Bromodomains and Extra-Terminal (BET) Inhibitor JQ1 Suppresses Proliferation of Acute Lymphocytic Leukemia by Inhibiting c-Myc-Mediated Glycolysis.

BACKGROUND Acute lymphocytic leukemia (ALL) is a common blood cancer which induces high mortality in children. Bromodomains and extra-terminal (BET) protein inhibitors, such as JQ1 and ARV-825, are promising cancer therapeutic agents that can be used by targeting c-Myc. A recent work reported that JQ1 effectively attenuates ALL in vitro by suppressing cell proliferation and accelerating apoptosis. The purpose of this research was to probe into the potential mechanism of how JQ1 inhibits ALL cell proliferation in vitro. MATERIAL AND METHODS Cell viability of ALL cells were measured by CTG after treatment by JQ1. Cell cycle analysis was done by EdU and PI staining. Cell apoptosis was assessed by Annexin V/PI staining. Glycolysis was detected using Seahorse and LC-MS kits. The expression of glycolytic rate-limiting enzymes was assessed by RNA-seq, qRT-PCR, and Western blot. RESULTS JQ1 suppressed cell proliferation by arresting the cell cycle and inducing the apoptosis of acute lymphocytic leukemia cells. JQ1 inhibited cell proliferation of B-ALL cells by restraining glycolysis. Conversely, the cell cycle block of B-ALL cells induced by JQ1 was partially abolished after pretreatment with 2-Deoxy-D-glucose (2-DG), an inhibitor of glycolysis. Furthermore, JQ1 restrained the glycolysis of B-ALL cell lines by remarkably downregulating the rate-limiting enzymes of glycolysis, such as hexokinase 2, phosphofructokinase, and lactate dehydrogenase A. Moreover, the cell cycle arrest was reversed in B-ALL cells with overexpressed c-Myc treated by JQ1, which is involved in the enhancement of glycolysis. CONCLUSIONS The BET inhibitor JQ1 suppresses the proliferation of ALL by inhibiting c-Myc-mediated glycolysis, thus providing a new strategy for the treatment of ALL.

Rapamycin ameliorates immune-mediated aplastic anemia by inhibiting the proliferation and metabolism of T cells.

Aplastic anemia (AA) is a serious blood system disease that threatens human health. At present, the main cause of this disease is believed to be immune hyperfunction. However, the specific metabolic mode involved in the occurrence of lymphocytes in AA is still unknown. In addition, whether rapamycin, a specific blocker of the mTOR signaling pathway, plays a therapeutic role by inhibiting lymphocyte metabolism remains unclear. We induced an AA mouse model through the classical immune-mediated pathway and simultaneously administered rapamycin intervention therapy. First, the AA-associated phenotypic changes and the efficacy of rapamycin in the treatment of AA were discussed. Second, the proliferation and metabolic pathway of bone marrow (BM) lymphocytes in AA and the effect of rapamycin on this process were determined. Finally, the expression levels of mTOR pathway-related proteins were analyzed. By inhibiting the mTOR signaling pathway, rapamycin could ameliorate the phenotype of the immune-mediated AA model and inhibit the proliferation of T cells by preventing cell cycle transition from G0 to G1 phase. Moreover, we found that mitochondrial oxidative phosphorylation is involved in the metabolic reprogramming of T cells in AA and that rapamycin can inhibit this process. We confirmed that mitochondrial oxidative phosphorylation is involved in the metabolic reprogramming of T cells in AA and further extended the mechanism of rapamycin in treating AA by inhibiting the mTOR signaling pathway. This viewpoint may provide a new therapeutic idea for clinical applications.

LGR6 promotes osteogenesis by activating the Wnt/ß-catenin signaling pathway.

Leucine-rich repeat containing G-protein-coupled receptor 6 (LGR6) is a member of the rhodopsin-like 7-transmembrane domain receptor superfamily and has high homology to LGR4 and LGR5. LGR6 is highly expressed in osteoblastic progenitors, and LGR6-deficient mice show nail and bone regeneration defect. However, the effect of LGR6 on the osteogenic differentiation of osteoblastic progenitors and its underlying mechanisms are largely unknown. In this study, we overexpressed and knockdown LGR6 with lentivirus in the preosteoblastic cell MC3T3-E1 to observe the effect of LGR6 on osteogenic differentiation and explore its possible molecular mechanism. LGR6 overexpression promoted osteogenic differentiation and mineralization by stabilizing ß-catenin to potentiate the Wnt/ß-catenin signaling pathway in MC3T3-E1 cells. Conversely, LGR6 knockdown inhibited osteogenic differentiation and mineralization by enhancing ß-catenin degradation to inactivate the Wnt/ß-catenin signaling pathway. These results reveal that LGR6 is highly expressed in osteoblastic progenitors, and promotes osteogenesis by enhancing ß-catenin stability to strengthen the Wnt signaling pathway. This study provides an important reference into the exact mechanisms of osteogenic differentiation.

