Analyzing the impact of acupuncture in conjunction with a Quantum lipid-lowering device on hyperlipidemic rats: insights into adenosine monophosphate-activated protein kinase signaling, blood lipids, and gut microbiota.

We explored the impact of acupuncture (ACUP) in conjunction with a quantum lipid-lowering device (Quantum) on the blood lipids and gut microbiota in hyperlipidemic rats, focusing on the adenosine monophosphate- (AMP)-activated protein kinase (AMPK) signaling pathway. Fifty Sprague-Dawley rats were randomly allocated into five groups: Normal, Model, Acup + Quantum, Acup, and Quantum. Hyperlipidemic models were established in all groups except Normal. The Model group did not receive any intervention after modeling. The Acup + Quantum group received both treatments, the Acup group received only acupuncture, and the Quantum group received only the quantum lipid-lowering device. We used ELISA to measure serum lipid and liver enzyme levels, hematoxylin and eosin (HE) staining for liver pathology, Western blot for protein expression, and 16S rRNA sequencing to analyze intestinal microbiota diversity in rats. Elisa results showed that compared with the model group, Acup + Quantum group could reduce the levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein-cholesterol (LDL-C), aspartate transaminase (AST) and aspartate transaminase (ALT) in rats with hyperlipidemia (P<0.01), and increase the level of high-density lipoprotein-cholesterol (HDL-C) (P<0.01). HE staining results showed that compared with the model group, the hepatocytes of rats in the Acup + Quantum group looked round and full, the liver plates were arranged regularly and neatly, and there was no obvious abnormality in the liver sinusoids. Western blot results showed that compared with the model group, the Acup + Quantum group inhibited AMPK activation, increased P-AMPK/AMPK protein expression (P<0.05), and decreased phospho-acetyl-CoA carboxylases (P-ACC/ACC), Sterol regulatory element-binding transcription factor-1C (SREBP-1C), and FAS protein expression (P<0.05; P<0.01; P<0.01), which resulted in lipid-lowering effect. The results of intestinal flora showed that Acup + Quantum group improved the intestinal microbial microenvironment of hyperlipidemic rats by regulating the structure of intestinal microflora, increasing the abundance of Firmicutes flora, and decreasing the abundance of harmful bacteria, such as Bacteroidetes and Proteobacteria. Acupuncture combined with quantum lipid-lowering device can improve the blood lipid and liver function levels and regulate the intestinal microbial microenvironment of hyperlipidemic rats. This therapeutic outcome is likely achieved through the activation of the AMPK pathway and the beneficial modulation of the intestinal microbiota of rats.

Radiomics-based distinction of small (≤2 cm) hepatocellular carcinoma and precancerous lesions based on unenhanced MRI.

AIM: To assess the feasibility of a radiomics model based on unenhanced magnetic resonance imaging (MRI) to differentiate small hepatocellular carcinoma (S-HCC) (≤2 cm) and pre-hepatocellular carcinoma (Pre-HCC). MATERIALS AND METHODS: One hundred and fourteen histopathologically confirmed 114 hepatic nodules were analysed retrospectively. All patients had undergone MRI before surgery using a 3 T MRI system. Each nodule was segmented on unenhanced MRI sequences (T1-weighted imaging [T1] and T2WI with fat-suppression [FS-T2]). Radiomics features were extracted and the optimal features were selected using the least absolute shrinkage and selection operator (LASSO). The support vector machine (SVM) was used to establish the radiomics model. One abdominal radiologist performed the conventional qualitative analysis for classification of S-HCC and Pre-HCC. The diagnostic performances of the radiomics and radiologist models were evaluated using receiver operating characteristic (ROC) analysis. RESULT: Radiomics features (n=1,223) were extracted from each sequence and the optimal features were selected from T1, FS-T2, and T1+FS-T2 to construct the radiomics models. The radiomics model based on T1+FS-T2 showed the best performance among the three models, with areas under the ROC curves (AUCs) of 0.95 (95 % confidence interval [CI], 0.875-0.986) and 0.942 (95 % CI, 0.775-0.985), accuracies of 86 % and 88.5 %, sensitivities of 94.12 % and 100 %, and specificities of 85.48 % and 85.19 %, respectively. The radiomics model on FS-T2 showed better performance on a single sequence than that of the T1-based model. The diagnostic performance for the radiomic model was significantly higher than that for the radiologist (AUC = 0.518, p<0.05). CONCLUSION: This study suggested that a radiomics model based on unenhanced MRI may serve as a feasible and non-invasive tool to classify S-HCC and Pre-HCC.

