Molecular-Sieving Separation of Methanol/Benzene Azeotrope by a Flexible Metal-Organic Framework.

Separation of methanol/benzene azeotrope mixtures is very challenging not only by the conventional distillation technique but also by adsorbents. In this work, we design and synthesize a flexible Ca-based metal-organic framework MAF-58 consisting of cheap raw materials. MAF-58 shows selective methanol-induced pore-opening flexibility. Although the opened pores are large enough to accommodate benzene molecules, MAF-58 shows methanol/benzene molecular sieving with ultrahigh experimental selectivity, giving 5.1 mmol g-1 high-purity (99.99%+) methanol and 2.0 mmol g-1 high-purity (99.97%+) benzene in a single adsorption/desorption cycle. Computational simulations reveal that the preferentially adsorbed, coordinated methanol molecules act as the gating component to selectively block the diffusion of benzene, offering a new gating adsorption mechanism.

[Effect of Recombinant Human Thrombopoietin (rhTPO) on Long-term Hematopoietic Recovery in Mice with Acute Radiation Sickness and Relative Mechanism].

OBJECTIVE: To investigate the effect and relative mechanism of Recombinant Human Thrombopoietin (rhTPO) on long-term hematopoietic recovery in mice with acute radiation sickness. METHODS: Mice were intramuscularly injected with rhTPO (100 µg/kg) 2 hours after total body irradiation with 60Co γ-rays (6.5 Gy). Moreover, six months after irradiation, peripheral blood, hematopoietic stem cells (HSC) ratio, competitive transplantation survival rate and chimerization rate, senescence rate of c-kit+ HSC, and p16 and p38 mRNA expression of c-kit+ HSC were detected. RESULTS: Six months after 6.5 Gy γ-ray irradiation, there were no differences in peripheral blood white blood cells, red blood cells, platelets, neutrophils and bone marrow nucleated cells in normal group, irradiated group and rhTPO group (P>0.05). The proportion of hematopoietic stem cells and multipotent progenitor cells in mice of irradiated group was significantly decreased after irradiation (P<0.05), but there was no significant changes in rhTPO group (P>0.05). The counts of CFU-MK and BFU-E in irradiated group were significantly lower than that in normal group, and rhTPO group was higher than that of the irradiated group(P<0.05). The 70 day survival rate of recipient mice in normal group and rhTPO group was 100%, and all mice died in irradiation group. The senescence positive rates of c-kit+ HSC in normal group, irradiation group and rhTPO group were 6.11%, 9.54% and 6.01%, respectively (P<0.01). Compared with the normal group, the p16 and p38 mRNA expression of c-kit+ HSC in the irradiated mice were significantly increased (P<0.01), and it was markedly decreased after rhTPO administration (P<0.01). CONCLUSION: The hematopoietic function of mice is still decreased 6 months after 6.5 Gy γ-ray irradiation, suggesting that there may be long-term damage. High-dose administration of rhTPO in the treatment of acute radiation sickness can reduce the senescence of HSC through p38-p16 pathway and improve the long-term damage of hematopoietic function in mice with acute radiation sickness.

[Cell Cycle Arrest and Apoptosis Induced by Atovaquone in Non-Hodgkin's Lymphoma Raji Cells].

