Atypical teratoid rhabdoid tumor (AT/RT) is among the most fatal of all pediatric brain tumors. Aside from loss of function mutations in the SMARCB1 (BAF47/INI1/SNF5) chromatin remodeling gene, ...little is known of other molecular drivers of AT/RT. LIN28A and LIN28B are stem cell factors that regulate thousands of RNAs and are expressed in aggressive cancers. We identified high-levels of LIN28A and LIN28B in AT/RT primary tumors and cell lines, with corresponding low levels of the LIN28-regulated microRNAs of the let-7 family. Knockdown of LIN28A by lentiviral shRNA in the AT/RT cell lines CHLA-06-ATRT and BT37 inhibited growth, cell proliferation and colony formation and induced apoptosis. Suppression of LIN28A in orthotopic xenograft models led to a more than doubling of median survival compared to empty vector controls (48 vs 115 days). LIN28A knockdown led to increased expression of let-7b and let-7g microRNAs and a down-regulation of KRAS mRNA. AT/RT primary tumors expressed increased mitogen activated protein (MAP) kinase pathway activity, and the MEK inhibitor selumetinib (AZD6244) decreased AT/RT growth and increased apoptosis. These data implicate LIN28/RAS/MAP kinase as key drivers of AT/RT tumorigenesis and indicate that targeting this pathway may be a therapeutic option in this aggressive pediatric malignancy.
A method using capillary electrophoresis-laser induced fluorescence (CE-LIF) for HSP70_hom gene polymorphism detection has been developed, which was applied to analyze the correlation between ...rheumatoid arthritis (RA) and HSP70_hom gene polymorphism. The conditions of CE-LIF detection were optimized using DL-1000 DNA Marker, including the concentration of sieving matrix, separation voltage and the concentration of running buffer. The whole genome DNA was extracted from 101 cases of RA and 58 control subjects, amplified by specific primers for PCR, and then digested by NcoI restriction enzyme. The enzyme-digested products were detected by the optimized CE-LIF method and the results were analyzed by logistic regression. Under the optimized conditions of CE-LIF, DL-1000 DNA Marker was detected successively in the same day and the relative standard deviations (RSDs) of migration time was 0.29%–0.41%. There were 58 cases of TT genotype, 41 cases of TC genotype and 2 cases of CC genotype in the case group; 34 cases of TT genotype, 21 cases of TC genotype and 3 cases of CC genotype in the control group. After adjusted age and gender, no significant difference was observed in the distribution of HSP70_hom gene polymorphism between the case group and the control group (P>0.05). The method of CE-LIF detection had the advantages of rapid analysis, high resolution and environmental friendliness, and could be applied to the detection of gene polymorphism; HSP70_hom gene polymorphism was not significantly associated with rheumatoid arthritis.
•A new CE-based method has been developed for the determination of gene polymorphism.•This method has advantages of highly efficient separation and ultrasensitive fluorescent detection.•This study investigated the association between HSP70_hom gene polymorphism and rheumatoid arthritis.•This approach can offer clues for early diagnosis of rheumatoid arthritis and intervention therapy.
Corneal endothelial cells (CECs) serve as a barrier and foothold for the corneal stroma to maintain the function and transparency of the cornea. Loss of CECs during aging or disease states leads to ...blindness, and cell replacement therapy using either donated or artificially differentiated CECs remains the only curative approach.
Human induced pluripotent stem cells (hiPSCs) that were cultured in chemically defined medium were induced with dual-SMAD inhibition to differentiate into neural crest cells (NCCs). A small-molecule library was screened to differentiate the NCCs into corneal endothelial-like cells. The characteristics of these cells were identified with real-time PCR and immunofluorescence. Western blotting was applied to detect the signaling pathways and key factors regulated by the small molecules.
We developed an effective protocol to differentiate hiPSCs into CECs with defined small molecules. The hiPSC-CECs were characterized by ZO-1, AQP1, Vimentin and Na
/K
-ATPase. Based on our small-molecule screen, we identified a small-molecule combination, A769662 and AT13148, that enabled the most efficient production of CECs. The combination of A769662 and AT13148 upregulated the PKA/AKT signaling pathway, FOXO1 and PITX2 to promote the conversion of NCCs to CECs.
We established an efficient small molecule-based method to differentiate hiPSCs into corneal endothelial-like cells, which might facilitate drug discovery and the development of cell-based therapies for corneal diseases.
We present here the first report of PID1 (Phosphotyrosine Interaction Domain containing 1; NYGGF4) in cancer. PID1 was identified in 2006 as a gene that modulates insulin signaling and mitochondrial ...function in adipocytes and muscle cells.
