Understanding the epidemiological characteristics of anaphylaxis-associated out-of-hospital cardiac arrest (OHCA) is the first step toward developing preventative strategies and optimizing care ...systems. We aimed to describe and compare epidemiological features and clinical outcomes among patients with anaphylaxis-associated OHCAs according to causative agent groups.
We identified emergency medical service (EMS)-treated anaphylaxis-associated OHCA patients from a nationwide OHCA registry between 2008 and 2015. We compared epidemiological characteristics and outcomes according to causal agents (a natural agents group and an iatrogenic agents group) and evaluated temporal variability in incidence. Multivariate logistic regression analysis was performed to compare survival to discharge between causative agent groups.
During the study period (8 years), the total number of anaphylaxis-associated OHCAs was 233. A total of 224 eligible cases were included in the analysis. There were 192 patients (85.6%) in the natural agents group and 32 patients (14.3%) in the iatrogenic agents group. There was significant diurnal and seasonal variability in the frequency of anaphylaxis-associated OHCAs (p values<0.01 for both), with the highest incidences occurring during the day (7:01 am to 3 pm; 64.6%) and in summer (June to August, 48.7%). Compared with the natural agents group, the adjusted odds ratio (AOR) for survival to discharge in the iatrogenic agents group was statistically insignificant (AOR 3.61, 95% CI 0.86 to 15.06).
The incidence of anaphylaxis-associated OHCA is considerably low, and significant temporal variability, with a peak during the day and in summer, is evident. Anaphylaxis-associated OHCA is more common by natural agents than by iatrogenic agents, but no difference in the survival-to-discharge rate is evident.
Neural stem cells (NSCs) have the ability to proliferate and differentiate into neurons and glia. Regulation of NSC fate by small molecules is important for the generation of a certain type of cell. ...The identification of small molecules that can induce new neurons from NSCs could facilitate regenerative medicine and drug development for neurodegenerative diseases. In this study, we screened natural compounds to identify molecules that are effective on NSC cell fate determination. We found that Kuwanon V (KWV), which was isolated from the mulberry tree (Morus bombycis) root, increased neurogenesis in rat NSCs. In addition, during NSC differentiation, KWV increased cell survival and inhibited cell proliferation as shown by 5-bromo-2-deoxyuridine pulse experiments, Ki67 immunostaining and neurosphere forming assays. Interestingly, KWV enhanced neuronal differentiation and decreased NSC proliferation even in the presence of mitogens such as epidermal growth factor and fibroblast growth factor 2. KWV treatment of NSCs reduced the phosphorylation of extracellular signal-regulated kinase 1/2, increased mRNA expression levels of the cyclin-dependent kinase inhibitor p21, down-regulated Notch/Hairy expression levels and up-regulated microRNA miR-9, miR-29a and miR-181a. Taken together, our data suggest that KWV modulates NSC fate to induce neurogenesis, and it may be considered as a new drug candidate that can regenerate or protect neurons in neurodegenerative diseases.
Triple-negative breast cancer (TNBC) is a heterogeneous disease comprising several subtypes. Androgen-receptor (AR) signaling has been targeted by several investigational agents in luminal AR subtype ...TNBCs. Bromodomain (BRD) and extra-terminal motif (BET) protein inhibitors have been shown to attenuate AR signaling in metastatic castration-resistant prostate cancer and to overcome enzalutamide resistance. We demonstrated potent anti-tumor effects of the BET inhibitor JQ1 against AR-positive TNBC cell lines using cell viability and cell cycle analysis. To reveal the mechanisms of JQ1 effects, multiplex gene expression analysis and immunoblotting assays were used. We examined in vivo effects of JQ1 in a xenograft model of AR expressing TNBC. JQ1 exhibited its anti-proliferative activity by inducing apoptosis and cell cycle arrest. JQ1 activity was not mediated by MYC downregulation. Instead, JQ1 blocked the interactions among the ATPase-family AAA-domain-containing 2 protein (ATAD2), BRD2, BRD4, and AR; effectively suppressing the expression of AR associated targets. In addition, JQ1 showed significant anti-tumor activity in vivo in TNBC xenograft mouse models as a monotherapy and in combination with anti-AR therapy. Taken together, our results showed that the BET inhibitor JQ1 is a promising therapeutic agent for the treatment of AR-positive TNBC.
The purpose of this study was to explain the process and results of implementing a bundle of two cardiopulmonary resuscitation (CPR) programs in Gwang-ju metropolitan city and to determine whether ...the use of these programs improved the clinical outcomes for out-of-hospital cardiac arrest (OHCA) patients.
This was a before- and after-intervention study of the implementation of a bundle of two CPR programs in Gwang-ju. The main intervention was a multi-tier response (MTR) system, with an emphasis on prolonged on-scene resuscitation. The primary outcome was good neurological recovery, and secondary outcomes were survival to discharge and prehospital return of spontaneous circulation (ROSC). A multivariable logistic regression model was used to estimate the association between the study period and outcomes, after adjusting for potential confounders. Interaction analysis was conducted to determine whether the location of arrest and witness status modified the effect of the study period on the study outcomes.
