Nucleolar HEAT Repeat Containing 1 Up-regulated by the Mechanistic Target of Rapamycin Complex 1 Signaling Promotes Hepatocellular Carcinoma Growth by Dominating Ribosome Biogenesis and Proteome Homeostasis.

BACKGROUND & AIMS: Hyperactivation of ribosome biogenesis leads to hepatocyte transformation and plays pivotal roles in hepatocellular carcinoma (HCC) development. We aimed to identify critical ribosome biogenesis proteins that are overexpressed and crucial in HCC progression. METHODS: HEAT repeat containing 1 (HEATR1) expression and clinical correlations were analyzed using The Cancer Genome Atlas and Gene Expression Omnibus databases and further evaluated by immunohistochemical analysis of an HCC tissue microarray. Gene expression was knocked down by small interfering RNA. HEATR1-knockdown cells were subjected to viability, cell cycle, and apoptosis assays and used to establish subcutaneous and orthotopic tumor models. Chromatin immunoprecipitation and quantitative polymerase chain reaction were performed to detect the association of candidate proteins with specific DNA sequences. Endogenous coimmunoprecipitation combined with mass spectrometry was used to identify protein interactions. We performed immunoblot and immunofluorescence assays to detect and localize proteins in cells. The nucleolus ultrastructure was detected by transmission electron microscopy. Click-iT (Thermo Fisher Scientific) RNA imaging and puromycin incorporation assays were used to measure nascent ribosomal RNA and protein synthesis, respectively. Proteasome activity, 20S proteasome foci formation, and protein stability were evaluated in HEATR1-knockdown HCC cells. RESULTS: HEATR1 was the most up-regulated gene in a set of ribosome biogenesis mediators in HCC samples. High expression of HEATR1 was associated with poor survival and malignant clinicopathologic features in patients with HCC and contributed to HCC growth in vitro and in vivo. HEATR1 expression was regulated by the transcription factor specificity protein 1, which can be activated by insulin-like growth factor 1-mammalian target of rapamycin complex 1 signaling in HCC cells. HEATR1 localized predominantly in the nucleolus, bound to ribosomal DNA, and was associated with RNA polymerase I transcription/processing factors. Knockdown of HEATR1 disrupted ribosomal RNA biogenesis and impaired nascent protein synthesis, leading to reduced cytoplasmic proteasome activity and inhibitory-κB/nuclear factor-κB signaling. Moreover, HEATR1 knockdown induced nucleolar stress with increased nuclear proteasome activity and inactivation of the nucleophosmin 1-MYC axis. CONCLUSIONS: Our study revealed that HEATR1 is up-regulated by insulin-like growth factor 1-mammalian target of rapamycin complex 1-specificity protein 1 signaling in HCC and functions as a crucial regulator of ribosome biogenesis and proteome homeostasis to promote HCC development.

[Diagnostic efficacy of serum 14-3-3ß protein combined with fractional exhaled nitric oxide and conventional ventilatory lung function parameters for bronchial asthma in children]. / è¡€æ¸ 14-3-3ß蛋白联合呼出气一氧化氮及常规通气肺功能参数对儿童支气管哮喘的诊断效能.

OBJECTIVES: To explore the diagnostic efficacy of serum 14-3-3ß protein combined with fractional exhaled nitric oxide (FeNO) and conventional ventilatory lung function parameters in diagnosing bronchial asthma (referred to as "asthma") in children. METHODS: A prospective study included 136 children initially diagnosed with asthma during an acute episode as the asthma group, and 85 healthy children undergoing routine health checks as the control group. The study compared the differences in serum 14-3-3ß protein concentrations between the two groups, analyzed the correlation of serum 14-3-3ß protein with clinical indices, and evaluated the diagnostic efficacy of combining 14-3-3ß protein, FeNO, and conventional ventilatory lung function parameters for asthma in children. RESULTS: The concentration of serum 14-3-3ß protein was higher in the asthma group than in the control group (P<0.001). Serum 14-3-3ß protein showed a positive correlation with the percentage of neutrophils and total serum immunoglobulin E, and a negative correlation with conventional ventilatory lung function parameters (P<0.05). Cross-validation of combined indices showed that the combination of 14-3-3ß protein, FeNO, and the percentage of predicted value of forced expiratory flow at 75% of lung volume had an area under the curve of 0.948 for predicting asthma, with a sensitivity and specificity of 88.9% and 93.7%, respectively, demonstrating good diagnostic efficacy (P<0.001). The model had the best extrapolation. CONCLUSIONS: The combination of serum 14-3-3ß protein, FeNO, and the percentage of predicted value of forced expiratory flow at 75% of lung volume can significantly improve the diagnostic efficacy for asthma in children. Citation:Chinese Journal of Contemporary Pediatrics, 2024, 26(7): 723-729.