OBJECTIVE: To investigate the effect of atovaquone on the cell cycle and apoptosis of non-Hodgkin's lymphoma Raji cells, and clarify the related mechanisms. METHODS: MTT assay and trypan blue dye exclusion method were used to evaluate the effect of atovaquone on the proliferation of Raji cells. After the cells were stained by PI staining, the cell cycle distribution was detected by flow cytometry. Cell apoptosis was analyzed by Annexin V/PI double binding assay. The intracellular alterations of reactive oxygen species were detected by 2', 7'-dichlorofluorescein diacetate (DCFH-DA). The protein expression of cell cycle and apoptosis related molecules were detected by Western blot. RESULTS: Various concentrations of atovaquone (5-40 µmol/L) inhibited the growth of Raji cells in a concentration-dependent manner (r=0.951). The proliferation of Raji cells was significantly inhibited after treated by atovaquone (20 and 30 µmol/L) for 24, 48 and 72 h, which showed statistically different with that in the control group (P<0.01, P<0.001, P<0.001). G1 phase arrest (P<0.01, P<0.001) and apoptosis (P<0.01) of Raji cells was induced by atovaquone (20 and 30 µmol/L) significantly for 24 h and 48 h, respectively. The expression of p-JAK2 and p-STAT3(Y705) protein were down-regulated significantly induced by atovaquone (P<0.001, P<0.05). Furthermore, atovaquone treatment could induce the decreasing of antiapoptotic protein Mcl-1, Bcl-2, and Bcl-xl expression level (P<0.05) and increasing of cleaved caspase-3 protein expression level. In addition, atovaquone could also induce the down-regulation of c-Myc (P<0.001, P<0.01) and cell cycle related molecules Cyclin D1, CDK4, and CDK6 (P<0.01, P<0.05) protein expression. CONCLUSION: Atovaquone effectively inhibits cell proliferation and induces cell cycle arrest and apoptosis by suppression of STAT3 signaling pathway in Raji cells. It can be a potential therapeutic agent against non-Hodgkin's lymphoma.

[Therapeutic Effect of Single Intramuscular Administration of Recombinant Human Thrombopoietin on Rhesus Monkeys with Acute radiation Sickness].

OBJECTIVE: To confirm the therapeutic effect of recombinant human thrombopoietin (rhTPO) on rhesus monkeys irradiated with 5.0 Gy 60Co γ-ray, and provide experimental basis for clinical treatment of similar patients. METHODS: Fourteen adult rhesus monkeys were irradiated with 60Co γ-ray on both sides at the dose of 5.0 Gy (dose rate 69.2 cGy/min) to establish the acute radiation sickness model. The monkeys were divided into irradiation group (n=5), rhTPO 5 µg/kg group (n=4) and rhTPO 10 µg/kg group (n=5). Two hours after irradiation, the three groups of monkeys were injected with saline 0.1 ml/kg, rhTPO 5 µg/kg（0.1 ml/kg） and rhTPO 10 µg/kg(0.2 ml/kg), respectively. The general signs, survival, peripheral hemogram and serum biochemistry of rhesus monkeys were observed before and after irradiation, and the differences between rhTPO group and irradiation control group were compared. RESULTS: After total body irradiation with 5.0 Gy60Co γ-ray, rhesus monkeys successively showed fever, hemorrhage, sharp decrease of whole blood cell counts in peripheral blood and disorder of serum biochemical indexes. Compared with the irradiated control group, a single intramuscular injection of rhTPO 5 µg/kg or 10 µg/kg 2 hours after irradiation could improve the symptoms of fever and bleeding, increase the nadir of peripheral red blood cells and platelets counts, shorten the duration of hemocytopenia, and advance the time for blood cells to return to the pre-irradiation level. The serum biochemical results showed that rhTPO could improve the abnormality of serum biochemical indexes in rhesus monkeys induced by 5.0 Gy total body irradiation to some extent. Compared with the two administration groups, the therapeutic effect of rhTPO 10 µg/ kg was better. CONCLUSION: A single injection of rhTPO 5 µg/ kg or 10 µg/ kg 2 hours after irradiation can alleviate the injury of multilineage hematopoiesis and promote the recovery in monkeys irradiated by 5.0 Gy γ-ray. It also improves animal signs and has obvious therapeutic effect on acute radiation sickness.

Exosomal miR-625-3p secreted by cancer-associated fibroblasts in colorectal cancer promotes EMT and chemotherapeutic resistance by blocking the CELF2/WWOX pathway.