Average and statistical properties of coherent radiation from steady-state microbunching.

A promising accelerator light source mechanism called steady-state microbunching (SSMB) is being actively studied. With the combination of strong coherent radiation from microbunching and high repetition rate of a storage ring, high-average-power narrow-band radiation can be anticipated from an SSMB storage ring, with wavelengths ranging from THz to soft X-ray. Such a novel light source could provide new opportunities for accelerator photon science like high-resolution angle-resolved photoemission spectroscopy and industrial applications like extreme ultraviolet (EUV) lithography. In this paper, a theoretical and numerical study of the average and statistical properties of coherent radiation from SSMB are presented. The results show that 1 kW average-power quasi-continuous-wave EUV radiation can be obtained from an SSMB ring provided that an average current of 1 A and a microbunch train with bunch length of 3 nm can be formed at the radiator which is assumed to be an undulator. Together with the narrow-band feature, the EUV photon flux can reach 6 × 1015 photons s-1 within a 0.1 meV energy bandwidth, which is three orders of magnitude higher than that in a conventional synchrotron source and is appealing for fundamental condensed matter physics and other research. In this theoretical investigation, we have generalized the definition and derivation of the transverse form factor of an electron beam which can quantify the impact of its transverse size on coherent radiation. In particular, it has been shown that the narrow-band feature of SSMB radiation is strongly correlated with the finite transverse electron beam size. Considering the pointlike nature of electrons and quantum nature of radiation, the coherent radiation fluctuates from microbunch to microbunch, or for a single microbunch from turn to turn. Some important results concerning the statistical properties of SSMB radiation are presented, with a brief discussion on its potential applications, for example the beam diagnostics. The presented work is of value for the development of SSMB to better serve potential synchrotron radiation users. In addition, this also sheds light on understanding the radiation characteristics of free-electron lasers, coherent harmonic generation, etc.

Neoadjuvant weekly paclitaxel and carboplatin with trastuzumab and pertuzumab in HER2-positive breast cancer: a Brown University Oncology Research Group (BrUOG) study.

PURPOSE: In HER2-positive breast cancer (HER2+ BC), neoadjuvant chemotherapy (NACT) with dual HER2-targeted therapy achieves high pathologic complete response (pCR) rates. Anthracycline-free NACT regimens avoid toxicities associated with anthracyclines, but every 3-week TCHP also has substantial side effects. We hypothesized that a weekly regimen might have equivalent efficacy with less toxicity; we also investigated whether poorly responding patients would benefit from switching to AC. METHODS: Patients with clinical stage II-III HER2+ BC received weekly paclitaxel 80 mg/m2 and carboplatin AUC2 with every 3-week trastuzumab and pertuzumab (wPCbTP), with the option of splitting the pertuzumab loading dose. After 12 weeks, responding patients continued wPCbTP for another 6 weeks, while non-responders switched to AC. Dose modifications and post-op therapy were at investigator discretion. RESULTS: In 30 evaluable patients, the pCR rate was 77% (95% CI 58-90%); 12/14 (86%) in ER-negative and 11/16 (69%) in ER-positive. Only two patients transitioned to AC for non-response, of which one achieved pCR. There were no episodes of febrile neutropenia or grade ≥ 3 peripheral neuropathy, though several patients who continued wPCbTP stopped before week 18. Split-dose pertuzumab was associated with less grade ≥ 2 diarrhea (40%) than the standard loading dose (60%). CONCLUSION: pCR rates with our regimen were as high as reported with TCHP with fewer grade ≥ 3 toxicities, though diarrhea remains a concern. Too few patients had a suboptimal response to adequately test switching to AC. The wPCbTP regimen should be considered an alternative to TCHP as neoadjuvant therapy for HER2+ BC. TRAIL REGISTRATION: ClinicalTrials.gov identifier: NCT02789657.

