CycC1;1 negatively modulates ABA signaling by interacting with and inhibiting ABI5 during seed germination.

Regulation of seed germination is important for plant survival and propagation. ABSCISIC ACID (ABA) INSENSITIVE5 (ABI5), the central transcription factor in the ABA signaling pathway, plays a fundamental role in the regulation of ABA-responsive gene expression during seed germination; however, how ABI5 transcriptional activation activity is regulated remains to be elucidated. Here, we report that C-type Cyclin1;1 (CycC1;1) is an ABI5-interacting partner affecting the ABA response and seed germination in Arabidopsis (Arabidopsis thaliana). The CycC1;1 loss-of-function mutant is hypersensitive to ABA, and this phenotype was rescued by mutation of ABI5. Moreover, CycC1;1 suppresses ABI5 transcriptional activation activity for ABI5-targeted genes including ABI5 itself by occupying their promoters and disrupting RNA polymerase II recruitment; thus the cycc1;1 mutant shows increased expression of ABI5 and genes downstream of ABI5. Furthermore, ABA reduces the interaction between CycC1;1 and ABI5, while phospho-mimic but not phospho-dead mutation of serine-42 in ABI5 abolishes CycC1;1 interaction with ABI5 and relieves CycC1;1 inhibition of ABI5-mediated transcriptional activation of downstream target genes. Together, our study illustrates that CycC1;1 negatively modulates the ABA response by interacting with and inhibiting ABI5, while ABA relieves the CycC1;1 interaction with and inhibition of ABI5 to activate ABI5 activity for the ABA response, thereby inhibiting seed germination.

Massoia Lactone Displays Strong Antifungal Property Against Many Crop Pathogens and Its Potential Application.

Massoia lactone could be released from liamocins produced by Aureobasidium melanogenum M39. The obtained Massoia lactone was very stable and highly active against many fungal crop pathogens which cause many plant diseases and food unsafety. Massoia lactone treatment not only could effectively inhibit their hyphal growth and spore germination, but also caused pore formation in cell membrane, reduction of ergosterol content, rise in intracellular ROS levels, and leakage of intracellular components, consequently leading to cellular necrosis and cell death. The direct contact of Massoia lactone with Fusarium graminearum spores could stop the development of Fusarium head blight symptom in the diseased wheats. Therefore, Massoia lactone could be a promising candidate for development as an effective and green bio-fungicide because of its high anti-fungal activity and the multiplicity of mode of its action.

Effect of BMI on blood value of patients on HCG day with IUI treatment.

BACKGROUND: This study aims to analyze the effect of the body mass index (BMI) on E2, P and LH values in females who received intrauterine insemination (IUI) treatment on human chorionic gonadotropin (HCG) day. METHODS: A total of 2319 cycles of IUI-assisted pregnancy treatment were selected in our hospital. Based on the BMI, female infertility patients are divided into three groups: normal weight group, overweight and obese group. RESULTS: For patients with natural cycles and ≤ 35 years old, there were 440, 178 and 197 cases in the three groups, respectively. For patients with natural cycles and > 35 years old, there were 90, 83 and 81 cycles in the three groups, respectively. For patients with induced ovulation cycle and ≤ 35 years old, there were 425, 203 and 516 cases in the three groups, respectively. For patients with induced ovulation cycle and > 35 years old, there were 26, 26 and 54 cases in the three groups, respectively. CONCLUSION: When a patient is ≤35 years old, the BMI affects the E2, LH and P values on the day of artificial insemination. However, the BMI is negatively correlated with E2, LH and P in IUI on HCG day. After controlling for age and assisted pregnancy, the correlation analysis revealed that the BMI is negatively correlated with hormone E2 and LH. The higher the BMI was, the lower the levels of hormones E2, LH and P became. However, in the present study, the BMI did not significantly improve the clinical pregnancy rate of patients who received IUI.

Efficacy and adverse events of five targeted agents in the treatment of advanced or metastatic non-small-cell lung cancer: A network meta-analysis of nine eligible randomized controlled trials involving 5,059 patients.

