Targeting 5-Hydroxytryptamine receptor 1A in portal vein to decrease portal hypertension.

BACKGROUNDS & AIMS: Portal hypertension (PH) is one of the most frequent complications of chronic liver disease. The peripheral 5-Hydroxytryptamine (5-HT) level was increased in cirrhotic patients. We aimed to elucidate the function and mechanism of 5-HT receptor 1A (HTR1A) in portal vein (PV) on PH. METHODS: PH models were induced by thioacetamide (TAA) injection, bile duct ligation (BDL) or partial portal vein ligation (PPVL). HTR1A expression was detected using real-time PCR, in situ hybridization and immunofluorescence staining. In situ intraportal infusion was employed to assess the effects of 5-HT, the HTR1A agonist 8-OH-DPAT, and the HTR1A antagonist WAY-100635 on portal pressure (PP). Htr1a knock-out (Htr1a-/-) rats and vascular smooth muscle cell (VSMC)-specific Htr1a knock-out (Htr1aΔVSMC) mice were utilized to confirm the regulatory role of HTR1A on PP. RESULTS: HTR1A expression was significantly increased in the hypertensive PV of PH model rats and cirrhotic patients. Additionally, 8-OH-DPAT increased but WAY-100635 decreased PP in rats, without affecting liver fibrosis and systemic hemodynamics. Furthermore, 5-HT or 8-OH-DPAT directly induced the contraction of isolated PVs. Genetic deletion of Htr1a in rats and VSMCs-specific Htr1a knock-out in mice prevented the development of PH. Moreover, 5-HT triggered the cAMP pathway-mediated PVSMCs contraction via HTR1A in PV. We also confirmed alverine as an HTR1A antagonist and demonstrated its capacity to decrease PP in TAA-, BDL-, and PPVL-induced portal hypertensive rats. CONCLUSIONS: Our findings reveal that 5-HT promotes PH by inducing the contraction of PV, and identify HTR1A as a promising therapeutic target for attenuating PH. As an HTR1A antagonist, alverine is expected to become a candidate for clinical PH treatment.

Activation of aryl hydrocarbon receptor (AhR) alleviates depressive-like behaviors in LPS-induced mice.

The role of the aryl hydrocarbon receptor (AhR) in regulating oxidative stress and immune responses has been increasingly recognized. However, its involvement in depression and the underlying mechanisms remain poorly understood. This study aimed to investigate the effect of 6-formylindolo[3,2-b]carbazole (FICZ), an endogenous AhR ligand, on a lipopolysaccharide (LPS)-induced depression model and the underlying mechanism. After being treated with FICZ (50 mg/kg), male C57BL/6J mice received intraperitoneal injection of LPS and underwent behavioral tests 24 h later. The levels of inflammatory cytokines, including IL-1ß, IL-6, and TNF-α, were measured in the hippocampus and serum using enzyme-linked immunosorbent assay (ELISA). The expression levels of CYP1A1, AhR and NLRP3 were analyzed using qPCR and Western blot. The results showed that, compared with control group, LPS alone significantly down-regulated the expression levels of CYP1A1 mRNA and AhR protein in the hippocampus of mice, reduced glucose preference, prolonged immobility time in forced swimming test, increased IL-6 and IL-1ß levels in the hippocampus, increased serum IL-1ß level, and up-regulated NLRP3 mRNA and protein expression levels in mouse hippocampus, while FICZ significantly reversed the aforementioned effects of LPS. These findings suggest that AhR activation attenuates the inflammatory response associated with depression and modulates the expression of NLRP3. The present study provides novel insights into the role of AhR in the development of depression, and presents AhR as a potential therapeutic target for the treatment of depression.

Development and Validation of a New Integrative Score Based on Various Systemic Inflammatory and Nutritional Indicators in Predicting Prognosis in Patients With Resectable Esophageal Squamous Cell Carcinoma: A Retrospective Cohort Study.