Migration, invasion, epithelial-mesenchymal transformation (EMT), and chemotherapeutic resistance are the leading causes of therapeutic failure in people with colorectal cancer (CRC). The migration of exosomal miRNA between cancer cells and the tumor microenvironment is directly associated with malignant behavior in cancer-associated fibroblasts (CAFs). In the context of earlier research, the purpose of the current study was to assess the role and potential mechanism of miR-625-3p released by CAFs in CRC cells. Exosomes were extracted and purified from CAFs conditioned medium by ultracentrifugation. Western blot, immunohistochemistry, CCK-8, transwell assay, H&E staining, Tunnel, real-time PCR, double luciferase assay, RNA-binding protein immunoprecipitation (RIP), and immunofluorescence double staining experiments were used to investigate the effects of CAFs-Exo and miR-625-3p on CRC cell invasion, migration, proliferation, EMT, chemotherapeutic resistance, and molecular mechanisms. The current results indicated that CAFs-Exo was directly internalized by CRC cells, and exosomal miR-625-3p derived from CAFs might promote migration, invasion, EMT and chemotherapeutic resistance in CRC cells by inhibiting the CELF2/WWOX pathway, providing a potential candidate for CRC prediction and treatment.

[Effect of Interleukin-6 Gene Deletion on Radiation-Induced Mouse Hematopoietic Injury and Relative Mechanism].

OBJECTIVE: To study the effect of interleukin-6 (IL-6) gene deletion on radiation-induced hematopoietic injury in mice and relative mechanism. METHODS: Before and after whole body 60Co γ-ray irradiation, it was analyzed and compared that the difference of peripheral hemogram, bone marrow hematopoietic stem and progenitor cells conts in IL-6 gene knockout (IL-6-/-) and wild-type (IL-6+/+) mice and serum IL-6 and G-CSF expression levels in above- mentioned mouse were detected. Moreover, 30 days survival rate of IL-6-/- and IL-6+/+ mice after 8.0 Gy γ-ray irradiation were analyzed. RESULTS: IL-6 levels in serum of IL-6+/+ and IL-6-/- mice were respectively (98.95±3.85) pg/ml and (18.36±5.61) pg/ml, which showed a significant statistical differences (P<0.001). There were no significant differences of peripheral blood cell counts and G-CSF level in serum between IL-6+/+ and IL-6-/- mice before irradiation (P>0.05). However, the number of leukocytes, neutrophils, lymphocytes, monocytes, platelets in peripheral blood and G-CSF level in serum of IL-6-/- mice were significantly decreased at 6 h after 8.0 Gy γ-ray irradiation compared with that of IL-6+/+ mice. On days 30 after 8.0 Gy γ-ray irradiation, the survival rate of IL-6+/+ and IL-6-/- mice was 62.5% and 12.5%, and the mean survival time of dead mice was 16.0±1.0 and 10.6±5.3 days, respectively. On days 14 after 6.5 Gy γ-ray irradiation, bone marrow nucleated cells in IL-6+/+ and IL-6-/- mice were respectively (10.0±1.2)×106 and (8.3±2.2)×106 per femur. Compared with IL-6+/+ mice, the proportion of Lin-Sca-1-c-kit+ (LK) in bone marrow of IL-6-/- mice had no significant change (P>0.05), but the proportion of Lin-Sca-1+c-kit+ (LSK) was significantly decreased (P<0.05). CONCLUSION: IL-6 plays an obvious role in regulating hematopoietic radiation injury, and IL-6 deficiency can inhibit the radiation-induced increase of endogenous G-CSF level in serum, aggravates the damage of mouse hematopoietic stem cells（HSC） and the reduction of mature blood cells in peripheral blood caused by ionizing irradiation, resulting in the shortening of the survival time and significant decrease of the survival rate of mice exposed to lethal dose radiation.

Inhibition of pyrimidine biosynthesis by strobilurin derivatives induces differentiation of acute myeloid leukemia cells.

All-trans retinoic acid-based differentiation therapies have succeeded in the treatment of acute promyelocytic leukemia, which is a rare subtype of acute myeloid leukemia (AML). Their clinical efficacy is negligible, however, for other subtypes of AML. Here, we showed that strobilurin derivatives, a well-established class of inhibitors of mitochondrial electron transport chain (ETC) complex III, possessed differentiation-inducing activity in AML cells. Impairment of mitochondrial ETC activity was involved in the differentiation effects of strobilurin derivatives, where reactive oxygen species generation appeared unnecessary. Conversely, strobilurin derivative-mediated differentiation was triggered by pyrimidine deficiency, which resulted from the inhibition of the mitochondrial-coupled dihydroorotate dehydrogenase enzyme. Moreover, strobilurin derivative-mediated pyrimidine depletion led to the activation of the Akt/mTOR cascade, which was required for the differentiation. Our study provided evidence that strobilurin derivatives may represent a novel class of differentiation-inducing agents for the treatment of AML.