4-OI ameliorates bleomycin-induced pulmonary fibrosis by activating Nrf2 and suppressing macrophage-mediated epithelial-mesenchymal transition.

OBJECTIVES: Pulmonary fibrosis (PF) is a chronic and refractory interstitial lung disease with limited therapeutic options. 4-octyl itaconate (4-OI), a cell-permeable derivative of itaconate, has been shown to have anti-oxidative and anti-inflammatory properties. However, the effect and the underlying mechanism of 4-OI on PF are still unknown. METHODS: WT or Nrf2 knockout (Nrf2-/-) mice were intratracheally injected with bleomycin (BLM) to establish PF model and then treated with 4-OI. The mechanism study was performed by using RAW264.7 cells, primary macrophages, and conditional medium-cultured MLE-12 cells. RESULTS: 4-OI significantly alleviated BLM-induced PF and EMT process. Mechanism studies have found that 4-OI can not only directly inhibit EMT process, but also can reduce the production of TGF-ß1 by restraining macrophage M2 polarization, which in turn inhibits EMT process. Moreover, the effect of 4-OI on PF and EMT depends on Nrf2. CONCLUSION: 4-OI ameliorates BLM-induced PF in an Nrf2-dependent manner, and its role in alleviating PF is partly due to the direct inhibition on EMT, and partly through indirect inhibition of M2-mediated EMT. These findings suggested that 4-OI has great clinical potential to develop as a new anti-fibrotic agent for PF therapy.

Clinical efficacy of thymosin alpha 1 combined with multi-modality chemotherapy and its effects on immune function of patients with pulmonary tuberculosis complicated with diabetes.

OBJECTIVE: To observe the clinical efficacy of thymosin alpha 1 (Tα1) combined with multi-modality chemotherapy in patients with pulmonary tuberculosis (PTB) complicated with diabetes and discuss the effects of such combination therapy on lymphocyte subsets and sputum levels of cytokines. METHODS: A total of 120 patients with PTB complicated with diabetes admitted to the Affiliated Hospital of North China University of Science and Technology from January 2017 to January 2018 were included in this study and randomly divided into an experimental group (Tα1 group, n=60) and a control group (n=60). Clinical efficacy and adverse drug reactions were observed and compared between the two groups. Blood samples were collected for lymphocyte (NK cell and T cell subsets) levels by flow cytometry, and sputum samples were collected for cytokine (IL-2, IFN-γ, IL-4 and TNF-α) levels by ELISA. RESULTS: Two groups showed no statistically significant difference in sputum culture-negative conversion rate, chest lesion absorption rate, and cavity closure rate (P>0.05) after 6 months of treatment. However, after 12 months, the sputum culture-negative conversion rate, chest lesion absorption rate, and cavity closure rate in the Tα1 group increased compared with the control group, and the differences were statistically significant (P<0.05). There was a significant increase in CD3+, CD4+, NK-cells lymphocytes after six months in the Tα1 group than in the control group, whereas the CD8+, Th17, Treg lymphocytes in the Tα1 group were substantially lower than in the control group, with the differences showing statistical significance (P<0.05, respectively). After six months of treatment, the sputum supernatant levels of interleukin-4 (IL-4) and tumor necrosis factor α (TNF-α) in the Tα1 group were lower than in the control group, whereas the sputum supernatant levels of interleukin-2 (IL-2) and interferon gamma (IFN-γ) in the Tα1 group were higher than in the control group, and the differences were statistically significant (P<0.05, respectively). There was no statistically significant difference in the incidence of adverse reactions between the two groups (P>0.05). CONCLUSION: Tα1 combined with multi-modality chemotherapy has a visible curative effect on PTB patients with diabetes as it can regulate immune function and reduce the levels of inflammatory cytokines. As a safe combination therapy, it seems promising for further use in clinical practice.