miRNA-217 inhibits proliferation of hepatocellular carcinoma cells by regulating KLF5.

OBJECTIVE: The aim of this study was to figure out the effect of microRNA-217 on the proliferation of hepatocellular carcinoma (HCC) cells, and to explore its influence on KLF5 expression and the underlying regulatory mechanisms. PATIENTS AND METHODS: Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was used to detect the expression of microRNA-217 in tumor tissues and paracancerous tissues of 60 patients with HCC. Meanwhile, the relationship between microRNA-217 expression and HCC pathological parameters was analyzed. In HCC cell lines, including HepG2 and Bel-7402, negative control group (NC) and microRNA-217 overexpression group were set up, and qRT-PCR was performed to further verify their transfection efficiency. In addition, Cell Counting Kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU) assay were performed to analyze the effect of microRNA-217 on the biological function of HCC cells. Finally, the potential mechanism of KLF5, the downstream gene of microRNA-217, was explored using bioinformatics analysis and cell recovery experiments. RESULTS: QRT-PCR results showed that microRNA-217 level in tumor tissues of HCC patients was conspicuously lower than that in adjacent tissues, and the difference was statistically significant. Compared with patients with high expression of microRNA-217, the pathological stage was higher and the overall survival rate was lower in patients with low expression. Compared with the NC group, the cell proliferation ability of the microRNA-217 mimics group was conspicuously decreased. Subsequently, in the HCC cell line and tissue verification, the expression of KLF5 was found remarkably increased, and microRNA-217 exhibited a negative correlation with KLF5 level. In addition, the overexpression of microRNA-217 conspicuously reduced the protein expression of CD31, Ki-67, c-Myc, MMP-2, and MMP-9. In cell recovery experiment, it was found that the overexpression of KLF5 could counteract the effect of microRNA-217 mimics on the cell proliferation of HCC, thereby inhibiting the malignant progression of this disease. CONCLUSIONS: The above studies demonstrated that microRNA-217 was markedly associated with the pathological stage and poor prognosis of HCC, and could inhibit the malignant progression of this disease. In addition, our investigation has showed that microRNA-217 might be capable of inhibiting cell proliferation of HCC via regulating KLF5.

Contribution of biomimetic collagen-ligand interaction to intrafibrillar mineralization.

Contemporary models of intrafibrillar mineralization mechanisms are established using collagen fibrils as templates without considering the contribution from collagen-bound apatite nucleation inhibitors. However, collagen matrices destined for mineralization in vertebrates contain bound matrix proteins for intrafibrillar mineralization. Negatively charged, high-molecular weight polycarboxylic acid is cross-linked to reconstituted collagen to create a model for examining the contribution of collagen-ligand interaction to intrafibrillar mineralization. Cryogenic electron microscopy and molecular dynamics simulation show that, after cross-linking to collagen, the bound polyelectrolyte caches prenucleation cluster singlets into chain-like aggregates along the fibrillar surface to increase the pool of mineralization precursors available for intrafibrillar mineralization. Higher-quality mineralized scaffolds with better biomechanical properties are achieved compared with mineralization of unmodified scaffolds in polyelectrolyte-stabilized mineralization solution. Collagen-ligand interaction provides insights on the genesis of heterogeneously mineralized tissues and the potential causes of ectopic calcification in nonmineralized body tissues.

[Expression of Fermintin family homologous protein 2 in non-small cell lung cancer and its clinical significance].