Using four independent medulloblastoma datasets, we show that mean PID1 mRNA levels were lower in unfavorable medulloblastomas (groups 3 and 4, and anaplastic histology) compared with favorable medulloblastomas (SHH and WNT groups, and desmoplastic/nodular histology) and with fetal cerebellum. In two large independent glioma datasets, PID1 mRNA was lower in glioblastomas (GBM), the most malignant gliomas, compared with other astrocytomas, oligodendrogliomas and nontumor brains. Neural and proneural GBM subtypes had higher PID1 mRNA compared with classical and mesenchymal GBM. Importantly, overall survival and radiation-free progression-free survival were longer in medulloblastoma patients whose tumors had higher PID1 mRNA (univariate and multivariate analyses). Higher PID1 mRNA also correlated with longer overall survival in patients with glioma and GBM. In cell culture, overexpression of PID1 inhibited colony formation in medulloblastoma, atypical teratoid rhabdoid tumor (ATRT), and GBM cell lines. Increasing PID1 also increased cell death and apoptosis, inhibited proliferation, induced mitochondrial depolaization, and decreased serum-mediated phosphorylation of AKT and ERK in medulloblastoma, ATRT, and/or GBM cell lines, whereas siRNA to PID1 diminished mitochondrial depolarization.
These data are the first to link PID1 to cancer and suggest that PID1 may have a tumor inhibitory function in these pediatric and adult brain tumors.
•Demographic differences in scores of childhood maltreatment, self-compassion and depression were analyzed.•We analyzed the correlation among childhood maltreatment, self-compassion, and ...depression.•The mediating effect of self-compassion and its components of self-kindness, the sense of common humanity, and mindfulness on the relationship between childhood maltreatment and depression was tested.
Depression is the leading cause of suicide. Childhood maltreatment is an important influencing factor for depression in adulthood. However, the mediating effect of self-compassion between childhood maltreatment and depression has not yet been explored.
A cluster random sampling of 4189 students was selected from a university in Hebei Province, China. They completed the Childhood Trauma Questionnaire-Short Form, the Self-Compassion Scale, and the Self-Rating Depression Scale.
Depression is significantly positively correlated with childhood maltreatment and its subscales, including emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect. Childhood maltreatment can affect depression not only directly, but also indirectly through self-compassion and its components of self-kindness, the sense of common humanity, and mindfulness.
Potential sampling bias, subjective measures, and the cross-sectional design are the main limitations.
Self-compassion partly plays a mediating role between childhood maltreatment and depression. College educators and clinicians should actively help college students who experienced abuse during childhood to increase their level of self-compassion to reduce their depression.
Phosphotyrosine Interaction Domain containing 1 (PID1; NYGGF4) inhibits growth of medulloblastoma, glioblastoma and atypical teratoid rhabdoid tumor cell lines. PID1 tumor mRNA levels are highly ...correlated with longer survival in medulloblastoma and glioma patients, suggesting their tumors may have been more sensitive to therapy. We hypothesized that PID1 sensitizes brain tumors to therapy. We found that PID1 increased the apoptosis induced by cisplatin and etoposide in medulloblastoma and glioblastoma cell lines. PID1 siRNA diminished cisplatin-induced apoptosis, suggesting that PID1 is required for cisplatin-induced apoptosis. Etoposide and cisplatin increased NFκB promoter reporter activity and etoposide induced nuclear translocation of NFκB. Etoposide also increased PID1 promoter reporter activity, PID1 mRNA, and PID1 protein, which were diminished by NFκB inhibitors JSH-23 and Bay117082. However, while cisplatin increased PID1 mRNA, it decreased PID1 protein. This decrease in PID1 protein was mitigated by the proteasome inhibitor, bortezomib, suggesting that cisplatin induced proteasome dependent degradation of PID1. These data demonstrate for the first time that etoposide- and cisplatin-induced apoptosis in medulloblastoma and glioblastoma cell lines is mediated in part by PID1, involves NFκB, and may be regulated by proteasomal degradation. This suggests that PID1 may contribute to responsiveness to chemotherapy.
•Simulation of a coal-fired boiler with/without ammonia fuel blending is performed.•Co-firing ammonia in power plant can reduce the CO2 emission effectively.•Co-firing ammonia changes the composition ...and thermal properties of the flue gas.•Exergy efficiency of boiler system is only slightly reduced with ammonia addition.