Recently, targeted agents were reported to improve overall survival, progression-free survival (PFS), response rate, and quality of life compared with cytotoxic chemotherapies, which provides hope for the treatment of non-small-cell lung cancer (NSCLC). The network meta-analysis is applied to compare the efficacies and adverse events of five targeted agents (erlotinib, gefitinib, vandetanib, dacomitinib, and icotinib) for advanced or metastatic NSCLC. Nine eligible randomized controlled trials from PubMed and Cochrane Library database were included. Weighted mean difference, odds ratio, and surface under the cumulative ranking curve (SUCRA) values were evaluated for the efficacy and adverse events of the five targeted agents in the treatment of NSCLC. With regard to efficacy, the overall response rate (ORR) of advanced or metastatic NSCLC patients treated with gefitinib was relatively higher than those treated with placebo. Compared with patients treated with placebo, the disease control rate (DCR) of patients treated with erlotinib and with gefitinib was relatively higher. Furthermore, in terms of PFS and DCR, the SUCRA value of icotinib was the highest among the five targeted drugs. With regard to ORR, the SUCRA value of gefitinib was the highest among the five targeted drugs. In terms of fatigue, rash, and cough, erlotinib had the lowest SUCRA value, whereas vandetanib exhibited the lowest SUCRA value in terms of diarrhea. Our study suggests that the efficacies of gefitinib and icotinib for advanced or metastatic NSCLC were comparatively better, whereas the toxicities of erlotinib and vandetanib were relatively greater.

Analgesic effects of microRNA-129-5p against bone cancer pain through the EphB1/EphrinB2 signaling pathway in mice.

The study aims to investigate the analgesic effects of microRNA-129-5p (miR-129-5p) on bone cancer pain (BCP) by targeting Eph receptor B1 (EphB1) through the EphB1/EphrinB2 signaling pathway. BCP mice models were established, and C3H/HeJ female mice were classified into the normal, blank, negative control (NC), miR-129-5p mimics, miR-129-5p inhibitors, EphB1 knockout (KO), and miR-129-5p inhibitors + EphB1 KO groups. Quantitative reverse transcription polymerase chain reaction and Western blot analysis were used to evaluate the miR-129-5p expression, and messenger RNA (mRNA) and protein expressions of EphB1, p-EphB1, EphrinB2, and p-EphrinB2. EphB1 and EphrinB2 were highly activated in the tibias of BCP mice 7 days after the operation. EphB1 is a target gene of miR-129-5p. The mechanical withdrawal threshold increased in the miR-129-5p mimics, EphB1 KO and miR-129-5p inhibitors + EphB1 KO groups, but decreased in the miR-129-5p inhibitors group. Compared with the blank and the NC groups, the expression of miR-129-5p was significantly increased in the miR-129-5p mimics group, and the mRNA and protein expressions of EphrinB2, p-EphrinB2, EphB1, and p-EphB1 were significantly decreased, while in the miR-129-5p inhibitors group, the results were opposite (all P < 0.05); the mRNA and protein expressions of EphrinB2, p-EphrinB2, EphB1, and p-EphB1 were significantly decreased in the EphB1 KO group (all P < 0.05); the expression of miR-129-5p was significantly decreased in the miR-129-5p inhibitors + EphB1 KO group ( P < 0.05), while the mRNA and protein expressions of EphrinB2 and p-EphrinB2 were not significantly different ( P > 0.05). The results indicated that upregulated miR-129-5p alleviate BCP via downregulation of the EphB1/EphrinB2 signaling pathway.

Efficacy of different chemotherapy regimens in treatment of advanced or metastatic pancreatic cancer: A network meta-analysis.