Objective: To investigate the expression of Fermintin family homologous protein 2 (FERMT2) in non-small cell lung cancer and its clinical significance. Methods: Seventy-two patients with non-small cell lung cancer were collected at Xinxiang Central Hospital, Henan Province, from January 2015 to January 2017.There were 48 male and 24 female patients, the age ranged from 37 to 78 years (mean 58 years). The expression of FERMT2 in tumor samples and para-cancerous tissues were detected by immunohistochemistry. Protein and mRNA expression of FERMT2 were detected by Western blot and real-time fluorescence quantitative PCR, respectively. Western blot method was also used to detect integrin-related protein expression, including integrin beta 1 (CD29), vascular cell adhesion molecule (VCAM1), and mobile related protein-1 (MRP1). Results: Immunohistochemistry showed that the positive rates of FERMT2 expression were 81.9%(59/72)in carcinoma tissue and 15.4%(11/72) in para-cancerous tissues, and the difference was statistically significant (P<0.01). Positive FERMT2 expression was different in tumors at different tumor stages: 11/17 at stage Ⅰ, 16/20(80.0%)at stage Ⅱ, 17/20(85.0%)at stage Ⅲ, and 15/15 at stage Ⅳ, and there was a significant difference between each stage (P<0.01). By real-time PCR and Western blot, the expression of FERMT2 in non-small cell lung cancer tissues was significantly higher than that of para-cancerous tissue (P<0.01). The expression levels of integrin related proteins (integrin ß1, VCAM1 and MRP1) in tumor tissues were significantly higher than those in para-cancerous tissues, and positively correlated with the expression of FERMT2 (r=0.531, P<0.01; r=0.483, P<0.01; r=0.612, P<0.01). Conclusions: FERMT2 is highly expressed in non-small cell lung carcinomas. Its expression is closely correlated with the tumor clinical stage. It is hypothesized that FERMT2 may promote tumor metastasis through interactions with integrin-like protein.

Comparative study between mini-open TLIF via Wiltse's approach and conventional open TLIF in lumbar degenerative diseases.

OBJECTIVE: To compare the clinical effects, operation safety and radiation exposure of mini-open TLIF via Wiltse's approach (MOTLIF) and conventional open TLIF (COTLIF) in the treatment of single-segment lumbar degenerative disease via the prospective control study. PATIENTS AND METHODS: A total of 77 patients were enrolled from November 2012 to July 2014, including 42 patients in the mini-open group (MOTLIF) and 35 patients in the COTLIF group. Oswestry Disability Index (ODI) and Visual Analogue Scale (VAS) scores before operation, operation time, intraoperative blood loss, postoperative drainage volume, blood transfusion rates, postoperative bedridden time, postoperative hospital stays, intraoperative fluoroscopic time, levels of serum creatine phosphokinase (CPK) before operation, 3 days and 1 week after operation, VAS scores before operation, 3 days and 1 week after operation, and ODI and VAS scores in the last follow-up between the two groups were compared. RESULTS: There were significant differences between the two groups in the operation time, intraoperative blood loss, postoperative drainage, blood transfusion rates, postoperative bedridden time, postoperative hospital stays and intraoperative fluoroscopic time; all indicators in MOTLIF group were superior to those in COTLIF group (p<0.05). There were no significant differences between the two groups in levels of serum CPK before operation and 1 week after operation (p>0.05). However, 3 days after operation, the level of serum CPK in COTLIF group was increased more significantly than that in MOTLIF group (647.4±178.6 vs. 467.4±189.4). There were no differences between the two groups in ODI and VAS scores before operation; ODI score in MOTLIF group in the last follow-up was significantly superior to that in COTLIF group (p>0.05). And VAS scores at 3 days and 1 week after operation and the last follow-up in MOTLIF group were superior to those in COTLIF group (p<0.05). CONCLUSIONS: Compared with the conventional open TLIF, mini-open TLIF via Wiltse's approach using the self-designed operating apparatus is characterized by the convenient operation, small trauma and quick recovery after operation. At the same time, the radiation exposure is lower and long-term follow-up effect is superior. Its short-term and long-term effects in the treatment of lower lumbar degenerative disease are also superior.

