Neutrophil membrane-coated taurine nanoparticles protect against hepatic ischemia-reperfusion injury.

Hepatic ischemia-reperfusion (I/R) injury is a multifactorial process caused by transient tissue hypoxia and the following reoxygenation, commonly occurring in liver transplantation and hepatectomy. Hepatic I/R can induce a systemic inflammatory response, liver dysfunction, or even multiple organ failure. Although we have previously reported that taurine could attenuate acute liver injury after hepatic I/R, only a tiny proportion of the systemically injected taurine could reach the targeted organ and tissues. In this present study, we prepared taurine nanoparticles (Nano-taurine) by coating taurine with neutrophil membranes and investigated the protective effects of Nano-taurine against I/R-induced injury and the underlying mechanisms. Our results showed that Nano-taurine restored liver function by declining AST and ALT levels and reducing histology damage. Nano-taurine decreased inflammatory cytokines, including interleukin (IL)-6, tumor necrosis factor (TNF)-α, intercellular adhesion molecule (ICAM)-1, NLR pyrin domain containing 3 (NLRP3) and apoptosis-associated speck-like protein containing CARD (ASC) and oxidants including superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), catalase (CAT) and reactive oxygen species (ROS), exhibiting anti-inflammatory and antioxidant properties. The expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) was increased, while prostaglandin-endoperoxide synthase 2 (Ptgs2) was decreased upon administration of Nano-taurine, suggesting that inhibiting ferroptosis may be involved in the mechanism during hepatic I/R injury. These results suggest that Nano-taurine have a targeted therapeutic effect on hepatic I/R injury by inhibiting inflammation, oxidative stress, and ferroptosis.

LncRNA PTCSC3 Is a Biomarker for the Treatment and Prognosis of Gastric Cancer.

Background: Long noncoding RNA (lncRNA) papillary thyroid carcinoma susceptibility candidate 3 (PTCSC3) inhibits several types of cancer, whereas its role in gastric cancer is unknown. Materials and Methods: From May 2010 to May 2015, this study included 68 (36 males and 32 females, 35-69 years, 48.3 ± 7.1 years) gastric cancer patients and 60 healthy volunteers (32 males and 28 females, 34-67 years, 48.8 ± 6.5 years). Transient transfections, QPCR, CCK-8, transwell cell migration, and invasion assay were used for carrying out the research. Results: The authors found that plasma PTCSC3 was downregulated in gastric cancer patients. Downregulation of PTCSC3 distinguished early stage gastric cancer patients from healthy controls. LncRNA PTCSC3 expression levels were increased on the day of discharge in gastric cancer patients compared with pretreatment levels. During follow-up, patients with low plasma levels of PTCSC3 showed a significantly lower overall survival rate. PTCSC3 negatively regulated proliferation, invasion, and migration of gastric cancer cells. Conclusions: Therefore, lncRNA PTCSC3 may serve as a biomarker for the treatment and prognosis of gastric cancer.

Real-world EGFR testing in patients with stage IIIB/IV non-small-cell lung cancer in North China: A multicenter, non-interventional study.

BACKGROUND: Before tyrosine kinase inhibitor (TKI) therapy can be administered in patients with advanced non-small cell lung cancer (NSCLC), EGFR mutation testing is required. However, few studies have evaluated the extent of EGFR testing in real-world practice in China. METHODS: A multicenter, observational study of EGFR testing in NSCLC patients in North China was conducted. Treatment-naïve patients or those with postoperative recurrent stage IIIB/IV NSCLC were enrolled. The primary objective was EGFR testing rate. Secondary objectives included EGFR mutation status, EGFR testing methods and specimens, factors associated with EGFR testing, and overall survival with or without EGFR testing. RESULTS: Overall, 2809 patients with stage IIIB/IV NSCLC were enrolled; 90.78% had adenocarcinoma. The EGFR screening rate was 42.54%. EGFR testing rates were higher in tumor samples obtained by lymph node puncture, and in patients with urban medical insurance, adenocarcinoma, non-smokers, or those located in developed cities (all P < 0.001). The EGFR mutation rate was 46.44%. The most commonly used specimens for EGFR testing were biopsy tumor samples (67.53%). PCR-based methods (72.05%), Sanger sequencing (5.36%), and Luminex liquid chip (5.10%) were the most frequently used testing platforms. Similar positive EGFR mutation rates were achieved with different platforms. TKI therapy was the first-line treatment administered to most EGFR-positive patients (56.22%), and chemotherapy in EGFR-negative patients (84.88%). Overall survival was higher in EGFR-tested than in untested patients (27.50 vs. 19.73 months; P = 0.007). CONCLUSION: Real-world EGFR testing rates for NSCLC in North China were relatively low because of clinical and social factors, including medical insurance coverage.