Ikarugamycin inhibits pancreatic cancer cell glycolysis by targeting hexokinase 2.

Mangrove-derived actinobacteria strains are well-known for producing novel secondary metabolites. The polycyclic tetramate macrolactam (PTM), ikarugamycin (IKA) isolated from Streptomyces xiamenensis 318, exhibits antiproliferative activities against pancreatic ductal adenocarcinoma (PDAC) in vitro. However, the protein target for bioactive IKA is unclear. In this study, whole transcriptome-based profiling revealed that the glycolysis pathway is significantly affected by IKA. Metabolomic studies demonstrated that IKA treatment induces a significant drop in glucose-6-phosphate and a slight increase in intracellular glucose level. Analysis of glucose consumption, lactate production, and the extracellular acidification rate confirmed the inhibitory role of IKA on the glycolytic flux in PDAC cells. Surface plasmon resonance (SPR) experiments and docking studies identified the key enzyme of glycolysis, hexokinase 2 (HK2), as a molecular target of IKA. Moreover, IKA reduced tumor size without overt cytotoxicity in mice with PDAC xenografts and increased chemotherapy response to gemcitabine in PDAC cells in vitro. Taken together, IKA can block glycolysis in pancreatic cancer by targeting HK2, which may be a potential drug candidate for PDAC treatment.

Inhibition of TRIM8 restrains ischaemia-reperfusion-mediated cerebral injury by regulation of NF-κB activation associated inflammation and apoptosis.

Stroke is a leading global cause of mortality and disability. However, the pathogenesis that contributes to stroke has not been fully understood. The tripartite motif (TRIM)-containing proteins usually exhibit essential regulatory roles during various biological processes. TRIM8 is a RING domain-containing E3 ubiquitin ligase, playing crucial roles in regulating inflammation and apoptosis. In the present study, we reported that TRIM8 expression was significantly induced in the peri-infarct cortex area of mice after stroke onset. TRIM8 siRNA in vivo transfection resulted in the attenuated cognitive impairments in mice with cerebral ischaemia-reperfusion (IR) injury. In addition, TRIM8 knockdown was neuroprotective, as evidenced by the reduced infarct area, decreased neurological deficit score and down-regulated number of TUNEL-positive cells in the peri-infarct area. Moreover, TRIM8 inhibition obviously repressed glial fibrillary acidic protein (GFAP) expression in peri-hematoma cortex and hippocampus. Furthermore, inflammation induced by cerebral IR injury was highly restrained by TRIM8 knockdown in serum, peri-infarct area and hippocampus, which were along with the remarkable decreases in the phosphorylated expression of IκB kinase alpha (IKKα), inhibitory κB α (IκBα) and nuclear factor kappa B (NF-κB). Moreover, TRIM8 knockdown significantly reduced apoptosis in hippocampus of mice with cerebral IR injury by reducing Caspase-3 cleavage. The in vitro experiment confirmed the neuroprotective role of TRIM8-knockdown in regulating cerebral IR injury. Intriguingly, we found that TRIM8 over-expression-promoted inflammatory response and apoptosis could be markedly attenuated by the inactivation of NF-κB signaling through pre-treatment of JSH-23 or QNZ in lipopolysaccharide (LPS)-incubated astrocytes (ASTs). Therefore, TRIM8 positively regulated cerebral IR injury by activating NF-κB pathway to enhance inflammation and apoptosis. Targeting TRIM8 could provide feasible therapeutic treatment for stroke.

[Mechanism of oxymatrine in treatment of collagen-induced arthritis in mice].

