Comparison of pre- and postoperative myocardial injuries on mortality after non-cardiac surgery: a retrospective analysis using an inverse probability weighting adjustment.

Although both pre- and postoperative myocardial injuries are strongly associated with an increased postoperative mortality, no study has directly compared the effects of pre- and postoperative myocardial injuries on 30-day mortality after non-cardiac surgery. Therefore, we evaluated and compared the effects of pre- and postoperative myocardial injury on 30-day mortality after non-cardiac surgery. From January 2010 to December 2016, patients undergoing non-cardiac surgery were stratified into either the normal (n = 3182), preoperative myocardial injury (n = 694), or postoperative myocardial injury (n = 756) groups according to the peak cardiac troponin value. Myocardial injury was defined as a sole elevation of cardiac troponin value above the 99th percentile upper reference limit without ischemic symptom using the 4th universal definition of myocardial infarction. Patients in the preoperative myocardial injury group were further divided into the attenuated (n = 177) or persistent myocardial injury group (n = 517) according to the normalization of cardiac troponin level in postoperative period. As the primary outcome, postoperative 30-day mortalities were compared among the groups using the weighted Cox proportional-hazards regression models with the inverse probability weighting. Compared with the normal group, postoperative 30-day mortality was increased significantly both in the pre- and postoperative myocardial injury groups (1.4% vs. 10.7%; hazard ratio [HR] 3.12; 95% confidence interval [CI] 1.62-6.01; p = 0.001 and 1.4% vs. 7.4%; HR 4.49; 95% CI 2.34-8.60; p < 0.001, respectively), however, there was no difference between the pre- and postoperative myocardial injury groups (HR, 1.44; 95% CI 0.79-2.64; p = 0.45). In addition, the attenuated myocardial injury group showed a significantly lower postoperative 30-day mortality than the persistent myocardial injury group (5.6% vs. 12.4%; HR 2.23; 95% CI 1.17-4.44; p = 0.02). In patients undergoing non-cardiac surgery, preoperative myocardial injury also increased postoperative 30-day mortality to a similar degree of postoperative myocardial injury. Further studies on the importance of preoperative myocardial injury are needed.Clinical trial number and registry URL: KCT0004348 ( www.cris.nih.go.kr ).

Comparative Efficacy of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers after Coronary Artery Bypass Grafting.

Although angiotensin receptor blockers (ARBs) are considered as an alternative for those with angiotensin converting enzyme inhibitors (ACEi) intolerance, the comparative effectiveness of ARBs and ACEi remains controversial in patients who underwent coronary artery bypass grafting (CABG). We aimed to compare the clinical effects of the two types of renin-angiotensin-aldosterone system (RAAS) inhibitors in patients who underwent CABG. From January 2001 to January 2015, among the 5456 patients, data from 1198 (20.1%) patients who used a RAAS inhibitor at discharge were analyzed. These 1198 patients were classified into ACEi (N = 900) and ARB (N = 298) groups. The primary outcome was major adverse cardiovascular and cerebrovascular events (MACCE) during a median follow-up period of 48 months. Propensity-matched analysis revealed that the incidence of MACCE over a 48 month follow-up period did not differ between the groups (HR, 0.65; 95% CI, 0.36-1.21; p = 0.17), but it was significantly lower in the ARB group during the 12 month follow-up period (HR, 0.46; 95% CI, 0.22-0.96; p = 0.04). In conclusion, ARBs may have comparable protective effects to ACEi and be a reasonable alternative for intolerant patients after CABG. The beneficial effects of ARBs depending on follow-up period require further investigation.

Ascorbic acid improves thrombotic function of platelets during living donor liver transplantation by modulating the function of the E3 ubiquitin ligases c-Cbl and Cbl-b.