BACKGROUND: Recent studies revealed that various inflammatory and nutritional indexes were associated with prognosis in esophageal cancer (EC). However, these studies only evaluated one or two indexes, and the prognostic value of these indexes individually or in combination is unclear. This study aimed to construct an integrative score based on various inflammatory and nutritional indexes for prognosis in resectable esophageal squamous cell carcinoma (ESCC). METHODS: A total of 421 consecutive patients were randomly divided into either a training or validation cohort at a ratio of 7:3 for retrospective analysis. Using logic regression analyses, independent risk factors from peripheral blood indexes were screened to construct an integrative score. The associations regarding the integrative score, clinical characteristics, cancer-specific survival (CSS), and overall survival (OS) were analyzed. RESULTS: Out of 20 indexes, hemoglobin (HB), C-reactive protein to albumin ratio (CAR), and platelet to lymphocyte ratio (PLR) were independent risk factors based on logical regression analyses. Then, an integrative score with the optimal cut-off value of .67 was established according to the Combination Of HB, CAR, and PLR (COHCP). The area under the curve (AUC) indicated higher predictive ability of COHCP on prognosis than other indicators. Multivariate analyses revealed that COHCP serves as an independent prognostic score. Patients with COHCP low group (≤.67) had better 5-year CSS (57.3% vs 13.5%, P < .001) and OS (51.1% vs 12.3%, P < .001) than those with high group, respectively. Finally, the nomogram based on COHCP was established and validated regarding CSS and OS, which can accurately and effectively predict individual survival in resected ESCC. CONCLUSION: The COHCP was a novel, simple, and useful predictor in resectable ESCC. The COHCP-based nomogram may accurately and effectively predict survival.

Bortezomib in combination with fludarabine plus cyclophosphamide for patients with relapsed or refractory mantle-cell lymphoma: results of the LYM-4003 study.

This study aimed to identify the maximum-tolerated dose (MTD) of cyclophosphamide when combined with bortezomib and fludarabine (B-FC) in a phase 1b trial, and to assess the efficacy and safety of this combination in a phase 2 trial in patients with relapsed or refractory MCL (rrMCL). Forty patients were enrolled between April 8, 2011, and October 10, 2015. The MTD of cyclophosphamide was identified to be 250 mg/m2 days 1-2. At a median follow-up of 31.6 months (13.5-47.4), among 32 patients in phase 2, 10 (31%) had a complete response and 13 (41%) had a partial response. The median progression-free survival was 21 months (95% CI 7.3-34.7), and the median overall survival was 32.4 months (95% CI 17.8-47.0). Grade 3-4 hematologic AEs included neutropenia (27%) and thrombocytopenia (39%). The B-FC regimen has satisfactory responses and manageable toxicities in rrMCL patients (ClinicalTrials.gov NCT01322776).

miR-541 potentiates the response of human hepatocellular carcinoma to sorafenib treatment by inhibiting autophagy.

OBJECTIVE: Autophagy participates in the progression of hepatocellular carcinoma (HCC) and the resistance of HCC cells to sorafenib. We investigated the feasibility of sensitising HCC cells to sorafenib by modulating miR-541-initiated microRNA-autophagy axis. DESIGN: Gain- and loss-of-function assays were performed to evaluate the effects of miR-541 on the malignant properties and autophagy of human HCC cells. Autophagy was quantified by western blotting of LC3, transmission electron microscopy analyses and confocal microscopy scanning of mRFP-GFP-LC3 reporter construct. Luciferase reporter assays were conducted to confirm the targets of miR-541. HCC xenograft tumours were established to analyse the role of miR-541 in sorafenib-induced lethality. RESULTS: The expression of miR-541 was downregulated in human HCC tissues and was associated with malignant clinicopathologic phenotypes, recurrence and survival of patients with HCC. miR-541 inhibited the growth, metastasis and autophagy of HCC cells both in vitro and in vivo. Prediction software and luciferase reporter assays identified autophagy-related gene 2A (ATG2A) and Ras-related protein Rab-1B (RAB1B) as the direct targets of miR-541. Consistent with the effects of the miR-541 mimic, inhibition of ATG2A or RAB1B suppressed the malignant phenotypes and autophagy of HCC cells. Furthermore, siATG2A and siRAB1B partially reversed the enhancement of the malignant properties and autophagy in HCC cells mediated by the miR-541 inhibitor. More interestingly, higher miR-541 expression predicted a better response to sorafenib treatment, and the combination of miR-541 and sorafenib further suppressed the growth of HCC cells in vivo compared with the single treatment. CONCLUSIONS: Dysregulation of miR-541-ATG2A/RAB1B axis plays a critical role in patients' responses to sorafenib treatment. Manipulation of this axis might benefit survival of patients with HCC, especially in the context of the highly pursued strategies to eliminate drug resistance.

Protein C-ets-2 epigenetically suppresses TLRs-induced interleukin 6 production in macrophages.