Sophorae Flavescentis Radix, the root of Sophora flavescens Ait., has been widely applied in the medical field due to its anti-inflammatory, analgesic, bacteriostatic, antiviral, antitumor, and other pharmacological effects. The present study investigated the anti-rheumatoid arthritis effect of oxymatrine(OMT), the active component of Sophorae Flavescentis Radix by observing its effect on the function of B lymphocytes in collagen-induced arthritis(CIA) mice through the Toll-like receptor 9(TLR9)/myeloid differentiation factor 88(MyD88)/signal transducer and activator of transcription 3(STAT3) pathway. The CIA model in DBA/1 J mice was induced by bovine type Ⅱ collagen and complete Freund's adjuvant(CFA). Fifteen days after the primary immunization, mice were treated with OMT for 30 days by intraperitoneal injection. Paw swelling and arthritis index(AI) score were evaluated every 3 days. Joint histopathologic changes were observed by HE staining. Magnetic-activated cell sorting(MACS) was used to isolate B lymphocytes from the spleen of CIA mice spleen. The serum expression level of interleukin(IL)-21 was examined by the enzyme-linked immunosorbent assay(ELISA). The expression of TLR9, STAT3, p-STAT3, and IL-21 in B lymphocytes was detected by Western blot. The mRNA expression of TLR9, STAT3, and IL-21 in B lymphocytes was detected by real-time fluorescence-based quantitative PCR(qRT-PCR). The results showed that OMT could significantly alleviate the paw swelling, decrease the AI score, relieve synovial inflammatory cell infiltration and hyperplasia, reduce the level of inflammatory cytokines, and inhibit the expression of TLR9, STAT3, p-STAT3, and IL-21 of B lymphocytes in CIA mice. Therefore, OMT may alleviate rheumatoid arthritis by regulating TLR9/MyD88/STAT3 pathway in B lymphocytes, providing a valuable reference for the application of OMT in the clinical treatment of rheumatoid arthritis.

Mode locking of a coherent random fiber laser with selectable repetition rates.

Controlling emission of light in random structures/disordered systems, e.g., implementing mode-locked pulses in a laser system with a random structures/disordered systems, is a complex task. Usually, the generation of laser pulse by mode locking needs a stable fixed-length cavity that determines a specific repetition rate of the mode-locked pulses. Here, mode-locking laser pulses with selectable repetition rates are achieved in a typical one-dimensional disordered laser by passive mode locking. The laser includes disordered reflectors to provide multiple resonant modes associated with different cavity length. The regular pulses with adjustable repetition rates can be generated and selected by a nonlinear polarization rotator and a semiconductor saturable absorber mirror. The proposed work utilizing the advantages of multiple resonances in random lasers could pave a new way for regulating emission of light in the random structures/disordered system. And it displays an effective and realistic technical route to study ultrafast pulses generation and optical soliton dynamics in random structures/disordered systems.

Renoprotective Mono- and Triterpenoids from the Fruit of Gardenia jasminoides.

This paper describes the isolation and characterization of 17 new and 12 known terpenoids from the fruit of Gardenia jasminoides. The structures of eight new triterpenoids and nine new monoterpenoids, including their absolute configurations, were defined by spectroscopic analysis in combination of quantum chemical electronic circular dichroism (ECD), vibrational circular dichroism (VCD), and gauge-independent atomic orbital (GIAO) NMR calculations. The cytoprotective effects of the isolated compounds against lipopolysaccharide (LPS)-induced apoptosis in normal rat kidney tubule epithelioid (NRK 52e) cells were investigated in vitro. Compounds 10, 18, 20, 21, 24, and 26 exhibited significant protective effects with EC50 values from 14.2 nM to 1.6 µM.

Effects of branched-chain volatile fatty acids and fibrolytic enzyme on rumen development in pre- and post-weaned Holstein dairy calves.