OBJECTIVE: To investigate the effect of ascorbic acid (AA) on hemostatic function during living donor liver transplantation (LDLT). METHODS: Blood samples from 21 LDLT recipients were taken within 30 minutes after induction and at 120 minutes after reperfusion. Rotational thromboelastography (TEG) and western blot analysis were used to analyze for fibrinolysis and functional changes in c-Cbl and Cbl-b, respectively. TEG test samples were prepared as one of three groups: C group (0.36 mL of blood), N group (0.324 mL of blood + 0.036 mL of 0.9% normal saline), and A group (0.324 mL of blood + 0.036 mL of 200 µmol/L-AA dissolved in 0.9% normal saline). RESULTS: AA decreased fibrinolysis and increased clot rigidity at baseline and 120 minutes after reperfusion. Cbl-b expression was significantly increased at baseline and 120 minutes after reperfusion in the A group compared with the C and N groups. However, c-Cbl phosphorylation was most significantly decreased in the A group at baseline and 120 minutes after reperfusion. CONCLUSION: AA can significantly decrease fibrinolysis and improve clot rigidity in LT recipients during LDLT, and functional changes in Cbl-b and c-Cbl might represent the underlying mechanism. AA may be considered for use during LDLT to decrease hyperfibrinolysis.

Tumefactive demyelinating lesions as a first clinical event: Clinical, imaging, and follow-up observations.

BACKGROUND: Tumefactive demyelinating lesions (TDLs) are associated with a variety of demyelinating diseases in the central nervous system (CNS). However, there are no current guidelines describing how to classify and treat patients with this rare phenotype. Thus, the present study aimed to determine the long-term evolution and disease course of patients initially presenting with TDLs and to describe their clinical and radiographic characteristics. METHODS: From the National Cancer Center registry of inflammatory diseases of the CNS, 31 patients initially presenting with TDLs with follow-up for at least 12 months were enrolled and their demographic, clinical, and radiographic characteristics were evaluated. RESULTS: The median follow-up duration was 37.6 months, during which time 11 patients were diagnosed with neuromyelitis optica spectrum disorder (NMOSD), seven with multiple sclerosis (MS), and 11 remained idiopathic; six did not experience any further clinical events (isolated demyelinating syndrome), and five patients experienced recurrent demyelinating events that were not consistent with either MS or NMOSD. Of the remaining two patients, one was diagnosed with hyperthyroidism-associated demyelination and one with tacrolimus-induced demyelination. CONCLUSIONS: The majority of TDLs evolve into MS or NMOSD. However, despite extensive diagnostic work-ups and long-term follow-ups, the etiology of TDLs was unknown for some patients.

Angiomotin is a novel component of cadherin-11/ß-catenin/p120 complex and is critical for cadherin-11-mediated cell migration.

Loss of E-cadherin and up-regulation of mesenchymal cadherins, a hallmark of the epithelial-mesenchymal transition, contributes to migration and dissemination of cancer cells. Expression of human cadherin-11 (Cad11), also known as osteoblast cadherin, in prostate cancer increases the migration of prostate cancer cells. How Cad11 mediates cell migration is unknown. Using the human Cad11 cytoplasmic domain in pulldown assays, we identified human angiomotin (Amot), known to be involved in cell polarity, migration, and Hippo pathway, as a component of the Cad11 protein complex. Deletion analysis showed that the last C-terminal 10 amino acids in Cad11 cytoplasmic domain are required for Amot binding. Further, Cad11 preferentially interacts with Amot-p80 than Amot-p130 isoform and binds directly to the middle domain of Amot-p80. Cad11-Amot interaction affects Cad11-mediated cell migration, but not homophilic adhesion, as deletion of Amot binding motif of Cad11 (Cad11-ΔAmot) did not abolish Cad11-mediated cell-cell adhesion of mouse L cells, but significantly reduced Cad11-mediated cell migration of human C4-2B4 and PC3-mm2 prostate cancer cells and human HEK293T cells. Together, our studies identified Amot-p80 as a novel component of the Cad11 complex and demonstrated that Amot-p80 is critical for Cad11-mediated cell migration.

Alkali-metal ion catalysis and inhibition in SNAr displacement: relative stabilization of ground state and transition state determines catalysis and inhibition in SNAr reactivity.

We report here the first observation of alkali-metal ion catalysis and inhibition in SNAr reactions. The plot of kobsd versus [alkali-metal ethoxide] exhibits downward curvature for the reactions of 1-(4-nitrophenoxy)-2,4-dinitrobenzene with EtOLi, EtONa, and EtOK, but upward curvature for the corresponding reaction with EtOK in the presence of 18-crown-6-ether (18C6). Dissection of kobsd into the second-order rate constants for the reactions with the dissociated EtO(-) and the ion-paired EtOM (i.e., k EtO - and kEtOM , respectively) has revealed that the reactivity increases in the order EtOLi

Inhibition of cell adhesion by a cadherin-11 antibody thwarts bone metastasis.