Interleukin 6 (IL-6) is a major proinflammatory cytokine involved in several aspects of the immune response. Excessive IL-6 production and dysregulated IL-6 receptor signaling lead to multiple inflammatory and autoimmune diseases, such as asthma, even cancer. Thus, its precise regulatory mechanisms need to be fully addressed. Here we found that knockdown of protein C-ets-2 (Ets2) resulted in higher IL-6 production after TLRs activation in macrophages. Mechanistically, Ets2 associated with an epigenetic modifier histone deacetylase 1 (HDAC1) and promoted its recruitment to the Il6 promoter after TLRs activation. Subsequentially, it enhanced histone deacetylation and inhibited Il6 mRNA transcription. Thus, Ets2 epigenetically suppresses TLRs-induced IL-6 production in both human and murine macrophages via promoting histone deacetylation of the Il6 promoter, serving as a new potential therapeutic target in inflammatory diseases therapy.

Long non-coding RNA BCYRN1 exerts an oncogenic role in colorectal cancer by regulating the miR-204-3p/KRAS axis.

BACKGROUND: It has been well documented that long non-coding RNAs (lncRNAs) regulate numerous characteristics of cancer, including proliferation, migration, metastasis, apoptosis, and even metabolism. LncRNA BCYRN1 (BCYRN1) is a newly identified brain cytoplasmic lncRNA with 200 nucleotides that was discovered to be highly expressed in tumour tissues, including those of hepatocellular carcinoma, gastric cancer and lung cancer. However, the roles of BCYRN1 in colorectal cancer (CRC) remain obscure. This study was designed to reveal the role of BCYRN1 in the occurrence and progression of CRC. METHODS: RT-PCR was used to detect the expression level of BCYRN1 in tumour tissues and CRC cell lines. BCYRN1 was knocked down in CRC cells, and cell proliferation changes were evaluated by cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), and Ki-67 and proliferating cell nuclear antigen (PCNA) expression assays. Cell migration and invasion changes were evaluated by wound healing, Transwell and invasion-related protein expression assays. Flow cytometry analysis was used to assess whether BCYRN1 regulates the apoptosis of CRC cells. The dual luciferase reporter gene detects the competitive binding of BCYRN1 to miR-204-3p. In vivo experiments were performed to evaluate the effect of BCYRN1 on tumour development. TargetScan analysis and dual luciferase reporter gene assays were applied to detect the target gene of miR-204-3p. Rescue experiments verified that BCYRN1 affects CRC by regulating the effect of miR-204-3p on KRAS. RESULTS: We found that compared with normal tissues and human intestinal epithelial cells (HIECs), CRC tumour tissues and cell lines had significantly increased BCYRN1 levels. We further determined that knockdown of BCYRN1 inhibited the proliferation, migration, and invasion and promoted the apoptosis of CRC cells. In addition, bioinformatics analysis and dual luciferase reporter assay showed that BCYRN1 served as a competitive endogenous RNA (ceRNA) to regulate the development of CRC through competitively binding to miR-204-3p. Further studies proved that overexpression of miR-204-3p reversed the effects of BCYRN1 on CRC. Next, TargetScan analysis and dual luciferase reporter assay indicated that KRAS is a target gene of miR-204-3p and is negatively regulated by miR-204-3p. A series of rescue experiments showed that BCYRN1 affected the occurrence and development of CRC by regulating the effects of miR-204-3p on KRAS. In addition, tumorigenesis experiments in a CRC mouse model confirmed that BCYRN1 downregulation effectively inhibited tumour growth. CONCLUSIONS: Our findings suggest that BCYRN1 plays a carcinogenic role in CRC by regulating the miR-204-3p/KRAS axis.

A NOVEL PROGNOSTIC INDEX IN PATIENTS WITH RESECTABLE ESOPHAGEAL SQUAMOUS CELL CARCINOMA: FIBRINOGEN/PREALBUMIN RATIO.