The study evaluated the effects of branched-chain volatile fatty acids (BCVFA) and fibrolytic enzyme (FE) on rumen development in calves. Forty Holstein male calves at the same ages (15 ± 2.5 days of age) and weights (45 ± 3.3 kg of body weight [BW]) were assigned randomly to four groups with a 2 × 2 factorial arrangement of treatments. Supplemental BCVFA (0 g/d or 18 g/d) and FE (0 g/d or 1.83 g/d) were fed to calves. Data were analyzed as a 2 × 2 factorial arrangement random design by the mixed procedure of SAS. The BCVFA × FE interaction was observed for ruminal propionate, blood growth hormone (GH) and insulin-like growth factor-1 (IGF-1), and GH receptor (GHR) and IGF-1 receptor (IGF-1R) expression in the rumen mucosa. Dry matter intake was higher for BCVFA addition. The higher average daily gain and ruminal volatile fatty acids were observed for BCVFA or FE addition. Stomach weight and the length and width of rumen papillae were higher for BCVFA addition. The higher expression of GHR, IGF-1R and 3-hydroxy-3-methylglutaryl-CoA synthase 1 in rumen mucosa, and blood GH and IGF-1 were observed with BCVFA or FE addition. Blood ß-hydroxybutyrate and acetoacetate were higher for BCVFA addition. The results indicated that rumen development was promoted by BCVFA, but was not affected with FE addition in calves.

Right coronary artery-coronary sinus fistula diagnosed by three-dimensional echocardiography.

Right coronary artery-coronary sinus fistula is a very rare congenital anomaly in which a right coronary artery fistula drains into the right atrium, right ventricle, or pulmonary artery. A right coronary artery-coronary sinus fistula was diagnosed in a 44-year-old man by three-dimensional echocardiography and confirmed by computed tomography angiography and surgery. Relevant published experience in diagnosing this kind of anomaly is summarized.

Rupture of Aortic Sinus Aneurysms Diagnosed by Left Ventricular Opacification.

Rupture of aortic sinus aneurysms is a rare cardiac malformation that is commonly observed in the right coronary sinus but is rarely observed in the noncoronary sinus. Here, we report a case of aneurysm of the aortic sinus that ruptured into the left ventricular outflow tract and was diagnosed with left ventricular opacification. Left heart echocardiography can clearly demonstrate the structure of the heart and is one of the important diagnostic methods for diagnosing ruptured aortic sinus aneurysms. This observes the perfusion sequence of blood flow to clearly reveal the source, direction, and location of the ruptured aortic sinus aneurysm.

Novel Long Non-coding RNA Markers for Prognostic Prediction of Patients with Bladder Cancer.

Objective To explore novel long non-coding RNA (lncRNA) molecular markers related to bladder cancer prognosis and to construct a prognostic prediction model for bladder cancer patients. Methods LncRNA expression data of patients with bladder cancer were downloaded from TCGA database. Univariate Cox regression and likelihood-based survival analysis were used to discover prognosis related lncRNAs. Functional studies of prognosis related lncRNAs were conducted by co-expression analysis and pathway enrichment analysis. Multivariate Cox regression analysis was used to establish risk score model, and Receiver Operating Characteristic analysis was used to determine the optimal cut-off point of the model. The risk score model was validated through Kaplan Meier estimation method and log-rank test. Results Seven prognosis related lncRNAs (OCIAD1-AS1, RP11-111J6.2, AC079354.3, RP11-553A21.3, RP11-598F7.3, CYP4F35P and RP11-113K21.4) which can predict survival of bladder cancer patient were discovered. Co-expression analysis and pathway analysis of these novel lncRNA signature and their target genes further revealed that these lncRNAs play important roles in the occurrence and development of bladder cancer. Additionally, a seven-lncRNA signature based risk score model for prognostic prediction of bladder cancer patients was established and validated. Notably, we identified the potential significance of two tumor-related antisense lncRNAs (OCIAD1-AS1 and RP11-553A21.3) in the prognosis of bladder cancer. Conclusion Our results suggest that these lncRNA markers may serve as potential prognosis predictors for bladder cancer and deserve further functional verification studies.

GABRP regulates chemokine signalling, macrophage recruitment and tumour progression in pancreatic cancer through tuning KCNN4-mediated Ca2+ signalling in a GABA-independent manner.