UNLABELLED: Cadherin-11 (CDH11) is a member of the cadherin superfamily mainly expressed in osteoblasts but not in epithelial cells. However, prostate cancer cells with a propensity for bone metastasis express high levels of cadherin-11 and reduced levels of E-cadherin. Downregulation of cadherin-11 inhibits interaction of prostate cancer cells with osteoblasts in vitro and homing of prostate cancer cells to bone in an animal model of metastasis. These findings indicate that targeting cadherin-11 may prevent prostate cancer bone metastasis. To explore this possibility, a panel of 21 monoclonal antibodies (mAb) was generated against the extracellular (EC) domain of cadherin-11. Two antibodies, mAbs 2C7 and 1A5, inhibited cadherin-11-mediated cell-cell aggregation in vitro using L-cells transfected with cadherin-11. Both antibodies demonstrated specificity to cadherin-11, and neither antibody recognized E-cadherin or N-cadherin on C4-2B or PC3 cells, respectively. Furthermore, mAb 2C7 inhibited cadherin-11-mediated aggregation between the highly metastatic PC3-mm2 cells and MC3T3-E1 osteoblasts. Mechanistically, a series of deletion mutants revealed a unique motif, aa 343-348, in the cadherin-11 EC3 domain that is recognized by mAb 2C7 and that this motif coordinated cell-cell adhesion. Importantly, administration of mAb 2C7 in a prophylactic setting effectively prevented metastasis of PC3-mm2 cells to bone in an in vivo mouse model. These results show that targeting the extracellular domain of cadherin-11 can limit cellular adhesion and metastatic dissemination of prostate cancer cells. IMPLICATIONS: Monotherapy using a cadherin-11 antibody is a suitable option for the prevention of bone metastases.

Interplay of reactive oxygen species, intracellular Ca2+ and mitochondrial homeostasis in the apoptosis of prostate cancer cells by deoxypodophyllotoxin.

The limited treatment option for recurrent prostate cancer and the eventual resistance to conventional chemotherapy drugs has fueled continued interest in finding new anti-neoplastic agents of natural product origin. We previously reported anti-proliferative activity of deoxypodophyllotoxin (DPT) on human prostate cancer cells. Using the PC-3 cell model of human prostate cancer, the present study reveals that DPT induced apoptosis via a caspase-3-dependent pathway that is activated due to dysregulated mitochondrial function. DPT-treated cells showed accumulation of the reactive oxygen species (ROS), intracellular Ca (i)(2+) surge, increased mitochondrial membrane potential (MMP, ΔΨ(m)), Bax protein translocation to mitochondria and cytochrome c release to the cytoplasm. This resulted in caspase-3 activation, which in turn induced apoptosis. The antioxidant N-acetylcysteine (NAC) reduced ROS accumulation, MMP and Ca (i)(2+) surge, on the other hand the Ca(2+) chelator BAPTA inhibited the Ca( i)(2+) overload and MMP without affecting the increase of ROS, indicating that the generation of ROS occurred prior to Ca(2+) flux. This suggested that both ROS and Ca( i)(2+) signaling play roles in the increased MMP via Ca (i)(2+)-dependent and/or -independent mechanisms, since ΔΨ(m) elevation was reversed by NAC and BAPTA. This study provides the first evidence for the involvement of both ROS- and Ca( i)(2+)-activated signals in the disruption of mitochondrial homeostasis and the precedence of ROS production over the failure of Ca(2+) flux homeostasis.

New signaling pathways from cancer progression modulators to mRNA expression of matrix metalloproteinases in breast cancer cells.