CTNND1 755 T>G Promoter Polymorphism and Risk of Pancreatic Carcinoma in Chinese.

OBJECTIVE: To investigate the relationship between 755 T>G polymorphisms in the CTNND1 gene, which is associated with the risk of pancreatic carcinoma in Chinese. METHODS: CTNND1 755 T>G genotypes were determined by PCR-RFLP in 122 pancreatic carcinoma patients and 180 healthy controls matched for age and sex, who did not receive radiotherapy or chemotherapy for newly diagnosed and histopathologically confirmed pancreatic carcinoma. RESULTS: In control subjects, the frequency of T/T and G/T genotypes, and T and G alleles was 79.4%, 17.2%, 88.1%, and 11.9%, respectively. The distribution of genotypes and allelotypes in the pancreatic carcinoma patients was significantly different from that in the controls (P = 0.007, P = 0.012). Combined GG and GT genotypes were found to have a higher OR in male pancreatic carcinoma patients and the group under the age of 70 years (males: OR, 1.409; 95%CI, 0.912~1.921; under 70 years: OR 1.626; 95% CI, 0.878~2.312). This study also showed a distinct difference in the distribution of P120ctn and single nucleotide polymorphisms (SNPs) between Chinese and Canadian (11.9% vs. 3.9%, P = 0.008). CONCLUSION: CTNND1 755 T>G polymorphism may be a stratification marker to predict the susceptibility to pancreatic carcinoma, at least in Chinese. CTNND1 promoter SNPs is diverse in ethnic populations.

Methane and nitrous oxide emissions under no-till farming in China: a meta-analysis.

No-till (NT) practices are among promising options toward adaptation and mitigation of climate change. However, the mitigation effectiveness of NT depends not only on its carbon sequestration potential but also on soil-derived CH4 and N2O emissions. A meta-analysis was conducted, using a dataset involving 136 comparisons from 39 studies in China, to identify site-specific factors which influence CH4 emission, CH4 uptake, and N2O emission under NT. Comparative treatments involved NT without residue retention (NT0), NT with residue retention (NTR), compared to plow tillage (PT) with residue removed (PT0). Overall, NT0 significantly decreased CH4 emission by ~30% (P < 0.05) compared to PT0 with an average emission 218.8 kg ha(-1) for rice paddies. However, the increase in N2O emission could partly offset the benefits of the decrease in CH4 emission under NT compared to PT0. NTR significantly enhanced N2O emission by 82.1%, 25.5%, and 20.8% (P < 0.05) compared to PT0 for rice paddies, acid soils, and the first 5 years of the experiments, respectively. The results from categorical meta-analysis indicated that the higher N2O emission could be mitigated by adopting NT within alkaline soils, for long-term duration, and with less N fertilization input when compared to PT0. In addition, the natural log (lnR) of response ratio of CH4 and N2O emissions under NT correlated positively (enhancing emission) with climate factors (temperature and precipitation) and negatively (reducing emission) with experimental duration, suggesting that avoiding excess soil wetness and using NT for a long term could enhance the benefits of NT. Therefore, a thorough understanding of the conditions favoring greenhouse gas(es) reductions is essential to achieving climate change mitigation and advancing food security in China.

The treatment of oily wastewater by thermo-responsive calcium alginate capsules immobilized Pseudomonas aeruginosa.

A microfluidic strategy of smart calcium alginate (CA) capsules is presented to immobilize Pseudomonas aeruginosa to treat oil slicks effectively. The capsule wall is embedded with poly (N-isopropyl acrylamide) sub-microspheres as thermo-responsive switches. CA capsules, with a diameter of 3.26 mm and a thin wall thickness about 12.8 µm, have satisfying monodispersity, cavity structure, and dense surface structures. The capsules possess excellent encapsulation of bacteria, which are fixed in a restricted space and become more aggregated. It overcomes the disadvantages of a long fermentation production cycle, easy loss of bacteria, and susceptibility to shear effect. The smart CA capsules immobilized with bacteria treat model wastewater containing soybean oil or diesel and display favorable fermentation ability. The capsules can effectively treat oil slicks with high concentration, and it is an economical way for processing oily wastewater. PRACTITIONER POINTS: A thermo-responsive calcium alginate capsule was prepared by microfluidic strategy. Pseudomonas aeruginosa is environmentally friendly in treating oil slicks. The capsules, immobilized bacteria, treat oil slicks effectively. This study provides an economical way for processing different oily water.

