Comparison of transabdominal and transthoracic surgical approaches in the treatment of Siewert type II esophagogastric junction cancers: A propensity score-matching analysis.

BACKGROUND: The appropriate surgical approach for Siewert type II esophagogastric junction (EGJ) cancer remains under discussion. We compared surgical outcomes between transabdominal (TA) and transthoracic (TT) approaches for treating type II EGJ cancers. MATERIALS AND METHODS: This retrospective study reviewed 397 type II EGJ cancer patients who underwent surgery from January 2001 to May 2019. We used a 1:3 propensity score-matching method for the analysis. The matching factors were age, sex, American Society of Anesthesiologists score, period of operation, and pathologic stage. Matching was performed using the MatchIt package of R 4.0.2. RESULTS: A total of 46 patients in the TT group was matched to 126 patients in the TA group. R0 resection was achieved in both groups and was not statistically different between groups (p = 0.455). In the TA group, the operation time and in-hospital stay length were significantly shorter (p < 0.001) and the intraoperative estimated blood loss (EBL) was significantly lower than in the TT group (p = 0.011). The postoperative complication rate between the two groups was significantly different (p = 0.003). There was marginal difference in the five-year OS rate (p = 0.049) and significant difference in the five-year DFS (p = 0.039). However, surgical approach was not a significant prognostic factor in multivariate analysis of OS or DFS. CONCLUSIONS: There was no clear survival benefit of one approach over the other. However, less intraoperative bleeding, lower postoperative complication rate, shorter operation time, and reduced in-hospital stay length were correlated with the TA approach.

Epigenetic regulation of p62/SQSTM1 overcomes the radioresistance of head and neck cancer cells via autophagy-dependent senescence induction.

Tumors are composed of subpopulations of cancer cells with functionally distinct features. Intratumoral heterogeneity limits the therapeutic effectiveness of cancer drugs. To address this issue, it is important to understand the regulatory mechanisms driving a subclonal variety within a therapy-resistant tumor. We identified tumor subclones of HN9 head and neck cancer cells showing distinct responses to radiation with different levels of p62 expression. Genetically identical grounds but epigenetic heterogeneity of the p62 promoter regions revealed that radioresistant HN9-R clones displayed low p62 expression via the creation of repressive chromatin architecture, in which cooperation between DNMT1 (DNA methyltransferases 1) and HDAC1 (histone deacetylases 1) resulted in DNA methylation and repressive H3K9me3 and H3K27me3 marks in the p62 promoter. Combined inhibition of DNMT1 and HDAC1 by genetic depletion or inhibitors enhanced the suppressive effects on proliferative capacity and in vivo tumorigenesis following irradiation. Importantly, ectopically p62-overexpressed HN9-R clones increased the induction of senescence along with p62-dependent autophagy activation. These results demonstrate the heterogeneous expression of p62 as the key component of clonal variation within a tumor against irradiation. Understanding the epigenetic diversity of p62 heterogeneity among subclones allows for improved identification of the functional state of subclones and provides a novel treatment option to resolve resistance to current therapies.

Spin currents and spin-orbit torques in ferromagnetic trilayers.

Magnetic torques generated through spin-orbit coupling1-8 promise energy-efficient spintronic devices. For applications, it is important that these torques switch films with perpendicular magnetizations without an external magnetic field9-14. One suggested approach 15 to enable such switching uses magnetic trilayers in which the torque on the top magnetic layer can be manipulated by changing the magnetization of the bottom layer. Spin currents generated in the bottom magnetic layer or its interfaces transit the spacer layer and exert a torque on the top magnetization. Here we demonstrate field-free switching in such structures and show that its dependence on the bottom-layer magnetization is not consistent with the anticipated bulk effects 15 . We describe a mechanism for spin-current generation16,17 at the interface between the bottom layer and the spacer layer, which gives torques that are consistent with the measured magnetization dependence. This other-layer-generated spin-orbit torque is relevant to energy-efficient control of spintronic devices.

Angiotensin II Causes Apoptosis of Adult Hippocampal Neural Stem Cells and Memory Impairment Through the Action on AMPK-PGC1α Signaling in Heart Failure.