Three-year Follow-up on the Safety and Effectiveness of Rituximab Plus Chemotherapy as First-Line Treatment of Diffuse Large B-Cell Lymphoma and Follicular Lymphoma in Real-World Clinical Settings in China: A Prospective, Multicenter, Noninterventional Study.

BACKGROUND: Prospective real-life data on the safety and effectiveness of rituximab in Chinese patients with diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) are limited. This real-world study aimed to evaluate long-term safety and effectiveness outcomes of rituximab plus chemotherapy (R-chemo) as first-line treatment in Chinese patients with DLBCL or FL. Hepatitis B virus (HBV) reactivation management was also investigated. METHODS: A prospective, multicenter, single-arm, noninterventional study of previously untreated CD20-positive DLBCL or FL patients receiving first-line R-chemo treatment at 24 centers in China was conducted between January 17, 2011 and October 31, 2016. Enrolled patients underwent safety and effectiveness assessments after the last rituximab dose and were followed up for 3 years. Effectiveness endpoints included progression-free survival (PFS) and overall survival (OS). Safety endpoints were adverse events (AEs), serious AEs, drug-related AEs, and AEs of special interest. We also reported data on the incidence of HBV reactivation. RESULTS: In total, 283 previously untreated CD20-positive DLBCL and 31 FL patients from 24 centers were enrolled. Three-year PFS was 59% (95% confidence interval [CI]: 50-67%) for DLBCL patients and 46% (95% CI: 20-69%) for FL patients. For DLBCL patients, multivariate analyses showed that PFS was not associated with international prognostic index, tumor maximum diameter, HBV infection status, or number of rituximab treatment cycles, and OS was only associated with age >60 years (P < 0.05). R-chemo was well tolerated. The incidence of HBV reactivation in hepatitis B surface antigen (HBsAg)-positive and HBsAg-negative/hepatitis B core antibody-positive patients was 13% (3/24) and 4% (3/69), respectively. CONCLUSIONS: R-chemo is effective and safe in real-world clinical practice as first-line treatment for DLBCL and FL in China, and that HBV reactivation during R-chemo is manageable with preventive measures and treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01340443; https://clinicaltrials.gov/ct2/show/NCT01340443.

Identification of a progression-associated long non-coding RNA signature for predicting the prognosis of lung squamous cell carcinoma.

Long non-coding RNAs (lncRNAs) have been indicated to have prognostic roles in various cancer types. However, the association between lncRNAs and lung squamous cell carcinoma (LSCC) progression, and the prognostic value of lncRNAs as a marker for early detection of LSCC have not been systematically investigated. The present study performed a genome-wide comparative analysis in order to determine the expression profiles of 10,207 lncRNAs to investigate the expression patterns between patients with early stages of LSCC (stage I-II) and those with late-stage disease (stage III-IV). It was found that 114 lncRNAs were significantly differentially expressed between late- and early-stage LSCC and therefore associated with the progression of the malignancy. By focusing on progression-associated lncRNAs, eight lncRNAs were found to be significantly associated with overall survival of LSCC patients according to univariate Cox proportional hazards regression analysis. These eight prognostic lncRNAs were integrated into a progression-associated eight-lncRNA signature, which stratified patients into two groups with significantly different overall survival (median survival, 2.25 vs. 7.68 years; P=2.06×10-5). In addition, the prognostic value of the progression-associated eight-lncRNA signature was independent of known clinical factors. Functional analysis suggested that eight prognostic lncRNAs may be involved in adipocytokine signaling pathway and glycerophospholipid metabolism. Taken together, the progression-associated eight-lncRNA signature identified by our study not only represents a candidate prognostic biomarker for LSCC patients but also provides insight into the molecular mechanisms in the progression of LSCC.

Transforming growth factor ß-activated kinase 1 inhibitor suppresses the proliferation in triple-negative breast cancer through TGF-ß/TGFR pathway.

Breast cancer is one of the most invasive cancer types in female population. The functional activity of Transforming growth factor ß-activated kinase 1 (TAK1) in breast cancer progression increasingly attracts attention as it provides a potential target for antibreast cancer drug development. However, the fundamental role of TAK1 for triple-negative breast cancer (TNBC) progression and the effect of potential anti-TAK1 drug candidate needs to be further evaluated. Herein, we focused on the role of TAK1 in human breast cancer cells, and we hypothesized that the inhibition of TAK1 activation can repress the growth of human TNBC cells. We found that the TAK1 is robustly activated within cancer cell population of clinic-derived TNBC samples and the human breast cancer cell lines in culture. Furthermore, we determined the effect of 5Z-7-oxozeaenol (5Z-O), a TAK1-specific small molecule inhibitor, on proliferation of human TNBC cell line. 5Z-O treatment significantly suppressed the proliferation of human TNBC cells. Collectively, these demonstrate the role of TAK1 in human breast cancer and the antiproliferate effect of TAK1 inhibitor. Our study sets the stage for further research on TAK1 as a promising target for development of anti-TNBC drugs and therapeutic strategies.

