widely used in esophageal squamous cell carcinoma (ESCC). Promoting radiation sensitivity is important. Recent studies have shown that fenofibrate can inhibit the growth of several cancer lines and hypoxia-inducible factor-1α (HIF-1α) expression in MCF-7 cells. However, few studies on the radiosensitive effect of fenofibrate on ESCCs under hypoxic condition have been conducted. In this study, we assessed the radiosensitive effects of fenofibrate on human ESCC cells. In vitro experiments showed the inhibition of cytotoxic effects after ionizing irradiation. We measured cell viability and clonogenic survival rate. Flow cytometry showed that fenofibrate pretreatment promoted apoptosis. The in vivo data also suggest that fenofibrate had radiosensitizing effects in ECA-109 cells xenografted into nude mice. Western blot and immunohistochemical analyses revealed that the HIF-1α and vascular endothelial growth factor (VEGF) protein content decreased by fenofibrate. Thus, the inhibition of HIF-1α and VEGF expression in ESCC cells contributed to the radiosensitive effect. These data suggest that fenofibrate may be a potential radiosensitive drug.