[Response and prognosis of neoadjuvant dose-dense or standard schedule chemotherapy with anthracyclines and taxanes for Luminal B breast cancer].

Objective: To evaluate the efficacy and safety of neoadjuvant dose-dense or standard schedule chemotherapy with anthracyclines and taxanes for Luminal B (HER2-)Breast Cancer. Methods: From January 2010 to December 2014, 168 Luminal B (HER2-) breast cancer patients with stageⅡA-ⅢC confirmed by pathology were randomly assigned to receive one of the following regimens: (group A) concurrent TEC× 4 every 3 weeks, ( group B ) sequential EC× 4-T × 4 every 3 weeks, (group C ) dose-dense TEC× 4 every 2 weeks with G-CSF, (group D) sequential EC× 4(dose-dense)-T × 4 with dose-dense every 2 weeks . Results: A total of 168 patients completed the neoadjuvant chemotherapy as planned. The pathologic complete response (pCR) was 16.8% in the 4 groups.The pCR were 30.9% and 26.1% in the group C and group D respectively, significantly higher than patients with group A and group B(9.5%and 7.1%) ( P<0.05). Median follow-up was 43 months (IQR 3-63). The 3-year disease free survival (DFS) rate was 64.7%, 55.5%, 87.8% and 92.1% and the 3-year overall survival(OS)rate was 79.4%, 77.7%, 95.1%, 97.3% in the 4 groups respectively. Patients in the dose-dense group had better 3-year DFS and 3-year OS than those with the regular group.The side-effects could be evaluated in 154 patients.The incidence of neutropenia was 29.2% and 21.9% in the group C and group D versus 65.7%and 51.3% in the regular group(P<0.05), the incidence of nervous toxicity was 54.2%, 18.9%, 60.0%, 26.8% in the 4 groups respectively. The incidence of nervous toxicity in the dose-dense group was lower than that in the regular regimen group(P<0.05). Conclusion: Neoadjuvant dose-dense chemotherapy with anthracyclines and taxanes for Luminal B (HER2-)Breast Cancer was effective and can improve the pCR, DFS and OS.Comparing the two dose dense regimens, sequentially with anthracyclines and taxanes, the incidence of nervous toxicity were lower.

[The surgical treatment of ovarian cancer metastasis between liver and diaphragm: a report of 83 cases].

Objective: To explore the safety and feasibility of associating diaphragm resection and liver-diaphragmatic metastasis lesions resection for patients with advanced ovarian cancer. Methods: Retrospectively analysis 83 cases(98 times) of advanced ovarian cancer with liver-diaphragmatic metastasis between January 2012 and December 2016 at Department of Liver Surgery, Peking Union Medical College Hospital.The patients were aged from 19 to 75 years.Surgical procedure included metastatic lesions resection(43 times) and stripping(55 times). Operation status, post-operative complications, pathology results and follow-up of the patients were analyzed. Results: Fifteen patients received twice surgical treatment and 68 patients received one time surgical treatment. Postoperative hemorrhage in chest and between liver and diaphragm was not occurred in all cases.Dyspnea and low oxygen saturation were occurred in two cases of stripping patients and 1 case of metastatic lesions resection patients.Results of CT examination indicated that there was medium to large amount of ascites in right chests.The symptoms were relieved after placing thoracic closed drainage.Other patients were recovered smoothly.All patients were diagnosed as ovarian cancer by pathological examination. Conclusion: Associating diaphragm resection is safe and feasible for liver-diaphragmatic metastasis lesions from ovarian cancer.

Comprehensive proteomics analysis of exosomes derived from human seminal plasma.