[Effects of expression ways and traits of anger emotion on autonomic nerve in the emotion recovery stage].

OBJECTIVE: To explore the effects of expression ways and traits of anger emotion on autonomic nerve in the emotion recovery stage. METHODS: The 48 healthy undergraduate students were recruited as subjects, who were assigned to four groups, i.e., anger-out of high trait group, anger-in of high trait group, anger-out of low trait group, anger-in of low trait group, 12 in each group. The changes of autonomic nerve in emotion recovery stage [mainly including heart rate (HR), finger pulse volume (FPV), heart rate variability (HRV), and galvanic skin response (GSR)] were observed in an experimental paradigm processed dynamically by emotion induction (by watching movie clips) and emotion regulation (by phraseology chewing and regulating body reaction to anger). RESULTS: In the emotion recovery stage all increased data of vegetative reactions decreased in the four groups. The decrease extent of HR, FPV, and GSR was lower in the anger-in groups than that in the anger-out groups (P < 0.05). The HRV showed a decreasing trend, but with no statistical significance (P > 0.05). The decrease extent of HR was lower in the low-anger groups than in the high-anger group (P < 0.05). CONCLUSIONS: Both expression ways and traits of anger exerted influence on the autonomic nerve in the emotion recovery stage. The former influenced more broadly. The influence of anger-in on the autonomic nerve would be more sustainable.

[The expression of P120 catenin in pancreatic carcinoma and the relationship between the T755G polymorphism of P120 catenin gene and pancreatic carcinoma].

OBJECTIVES: To investigate the expression of P120 catenin in pancreatic carcinoma and to explore the association between P120 catenin gene polymorphism at T755G position and pancreatic carcinoma. METHODS: The expression of P120 catenin in 52 cases of pancreatic carcinoma and normal pancreatic tissues on the mRNA and protein levels were evaluated by RT-PCR and Western Blot methods respectively. P120 catenin gene polymorphism at T755G position of in 52 patients and 60 healthy controls were examined by PCR-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS: The mRNA and protein expressions of P120 catenin in pancreatic carcinoma tissues were significantly lower than normal pancreatic tissues (P=0.000, P=0.002). Reduced expression of P120 catenin mRNA was significantly correlated with differentiated (P=0.033), lymph node metastasis (P=0.004), vascular invasion (P=0.022), and pTNM stage (P=0.003). Additionally, there were significant difference of P120 catenin gene polymorphism genotypes and alleles at T755G position between patients and healthy controls (P=0.008, P=0.016). The GG genotype of P120 catenin gene was associated with higher risk of incidence for pancreatic carcinoma compared with the TT genotype (OR=2.765, 95%CI=1.312-3.958). CONCLUSIONS: The reduced expressions of both P120 catenin mRNA and protein in pancreatic carcinoma suggest its association with pancreatic carcinoma development. Polymorphism of P120 catenin gene at T755G situation might be a risk factor for pancreatic carcinoma, and it may be used to diagnosis and prevent pancreatic carcinoma early.

[Effect of expanding training on prisoners' mental health].

OBJECTIVE: To study the effect of expanding training on the mental health of the prisoners and to provide the references to the innovation of the mental health education for the prisoners. METHODS: Questionnaire, observation, interview and mathematical statistic analysis were used. 100 male and 100 female prisoners from two prisons in East China were investigated by Symptom Checklist 90 (SCL-90). RESULTS: Eight of the ten factors in SCL-90 showed the level of statistically significance, which includes obsessive-compulsive symptoms, interpersonal sensitivity, depression, anxiety, compulsion, hostility, psychoticism and others. Expanding training could be helpful to improve the mental health of the prisoners. CONCLUSION: Expanding training can be used in mental health education of the prisoners.

Management-induced greenhouse gases emission mitigation in global rice production.