BACKGROUND: Fibrinogen (Fib) to albumin (ALB) fibrinogen-to-albumin ratio as a prognostic index for esophageal cancer has been confirmed. A novel prognostic index was initially proposed with fibrinogen to prealbumin ratio (FPR) in patients with resectable esophageal squamous cell carcinoma (ESCC). OBJECTIVE: The objective of the study was to study the prognostic role of the novel prognostic index (FPR) in patients with resectable ESCC without any neoadjuvant treatment. METHODS: In this retrospective study, a total of 372 resectable ESCC patients without any neoadjuvant treatment were included. The best cutoff values were selected by the receiver operating characteristic curves. Two Cox regression analyses with forward stepwise (one for categorical variables and the other for continuous variables) were used to evaluate the overall survival (OS) and cancer-specific survival (CSS). RESULTS: The best cutoff point was 0.014 for FPR. Patients with lower levels of FPR (≤0.014) had better CSS (50.7% vs. 18.0%, p < 0.001) and OS (48.0% vs. 17.6%, p < 0.001) than patients with higher levels of FPR (> 0.014). Multivariate Cox analyses (categorical and continuous) demonstrated that FPR was an independent prognostic factor in CSS (categorical: hazard ratio [HR]: 2.014, 95% confidence interval [CI]: 1.504-2.697, p < 0.001; continuous per 0.01: HR: 1.438, 95% CI: 1.154-1.793, p = 0.001) and OS (categorical: HR: 1.964, 95% CI: 1.475-2.617, p < 0.001; continuous per 0.01: HR: 1.429, 95% CI: 1.146-1.781, p = 0.002). CONCLUSIONS: Our study indicated that FPR served as an independent prognostic factor in patients with resectable ESCC.

MicroRNA-590-5p functions as a tumor suppressor in breast cancer conferring inhibitory effects on cell migration, invasion, and epithelial-mesenchymal transition by downregulating the Wnt-ß-catenin signaling pathway.

Breast cancer remains one of the foremost primary causes of female morbidity and mortality worldwide. During the current study, the effect of miR-590-5p and paired-like homeodomain transcription factor 2 (PITX2) on proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) of human breast cancer via the Wnt-ß-catenin signaling pathway was investigated. Breast cancer-related genes and related signaling pathways were obtained from KEGG database. The PITX2 regulatory microRNA was predicted. To define the contributory role by which miR-590-5p influences the progression of breast cancer, the interaction between miR-590-5p and PITX2 was explored; the proliferation, invasion, and migration abilities as well as the tumor growth and metastasis in nude mice were detected following the overexpression or silencing of miR-590-5p. PITX2 was determined to share a correlation with breast cancer and miR-590-5p was selected for further analysis. PITX2, Wnt-1, ß-catenin, N-cadherin, and vimentin all displayed higher levels, while miR-590-5p and E-cadherin expression were lower among breast cancer tissues than in the adjacent normal tissue. After overexpression of miR-590-5p or si-PITX2, the expression of E-cadherin was markedly increased, decreases in the expression of Wnt-1, ß-catenin, N-cadherin, and vimentin, as well as inhibited cell proliferation, invasion, migration, metastasis, and EMT were observed. This study provides evidence suggesting that the transfection of overexpressed miR-590-5p can act to alleviate the effects of breast cancer demonstrating an ability to inhibit the processes of cell proliferation, migration, and invasion as well as EMT by suppressing the expression of PITX2 and activation of the Wnt-ß-catenin pathway.

T-cell lymphomas associated gene expression signature: Bioinformatics analysis based on gene expression Omnibus.

OBJECTIVES: Due to the low incidence and the heterogeneity of subtypes, the biological process of T-cell lymphomas is largely unknown. Although many genes have been detected in T-cell lymphomas, the role of these genes in biological process of T-cell lymphomas was not further analyzed. METHODS: Two qualified datasets were downloaded from Gene Expression Omnibus database. The biological functions of differentially expressed genes were evaluated by gene ontology enrichment and KEGG pathway analysis. The network for intersection genes was constructed by the cytoscape v3.0 software. Kaplan-Meier survival curves and log-rank test were employed to assess the association between differentially expressed genes and clinical characters. RESULTS: The intersection mRNAs were proved to be associated with fundamental processes of T-cell lymphoma cells. These intersection mRNAs were involved in the activation of some cancer-related pathways, including PI3K/AKT, Ras, JAK-STAT, and NF-kappa B signaling pathway. PDGFRA, CXCL12, and CCL19 were the most significant central genes in the signal-net analysis. The results of survival analysis are not entirely credible. CONCLUSIONS: Our findings uncovered aberrantly expressed genes and a complex RNA signal network in T-cell lymphomas and indicated cancer-related pathways involved in disease initiation and progression, providing a new insight for biotargeted therapy in T-cell lymphomas.