Exosomes are membranous nanovesicles of endocytic origin that carry and transfer regulatory bioactive molecules and mediate intercellular communication between cells and tissues. Although seminal exosomes have been identified in human seminal plasma, their exact composition and possible physiologic function remain unknown. The objective of this study was to perform a comprehensive proteomics analysis of exosomes derived from human seminal plasma. Seminal exosomes were isolated and purified from 12 healthy donors using a 30% sucrose cushion-based exosome-isolation protocol, followed by characterization by western blot, transmission electron microscopy, and nanoparticle tracking analysis before performing extensive liquid chromatography tandem mass spectrometry proteomics analysis. The identified proteins were analyzed by bioinformatics analysis, and seminal exosomes-associated proteins were selectively validated by western blot. A total of 1474 proteins were identified in all seminal exosomes samples, with Gene Ontology analysis demonstrating that these identified seminal exosomes-associated proteins were mostly linked to 'exosomes,' 'cytoplasm,' and 'cytosol.' Bioinformatics analysis indicated that these proteins were mainly involved in biologic processes, including metabolism, energy pathways, protein metabolism, cell growth and maintenance, and transport. Of these identified proteins, PHGDH, LGALS3BP, SEMG1, ACTB, GAPDH, and the exosomal-marker protein ALIX were validated by western blot. This study provided a more comprehensive description of the seminal exosomes proteome and could also be a resource for further screening of biomarkers and comparative proteomics studies, including those associated with male infertility and prostate cancer.

Regulation of oncogenes and gap junction intercellular communication during the proliferative response of zearalenone in TM3 cells.

Zearalenone (ZEA) is a nonsteroidal estrogenic mycotoxin produced by Fusarium species. The exposure risk to humans and animals is the consumption of contaminated food and animal feeds. The aim of this study was to investigate ZEA-induced effects and its tumorigenic mechanism in TM3 cells (mouse Leydig cells). Cell proliferation, apoptosis, and gap junction intercellular communication (GJIC) were assessed in this study. Results showed that low concentrations of ZEA could significantly promote the growth of TM3 cells. The percentage of cell distribution was decreased significantly in G1/G0 phase and was increased significantly in S phase with 10 and 20 µg/L of ZEA for 72 h ( p < 0.05, p < 0.01). The expressions of cyclin D1 and Cdk4 were significantly increased in the exposure groups compared with the control group ( p < 0.05, p < 0.01). Compared with the control group, the apoptosis was significantly decreased in 10 and 20 µg/L groups ( p < 0.01), and the ratio of Bax/Bcl-2 protein level was significantly decreased in a dose-dependent manner. The protein levels of proto-oncogene c-Myc, c-Jun, and c-Fos were significantly elevated and the protein levels of anti-oncogene p53 and phosphatase and tensin homolog (PTEN) were decreased obviously compared with the control group ( p < 0.05, p < 0.01). ZEA affected the expressions of connexins and inhibited the activity of GJIC. These results demonstrated that ZEA can disturb the dynamic balance between proliferation and apoptosis and causes abnormal regulation of oncogenes, GJIC, and connexins in TM3 cells, which may easily induce the translation of normal cells into tumor cells.

[Identification and significance of myeloid-derived suppressor cells in peripheral blood of breast cancer patients].