Mitigating greenhouse gases (GHGs) emissions from rice paddy (Oryza sativa L.) and balancing the trade-offs between reducing emission and sustaining food security have raised global concerns. A global meta-analysis of rice experimental data was conducted to assess changes in emissions of GHGs (CH4 and N2O) and global warming potential (GWP) in response to improvements through 12 field management practices. The results indicated that changes in GWP were mainly attributed to CH4 emission even though N2O emission was significantly affected by conversion of field management practices. Specifically, GWP per unit rice plant area (area-scaled) was significantly increased by 20.1%, 66.2%, and 84.5% with nitrogen (N) fertilizer input, manuring, and residue retention (P < 0.05), along with significant increments in area-scaled CH4 emission under the above management practices by 8.9%, 60.4%, and 91.8%, respectively (P < 0.05). Due to the significant increase in rice yield, a decreasing trend for GWP per unit rice yield (yield-scaled) was observed with N fertilizer input. In addition, CH4 and GWP decreased significantly at both area- and yield-scale under non-flooding irrigation but with a reduction in rice yield by 3.3% (P < 0.05). Improvement in rice variety significantly enhanced crop yield by 15.3% while reducing area-scaled GWP by 27.7% (P < 0.05). Furthermore, other management practices, such as application of herbicides, biochar, and amendments (non-fertilizer materials) reduced yield-scaled GWP while increasing rice yield. Thus, changes in field management practices have the potential to balance the trade-offs between high yield and low emission of GHGs. However, in-depth studies are needed to determine the interactions between field management practices and site-specific soil/climate conditions.

Blocking ATM-dependent NF-κB pathway overcomes niche protection and improves chemotherapy response in acute lymphoblastic leukemia.

Bone marrow (BM) niche responds to chemotherapy-induced cytokines secreted from acute lymphoblastic leukemia (ALL) cells and protects the residual cells from chemotherapeutics in vivo. However, the underlying molecular mechanisms for the induction of cytokines by chemotherapy remain unknown. Here, we found that chemotherapeutic drugs (e.g., Ara-C, DNR, 6-MP) induced the expression of niche-protecting cytokines (GDF15, CCL3 and CCL4) in both ALL cell lines and primary cells in vitro. The ATM and NF-κB pathways were activated after chemotherapy treatment, and the pharmacological or genetic inhibition of these pathways significantly reversed the cytokine upregulation. Besides, chemotherapy-induced NF-κB activation was dependent on ATM-TRAF6 signaling, and NF-κB transcription factor p65 directly regulated the cytokines expression. Furthermore, we found that both pharmacological and genetic perturbation of ATM and p65 significantly decreased the residual ALL cells after Ara-C treatment in ALL xenograft mouse models. Together, these results demonstrated that ATM-dependent NF-κB activation mediated the cytokines induction by chemotherapy and ALL resistance to chemotherapeutics. Inhibition of ATM-dependent NF-κB pathway can sensitize ALL to chemotherapeutics, providing a new strategy to eradicate residual chemo-resistant ALL cells.

Synthesis and photoluminescence properties of novel europium complexes of 2'-hydroxyacetophenone and 4,6-diacetylresorcinol.

Novel europium (III) complexes of the formulae Eu(OHAP)(3).2H2O, Eu(OHAP)(3)Phen, Eu2(DAR)(3).4H2O and Eu2(DAR)(3)Phen2 (HOHAP=2'-hydroxyacetophenone, H2DAR=4,6-diacetylresorcinol, Phen=1,10-phenanthroline) have been designed and synthesized in this paper. These complexes were characterized by elemental analysis, FT-IR, and UV-vis. Based on these observations, the ligands are coordinated to Eu(III) via the acetyl and phenolic oxygens, and H2DAR is concluded to be bis-bidentate donor. Photoluminescence studies showed that the several complexes emitted red luminescence. Thermo-gravimetric analysis showed that the complexes possess good thermal stability. Also, it was found that Phen as a synergic ligand, coordinated to Eu(III) in a composite system like 2'-hydroxyacetophenone and 4,6-diacetylresorcinol, could enhance the complexes luminescence intensity, quantum yield and lifetime.

Chemotherapy-induced niche perturbs hematopoietic reconstitution in B-cell acute lymphoblastic leukemia.