We observed previously that each of seven cancer progression inhibitors suppresses the mRNA expression of some matrix metalloproteinases (MMPs), but stimulates that of others, in breast cancer cells. In the present study we tested the effect of overexpressing other cancer modulators on MMP expression. The MMPs tested are MMP1, MMP2, MMP7, MMP13, MMP14, MMP16, MMP19, and MMP25. The proteins that were overexpressed are cancer inhibitors (NME, DRG1, IL10), enhancers (SOD2, FAK, IL17, and CREB), and proteins that suppress cancer progression in cells of some cancers and promote it in others (FUT1, integrin beta3, serpin E1, TIAM1, and claudin 4). Unexpectedly, all of them only lowered MMP mRNA expression, mainly of MMP16, MMP2, and MMP13, in breast cancer cells. Signaling from SOD2 uncoupled the accumulation of two MMP16 mRNA splice variants, suggesting signaling to a late step in MMP16 mRNA accumulation, such as MMP16 mRNA stabilization or late mRNA processing. Signaling that modulates MMP expression differed widely among the total population of MDA-MB-231 cells and single-cell progenies cloned from that population. It also differed substantially between cells of two metastatic breast basal adenocarcinomas, MDA-MB-231 and MDA-MB-468. The present study detected 37 new signaling pathways from cancer progression modulators located upstream of MMP mRNA expression in human breast cancer cells. Our siRNA-induced MMP knockdown data support the interpretation that signaling from MMP19, MMP1, MMP7, MMP12, MMP14, and MMP11 each stimulates the mRNA expression of other MMPs in breast cancer cells.

Many new down- and up-regulatory signaling pathways, from known cancer progression suppressors to matrix metalloproteinases, differ widely in cells of various cancers.

Previously we detected new signaling pathways, some downregulatory and others upregulatory, from seven known suppressors of cancer progression to the expression of eight cancer-promoting matrix metalloproteinases (MMPs) in breast cancer cells. The goals of the present study were to test whether the preceding observations occur only in breast cancer cells and, if not, whether the same downregulatory and upregulatory signaling pathways are active in cells of other human cancers, focusing on activator protein-2alpha, E-cadherin, fibulin1D, interleukin 4, p16(INK4alpha), p53, PTEN, and RKIP, and on MMP1, MMP2, MMP7, MMP13, MMP14, MMP16, MMP19, and MMP25. To this end, in the present study we tested the effects of raising the cellular levels of wild-type copies of these known suppressors of cancer progression on the expression of these MMPs. This study yielded several unexpected results. We have detected 53 new signaling pathways in cells of prostate, brain, lung, ovarian and breast human cancers, with an abundance of signaling pathways as high as approximately 40% of the cancer progression regulator/MMP pairs tested in cells of prostate and breast cancers. Cells of various cancers differed widely and sequence-specifically in the identity of their signaling pathways, so that almost 90% of the pathways were different in cells from one cancer to another. In each of 18 out of 51 signaling pathways, a known suppressor of cancer progression stimulated, rather than inhibited, the expression of a cancer-promoting MMP. Ten signaling pathways were upregulatory in cells of some cancers and downregulatory in cells of other cancers.

Piplartine induces caspase-mediated apoptosis in PC-3 human prostate cancer cells.

The present study examined the anti-proliferative effects of piplartine on the human prostate cancer cell line PC-3. This is the first report demonstrating the piplartine anti-cancer activity toward prostate cancer cell lines, although its precise mechanism of action is still not completely defined. In MTT assays, it preferentially inhibited growth of androgen-independent PC-3 cells in a dose-dependent (3-30 microM) and time-dependent (12-48 h) manner. In PC-3 cells, it showed an IC50 of 15 microM after 24 h of treatment. After a 24-30 microM treatment for 24 h, there were some reduction of cell volume, cell vacuolization, chromatin condensation and increased number of apoptotic cells visible by light and fluorescence microscopy. Agarose gel electrophoresis revealed that cells treated with piplartine exhibited DNA fragmentation. In addition, growth inhibition of PC-3 cells was associated with G2/M arrest and sub-G1 accumulation. Higher concentrations (24-30 microM) of piplartine modulated apoptosis-related protein expression by down-regulating cdc-2 expression and up-regulating PARP/procaspase-3 cleavage. Also, PC-3 cells treated with piplartine demonstrated caspase-3 activation, as observed with an in vitro caspase-3 colorimetric assay kit. Taken together, these results demonstrated that high concentrations of piplartine exhibited anti-proliferative and anti-cancer effects on PC-3 cells and that caspase-3-mediated PARP cleavage and cell cycle arrest at G2/M phase are involved in the underlying cellular mechanism of the apoptosis process.

New pathway links from cancer-progression determinants to gene expression of matrix metalloproteinases in breast cancer cells.