We performed a network meta-analysis (NMA) to compare the short- and long-term efficacy of Gemcitabine, Gemcitabine + S-1 (tegafur), Gemcitabine + nab-paclitaxel, Gemcitabine + Capecitabine, Gemcitabine + Cisplatin, FOLFIRINOX (oxaliplatin + irinotecan + fluorouracil + leucovorin), Gemcitabine + oxaliplatin, Gemcitabine + irinotecan, Gemcitabine + Exatecan, Gemcitabine + pemetrexed, Gemcitabine + 5-FU, and S-1 in treating advanced or metastatic pancreatic cancer (PC). The odds radios (OR) or weighted mean difference (WMD) and surface under the cumulative ranking curves (SUCRA) were evaluated by a combination of direct evidence and indirect evidence. In total twenty studies were included in this paper. For short-term efficacy, the overall response rate (ORR) was lower for patients treated with Gemcitabine compared with Gemcitabine + S-1, Gemcitabine + Cisplatin, Gemcitabine + irinotecan and S-1. The ORR for FOLFIRINOX was higher compared with Gemcitabine, Gemcitabine + Capecitabine and Gemcitabine + Cisplatin. The disease control rate (DCR) for Gemcitabine was lower compared with Gemcitabine + S-1, Gemcitabine + Cisplatin, and FOLFIRINOX. For long-term efficacy, the 12-month overall survival (OS) rate for FOLFIRINOX was higher compared with Gemcitabine, Gemcitabine + Capecitabine, Gemcitabine + Cisplatin, Gemcitabine + irinotecan, Gemcitabine + Exatecan, and Gemcitabine + pemetrexed. The SUCRA revealed that FOLFIRINOX was relatively better in both short- and long-term efficacy, while Gemcitabine was relatively poorer. In both short- and long-term efficacy, FOLFIRINOX had the best short- and long-term efficacy among the 12 chemotherapy regimens while efficacy of Gemcitabine was relatively poorer in the treatment of advanced or metastatic PC.

Evaluation of Prediction of Polymorphisms of DNA Repair Genes on the Efficacy of Platinum-Based Chemotherapy in Patients With Non-Small Cell Lung Cancer: A Network Meta-Analysis.

This network meta-analysis (NMA) was conducted to compare the predictive value of 14 SNPs in eight DNA repair genes on the efficacy of platinum-based chemotherapy in patients with non-small cell lung cancer (NSCLC). These included ERCC1 (rs11615, rs3212986, rs3212948), XRCC1 (rs25487, rs25489, rs1799782), XPD (rs13181, rs1799793), XPG (rs1047768, rs17655), XPA (rs1800975), XRCC3 (rs861539), APE1 (rs3136820), and RRM1 (rs1042858). The PubMed and Cochrane library databases were reviewed from their inception to February 2017 and studies which met our inclusion criteria were included in our investigation. This network meta-analysis combines direct and indirect evidence to assess the predictive value of 14 SNPs in eight DNA repair genes on the efficacy of platinum-based chemotherapy in NSCLC. We evaluated the predictive value through the use of the odd ratios (OR) and drawing surface under the cumulative ranking curves (SUCRA). A total of 26 eligible cohort studies were enrolled in this NMA. The pairwise meta-analysis indicated that in terms of overall response ratio (ORR), ERCC1 (rs11615), XRCC1 (rs25487, rs1799782), and XPD (rs13181) polymorphisms are associated with the efficacy of platinum-based chemotherapy in NSCLC. The result of this NMA suggests that there is no significant difference in predictive value of 8 DNA repair genes on the efficacy of platinum-based chemotherapy in NSCLC patients. The rank of SUCRA values of the 14 SNPs in the eight DNA repair genes were: XPD (rs1799793)→ERCC1 (rs3212986)→XPA(rs1800975)→ERCC1(rs3212948)→XRCC1(rs25487)→XRCC3(rs861539)→APE1(rs3136820)→ERCC1(rs11615)→XRCC1(rs1799782)→RRM1(rs1042858)→XPD(rs13181)→XPG (rs1047768)→XPG(rs17655)→XRCC1(rs25489). ERCC1(rs11615), XRCC1(rs25487, rs1799782) and XPD(rs13181) polymorphisms were better predictors in evaluating the efficacy of platinum-based chemotherapy in NSCLC patients. J. Cell. Biochem. 118: 4782-4791, 2017. © 2017 Wiley Periodicals, Inc.

Percutaneous Balloon Kyphoplasty in Treatment of Painful Osteoporotic Occult Vertebral Fracture: A Retrospective Study of 89 Cases.