BACKGROUND AND AIMS: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death worldwide. Neurotransmitter-initiated signalling pathway is profoundly implicated in tumour initiation and progression. Here, we investigated whether dysregulated neurotransmitter receptors play a role during pancreatic tumourigenesis. METHODS: The Cancer Genome Atlas and Gene Expression Omnibus datasets were used to identify differentially expressed neurotransmitter receptors. The expression pattern of gamma-aminobutyric acid type A receptor pi subunit (GABRP) in human and mouse PDAC tissues and cells was studied by immunohistochemistry and western blot analysis. The in vivo implications of GABRP in PDAC were tested by subcutaneous xenograft model and lung metastasis model. Bioinformatics analysis, transwell experiment and orthotopic xenograft model were used to identify the in vitro and in vivo effects of GABRP on macrophages in PDAC. ELISA, co-immunoprecipitation, proximity ligation assay, electrophysiology, promoter luciferase activity and quantitative real-time PCR analyses were used to identify molecular mechanism. RESULTS: GABRP expression was remarkably increased in PDAC tissues and associated with poor prognosis, contributed to tumour growth and metastasis. GABRP was correlated with macrophage infiltration in PDAC and pharmacological deletion of macrophages largely abrogated the oncogenic functions of GABRP in PDAC. Mechanistically, GABRP interacted with KCNN4 to induce Ca2+ entry, which leads to activation of nuclear factor κB signalling and ultimately facilitates macrophage infiltration by inducing CXCL5 and CCL20 expression. CONCLUSIONS: Overexpressed GABRP exhibits an immunomodulatory role in PDAC in a neurotransmitter-independent manner. Targeting GABRP or its interaction partner KCNN4 may be an effective therapeutic strategy for PDAC.

Overexpression of Rac GTPase Activating Protein 1 Contributes to Proliferation of Cancer Cells by Reducing Hippo Signaling to Promote Cytokinesis.

BACKGROUND & AIMS: Agents designed to block or alter cytokinesis can kill or stop proliferation of cancer cells. We aimed to identify cytokinesis-related proteins that are overexpressed in hepatocellular carcinoma (HCC) cells and might be targeted to slow liver tumor growth. METHODS: Using the Oncomine database, we compared the gene expression patterns in 16 cancer microarray datasets and assessed gene enrichment sets using gene ontology. We performed immunohistochemical analysis of an HCC tissue microarray and identified changes in protein levels that are associated with patient survival times. Candidate genes were overexpressed or knocked down with small hairpin RNAs in SMMC7721, MHCC97H, or HCCLM3 cell lines; we analyzed their proliferation, viability, and clone-formation ability and their growth as subcutaneous or orthotopic xenograft tumors in mice. We performed microarray analyses to identify alterations in signaling pathways and immunoblot and immunofluorescence assays to detect and localize proteins in tissues. Yeast 2-hybrid screens and mass spectrometry combined with co-immunoprecipitation experiments were used to identify binding proteins. Protein interactions were validated with co-immunoprecipitation and proximity ligation assays. Chromatin immunoprecipitation, promoter luciferase activity, and quantitative real-time polymerase chain reaction analyses were used to identify factors that regulate transcription of specific genes. RESULTS: The genes that were most frequently overexpressed in different types of cancer cells were involved in cell division processes. We identified 3 cytokinesis-regulatory proteins among the 10 genes most frequently overexpressed by all cancer cell types. Rac GTPase activating protein 1 (RACGAP1) was the cytokinesis-regulatory protein that was most highly overexpressed in multiple cancers. Increased expression of RACGAP1 in tumor tissues was associated with shorter survival times of patients with cancer. Knockdown of RACGAP1 in HCC cells induced cytokinesis failure and cell apoptosis. In microarray analyses, we found knockdown of RACGAP1 in SMMC7721 cells to reduce expression of genes regulated by yes-associated protein (YAP) and WW domain containing transcription regulator 1 (WWTR1 or TAZ). RACGAP1 reduced activation of the Hippo pathway in HCC cells by increasing activity of RhoA and polymerization of filamentous actin. Knockdown of YAP reduced phosphorylation of RACGAP1 and redistribution at the anaphase central spindle. We found transcription of the translocated promoter region, nuclear basket protein (TPR) to be regulated by YAP and coordinately expressed with RACGAP1 to promote proliferation of HCC cells. TPR redistributed upon nuclear envelope breakdown and formed complexes with RACGAP1 during mitosis. Knockdown of TPR in HCC cells reduced phosphorylation of RACGAP1 by aurora kinase B and impaired their redistribution at the central spindle during cytokinesis. STAT3 activated transcription of RACGAP in HCC cells. CONCLUSIONS: In an analysis of gene expression patterns of multiple tumor types, we found RACGAP1 to be frequently overexpressed, which is associated with shorter survival times of patients. RACGAP1 promotes proliferation of HCC cells by reducing activation of the Hippo and YAP pathways and promoting cytokinesis in coordination with TPR.