Prognostic significance of preoperative systemic inflammatory biomarkers in patients with hepatocellular carcinoma after microwave ablation and establishment of a nomogram.

The study aimed to evaluate the prognostic significance of preoperative systemic inflammatory biomarkers including albumin to globulin ratio (AGR), neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), and platelet to lymphocyte ratio (PLR) and establish a nomogram in hepatocellular carcinoma (HCC) patients after microwave ablation (MWA). 192 HCC patients receiving MWA as initial therapy from the first ward of hepatobiliary surgery were classified as training cohort. Whereas, 84 patients from the second of hepatobiliary surgery were classified as validation cohort. Kaplan-Meier (KM) method and univariate analyses showed that AGR, NLR, LMR, and PLR were significantly associated with OS in the training cohort. Multivariate analysis including clinicopathologic features screened out independent predictors including ascites, tumor size, cancer embolus, AGR, and PLR. Based on those variables, a nomogram for predicting OS was established. The C-index was 0.794 in the training cohort and 0.772 in the validation cohort. Calibration plots identified the nomogram performed well with an ideal model. Compared with Barcelona Clinic Liver Cancer (BCLC) staging system and simple tumor size, the nomogram showed better predictive ability. Besides, the nomogram discovered the highest diagnostic accuracy in predicting postoperative clinical outcome than the combination of the present models with tumor size. In conclusion, the constructed nomogram could accurately predict individualized survival probability and might support clinician in individual treatment optimization and clinical decision-making.

Salt-inducible kinase inhibition sensitizes human acute myeloid leukemia cells to all-trans retinoic acid-induced differentiation.

Differentiation therapies with all-trans retinoic acid (ATRA) have been successful in treating acute promyelocytic leukemia, a rare subtype of acute myeloid leukemia (AML). However, their efficacy is limited in the case of other AML subtypes. Here, we show that the combination of ATRA with salt-inducible kinase (SIK) inhibition significantly enhances ATRA-mediated AML differentiation. SIK inhibition augmented the ability of ATRA to induce growth inhibition and G1 cell cycle arrest of AML cells. Moreover, combining ATRA and SIK inhibition synergistically activated the Akt signaling pathway but not the MAPK pathway. Pharmacological blockade of Akt activity suppressed the combination-induced differentiation, indicating an essential role for Akt in the action of the combination treatment. Taken together, our study reveals a novel role for SIK in the regulation of ATRA-mediated AML differentiation, implicating the combination of ATRA and SIK inhibition as a promising approach for future differentiation therapy.

Prognostic value of preoperative lymphocyte-to-monocyte ratio in gallbladder carcinoma patients and the establishment of a prognostic nomogram.

The purpose of this study was to investigate the potential prognostic value of preoperative lymphocyte-to-monocyte ratio (LMR) and establishment of a prognostic nomogram in post surgical patients with gallbladder carcinoma (GBC).Receiver operating characteristic curve analysis was performed to determine the optimal cut-off value of LMR. The correlation between preoperative LMR and overall survival (OS) was analyzed using univariate and multivariate Cox regression analyses. A relevant prognostic nomogram was established.Three hundred fifteen GBC patients were retrospectively enrolled. Based on receiver operating characteristic curve analysis, the optimal cutoff value of LMR was 2.685. Patients were categorized into high-LMR group (n = 143) or low-LMR group (n = 172). Low-LMR value was significantly associated with elderly age, advanced tumor, and the performance of a palliative cholecystectomy. The results of the univariate and multivariate analyses eliminated the degree of tumor differentiation, tumor-node-metastasis stages, surgery types, and LMR as independent predictors of OS. Based on those independent predictors, a predictive nomogram for OS was generated with an accuracy of 0.848.Based on our findings, the predictive nomogram should be included in the routine assessment of GBC patients.