BACKGROUND The definition of a vertebral fracture is usually based on the presence of a deformation of the vertebral body and this can be misleading in the presence of a fracture without radiologic collapse with the definition of occult osteoporotic vertebral fractures (OOVFs). STIR sequence of MRI images showing hyperintensity signal was the most confirmative screening examination used to determine the presence of painful OOVFs. To date, clinical management of OOVFs has been rarely discussed. MATERIAL AND METHODS Between 2011 and 2013, 89 patients suffering from painful OOVFs underwent 142 percutaneous balloon kyphoplasty (PKP) procedures. Outcome data (mean variation of anterior and middle vertebral body height, visual analog scale [VAS] scores, Oswestry Disability Index [ODI] scores, and SF-36 scores) were recorded preoperatively, postoperatively, and at 1 month, 6 months, and 2 year after treatment, to evaluate the results. RESULTS We successfully treated 89 patients (142 vertebral bodies) with PKP. Cement leakages were observed in 12 (8.45%) treated vertebral bodies and there were 5 new adjacent vertebral fractures during the follow-up period. The mean variation of anterior and middle vertebral body height changed from 96.5±3.4% preoperatively to 97.2±2.5% postoperatively (p>0.05) and from 96.3±2.8% preoperatively to 97.9±3.1% postoperatively (p>0.05), respectively. The mean VAS scores were reduced significantly from pre-surgery to post-surgery (8.3±1.2 to 2.9±0.7; p<0.05), as was the ODI score (76.4±12.5 to 26.7±5.6; p<0.05). The SF-36 scores, including Bodily Pain (BF), Vitality (VT), Physical Function (PF), and Social Functioning (SF), all showed notable improvement (P<0.05). These variations were maintained during the 2-year follow-up period. CONCLUSIONS PKP is a safe and effective method in the treatment of painful OOVFs.

[Dynamic changes of pH2AX expression in the reversibility of mouse testicular reproductive function impaired by single heat stress].

OBJECTIVE: To investigate the role of pH2AX in the reversibility of mouse testicular reproductive function impaired by single heat stress. METHODS: Twenty-four C57 male mice were randomly divided into heat stress and control groups and immersed in water at 43℃ and 25℃, respectively, for 15 minutes. At 1, 7, and 14 days of heat exposure, all the mice were sacrificed and their testis tissues collected for determining the apoptosis of the germ cells by TUNEL and measuring the expression level of the pH2AX protein by immunohistochemistry and Western blot. RESULTS: The highest percentage of apoptotic cells were found in the seminiferous tubules of the mice in the heat stress group on the 1st day of the exposure and almost no apoptosis was observed at 7 and 14 days. The pH2AX protein was expressed in the nuclei of the basement membrane of adjacent seminiferous tubules. Compared with the control group, the expression of pH2AX was significantly increased on the 1st day of exposure (0.47 ± 0.02 vs 1.61 ± 0.04, P <0.01), then decreased at 7 days (0.85 ± 0.03) in comparison with that on the 1st day (P <0.01), and again elevated at 14 days (1.72 ± 0.02) as compared with either those at 1 and 7 days (P <0.01) or that of the control (P <0.01). CONCLUSIONS: Heat stress causes dynamic changes of the pH2AX expression in the testis of the mouse, which are associated with heat stress-induced proliferation and division of the testicular spermatogenic cells.

Prevalence and Predictors of Hypertension in the Labor Force Population in China: Results from a Cross-sectional Survey in Xinjiang Uygur Autonomous Region.

The objective of this study was to examine the prevalence of hypertension and identify its contributory factors in the labor force population in Karamay. A total of 2819 adults (55.9% male adults) were interviewed and examined. The overall crude prevalence of hypertension was 32.4%. Among 914 hypertensive patients, 34.8% were aware of their diagnosis, 22.1% received treatment, and 5.6% achieved blood pressure control. Hypertension was significantly correlated with age, overweight/obesity, central obesity, diabetes, and dyslipidemia in both men and women. In addition, less education, alcohol consumption, and less walking were risk factors for men. Effective hypertension prevention and control programs are urgently needed to decrease the burden of hypertension in this region.

Increased autophagy sustains the survival and pro-tumourigenic effects of neutrophils in human hepatocellular carcinoma.