OBJECTIVE: To investigate the presence, biological features, and clinical significance of myeloid-derived suppressor cells (MDSCs) in breast cancer patients. METHODS: Eighty-four cases of breast cancer, 37 cases of benign breast tumor and 21 cases of healthy individuals were included in this study. Samples of peripheral blood (2 ml) were collected, and in the breast cancer patients, blood samples were taken both before and after treatment. Flow cytometry using anti-CD11b, CD33, CD14 and HLA-DR antibody was conducted to identify the unique membrane markers of MDSCs, and statistical analysis was performed to explore the relationship between MDSCs and clinical factors. Cell isolation and in vitro assay were used to test T cell function. RESULTS: CD11b(+) CD33(+) CD14(-) MDSCs were present in the blood of breast cancer patients, and these MDSCs were histologically of mononuclear cells. Cell proliferation assay confirmed that MDSCs inhibited proliferation of homologous T cells in vitro. MDSCs levels in patients with breast cancer, benign disease and the health control were (15.93±3.17)%, (8.92±4.42)% and (5.02±2.75)%, respectively, with a statistically significant difference (P<0.001) between breast cancer patients and the other subjects (patients with benign lesions and healthy controls). The expression level of MDSCs in patients with breast cancer was associated with surgical treatment, but not with age, disease stage, lymph node metastasis, ER or PR expression. MDSCs levels were significantly lower in post-operative patients[(7.83±3.78) %] than the (15.37±2.49) % in patients before surgery (P<0.001). CONCLUSIONS: The results of this study demonstrate that MDSCs are present in the peripheral blood of breast cancer patients and the level of MDSCs is associated with surgical treatment. Our findings suggest that CD11b(+) CD33(+) CD14(-) MDSCs are likely involved in breast cancer initiation and development, and may become a novel biomarker to facilitate diagnosis and to predict clinical outcomes of breast cancer.

Dysregulated choline metabolism in T-cell lymphoma: role of choline kinase-α and therapeutic targeting.

Cancer cells have distinct metabolomic profile. Metabolic enzymes regulate key oncogenic signaling pathways and have an essential role on tumor progression. Here, serum metabolomic analysis was performed in 45 patients with T-cell lymphoma (TCL) and 50 healthy volunteers. The results showed that dysregulation of choline metabolism occurred in TCL and was related to tumor cell overexpression of choline kinase-α (Chokα). In T-lymphoma cells, pharmacological and molecular silencing of Chokα significantly decreased Ras-GTP activity, AKT and ERK phosphorylation and MYC oncoprotein expression, leading to restoration of choline metabolites and induction of tumor cell apoptosis/necropotosis. In a T-lymphoma xenograft murine model, Chokα inhibitor CK37 remarkably retarded tumor growth, suppressed Ras-AKT/ERK signaling, increased lysophosphatidylcholine levels and induced in situ cell apoptosis/necropotosis. Collectively, as a regulatory gene of aberrant choline metabolism, Chokα possessed oncogenic activity and could be a potential therapeutic target in TCL, as well as other hematological malignancies with interrupted Ras signaling pathways.

Mitochondrial inhibitor sensitizes non-small-cell lung carcinoma cells to TRAIL-induced apoptosis by reactive oxygen species and Bcl-X(L)/p53-mediated amplification mechanisms.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for anticancer therapy; however, non-small-cell lung carcinoma (NSCLC) cells are relatively TRAIL resistant. Identification of small molecules that can restore NSCLC susceptibility to TRAIL-induced apoptosis is meaningful. We found here that rotenone, as a mitochondrial respiration inhibitor, preferentially increased NSCLC cells sensitivity to TRAIL-mediated apoptosis at subtoxic concentrations, the mechanisms by which were accounted by the upregulation of death receptors and the downregulation of c-FLIP (cellular FLICE-like inhibitory protein). Further analysis revealed that death receptors expression by rotenone was regulated by p53, whereas c-FLIP downregulation was blocked by Bcl-X(L) overexpression. Rotenone triggered the mitochondria-derived reactive oxygen species (ROS) generation, which subsequently led to Bcl-X(L) downregulation and PUMA upregulation. As PUMA expression was regulated by p53, the PUMA, Bcl-X(L) and p53 in rotenone-treated cells form a positive feedback amplification loop to increase the apoptosis sensitivity. Mitochondria-derived ROS, however, promote the formation of this amplification loop. Collectively, we concluded that ROS generation, Bcl-X(L) and p53-mediated amplification mechanisms had an important role in the sensitization of NSCLC cells to TRAIL-mediated apoptosis by rotenone. The combined TRAIL and rotenone treatment may be appreciated as a useful approach for the therapy of NSCLC that warrants further investigation.