High YBX1 expression indicates poor prognosis and promotes cell migration and invasion in nasopharyngeal carcinoma.

Y-box binding protein-1 (YBX1) is a multifunctional protein and often acts as an indicator of poor prognosis in cancers. Increasing evidence has shown that the levels of YBX1 protein were closely associated with multidrug resistance, relapse, metastasis and poor prognosis in cancers. However, its role in nasopharyngeal carcinoma (NPC) metastasis remains unknown. In our study, we discovered that the expression of YBX1 was increased in nasopharyngeal carcinoma tissues. YBX1 protein levels positively correlated with T stage and metastasis of NPC patients. Moreover, expression of YBX1 was negatively correlated with membrane E-cadherin levels and positively correlated with Vimentin expression. In vitro, the expression of YBX1 was closely related to the invasive and migratory ability of nasopharyngeal carcinoma cells. Knockdown of YBX1 inhibited migration and invasion in 5-8F cells, and over-expression of YBX1 promoted CNE1 cells migration and invasion. Transforming growth factor-ß1 (TGF-ß1) treatment led to epithelial-to-mesenchymal transition (EMT) in CNE1 cells accompanied by elevated YBX1 expression. On the contrary, knockdown of YBX1 partially inhibited the TGF-ß1-induced CNE1 cell migration, together with changes of EMT-associated markers. Our study revealed that TGF-ß1/YBX1 signaling might be one of novel mechanisms mediating EMT in NPC, providing a new target for the treatment of nasopharyngeal carcinoma.

MiR-138: A promising therapeutic target for cancer.

MicroRNAs are small noncoding RNAs which regulate gene expressions at post-transcriptional level by binding to the 3'-untranslated region of target messenger RNAs. Growing evidences highlight their pivotal roles in various biological processes of human cancers. Among them, miR-138, generating from two primary transcripts, pri-miR-138-1 and pri-miR-138-2, expresses aberrantly in different cancers and is extensively studied in cancer network. Importantly, studies have shown that miR-138 acts as a tumor suppressor by targeting many target genes, which are related to proliferation, apoptosis, invasion, and migration. Additionally, some researches also discover that miR-138 can sensitize tumors to chemotherapies. In this review, we summarize the expression of miR-138 on regulatory mechanisms and tumor biological processes, which will establish molecular basis on the usage of miR-138 in clinical applications in the future.

WITHDRAWN: The long non-coding RNA, LINC00635-001, sensitizes EGFR-TKI-resistant human lung cancer cells in vitro by inhibiting Akt activation.

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Liver X receptor as a drug target for the treatment of breast cancer.

Liver X receptor (LXR) has been exploited widely as a drug target in breast cancer treatment, and various mechanisms underlying the effects of LXR in this area are well studied. The activated LXR plays important roles in estrogen receptor α (ERα) breast cancer cells, such as reducing cell proliferation and arresting cell cycle progression. Different LXR ligands have diverse effects on the development of breast cancer, such as the inhibitory effect of oxysterol, which can return cells to normocholesterol conditions and target other metabolic genes. Moreover, 27-hydroxycholesterol, a locally produced cholesterol metabolite, reportedly promotes the proliferation of ERα breast cancer cells in vitro and facilitates tumor metastasis with other LXR ligands. Moreover, the expression of LXR also exerts potential effects on immune surveillance, tumor immunity, and tumor microenvironment. These advances in breast cancer research indicate that LXR may be a new therapeutic target to treat the refractory or drug-resistant subtypes of breast cancer.

Co-localization of Pirt protein and P2X2 receptors in the mouse enteric nervous system.

P2X2 receptors, with other P2X receptor subtypes, have an important role mediating synaptic transmission in regulating the functions of the gastrointestinal tract. Our recent work has found a new regulator of P2X receptor function, called phosphoinositide-interacting regulator of transient receptor potential channels (Pirt). In the present work, we have shown that Pirt immunoreactivity was localized in nerve cell bodies and nerve fibers in the myenteric plexus of the stomach, ileum, proximal, and distal colon and in the submucosal plexus of the jejunum, ileum, proximal, and distal colon. Almost all the Pirt-immunoreactive (ir) neurons were also P2X2-ir, and co-immunoprecipitation experiments have shown that Pirt co-precipitated with the anti-P2X2 antibody. This work provides detailed information about the expression of Pirt in the gut and its co-localization with P2X2, indicating its potential role in influencing P2X2 receptor function.