Data are limited on the mechanisms underlying memory impairment in heart failure (HF). We hypothesized that angiotensin II (Ang II) may determine the fate of adult hippocampal neural stem cells (HCNs), a cause of memory impairment in HF. HCNs with neurogenesis potential were isolated and cultured from adult rat hippocampi. Ang II decreased HCN proliferation in dose- and time-dependent manners. Moreover, Ang II treatment (1 µM) for 48 hours induced apoptotic death, which was attenuated by pretreatment with Ang II receptor blockers (ARBs). Ang II increased mitochondrial reactive oxygen species (ROS) levels, which was related to mitochondrial morphological changes and functional impairment. Moreover, ROS activated the AMP-activated protein kinase (AMPK) and consequent peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) expression, causing cell apoptosis. In the HF rat model induced by left anterior descending artery ligation, ARB ameliorated the spatial memory ability which decreased 10 weeks after ischemia. In addition, neuronal cell death, especially of newly born mature neurons, was observed in HF rat hippocampi. ARB decreased cell death and promoted the survival of newly born neural precursor cells and mature neurons. In conclusion, Ang II caused HCN apoptosis through mitochondrial ROS formation and subsequent AMPK-PGC1α signaling. ARB improved learning and memory behaviors impaired by neuronal cell death in the HF animal model. These findings suggest that HCN is one treatment target for memory impairment in HF and that ARBs have additional benefits in HF combined with memory impairment. Stem Cells Translational Medicine 2017;6:1491-1503.

Dexamethasone inhibits in vivo tumor growth by the alteration of bone marrow CD11b⁺ myeloid cells.

Inflammation is closely associated with tumor growth, which is mediated by the activation of bone marrow-derived CD11b(+) cells. Here, we investigated whether anti-inflammatory dexamethasone (Dex), a synthetic glucocorticoid (GC), could regulate tumor growth and CD11b(+) myeloid bone marrow cells (BMCs) in lymphocyte (R1), monocyte (R2) and granulocyte (R3) regions of FSC-SSC dot plot. The growth of B16F10 mouse melanoma tumor was inhibited in Dex-injected group. Lung metastasis was decreased and the lifespan was elongated in Dex-injected mice with tumor resection. Intravenous injection of B16F10 cells increased the percentage of CD11b(+) myeloid BMCs in R1 and R2 regions from 3h to 72h. In contrast, little changes in the percentage of CD11b(+) myeloid BMCs were detected in R3 region. Among CD11b(+) myeloid BMCs, the percentage of CD11b(+)Gr-1(+) cells was increased in R1, R2 and R3 regions. Absolute number of CD11b(+) and CD11b(+)Gr-1(+) cells was enhanced in R1 region from 3h to 72 h. B16F10 tumor growth was significantly increased by intravenous injection of CD11b(+) BMCs. Tumor-bearing mice showed an increase in the percentage of CD11b(+) myeloid BMCs in R2 region and CD11b(+)Gr-1(+) cells in R2 and R3 regions, which are reduced by intravenous injection with Dex. Absolute number of CD11b(+)Gr-1(+) cells was enhanced in R2 and R3 regions. Tumor growth was significantly inhibited by intravenous injection of BMCs collected from Dex-treated tumor-bearing mice. Taken together, data demonstrate that tumor regression by Dex was resulted from the alteration of CD11b(+) myeloid BMCs and their inhibitory function to tumor growth. It suggests that CD11b(+) myeloid BMCs could regulate antitumor efficacy of GCs such as Dex.

B cell activating factor-dependent expression of vascular endothelial growth factor in MH7A human synoviocytes stimulated with tumor necrosis factor-α.

Angiogenesis in rheumatoid arthritis (RA) is one of the histological hallmarks, which is mediated by expression of vascular endothelial growth factor (VEGF) in RA synovium. VEGF expression is enhanced by TNF-α, the main pro-inflammatory cytokine in RA. B cell activating factor (BAFF) which plays a role in maturation and maintenance of B cells is also associated with autoimmune RA. Here, we investigated whether BAFF could regulate VEGF expression in TNF-α-stimulated synovium using MH7A synovial cells that are established by transfection with the SV40 T antigen. Changes in hBAFF and hVEGF were measured by western blotting, RT-PCR and luciferase promoter assay. When MH7A cells were treated with TNF-α, we observed that TNF-α increased the expression of hBAFF and hVEGF. TNF-α also increased transcriptional activity of hBAFF and hVEGF as judged by luciferase promoter assay. Inhibition of hBAFF expression with BAFF-siRNA decreased transcriptional level and activity of hVEGF. In addition, when c-fos expression was inhibited by the transfection of MH7A cells with c-fos-siRNA, data showed that transcriptional level and activity of both hBAFF and hVEGF were attenuated by the activation with TNF-α. Our results demonstrate for the first time that VEGF-mediated angiogenesis in RA could be controlled by TNF-α-induced BAFF expression through c-Fos. Data suggest that TNF-α-induced BAFF expression and BAFF-mediated VEGF expression in synovium may cooperate to maintain the capacity of such cells to protect B cells from apoptosis and the supply of nutrients and oxygen in inflammatory microenvironments.