Single-Dose Administration of Recombinant Human Thrombopoietin Mitigates Total Body Irradiation-Induced Hematopoietic System Injury in Mice and Nonhuman Primates.

PURPOSE: Recombinant human thrombopoietin (rhTPO) has been evaluated as a therapeutic intervention for radiation-induced myelosuppression. However, the immunogenicity induced by a repeated-dosing strategy raises concerns about the therapeutic use of rhTPO. In this study, single-dose administration of rhTPO was evaluated for efficacy in the hematopoietic response and survival effect on mice and nonhuman primates exposed to total body irradiation (TBI). METHODS AND MATERIALS: Survival of lethally (9.0 Gy) irradiated C57BL/6J male mice was observed for 30 days after irradiation. Hematologic evaluations were performed on C57BL/6J male mice given a sublethal dose of radiation (6.5 Gy). Furthermore, in sublethally irradiated mice, we performed bone marrow (BM) histologic evaluation and evaluated BM-derived clonogenic activity. Next, the proportion and number of hematopoietic stem cells (HSCs) were analyzed. Competitive repopulation experiments were conducted to assess the multilineage engraftment of irradiated HSCs after BM transplantation. Flow cytometry was used to evaluate DNA damage, cell apoptosis, and cell cycle stage in HSCs after irradiation. Finally, we evaluated the efficacy of a single dose of rhTPO administered after 7 Gy TBI in male and female rhesus monkeys. RESULTS: A single administration of rhTPO 2 hours after irradiation significantly mitigated TBI-induced death in mice. rhTPO promoted multilineage hematopoietic recovery, increasing peripheral blood cell counts, BM cellularity, and BM colony-forming ability. rhTPO administration led to an accelerated recovery of BM HSC frequency and multilineage engraftment after transplantation. rhTPO treatment reduced radiation-induced DNA damage and apoptosis and promoted HSC proliferation after TBI. Notably, a single administration of rhTPO significantly promoted multilineage hematopoietic recovery and improved survival in nonhuman primates after TBI. CONCLUSIONS: These findings indicate that early intervention with a single administration of rhTPO may represent a promising and effective radiomitigative strategy for victims of radiation disasters.

Expression of PD-L1 on Monocytes Is a Novel Predictor of Prognosis in Natural Killer/T-Cell Lymphoma.

Background: Natural killer/T-cell lymphoma (NKTCL) is a highly aggressive lymphoma with a dismal prognosis, and novel therapeutic targets are urgently needed. Programmed death-ligand 1 (PD-L1) has become a promising therapeutic target for various cancers, but most of the studies have focused on expression of PD-L1 on tumor cells. Expression of PD-L1 on tumor-infiltrating non-malignant cells, especially monocytes, has not been studied in NKTCL, and its prognostic value remains unknown. Materials and Methods: Expression of PD-L1 on tumor-infiltrating stromal cells was measured in NKTert and HS5 cells when cultured alone or co-cultured with NKTCL cell lines. Clinical samples were collected from 42 patients with newly diagnosed NKTCL. Expression of PD-L1 on monocytes was analyzed in patients' peripheral blood and tumor tissues using flow cytometry and immunofluorescent staining, respectively. Survival data were retrospectively collected and the prognostic significance of PD-L1 expression on monocytes was analyzed. Results: PD-L1 expression on tumor-infiltrating stromal cells was remarkably elevated when co-cultured with NKTCL cells. The percentage of PD-L1+ monocytes among all monocytes in peripheral blood was significantly higher in NKTCL patients than that in healthy individuals. Among NKTCL patients, percentage of PD-L1+ monocytes in blood positively correlated with that in tumor tissues. Patients with a higher percentage (≥78.2%) of PD-L1+ monocytes in blood or with a higher percentage (≥24.2%) of PD-L1+ monocytes in tumor tissues exhibited a significantly inferior survival, compared with their counterparts. A higher percentage of PD-L1+ monocytes in blood or tumor tissues was an independent adverse prognostic factor. Conclusions: Expression of PD-L1 on monocytes is up-regulated and has significant prognostic value in patients with NKTCL.