Upregulation of circulating miR-21 is associated with poor prognosis of nasopharyngeal carcinoma.

MicroRNAs (miRNAs) have been demonstrated to be implicated in the pathogenesis of a number of human diseases including cancer. The aim of current study was to reveal the potential clinical significance of serum miR-21 in nasopharyngeal carcinoma (NPC). CCK8 assay was used to evaluate the effects of miR-21 overexpression/downregulation on the chemoresistance of NPC cells. Real-time PCR was performed to detect the expression level of serum miR-21 in NPC patients and healthy volunteers. Then clinical significance of serum miR-21 was further investigated. Our results showed that miR-21 overexpression could enhance the chemoresistance of NPC cells to cisplatin, and vice versa. In addition, serum miR-21 was significantly upregulated in NPC patients and enhanced serum miR-21 level was associated with poor prognosis of NPC. Furthermore, its level was much higher in NPC patients resistant to cisplatin based chemotherapy and could discriminate the patients in the responding group from the non-responding group with high accuracy. The proportions of patients that resistant to chemotherapy were higher in the high serum miR-21 group. Finally, Kaplan-Meier survival analysis showed that enhanced serum miR-21 was a poor indicator of both overall and disease free survival among the patients who received cisplatin based chemotherapy. Taken together, serum miR-21 might be employed as a potential biomarker for predicting the clinical outcome and chemoresistance of NPC patients.

Rituximab plus chemotherapy as first-line treatment in Chinese patients with diffuse large B-cell lymphoma in routine practice: a prospective, multicentre, non-interventional study.

BACKGROUND: The efficacy and safety of rituximab-based chemotherapy (R-chemo), the standard regimen for patients with diffuse large B-cell lymphoma (DLBCL), which is more common in Asia than in Western countries, are well confirmed in randomized controlled trials (RCTs). However, the safety and effectiveness of R-chemo in patients who are largely excluded from RCTs have not been well characterized. This real-world study investigated the safety and effectiveness of R-chemo as first-line treatment in Chinese patients with DLBCL. METHODS: Treatment-naive DLBCL patients who were CD20 positive and eligible to receive R-chemo were enrolled with no specific exclusion criteria. Data collected at baseline included age, gender, disease stage, international prognostic index (IPI), B symptoms, extranodal involvement, performance status, and medical history. In the present study, data on safety, treatment effectiveness, and HBV infection management were collected 120 days after the last R-chemo administration. RESULTS: Overall, R-chemo was well tolerated. The safety profile of R-chemo in patients with a history of heart or liver disease was well described without any additional unexpected safety concerns. The overall response rate (ORR) in the Chinese patients from this study was 94.2 % (complete response [CR], 55.0 %; CR unconfirmed [CRu] 18.2 %; and partial response [PR], 20.9 %). Compared to patients with no history of disease, the CR and PR rates of patients with a history of heart or liver disease were lower and higher, respectively; this tendency could be in part explained by treatment interruptions in patients with heart or liver diseases. HBsAg positivity and a maximum tumor diameter of ≥7.5 cm negatively correlated with CR + CRu, whereas age and HBsAg positivity negatively correlated with CR. CONCLUSIONS: This study further validated the safety and effectiveness of R-chemo in Chinese patients with DLBCL. Patients with a history of heart or liver disease may further benefit from R-chemo if preventive measures are taken to reduce hepatic and cardiovascular toxicity. In addition to IPI and tumor diameter, HBsAg positivity could also be a poor prognostic factor for CR in Chinese patients with DLBCL. TRIAL REGISTRATION: ClinicalTrials.gov # NCT01340443 , April 20, 2011.

SRPX2 Enhances the Epithelial-Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Cells.