Protein kinase C stimulates human B cell activating factor gene expression through reactive oxygen species-dependent c-Fos in THP-1 pro-monocytic cells.

BAFF is associated with various immunological diseases. Previously, we have reported that mouse B cell activating factor (mBAFF) expression was dependent on nuclear localization of co-activator, p300 and the activation of transcription factors including NF-κB and CREB. Here, we investigated whether transcription factor, c-Fos, regulates human (h) BAFF expression through promoter activation by PMA-induced reactive oxygen species (ROS) production. We cloned hBAFF promoter into luciferase-expressing pGL3-basic vector. The activity of 1.0 kb hBAFF promoter was higher than that in 0.75, 0.5 or 0.25 kb hBAFF promoter. The existence of three AP-1 binding motifs was computer-analyzed in hBAFF promoter. The stimulation with PMA and ionomycin (IOM) increased 1.0 kb hBAFF promoter activity, time-dependently. PMA/IOM-stimulation rapidly enhanced c-Fos expression in THP-1 human pro-monocytic cells. Binding of c-Fos to hBAFF promoter was detected by chromatin immunoprecipitation (ChIP) assay. hBAFF expression and its promoter activity were decreased by the transfection with small interference (si) RNA of c-Fos. ROS production in THP-1 cells was increased by PMA/IOM-stimulation. In addition, hBAFF activity stimulated by PMA/IOM was reduced by N-acetyl-cysteine (NAC), a well-known ROS scavenger. Serum starvation (0.5% FBS) producing ROS and the exogenous H(2)O(2) treatment also enhanced hBAFF promoter activity. c-Fos expression and AP-1 binding to oligonucleotide were reduced by the treatment with NAC. H(2)O(2) was not able to induce hBAFF expression in the presence of staurosporine, PKC inhibitor. Data suggest that hBAFF expression could be regulated by promoter activation through c-Fos association, which might be dependent on PMA-induced ROS production.

Regulation of glycogen synthase kinase-3 by thymosin beta-4 is associated with gastric cancer cell migration.

Thymosin beta-4 (Tß4), actin-sequestering protein, plays important roles in many cellular functions including cancer cell migrations. Glycogen synthase kinase (GSK) in Wnt signaling pathway is a key molecule to control intercellular interaction. Here, we investigated whether GSK-3 activity is regulated by Tß4 and it is associated with Tß4-mediated migration in gastric cancer cells. Various expression level of Tß4 was observed in human gastric tumor tissues. Migration in gastric cancer cells, SNU638 and SNU668, was dependent on a relative expression level of Tß4. Cell migration was higher in SNU668 with a higher expression level of Tß4 than that in SNU638 with a lower Tß4. Although the level of phosphorylated(p)-GSK-3α (inactive), ß-catenin, E-cadherin and E-cadherin:ß-catenin complex was relatively higher, p-GSK-3ß (inactive) was lower in SNU638 compared to those in SNU668 cells. LiCl, GSK-3α/ß inhibitor, reduced lung metastasis of B16F10 mouse melanoma cells and SNU668 cell migration. Small interference (si)RNA of GSK-3α increased SNU638 cell migration in accordance with the reduction of E-cadherin:ß-catenin complex formation through a decrease in ß-catenin and E-cadherin. Expression level of GSK-3α/ß, ß-catenin and E-cadherin in SNU668 and SNU638 was reversed by Tß4-siRNA and by the treatment with acetylated-serine-aspartic acid-lysine-proline (SDKP) tetrapeptide of Tß4, respectively. E-cadherin expression in SNU638 cells was decreased by ß-catenin-siRNA. PD98059, MEK inhibitor, or U0126, ERK inhibitor, reduced SNU668 cell migration accompanying an increase in p-GSK-3α, ß-catenin and E-cadherin. Taken together, data indicated that the expression of GSK-3α, ß-catenin and E-cadherin could be negatively regulated by Tß4-induced ERK phosphorylation. It suggests that Tß4 could be a novel regulator to control Wnt signaling pathways.