Retrospective analysis of the efficacy and influencing factors of autologous hematopoietic stem cell transplantation for multiple myeloma.

This study aims to review the clinical efficacy and factors affecting the treatment of multiple myeloma (MM) by autologous hematopoietic stem cell transplantation (ASCT). The clinical data of 47 patients with MM from the Department of Hematology of Henan Cancer Hospital from September 2010 to July 2018 were retrospectively analyzed. At pre-transplantation of autologous cells, 25.5% were in complete remission (CR), 14.9% were in very good partial remission (VGPR) and 59.6% were in partial remission (PR). Among these cases, one case had PR after three recurrences. At post-transplantation, 51% were in CR, including two cases who received double transplantations, 27.7% were in VGPR, and 21.3% were in PR. The median follow-up time was 27.6 months (4-96 months). The 3-year progression free survival (PFS) and overall survival (OS) were 47.9% and 79.6%, respectively. The Analysis of variance (ANOVA) results revealed that factors that affected OS were international staging system (ISS) stage (P = 0.002), CR and VGPR post-transplantation (P = 0.002), while factors that affected PFS were ISS stage (P = 0.005), pre-transplant induction therapy (P = 0.032), and disease risk stratification (P = 0.017). The curative effects for PFS were CR and VGPR pre-transplantation (P = 0.013) and post-transplantation (P = 0.011). The Cox multivariate regression analysis revealed that ISS stage and CR and VGPR post-transplantation were independent prognostic factors of OS. At post-transplantation, CR and VGPR, ISS stage, and pre-transplant induction therapy were independent prognostic factors for PFS. In conclusion, ASCT can improve the clinical efficacy and survival rate of MM patients. ISS stage, CR and VGPR post-transplantation are independent prognostic factors of OS and PFS, while pre-transplant induction therapy is an independent prognostic factor for PFS.

Populus euphratica JRL Mediates ABA Response, Ionic and ROS Homeostasis in Arabidopsis under Salt Stress.

Sodium chloride (NaCl) induced expression of a jacalin-related mannose-binding lectin (JRL) gene in leaves, roots, and callus cultures of Populus euphratica (salt-resistant poplar). To explore the mechanism of the PeJRL in salinity tolerance, the full length of PeJRL was cloned from P. euphratica and was transformed into Arabidopsis. PeJRL was localized to the cytoplasm in mesophyll cells. Overexpression of PeJRL in Arabidopsis significantly improved the salt tolerance of transgenic plants, in terms of seed germination, root growth, and electrolyte leakage during seedling establishment. Under NaCl stress, transgenic plants retained K⁺ and limited the accumulation of Na⁺. PeJRL-transgenic lines increased Na⁺ extrusion, which was associated with the upward regulation of SOS1, AHA1, and AHA2 genes encoding plasma membrane Na⁺/proton (H⁺) antiporter and H⁺-pumps. The activated H⁺-ATPases in PeJRL-overexpressed plants restricted the channel-mediated loss of K⁺ that was activated by NaCl-induced depolarization. Under salt stress, PeJRL⁻transgenic Arabidopsis maintained reactive oxygen species (ROS) homeostasis by activating the antioxidant enzymes and reducing the production of O2- through downregulation of NADPH oxidases. Of note, the PeJRL-transgenic Arabidopsis repressed abscisic acid (ABA) biosynthesis, thus reducing the ABA-elicited ROS production and the oxidative damage during the period of salt stress. A schematic model was proposed to show the mediation of PeJRL on ABA response, and ionic and ROS homeostasis under NaCl stress.