BACKGROUND & AIMS: Neutrophils are common cells of the inflammatory infiltrate and are predominantly enriched in many cancers. We recently found that neutrophils are accumulated in human hepatocellular carcinoma (HCC), where they promote disease progression by releasing matrix metalloproteinase-9 (MMP9). The underlying mechanisms, however, that allow tumour microenvironments to educate neutrophils are largely unknown. METHODS: Neutrophils were purified from HCC patients and healthy donors. Immunohistochemistry and immunoblotting were used for the evaluation of autophagy in neutrophils. The regulation and function of increased neutrophil autophagy were assessed by both in vitro and ex vivo studies. RESULTS: Most neutrophils in HCC intratumoural regions, in contrast to those located in the paired non-tumoural areas and within tumour vessels, substantially expressed autophagy-specific protein LC3. Soluble factors derived from hepatoma, including hyaluronan fragments, triggered a considerable increase of functional LC3 and autophagosomes in neutrophils, but this was unrelated to the deactivation of mTOR signalling. Inhibiting the activation of Erk1/2, p38, and NF-κB signals could significantly attenuate such tumour-elicited autophagy. These neutrophils, undergoing autophagy, exhibited long-lived phenotypes with retained Mcl-1 and significantly more intact mitochondria as well as low cleaved caspase-3, which could be abolished by inhibiting the initiation of autophagy. Moreover, increased neutrophil autophagy also correlated with sustained production of pro-metastatic oncostatin M and MMP9 and advanced migration of cancer cells. CONCLUSIONS: Increased autophagy in neutrophils may represent a novel mechanism that links the innate response to neoplastic progression in humans. Studying the mechanisms that selectively modulate neutrophil autophagy will provide a novel strategy for anti-cancer therapy.

Tribenuron-methyl resistance and mutation diversity of Pro197 in flixweed (Descurainia Sophia L.) accessions from China.

Flixweed (Descurainia Sophia L.) is a problematic weed in winter wheat fields in China, which causes great loss of wheat yield. A total of 46 flixweed accessions from winter wheat-planting areas were collected and used for the survey of resistance to tribenuron-methyl and Pro197 mutation diversity. According to the "R" resistance rating system, 16 flixweed accessions have evolved resistance to tribenuron-methyl, 13 accessions have high risk of developing resistance to this herbicide and 17 accessions are susceptible. The mutation of Pro197 codon (CCT) changed proline (Pro) into leucine (Leu) (homozygous, RR), serine (Ser, RR), histidine (His, RR), threonine (Thr, RR), Pro/Leu (heterozygous, RS), Pro/Ser (RS), Pro/His, Pro/Thr (RS) and Pro/Tyr (RS). Among these amino acid changes, a Pro197-Pro/Tyr (heterozygous, RS) substitution caused by the mutation of two successive nucleotides was identified for the first time in resistant weed species. In addition, the Pro197-His and Pro197-Pro/His mutations have not been reported previously in flixweed. Finally, a CPAS marker was developed to identify flixweed plants with or without Pro197 mutation.

[Optimization on alcohol precipitation techniques of Liuwei Dihuang decoction by response surface methodology].

The theoretical basis of the alcohol precipitation process control was provided, the alcohol precipitation was optimized and the relationship equation was got. The monod glycoside, loganin and paeoniflorin were used as the evaluation indexes to determine the impact factors of alcohol precipitation techniques of Liuwei Dihuang decoction by the Plackett-Burman experimental design and the levels of non-significant factors were identified. Then, Box-Behnken response surface methodology was used to research and discuss the critical process parameters influence the effect of alcohol precipitation and draw interaction between key process parameters and the correlation equation with index components. Through the establishment and solving the quadratic regression model of composite score, the optimum preparation conditions of alcohol precipitation techniques of liuwei were as follows: stirring speed was 580 r x min(-1), standing time was 17 hours, alcohol concentration was 34%, the density of Liuwei Dihuang decoction was 1.13. The response surface methodology for optimized alcohol precipitation techniques of Liuwei Dihuang decoction is. reasonable and feasible.

[Optimization of dry granulating technique of Qibai Pingfei granule through response surface methodology].

To determine the optimum process conditions for dry granulating technique of Qibai Pingfei granule, granule excipient type, rolling wheel speed and pressure and feeding speed were studied. Taking shaping rate at a time, moisture absorption and dissolubility as index, the type and amount of granule excipient were determined. In addition, taking shaping rate at a time as index, parameters of rolling wheel speed and pressure and feeding speed were researched through single factor test and response surface methodology. The optimum parameters were as follows: lactose as excipient, dry extract powder to excipient at 1:2, rolling wheel speed and pressure at 10.9 Hz and 6.4 MPa and feeding speed at 7.2 Hz. After validation of three batches pilot-scale production, the optimum processing parameters for dry granulating technique of Qibai Pingfei granule is reasonable and feasible, which can provide reliable basis for production.