Characteristics, Prognostic Factors, and Survival of Patients with NK/T-Cell Lymphoma of Non-upper Aerodigestive Tract: A 17-Year Single-Center Experience.

PURPOSE: The extranodal natural killer (NK)/T-cell lymphoma (NKTCL) of non-upper aerodigestive tract (NUAT) was found to have clinical heterogeneity compared with NKTCL of the upper aerodigestive tract (UAT) in small scale studies. We conducted this study in a much larger cohort to analyze the clinical characteristics, prognostic factors, treatment modality, and clinical outcomes of patients with NUAT-NKTCL. MATERIALS AND METHODS: From January 2001 to December 2017, a total of 757 NKTCL patients were identified and included in this study, including 92 NUAT-NKTCL patients (12.2%) and 665 UAT-NKTCL patients (87.8%). RESULTS: NUAT-NKTCL patients had relatively poorer performance status, more unfavorable prognostic factors, and more advanced stage, compared with UAT-NKTCL patients. The 5-year overall survival (OS) was 34.7% for NUAT-NKTCL, which was significantly worse than UAT-NKTCL (64.2%, p<0.001). The median OS duration was 30.9 months for NUAT-NKTCL. Multivariate analysis showed that presence with B symptoms and elevated serum lactate dehydrogenase independently predicted worse OS. International prognostic index score and prognostic index of natural killer lymphoma score still had prognostic values in NUAT-NKTCL, while the Ann Arbor system could not accurately predict the OS. CONCLUSION: NUAT-NKTCL is a distinctive subtype of NKTCL in many aspects. Patients with NUAT-NKTCL have relatively poorer performance status, more unfavorable prognostic factors, more advanced stage, and poorer prognosis.

High-dose Methotrexate plus temozolomide with or without rituximab in patients with untreated primary central nervous system lymphoma: A retrospective study from China.

The purpose of this retrospective study was to compare the efficacy and toxicity of high-dose methotrexate plus temozolomide (MT regimen) and rituximab plus MT (RMT regimen) in patients with untreated primary central nervous system lymphoma (PCNSL). A total of 62 patients with untreated PCNSL were enrolled between January 2005 and December 2015, with the median age of 53.5 years (range 29-77).In this study, 32 patients received RMT as induction therapy, and 30 received MT. Objective responses were noted in 93.7% of the patients in the RMT group and in 69.0% of the patients in the MT group (P = 0.018), while complete responses were noted in 53.2% of the patients in the RMT group and 27.6% of the patients in the MT group (P < 0.001). The 2- and 5-year PFS rates were 81.3% and 53.3%, respectively, for the RMT group and 46.5% and 29.1%, respectively, for the MT group (P = 0.019). The 2- and 5-year overall survival (OS) rates were 82.3% and 82.3%, respectively, for the RMT group and 65.7% and 50.0%, respectively, for the MT group (P = 0.015). Multivariate analyses showed that therapeutic regimen (RMT vs MT) was an independent prognostic factor for PFS and OS. Our encouraging results suggest that the RMT regimen may be a feasible and safe therapeutic approach for first-line treatment of PCNSL.

Mutation Profiling of Malignant Lymphoma by Next-Generation Sequencing of Circulating Cell-Free DNA.

Background: Malignant lymphomas are a group of distinct lymphoid neoplasms, exhibiting marked diversity in biological behaviors and clinical outcomes. Liquid biopsy, such as circulating cell-free DNA (cfDNA), has recently been attempted to be used for mutation profiling of lymphomas using next-generation sequencing (NGS). However, only limited data about cfDNA are restricted in Hodgkin's lymphoma and B cell lymphoma, and there is no report in the T cell lymphoma so far. Patient and Methods: Medical records of a total of 50 lymphoma patients were retrospectively reviewed, and cfDNA samples were analyzed by capture-based NGS targeting 390 lymphoma- and cancer- relevant genes. We sought to explore the clinical utility of cfDNA in establishing the mutation profiles of different lymphoma subtypes and analyze the correlation between cfDNA concentration and other clinical indices such as serum LDH and IPI. Results: Somatic alterations were identified in cfDNA samples with a median of 64 variants per sample. The concentration of cfDNA in the plasma was found to be significantly correlated with the clinical indices in diffuse large B cell lymphoma (DLBCL). The genetic heterogeneity of different lymphoma subtypes was clearly observed in cfDNAs from germinal center B-cell (GCB) DLBCL, non-GCB DLBCL and natural killer/T-cell lymphoma (NKTCL), confirming that distinct molecular mechanisms are involved in the pathogenesis of different lymphomas. Conclusion: Our findings demonstrate that NGS-based cfDNA mutation profiling reveals genetic heterogeneity across lymphoma subtypes, with potential implications for the discovery of therapeutic targets, the exploration of genome evolution and the development of risk-adapted treatment.