Effects of rumen-protected folic acid and rumen-protected sodium selenite supplementation on lactation performance, nutrient digestion, ruminal fermentation and blood metabolites in dairy cows.

BACKGROUND: Considering the insufficient ruminal synthesis of folic acid (FA), the higher degradability of FA, and the reduction of sodium selenite (SS) by ruminal microbes into non-absorbable elemental Se, this study evaluated the effects of rumen-protected FA (RPFA) and rumen-protected SS (RPSS) on lactation performance, nutrient digestion and blood metabolites in dairy cows. RESULTS: Dry matter (DM) intake and milk composition were unaltered, milk and milk fat yields were higher for both supplements, and milk protein yield was higher for RPFA addition. Digestibility of DM, neutral detergent fibre and acid detergent fibre was higher for both supplements, whereas that of organic matter and crude protein was higher for RPFA addition. Ruminal pH and ammonia N were lower, and concentration of total volatile fatty acids was higher for both supplements. Activity of cellobiase and xylanase was higher for RPFA addition, whereas that of pectinase and protease was higher for both supplements. The populations of total ruminal fungi, protozoa, Ruminococcus flavefaciens and Butyrivibrio fibrisolvens were higher for both supplements. The RPFA × RPSS interaction was significant for α-amylase activity, total ruminal bacteria and R. albus populations; these three variables were increased by RPSS but the increase was greater when cows were also fed RPFA. CONCLUSION: The results indicated that addition of RPFA or RPSS improved lactation performance, nutrient digestibility and ruminal fermentation in dairy cows by stimulating ruminal microbial growth and enzyme activity. © 2019 Society of Chemical Industry.

A Case of Massive Cerebral Arterial Air Embolism Induced by Artificial Pneumothorax and Its Analysis.

OBJECTIVE: This study aimed to investigate the characteristics of cerebral arterial air embolism. CLINICAL PRESENTATION AND INTERVENTION: The clinical data of a patient with cerebral arterial air embolism induced during artificial pneumothorax were retrospectively analyzed. The patient needed the induction of artificial pneumothorax for medical thoracoscopy but developed hemiplegia and disturbance of consciousness during the induction. Cerebral arterial air embolism was detected by head computed tomography. CONCLUSION: Artificial pneumothorax may induce cerebral arterial air embolism.

Endothelial GPR124 Exaggerates the Pathogenesis of Atherosclerosis by Activating Inflammation.

BACKGROUND/AIMS: Endothelial cell dysfunction is the principal pathological process underlying atherosclerotic cardiovascular disease. G protein-coupled receptor 124 (GPR124), an orphan receptor in the adhesion GPCR subfamily, promotes angiogenesis in the brain. In the present study, we explored the role of endothelial GPR124 in the development and progression of atherosclerosis in adult mice. METHODS: Using tetracycline-inducible transgenic systems, we generated mice expressing GPR124 specifically under control of the Tie-2 promoter. The animal model of atherosclerosis was constructed by intravenously injecting AAV-PCSK9DY into tetracycline-regulated mice and feeding the mice a high-fat diet for 16 consecutive weeks. Biochemical analysis and immunohistochemistry methods were used to address the role and mechanism of GPR124 in the pathological process of atherosclerosis. RESULTS: Higher TC (total cholesterol) and LDL-C (low density lipoprotein cholesterol) levels in serum and greater lipid deposition in the aortic sinus were found in atherosclerotic mice with GPR124 overexpression, coincident with the elevated proliferation of smooth muscle cells. We observed an elevation of ONOO- in the aortic sinus in this model by using immunofluorescence, and the experiments showed that the specific overexpression of GPR124 in the endothelium induced the up-regulation of CD68, NLRP3 and caspase-1 levels in the aortic sinus. CONCLUSION: The above results indicate that manipulating GPR124 in the endothelium may contribute to delayed pathological progression of atherosclerosis.