BACKGROUND: Considerable efforts have been devoted toward the uncovering of the molecular mechanisms underlying the maintenance of hematopoietic stem cells (HSCs) by the normal bone marrow (BM) niche. Previously, we demonstrated that a chemotherapy-induced niche, which is mainly composed of mesenchymal stem cells (MSCs), protects the residual B-cell acute lymphoblastic leukemia (B-ALL) cells from the insult of chemotherapeutic drugs. However, the roles of chemotherapy-induced niche on HSCs functions in B-ALL remain unclear. METHODS: We established an oncogenic N-MYC-driven B-ALL mouse model, which were subsequently treated with common chemotherapy drug cytarabine (Ara-C) and daunorubicin (DNR). After treatment, the structures of the BM niche were imaged by immunofluorescence staining. Then, the self-renewal and differentiation capability of the MSCs in the BM after Ara-C and DNR treatment were studied by ex vivo culture and gene expression analysis with RNA-seq and qRT-PCR. The effects of chemotherapy-induced niche on the hematopoietic reconstitution of HSCs were determined with series transplantation assay. Furthermore, the cell cycle, ROS level, mitochondrial membrane potential and cell apoptosis of HSCs were detected by flow cytometry. RESULTS: The MSCs, which is the main component of chemotherapy-induced BM niche, have decreased self-renewal capability and are prone to differentiate into adipocytes and chondrocytes. The results of gene expression analysis with RNA-seq showed that the MSCs have reduced levels of cytokines, including SCF, CXCL12, ANGPT1, VCAM1, and IL7. Furthermore, the chemotherapy-induced niche perturbed the hematopoietic reconstitution of HSCs in our N-MYC-driven B-ALL mouse model by promoting HSCs to enter cell cycle and increasing intracellular ROS levels and mitochondrial membrane potential of HSCs, which lead to the cell apoptosis of HSCs. CONCLUSIONS: Chemotherapy-induced BM niche perturbs the hematopoietic reconstitution of HSCs by increasing intracellular ROS level and inducing cell apoptosis.

NEDD4 single nucleotide polymorphism rs2271289 is associated with keloids in Chinese Han population.

Keloids are abnormally raised fibroproliferative lesions that usually occur following cutaneous traumas. Recently, a large-scale genome-wide association study (GWAS) has identified multiple single nucleotide polymorphisms (SNPs) in three genetic loci that are associated with keloids in Japanese population. Subsequently, two reported loci 1q41 (rs873549 and rs1442440) and 15q21.3 (rs2271289) for keloids were confirmed in selected Chinese population. The association of these SNPs with clinical features of keloids, has not yet been studied. To explore the role of these SNPs in the pathogenesis of keloids, we performed a case-controlled study in another independent Chinese Han population to analyze the correlation between 4 SNPs (rs873549, rs2118610, rs1511412, rs2271289) and keloids phenotypes. 309 keloids patients and 1080 control subjects were included. The results showed that, in the dominant mode of inheritance, the minor allele T of SNP rs2271289 had significantly higher odd ratios (ORs) in the severe keloid group compared with both the controls and the mild keloid group. The ORs were maintained after Bonferroni's correction (OR: 4.09, 95% CI: 1.78-9.37, P-value 3.25E-04). The ratio of the severe: mild OR for rs2271289 (dominant model) is (4.73/1.84=2.57). Similar associations in SNP rs2271289 were seen for groups with no family history and multiplesite compared with the control groups. No associations between keloid number, family history or severity relative to the controls were observed for the other three SNPs. Our data support that rs2271289 is strongly associated with severe keloids and might contribute to the complexity of clinical features of keloids.

Surgical approaches for resection of pancreatic cancer: an overview.

OBJECTIVE: To overview the different surgical approaches for the resection of pancreatic cancer and our experience with these techniques. METHODS: Surgical procedures including the Whipple resection, Pylorus-preserving resection, total and subtotal panreatectomies, regional pancreatectomy and the extended lymph node resection were discussed. RESULTS: Studies have shown that no operation seems to produce significantly improved results in terms of survival, mortality and resection rates compared to the standard Whipple resection and pylorus-preserving duodenopancreatectomy. CONCLUSION: Despite the progress in the surgical treatment of pancreatic cancer, the overall prognosis after resection remains unsatisfied. Surgery is likely to be optional for the treatment of pancreatic cancer.

Solving geometric constraints with genetic simulated annealing algorithm.

This paper applies genetic simulated annealing algorithm (SAGA) to solving geometric constraint problems. This method makes full use of the advantages of SAGA and can handle under-/over- constraint problems naturally. It has advantages (due to its not being sensitive to the initial values) over the Newton-Raphson method, and its yielding of multiple solutions, is an advantage over other optimal methods for multi-solution constraint system. Our experiments have proved the robustness and efficiency of this method.