The role of plasma miRNAs in the diagnosis of pulmonary nodules.

BACKGROUND: In this study, we aimed to assess the clinical utility of detection of plasma microRNAs (miRNAs) in the diagnosis of pulmonary nodules. METHODS: Fifty-seven patients with pulmonary nodules who had undergone surgery were enrolled in our study from July 2016 to July 2017 at Sun Yat-sen University Cancer Center. We measured the expression levels of 12 miRNAs (miRNA-17, -146a, -200b, -182, -155, -221, -205, -126, -7, -21, -145, and miRNA-210) in plasma samples of 57 patients, including 15 benign pulmonary nodules patients and 42 malignant pulmonary nodules patients. The levels of these miRNAs were detected by Real-time quantitative polymerase chain reaction (RT-PCR). The receiver operating characteristic (ROC) curve was used to assess the diagnostic performance of plasma miRNAs for non-small cell lung cancer (NSCLC). RESULTS: The expression levels of plasma miRNA-17, -146a, -200b, -182, -155, -221, -205, -126, -7, -21, -145, and miRNA-210 are not associated with gender, age, pTNM stage, differentiation grade. The levels of miRNA-17, -146a, -200b, -182, -221, -205, -7, -21, -145, and miRNA-210 in NSCLC patients are significantly higher than those in benign pulmonary nodules patients (P<0.05). However, there are no significant differences for the expression levels of miRNA-155 and miRNA-126. For diagnosing NSCLC, the sensitivity and specificity was 66.7% and 80.0% for miRNA-17, 54.8% and 86.7% for miRNA-146a, 64.3% and 86.7% for miRNA-200b, 83.3% and 73.3% for miRNA-182, 54.8% and 80.0% for miRNA-221, 73.8% and 80.0% for miRNA-205, 78.6% and 73.3% for miRNA-7, 78.6% and 60.0% for miRNA-21, 78.6% and 73.3% for miRNA-145, 76.2% and 73.3% for miRNA-210. CONCLUSIONS: Plasma miRNAs (miRNA-17, -146a, -200b, -182, -221, -205, -7, -21, -145, and miRNA-210) have relatively high sensitivity and specificity for the diagnosis of NSCLC. These plasma miRNAs may be the potential biomarkers for early diagnosis of lung cancer.

Chimeric antigen receptor-engineered T-cell therapy for liver cancer.

BACKGROUND: Chimeric antigen receptor-engineered T-cell (CAR-T) therapy is a newly developed immunotherapy used in the treatment of cancers. Because CAR-T therapy has shown great success in treating CD19-positive hematological malignancies, its application has been explored in the treatment of solid tumors, such as liver cancer. In this review, we discuss the immune characteristics of liver cancer, the obstacles encountered during the application of CAR-T therapy, and preclinical and clinical progress in the use of CAR-T therapy in patients with liver cancer. DATA SOURCES: The data on CAR-T therapy related to liver cancers were collected by searching PubMed and the Web of Science databases prior to December 2017 with the keywords "chimeric antigen receptor", "CAR-T", "liver cancer", "hepatocellular carcinoma", and "solid tumor". Additional articles were identified by manual search of references found in the primary articles. The data for clinical trials were collected by searching ClinicalTrials.gov. RESULTS: The liver has a tolerogenic nature in the intrahepatic milieu and its tumor microenvironment significantly affects tumor progression. The obstacles that reduce the efficacy of CAR-T therapy in solid tumors include a lack of specific tumor antigens, limited trafficking and penetration of CAR-T cells to tumor sites, and an immunosuppressive tumor microenvironment. To overcome these obstacles, several strategies have emerged. In addition, several strategies have been developed to manage the side effects of CAR-T, including enhancing the selectivity of CARs and controlling CAR-T activity. To date, no clinical trials of CAR-T therapy against HCC have been completed. However, preclinical studies in vitro and in vivo have shown potent antitumor efficacy. Glypican-3, mucin-1, epithelial cell adhesion molecule, carcinoembryonic antigen, and other targets are currently being studied. CONCLUSIONS: The application of CAR-T therapy for liver cancer is just beginning to be explored and more research is needed. However, we are optimistic that CAR-T therapy will offer a new approach for the treatment of liver cancers in the future.