[Optimization for vacuum belt drying process of Qibai Pingfei granule through response surface methodology].

Based on single factor tests,the optimum vacuum belt drying conditions of Qibai Pingfei granule were obtained through Box-Benhnken central combination design and RSM. In this study, drying time, drying temperature and extract density were chosen as independent variables, while transferring rate ginsenoside Rg1, Re, Rb1and astragaloside IV were taken as dependent variables. The optimum parameters are as follows: drying time of 112 min, drying temperature of 87 °C and extract density of 1.30 g · mL⁻¹. At the optimum condition, transferring rate ginsenoside Rg1+ Re, Rb1and astragaloside IV were 88.01%, 87.31%, 84. 34%. Above all, the optimum processing parameters of vacuum belt drying of Qibai Pingfei granule is reasonable and feasible, which can provide reliable basis for production.

FIP200 is involved in murine pseudomonas infection by regulating HMGB1 intracellular translocation.

BACKGROUND: FIP200, a critical autophagy initiating protein, can participate in numerous cellular functions including cancer development; however, its functional role in P. aeruginosa infection of alveolar macrophages is unknown. METHODS: To investigate the role of FIP200 in host defense, we transfected murine alveolar macrophage MH-S cells with FIP200 siRNA. Having confirmed that FIP200 knockdown inhibited PAO1-induced autophagosme formation, we sought to characterize the underlying signaling pathways by immunoblotting. Further, we used fip200 KO mice to study the effects of fip200 deficiency on HMGB1 translocation. RESULTS: We showed that Pseudomonas PAO1 strain infection facilitated autophagosome formation, whereas knockdown of FIP200 inhibited autophagosome formation and HMGB1 expression in MH-S cells. Silencing FIP200 impaired the translocation of HMGB1 to cytosol of MH-S cells and almost abolished acetylation of HMGB1 during PAO1 infection. In contrast, FIP200 overexpression facilitated the cytosol translocation of HMGB1 from nuclei and increased acetylation of HMGB1 in PAO1-infected MH-S cells. Importantly, expression and acetylation of HMGB1 were also significantly down-regulated in fip200 KO mice following PAO1 infection. CONCLUSIONS: Collectively, these findings elucidate that FIP200 may regulate expression and translocation of HMGB1 during PAO1 infection, which may indicate novel therapeutic targets to control pulmonary infection.

Activation of RAS/ERK alone is insufficient to inhibit RXRα function and deplete retinoic acid in hepatocytes.

Activation of RAS/ERK signaling pathway, depletion of retinoid, and phosphorylation of retinoid X receptor alpha (RXRα) are frequent events found in liver tumors and thought to play important roles in hepatic tumorigenesis. However, the relationships among them still remained to be elucidated. By exploring the transgenic mouse model of hepatic tumorigenesis induced by liver-specific expression of H-ras12V oncogene, the activation of RAS/ERK, the mRNA expression levels of retinoid metabolism-related genes, the contents of retinoid metabolites, and phosphorylation of RXRα were determined. RAS/ERK signaling pathway was gradually and significantly activated in hepatic tumor adjacent normal liver tissues (P) and hepatic tumor tissues (T) of H-ras12V transgenic mice compared with normal liver tissues (Wt) of wild type mice. On the contrary, the mRNA expression levels of retinoid metabolism-related genes were significantly reduced in P and T compared with Wt. Interestingly, the retinoid metabolites 9-cis-retinoic acid (9cRA) and all-trans-retinoic acid (atRA), the well known ligands for nuclear transcription factor RXR and retinoic acid receptor (RAR), were significantly decreased only in T compared with Wt and P, although the oxidized polar metabolite of atRA, 4-keto-all-trans-retinoic-acid (4-keto-RA) was significantly decreased in both P and T compared with Wt. To our surprise, the functions of RXRα were significantly blocked only in T compared with Wt and P. Namely, the total protein levels of RXRα were significantly reduced and the phosphorylation levels of RXRα were significantly increased only in T compared with Wt and P. Treatment of H-ras12V transgenic mice at 5-week-old or 5-month-old with atRA had no effect on the prevention of tumorigenesis or cure of developed nodules in liver. These events imply that the depletion of 9cRA and atRA and the inhibition of RXRα function in hepatic tumors involve more complex mechanisms besides the activation of RAS/ERK pathway.