A Novel Inflammation-Based Stage (I Stage) in Patients with Resectable Esophageal Squamous Cell Carcinoma.

BACKGROUND: Inflammation plays a key role in cancer. In the current study, we proposed a novel inflammation-based stage, named I stage, for patients with resectable esophageal squamous cell carcinoma (ESCC). METHODS: Three hundred and twenty-three patients with resectable ESCC were enrolled in the current study. The I stage was calculated as follows: patients with high levels of C-reactive protein (CRP) (>10 mg/L), neutrophil-to-lymphocyte ratio (NLR) (>3.5), and platelet-count-to-lymphocyte ratio (PLR) (>150) were defined as I3. Patients with two, one, or no abnormal value were defined as I2, I1, or I0, respectively. The prognostic factors were evaluated by univariate and multivariate analyses. RESULTS: There were 112 patients for I0, 97 patients for I1, 66 patients for I2, and 48 patients for I3, respectively. The 5-year cancer-specific survival (CSS) in patients with I0, I1, I2, and I3 was 50.0%, 30.9%, 18.2%, and 8.3%, respectively (I0 versus I1, P = 0.002; I1 versus I2, P = 0.012; I2 versus I3, P = 0.020). Multivariate analyses revealed that I stage was an independent prognostic factor in patients with resectable ESCC (P < 0.001). CONCLUSION: The inflammation-based stage (I stage) is a novel and useful predictive factor for CSS in patients with resectable ESCC.

Cisplatin plus gemcitabine versus paclitaxel plus gemcitabine as first-line therapy for metastatic triple-negative breast cancer (CBCSG006): a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: Platinum chemotherapy has a role in the treatment of metastatic triple-negative breast cancer but its full potential has probably not yet been reached. We assessed whether a cisplatin plus gemcitabine regimen was non-inferior to or superior to paclitaxel plus gemcitabine as first-line therapy for patients with metastatic triple-negative breast cancer. METHODS: For this open-label, randomised, phase 3, hybrid-designed trial undertaken at 12 institutions or hospitals in China, we included Chinese patients aged 18-70 years with previously untreated, histologically confirmed metastatic triple-negative breast cancer, and an ECOG performance status of 0-1. These patients were randomly assigned (1:1) to receive either cisplatin plus gemcitabine (cisplatin 75 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1 and 8) or paclitaxel plus gemcitabine (paclitaxel 175 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1 and 8) given intravenously every 3 weeks for a maximum of eight cycles. Randomisation was done centrally via an interactive web response system using block randomisation with a size of eight, with no stratification factors. Patients and investigator were aware of group assignments. The primary endpoint was progression-free survival and analyses were based on all patients who received at least one dose of assigned treatment. The margin used to establish non-inferiority was 1·2. If non-inferiority of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine was achieved, we would then test for superiority. The trial is registered with ClinicalTrials.gov, number NCT01287624. FINDINGS: From Jan 14, 2011, to Nov 14, 2013, 240 patients were assessed for eligibility and randomly assigned to treatment (120 in the cisplatin plus gemcitabine group and 120 in the paclitaxel plus gemcitabine group). 236 patients received at least one dose of assigned chemotherapy and were included in the modified intention-to-treat analysis (118 per group). After a median follow-up of 16·3 months (IQR 14·4-26·8) in the cisplatin plus gemcitabine group and 15·9 months (10·7-25·4) in the paclitaxel plus gemcitabine group, the hazard ratio for progression-free survival was 0·692 (95% CI 0·523-0·915; pnon-inferiority<0·0001, psuperiority=0·009, thus cisplatin plus gemcitabine was both non-inferior to and superior to paclitaxel plus gemcitabine. Median progression-free survival was 7·73 months (95% CI 6·16-9·30) in the cisplatin plus gemcitabine group and 6·47 months (5·76-7·18) in the paclitaxel plus gemcitabine group. Grade 3 or 4 adverse events that differed significantly between the two groups included nausea (eight [7%] vs one [<1%]), vomiting (13 [11%] vs one [<1%]), musculoskeletal pain (none vs ten [8%]), anaemia (39 [33%] vs six [5%]), and thrombocytopenia (38 [32%] vs three [3%]), for the cisplatin plus gemcitabine compared with the paclitaxel plus gemcitabine groups, respectively. In addition, patients in the cisplatin plus gemcitabine group had significantly fewer events of grade 1-4 alopecia (12 [10%] vs 42 [36%]) and peripheral neuropathy (27 [23%] vs 60 [51%]), but more grade 1-4 anorexia (33 [28%] vs 10 [8%]), constipation (29 [25%] vs 11 [9%]), hypomagnesaemia (27 [23%] vs five [4%]), and hypokalaemia (10 [8%] vs two [2%]). Serious drug-related adverse events were seen in three patients in the paclitaxel plus gemcitabine group (interstitial pneumonia, anaphylaxis, and severe neutropenia) and four in the cisplatin plus gemcitabine group (pathological bone fracture, thrombocytopenia with subcutaneous haemorrhage, severe anaemia, and cardiogenic syncope). There were no treatment-related deaths. INTERPRETATION: Cisplatin plus gemcitabine could be an alternative or even the preferred first-line chemotherapy strategy for patients with metastatic triple-negative breast cancer. FUNDING: Shanghai Natural Science Foundation.