Unexpected link between insect innexins and apoptosis of HeLa cells.

Little is known about how mammalian cells respond to the expression of innexins (Inxs), which are known to mediate cell-to-cell communication that causes apoptosis in the cells of the insect Spodoptera litura. The mammalian expression system, p3xFLAG tag protein, containing the CMV promoter, allowed us to construct two C-terminally elongated innexins (Cte-Inxs), SpliInx2 (Inx2-FLAG), and SpliInx3 (Inx3-FLAG), which were predicted to have the same secondary topological structures as the native SpliInx2 and SpliInx3. Here, we found that only the mRNAs of the two Cte-Inxs were expressed under the control of the CMV promoter in HeLa cells. Unexpectedly, mRNA expression of the two Cte-Inxs enhanced apoptosis of HeLa cells. The two Cte-Inx mRNAs were associated with a significant decrease in Akt phosphorylation in HeLa cells undergoing apoptosis. Furthermore, Inx3-FLAG mRNA expression in nonapoptotic HCT116 cells was also associated with a significant decrease in the levels of phosphorylated Akt. Intriguingly, expression of the mRNAs of the two Cte-Inxs did not activate caspase 3, but it markedly reduced Bid levels in HeLa cells undergoing apoptosis. These results suggest that mRNA expression of the two Cte-Inxs may activate a Bid-dependent apoptotic pathway in HeLa cells. Our study demonstrates that invertebrate gap junction mRNAs can function in vertebrate cancer cells as tumor suppressors.

Effect of Huaier granule on recurrence after curative resection of HCC: a multicentre, randomised clinical trial.

OBJECTIVE: There is little evidence that adjuvant therapy after radical surgical resection of hepatocellular carcinoma (HCC) improves recurrence-free survival (RFS) or overall survival (OS). We conducted a multicentre, randomised, controlled, phase IV trial evaluating the benefit of an aqueous extract of Trametes robinophila Murr (Huaier granule) to address this unmet need. DESIGN AND RESULTS: A total of 1044 patients were randomised in 2:1 ratio to receive either Huaier or no further treatment (controls) for a maximum of 96 weeks. The primary endpoint was RFS. Secondary endpoints included OS and tumour extrahepatic recurrence rate (ERR). The Huaier (n=686) and control groups (n=316) had a mean RFS of 75.5 weeks and 68.5 weeks, respectively (HR 0.67; 95% CI 0.55 to 0.81). The difference in the RFS rate between Huaier and control groups was 62.39% and 49.05% (95% CI 6.74 to 19.94; p=0.0001); this led to an OS rate in the Huaier and control groups of 95.19% and 91.46%, respectively (95% CI 0.26 to 7.21; p=0.0207). The tumour ERR between Huaier and control groups was 8.60% and 13.61% (95% CI -12.59 to -2.50; p=0.0018), respectively. CONCLUSIONS: This is the first nationwide multicentre study, involving 39 centres and 1044 patients, to prove the effectiveness of Huaier granule as adjuvant therapy for HCC after curative liver resection. It demonstrated a significant prolongation of RFS and reduced extrahepatic recurrence in Huaier group. TRIAL REGISTRATION: NCT01770431; Post-results.