Glioblastoma (GBM) is the most common and most aggressive central nervous system tumor in adults. Due to GBM cell invasiveness and resistance to chemotherapy, current medical interventions are not satisfactory, and the prognosis for GBM is poor. It is necessary to investigate the underlying mechanism of GBM metastasis and drug resistance so that more effective treatments can be developed for GBM patients. sushi repeat-containing protein, X-linked 2 (SRPX2) is a prognostic biomarker in many different cancer cell lines and is associated with poor prognosis in cancer patients. SRPX2 overexpression promotes interactions between tumor and endothelial cells, leading to tumor progression and metastasis. We hypothesize that SRPX2 also contributes to GBM chemotherapy resistance and metastasis. Our results revealed that GBM tumor samples from 42 patients expressed higher levels of SRPX2 than the control normal brain tissue samples. High-SRPX2 expression levels are correlated with poor prognosis in those patients, as well as resistance to temozolomide in cultured GBM cells. Up-regulating SRPX2 expression in cultured GBM cell lines facilitated invasiveness and migration of GBM cells, while down-regulating SRPX2 through RNA interference was inhibitory. These results suggest that SRPX2 plays an important role in GBM metastasis. Epithelial to mesenchymal transition (EMT) is one of the processes that facilitate GBM metastasis and resistance to chemotherapy. EMT marker expression was decreased in SRPX2 down-regulated GBM cells, and MAPK signaling pathway marker expression was also decreased when SRPX2 is knocked down in GBM-cultured cells. Blocking the MAPK signaling pathway inhibited GBM metastasis but did not inhibit cell invasion and migration in SRPX2 down-regulated cells. Our results indicate that SRPX2 facilitates GBM metastasis by enhancing the EMT process via the MAPK signaling pathway.

The complete mitochondrial genome sequence and mutations of the lung cancer model inbred rat strain (Muridae; Rattus).

We reported the complete mitochondrial genome sequencing of an important Lung cancer model inbred rat strain for the first time. The total length of the mitogenome was 16,312 bp. It harbored 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes and 1 non-coding control region. The mutation sites were analyzed by comparing with the reference BN strain.

[Clinical features of rituximab plus chemotherapy as first-line treatment in patients with diffuse large B-cell lymphoma].

OBJECTIVE: A prospective, multicenter and non-interventional prospective study was conducted to evaluate the clinical features of rituximab combined with chemotherapy (R-Chemo) as first-line treatment on newly diagnosed Chinese patients with diffuse large B-cell lymphoma (DLBCL). METHODS: This was a single arm, prospective, observational multicenter and phase IV clinical trial for 279 patients, who were newly diagnosed as CD20-positive DLBCL from 24 medical centers in China 2011 and 2012, no special exclusion criteria were used. All patients received rituximab based R-Chemo regimes, such as R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone) and other regimes as the first-line treatment. The treatment strategies were determined by physicians and patients without detailed description for treatment course, dose, interval time and examination. Clinical response and safety of all patients were investigated in 120 days after completion of last dose of rituximab. RESULTS: Of 279 patients, 258 with stage I-IV who received at least 1 cycle of rituximab treatment and completed at least one time of tumor assessment were enrolled into intention-to-treat analysis, including 148 male and 110 female. The median age of all patients was 57.2(12.8-88.4) years. ECOG performance statuses of 0 or 1 were observed in 91.1% of patients, international prognostic index levels in the low-risk and low-middle-risk groups in 76.4% of patients, the tumor diameters smaller than 7.5 cm in 69.0% of patients. All patients received 6 median cycles of R-Chemo treatment every 24.4 days. R-CHOP treatment was shown to improve the clinical response with overall response rates of 94.2%. Common adverse events included anemia, marrow failure, leukopenia, thrombocytopenia, digestive diseases, infection and liver toxicity. All adverse events are manageable. CONCLUSION: Non-interventional clinical trial of R-Chemo remains the standard first-line treatment for newly diagnosed patients with DLBCL in real clinical practice, which is consistent with international treatment recommendations for DLBCL patients. R-Chemo can provide the clinical evidence and benefit as the first-line standard treatment for Chinese patients with DLBCL.

The effect of biweekly CHOP and standard CHOP in different subgroups of diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma. Conventional chemotherapy (CHOP: cyclophosphamide, doxorubicin, vincristine, prednisone) seems unsatisfactory, so modifications of CHOP are used to improve the efficacy. DLBCL is a highly variable tumor, with different responses to therapy. The aim of this study is to explore the association between immunophenotype and treatment response. PATIENTS AND METHODS: We analyzed the expression of Bcl-6, CD10, and MUM1 in 130 cases of DLBCL using immunohistochemistry. The cases were subdivided into germinal center B-cell-like (GCB) and non-GCB subtypes, and were randomly assigned to receive either 6-8 cycles of CHOP every 2 weeks or standard CHOP every 3 weeks. RESULTS: After a median followup duration of 40 months, 3-year overall survival of biweekly CHOP was better than standard CHOP in the non-GCB group (58.3 vs. 38.6%, p < 0.05). However, the therapeutic effect of biweekly CHOP and standard CHOP was not different in the GCB group (64.8 vs. 57.5%, p > 0.05). CONCLUSIONS: Immunohistochemistry analysis of different subgroups is useful to find the suitable therapy. Biweekly CHOP showed higher efficacy than standard treatment in the non-GCB subgroup.