LXR ligands sensitize EGFR-TKI-resistant human lung cancer cells in vitro by inhibiting Akt activation.

Lung adenocarcinoma cells harboring epidermal growth factor receptor (EGFR) mutations are sensitive to EGFR tyrosine kinase inhibitors (TKIs). Prolonged cancer treatment will induce the development of acquired resistance to EGFR TKI. Here we investigate the effects of two novel liver x receptor (LXR) ligands (T0901317 or GW3965) on the development of acquired resistance to an EGFR TKI gefitinib. We observed known mechanisms of acquired resistance to EGFR TKI, including the EGFR T790M mutation, MET gene amplification and loss of PTEN in the gefitinib-resistant HCC827-8-1 cells. However, we found expression of MET was lower in HCC827-8-1 cells than in HCC827 cells. T0901317 or GW3965 inhibited Akt activation and sensitized HCC827-8-1 cells to gefitinib-induced cytotoxicity. In contrast, LXR ligands alone had no significant effect on HCC827-8-1 cells. In conclusion, this combined treatment may be of interest for treatment of lung adenocarcinomas harboring EGFR mutations and acquired resistance to gefitinib.

P2X7 receptors and Fyn kinase mediate ATP-induced oligodendrocyte progenitor cell migration.

Recruitment of oligodendrocyte precursor cells (OPCs) to the lesions is the most important event for remyelination after central nervous system (CNS) injury or in demyelinating diseases. However, the underlying molecular mechanism is not fully understood. In the present study, we found high concentrations of ATP could increase the number of migrating OPCs in vitro, while after pretreatment with oxidized ATP (a P2X7 receptor antagonist), the promotive effect was attenuated. The promotive effect of 2'(3')-O-(4-benzoylbenzoyl) adenosine 5'-triphosphate (BzATP) (a P2X7 receptor agonist) was more potent than ATP. After incubation with BzATP, the activity of Fyn, one member of the Src family of kinases, was enhanced. Moreover, the interaction between P2X7 and Fyn was identified by co-immunoprecipitation. After blocking the activity of Fyn or down-regulating the expression of Fyn, the migration of OPCs induced by BzATP was inhibited. These data indicate that P2X7 receptors/Fyn may mediate ATP-induced OPC migration under pathological conditions.

A Nomogram to Predict Prognostic Value of Red Cell Distribution Width in Patients with Esophageal Cancer.

OBJECTIVES: The prognostic value of inflammatory index in esophageal cancer (EC) was not established. In the present study, we initially used a nomogram to predict prognostic value of red cell distribution width (RDW) in patients with esophageal squamous cell carcinoma (ESCC). METHODS: A total of 277 ESCC patients were included in this retrospective study. Kaplan-Meier method was used to calculate the cancer-specific survival (CSS). A nomogram was established to predict the prognosis for CSS. RESULTS: The mean value of RDW was 14.5 ± 2.3%. The patients were then divided into two groups: RDW ≥ 14.5% and RDW < 14.5%. Patients with RDW < 14.5% had a significantly better 5-year CSS than patients with RDW ≥ 14.5% (43.9% versus 23.3%, P < 0.001). RDW was an independent prognostic factor in patients with ESCC (P = 0.036). A nomogram could be more accurate for CSS. Harrell's c-index for CSS prediction was 0.68. CONCLUSION: RDW was a potential prognostic biomarker in patients with ESCC. The nomogram based on CSS could be used as an accurately prognostic prediction for patients with ESCC.