Monocyte/macrophage-elicited natural killer cell dysfunction in hepatocellular carcinoma is mediated by CD48/2B4 interactions.

UNLABELLED: Defects in natural killer (NK) cell functions are necessary for tumor immune escape, but their underlying regulatory mechanisms in human cancers remain largely unknown. Here we show, in detailed studies of NK cells in 294 untreated patients with hepatocellular carcinoma (HCC), that accumulation of functional NK cells in HCC tissues could predict improved survival of patients. However, in patients with advanced-stage HCC, NK cells were significantly decreased in number with impaired tumor necrosis factor alpha (TNF-α) and interferon-gamma (IFN-γ) production. High infiltration of peritumoral stroma monocytes/macrophages was positively correlated with impaired functional activities of NK cells in intratumoral areas. Further kinetic experiments revealed that soon after exposure to tumor-derived monocytes, NK cells underwent a rapid, transient activation, but then they became exhausted, and eventually died. The monocytes from HCC tissues, but not from nontumoral liver, strongly express CD48 proteins; and such monocyte-induced NK cell dysfunction was markedly attenuated by blocking CD48 receptor 2B4 on NK cells, but not by blockade of NKG2D and NKp30. CONCLUSION: These data reveal that human NK cells are regulated by a fine-tuned collaborative action between different types of immune cells, which may reflect a novel immune-escape mechanism by which tumors dynamically regulate their functions at distinct tumor microenvironments.

Activated CD69+ T cells foster immune privilege by regulating IDO expression in tumor-associated macrophages.

Substantial evidence indicates that immune activation at stroma can be rerouted in a tumor-promoting direction. CD69 is an immunoregulatory molecule expressed by early-activated leukocytes at sites of chronic inflammation, and CD69(+) T cells have been found to promote human tumor progression. In this study, we showed that, upon encountering autologous CD69(+) T cells, tumor macrophages (MΦs) acquired the ability to produce much greater amounts of IDO protein in cancer nests. The T cells isolated from the hepatocellular carcinoma tissues expressed significantly more CD69 molecules than did those on paired circulating and nontumor-infiltrating T cells; these tumor-derived CD69(+) T cells could induce considerable IDO in monocytes. Interestingly, the tumor-associated monocytes/MΦs isolated from hepatocellular carcinoma tissues or generated by in vitro culture effectively activated circulating T cells to express CD69. IL-12 derived from tumor MΦs was required for early T cell activation and subsequent IDO expression. Moreover, we found that conditioned medium from IDO(+) MΦs effectively suppressed T cell responses in vitro, an effect that could be reversed by adding extrinsic IDO substrate tryptophan or by pretreating MΦs with an IDO inhibitor 1-methyl-DL-tryptophan. These data revealed a fine-tuned collaborative action between different types of immune cells to counteract T cell responses in tumor microenvironment. Such an active induction of immune tolerance should be considered for the rational design of effective immune-based anticancer therapies.

Toxicity of multi-walled carbon nanotubes, graphene oxide, and reduced graphene oxide to zebrafish embryos.

OBJECTIVE: This study was aimed to investigate the toxic effects of 3 nanomaterials, i.e. multi-walled carbon nanotubes (MWCNTs), graphene oxide (GO), and reduced graphene oxide (RGO), on zebrafish embryos. METHODS: The 2-h post-fertilization (hpf) zebrafish embryos were exposed to MWCNTs, GO, and RGO at different concentrations (1, 5, 10, 50, 100 mg/L) for 96 h. Afterwards, the effects of the 3 nanomateria on spontaneous movement, heart rate, hatching rate, length of larvae, mortality, and malformations ls were evaluated. RESULTS: Statistical analysis indicated that RGO significantly inhibited the hatching of zebrafish embryos. Furthermore, RGO and MWCNTs decreased the length of the hatched larvae at 96 hpf. No obvious morphological malformation or mortality was observed in the zebrafish embryos after exposure to the three nanomaterials. CONCLUSION: MWCNTs, GO, and RGO were all toxic to zebrafish embryos to influence embryos hatching and larvae length. Although no obvious morphological malformation and mortality were observed in exposed zebrafish embryos, further studies on the toxicity of the three nanomaterials are still needed.