Coal-fired power plants are one of the major sources of CO2 emission, and the novel application of directly co-firing the carbon-free fuel ammonia into the coal-fired power plants is emerging as a promising method of CO2 emission reduction. In this study, simulations of the boiler system of a 600 MWe coal-fired power plant unit were performed in both coal-fired condition and ammonia-coal co-firing conditions, and the impacts of ammonia co-firing on the emission and thermal properties of flue gas, exergy loss, and exergy efficiency were analyzed. Two co-firing scenarios (identical adiabatic flame temperature scenario and identical excess air coefficient scenario) were compared, both assuming that the total heating value of the fuel into the furnace kept unchanged with different ammonia co-firing ratios (5%, 10%, 15%, 20% on heating value basis). The results showed that CO2 emission was effectively reduced by 24.08 t/h for every 5% increase in the ammonia co-firing ratio. The amount of total flue gas was also reduced while both the content and the emission rate of H2O were increased with ammonia co-firing. Consequently, the specific heat capacity of flue gas increased and further changed its temperature distribution profile. Compared with the coal-fired base case, the exergy loss in the furnace under the ammonia co-firing conditions increased continuously as the ammonia co-firing ratio increased, suggesting that the irreversible loss of the ammonia combustion process was greater than that of coal. By contrast, the exergy loss of heat exchangers and fans decreased in ammonia co-firing conditions. Finally, the exergy efficiency of the boiler system was only slightly reduced (53.82% vs. 53.27%–53.22%) in ammonia co-firing conditions, showing that co-firing ammonia in coal-fired power plant would not significantly deteriorate the thermal economy.
Inhibition of integrins αvβ3 and αvβ5 in human brain microvascular endothelial cells (HBMECs) by the function-blocking peptide RGDfV induces loss of spreading on vitronectin, cell detachment, and ...apoptosis. We demonstrate that cell detachment is not required for apoptosis because plating on bovine serum albumin–blocked poly-L-lysine (allows attachment, but not integrin ligation and cell spreading) also induced apoptosis. Latrunculin B (LatB), which inhibits F-actin polymerization, induced transient loss of HBMEC spreading on vitronectin, but not their detachment, and induced apoptosis despite recovery of cell spreading. However, LatB did not cause apoptosis in 5 tumor cell lines. In HBMECs, both LatB and RGDfV induced transient Y412 and Y245 phosphorylation of endogenous c-Abl, a nonreceptor tyrosine kinase that reciprocally regulates F-actin. LatB also induced nuclear translocation of c-Abl in HBMECs. STI-571 (imatinib), a targeted therapy for BCR-ABL1+ leukemias and inhibitor of c-Abl, platelet-derived growth factor receptor, and c-Kit, decreased endothelial apoptosis. LatB-induced HBMEC apoptosis, and its inhibition by STI-571 also occurred in a 3-dimensional collagen model, supporting physiologic relevance. Last, siRNA to c-Abl (but not nonspecific siRNA) also inhibited RGDfV- and LatB-induced apoptosis. Thus, endogenous c-Abl mediates endothelial apoptosis induced by inhibition of integrins αvβ3/αvβ5 or by LatB-induced disruption of F-actin.
•The double-layer-shell sand mold effectively reduces the mold crack tendency.•The double-layer-shell sand mold reduces the residual stress of casting.•The crack initiation mechanism of different ...mold structures was investigated.
Controlling the solidification of metals is the most essential to prevent defects and realize required quality and mechanical properties of castings. However, the conventional sand mold structure is generally dense and thick, which makes it difficult to accurately control the solidification process of castings. The hollow sand molds prepared by 3D printing technology provide the possibility to adopt measures to control the cooling of castings, but the crack on the mold itself is a new problem. Here, a kind of double-layer-shell structure of hollow sand mold is designed. It is proved that it can effectively reduce the crack tendency of the hollow sand mold, the residual stress of the casting decreases as well. Both experiment and numerical simulation results unveil the mechanism.
Co-firing of ammonia (NH3) and coal in boilers is a promising technology to reduce CO2 emissions from power plants. However, NH3/coal co-firing in swirl burners can impact the original flame ...structures and may lead to serious NOx emission issues due to the high concentration of nitrogen in NH3. In this study, a numerical simulation of a low-NOx swirl burner was carried out to investigate the changes in flame structure, carbon emission, and characteristics of NOx generation. The results show that, when the NH3 co-firing ratio is 10 cal%, the flame retains its original swirl structure, and a significant increase in NO formation is observed in situations with different injection positions. When the co-firing ratio increases to 20 cal% and 30 cal% and NH3 is injected through the central air pipe, the flame changes from a swirl flame to an elongated flame. The injected NH3 is wrapped by the low-temperature primary air, separating the NH3 from the high-temperature zone, and pyrolysis becomes the primary reaction pathway for NH3 consumption rather than oxidation. The NO concentrations measured at the chamber outlet can be reduced to 11.2mg/Nm3, which is lower than that from coal combustion. As the co-firing ratio further increases to 50 cal%, NH3 and air are well mixed and burned, forming a “candle-type” flame. This results in a significant rise in NO emissions.
•NH3/coal co-firing was simulated on an industry-scale low-NOx swirl burner.•Coupling effect of NH3 and coal on NO formation and reduction was considered.•Role injection positions and co-firing ratios on NOx emission was investigated.•Optimal strategy for NH3/coal co-firing in the swirl burner was proposed.
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