AP-2alpha, interleukin-4 (IL-4), E-cadherin, fibulin 1D, p16(INK4alpha), PTEN, RKIP, and S100A4 are determinants (suppressors, except for S100A4) of cancer cell invasiveness and other traits of cancer progression, which are located upstream of matrix metalloproteinases (MMPs) in cell signaling pathways. We will refer to them as upstream cancer-progression determinants (UCPDs, for brevity). MMP-1, MMP-2, MMP-9, MMP-11, MMP-13, MMP-14, MMP-16, and MMP-19 are enhancers of cancer cell invasiveness and other traits of cancer progression, in MDA-MB-231 breast cancer cells. We are interested in pathway links from UCPDs to gene expression of cancer cell MMPs in MDA-MB-231 cells. To test models about these links, wild-type copies of UCPDs were transiently overexpressed and then MMP mRNAs were measured by reverse transcription real-time PCR. The present results show that each of eight UCPDs is linked to the gene expression of a unique set of MMPs. This indicates that the effects are sequence-specific and that each UCPD reaches these MMP expressions through different sets of signaling pathways. We have detected 20 new pathway links, 11 are downregulatory and nine are upregulatory; 15 are new links in any cell, and five are new links in breast cancer. In seven links, three cancer-progression suppressing UCPDs unexpectedly enhance the gene expression of five cancer-progression promoting MMPs.

Additional MDA-MB-231 breast cancer cell matrix metalloproteinases promote invasiveness.

We are interested in two aspects of a given type of metastatic breast cancer: which potentially cancer-relevant genes are expressed and which factors determine invasiveness. Using reverse transcription real-time PCR, we detected gene expression of 26 matrix metalloproteinases (MMPs) in MDA-MB-231 breast cancer cells, including those of MMP-12, MMP-16 variant 2, MMP-19, MMP-20, MMP-21, MMP-23, MMP-24, MMP-25, MMP-25 variant 2, MMP-L1, MMP-26, MMP-27, and MMP-28, in contrast to the 13 MMPs detected until now in these cells. We found that MMP genes are expressed at widely different levels in these cells, over five orders of magnitude. After individual siRNA-induced depletions, we found that six additional species of cancer cell MMPs promote invasiveness in MDA-MB-231 cells: MMP-3, MMP-11, MMP-12, MMP-17, MMP-19, and MMP-23, thus raising the total to 12 endogenous MMPs which do so in these cells. The data support the conclusion that some cancer cell MMPs, although expressed at low levels, are needed for cancer trait in MDA-MB-231 cells, and that several endogenous MMPs play non-redundant roles in this process. The mRNA level of MMP-11, but not of other MMPs, rose substantially following individual siRNA-targeted depletion of cancer cell MMP-17 mRNA, while no MMP mRNA increased appreciably after degradation of other MMP mRNAs. This supports the conclusion that MMP-17 may be a member of an intracellular signaling pathway which downregulates MMP-11 mRNA.

Biotransformation of Korean Panax ginseng by Pectinex.

Ginsenosides comprise the major component of ginseng exhibit various types of biological activity, including antiinflammatory and antitumor effects. In these pharmacological actions, it is thought that these activities are carried out by the metabolites of ginsenosides metabolized by human intestinal microflora. It has also been reported that their clinical efficacy varies with the hydrolyzing potential of the components of the intestinal microflora. We tried to develop a process for metabolizing ginsenosides to compound K using food-grade enzymes, which can be used commercially. Among these, Pectinex proved to be the most effective mediator of the catabolism of ginsenosides to compound K. The optimal conditions for this biotransformation were determined to be as follows: 10 to 15% rootlet ginseng, pH 5, 50 degrees C, and 2 to 3 d of incubation, to yield 20.0 mg of compound K/g of rootlet ginseng. We suggest that the metabolism of ginseng to compound K in the presence of Pectinex has many advantages over previous methods, in respects of use of raw, non-extracted rootlet ginseng, which do not require more organic solvents and evaporation apparatus. Potential metabolites PG1, PG2, PG3, and PG4 were detected in Pectinex-treated rootlet ginseng using by TLC and HPLC and, among them, PG4 was identified as compound K by TLC, HPLC, and MS. Additional studies will be carried out to determine the structure of these metabolites of ginseng and to understand the relationship between their structures and activities.