Phosphodiesterase inhibitors control A172 human glioblastoma cell death through cAMP-mediated activation of protein kinase A and Epac1/Rap1 pathways.

AIMS: We investigated whether cAMP-mediated protein kinase A(PKA) and Epac1/Rap1 pathways differentially affect brain tumor cell death using 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone(rolipram), specific phosphodiesterase type IV(PDE IV) inhibitor. MAIN METHODS: A172 and U87MG human glioblastoma cells were used. Percentage of cell survival was determined by MTT assay. PKA and Epac1/Rap1 activation was determined by western blotting and pull-down assay, respectively. Cell cycle and hypodiploid cell formation were assessed by flow cytometry analysis. KEY FINDINGS: Non-specific PDE inhibitors, isobutylmethylxanthine(IBMX) and theophylline reduce survival percentage of A172 and U87MG cells. The expression of PDE4A and PDE4B was detected in A172 and U87MG cells. Rolipram-treated A172 or U87MG cell survival was lower in the presence of forskolin, adenylate cyclase activator, than that in its absence. Co-treatment with rolipram and forskolin also enhanced CREB phosphorylation on serine 133 that was inhibited by H-89, PKA inhibitor and cAMP-responsive guanine nucleotide exchange factor 1(Epac1), a Rap GDP exchange factor-mediated Rap1 activity in A172 cells. When A172 cells were treated with cell-permeable dibutyryl-cAMP(dbcAMP), PKA activator or 8-(4-chloro-phenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate(CPT), Epac1 activator, basal level of cell death was increased and cell cycle was arrested at the phase of G2/M. Rolipram-induced A172 cell death was also increased by the co-treatment with dbcAMP or CPT, but it was inhibited by the pre-treatment with H-89. SIGNIFICANCE: These findings demonstrate that PKA and Epac1/Rap1 pathways could cooperatively play a role in rolipram-induced brain tumor cell death. It suggests that rolipram might regulate glioblastoma cell density through dual pathways of PKA- and Epac1/Rap1-mediated cell death and cell cycle arrest.

KR33426, [2-(2,5-dichlorophenyl)-5-methyloxazol-4yl]carbonylguanidine, is a novel compound to be effective on mouse systemic lupus erythematosus.

B cell-activating factor (BAFF) is a key regulator of B lymphocyte development. Signals from BAFF are transmitted through binding to a specific BAFF receptor (BAFF-R). Here, we established screening method to find a specific inhibitor for the interference of BAFF-BAFF-R interactions. We screened oxazole-4-carbonylguanidine derivatives and selected KR33426, [2-(2,5-dichlorophenyl)-5-methyloxazol-4yl]carbonylguanidine, as a candidate to interfere BAFF-BAFF-R interactions. KR33426 inhibited BAFF-mediated anti-apoptotic effect on splenocytes as judged by hypodiploid cell formation. KR33426 also increased the degradation of procaspase-3 that was inhibited by BAFF protein. In addition, we examined whether KR33426 was effective on the treatment of systemic lupus erythematosus-like symptom in MRL(lpr/lpr) mouse. When 5 or 10mg/kg KR33426 was intraperitoneally administered to MRL(lpr/lpr) mice for 4 weeks, histopathological changes were ameliorated in the narrowed space between renal glomerulus and glomerulus capsule. KR33426 reduced B220(+) B cell population and B cell mitogen, lipopolysaccharide-stimulated lymphocyte proliferation in splenocytes. KR33426 attenuated an increase in CD43(-)IgM(+) immature pro-B and a decrease in CD21(+) IgM(+) T2-B and IgD(+) IgM(-)recirculating-B cells on B cell development. Data show that KR33426 inhibits BAFF-BAFF-R interactions and it is effective on the treatment of systemic lupus erythematosus-like symptom in MRL(lpr/lpr) mice. Thus, it suggests that KR33426 is a novel candidate to develop anti-autoimmune therapeutics by the interference of BAFF-BAFF-R interactions, specifically.