The adjusted odds ratios (AORs) for the intervention were 1.35 (0.96–1.90) for pre-hospital ROSC, 1.19 (0.49–2.86) for survival to discharge, and 3.45 (1.01–11.80) for good CPC. The AORs for good neurological recovery of the after-intervention period were 2.93 (0.73–11.77) for a private place, 4.82 (1.04–22.39) for a public place, 5.88 (1.47–23.57) for a witnessed arrest, and 1.49 (0.28–7.86) for a non-witnessed arrest.
OHCA patients treated in the after-intervention period with the bundle of CPR programs including MTR and prolonged on-scene resuscitation showed better clinical outcomes, especially pre-hospital ROSC, and neurological recovery at hospital discharge than those treated in the before-intervention period.
Bruton tyrosine kinase (Btk) has a well-defined role in B-cell development, whereas its expression in osteoclasts (OCs) further suggests a role in osteoclastogenesis. Here we investigated effects of ...PCI-32765, an oral and selective Btk inhibitor, on osteoclastogenesis as well as on multiple myeloma (MM) growth within the BM microenvironment. PCI-32765 blocked RANKL/M-CSF–induced phosphorylation of Btk and downstream PLC-γ2 in OCs, resulting in diminished TRAP5b (ED50 = 17nM) and bone resorption activity. PCI-32765 also inhibited secretion of multiple cytokines and chemokines from OC and BM stromal cell cultures from both normal donors (ED50 = 0.5nM) and MM patients. It decreased SDF-1–induced migration of MM cells, and down-regulated MIP1-α/CCL3 in MM cells. It also blocked MM cell growth and survival triggered by IL-6 or coculture with BM stromal cells or OCs in vitro. Importantly, PCI-32765 treatment significantly inhibits in vivo MM cell growth (P < .03) and MM cell–induced osteolysis of implanted human bone chips in SCID mice. Moreover, PCI-32765 prevents in vitro colony formation by stem-like cells from MM patients. Together, these results delineate functional sequelae of Btk activation mediating osteolysis and growth of MM cells, supporting evaluation of PCI-32765 as a novel therapeutic in MM.
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignant tumor and more than 50% patients are diagnosed at metastatic stage. The preclinical model systems that reflect the genetic ...heterogeneity of metastatic tumors are urgently needed to guide optimal treatment. This study describes the development of patient-derived preclinical platform using very small sized-percutaneous liver gun biopsy (PLB) of metastatic pancreatic cancer, based on patient-derived xenograft (PDX)-mediated tissue amplification and subsequent organoid generation. To increase the success rate and shorten the tumor growth period, patient-derived orthotopic xenograft (PDOX) model was developed to directly implant threadlike PLB samples into the pancreas. The engraftment success rate of PDOX samples from 35 patients with metastatic PDAC was 47%, with these samples showing the potential to metastasize to distant organs, as in patients. The PDOX models retained the genetic alterations and histopathological features of the primary tumors. Tumor organoids were subsequently generated from first passage cancer cells isolated from F1 tumor tissue of PDOX that preserve the epithelial cancer characteristics and KRAS mutations of primary tumors. The response to gemcitabine of PDOX-derived organoids correlated with clinical outcomes in corresponding patients as well as PDOX models
in vivo
, suggesting that this PDOX-organoid system reflects clinical conditions. Collectively, these findings indicate that the proposed PDOX-organoid platform using PLB samples assessed both
in vitro
and
in vivo
could predict drug response under conditions closer to those found in actual patients, as well as enhancing understanding of the complexity of metastatic PDAC.
Malignant cells have a higher nicotinamide adenine dinucleotide (NAD+) turnover rate than normal cells, making this biosynthetic pathway an attractive target for cancer treatment. Here we ...investigated the biologic role of a rate-limiting enzyme involved in NAD+ synthesis, Nampt, in multiple myeloma (MM). Nampt-specific chemical inhibitor FK866 triggered cytotoxicity in MM cell lines and patient MM cells, but not normal donor as well as MM patients PBMCs. Importantly, FK866 in a dose-dependent fashion triggered cytotoxicity in MM cells resistant to conventional and novel anti-MM therapies and overcomes the protective effects of cytokines (IL-6, IGF-1) and bone marrow stromal cells. Nampt knockdown by RNAi confirmed its pivotal role in maintenance of both MM cell viability and intracellular NAD+ stores. Interestingly, cytotoxicity of FK866 triggered autophagy, but not apoptosis. A transcriptional-dependent (TFEB) and independent (PI3K/mTORC1) activation of autophagy mediated FK866 MM cytotoxicity. Finally, FK866 demonstrated significant anti-MM activity in a xenograft-murine MM model, associated with down-regulation of ERK1/2 phosphorylation and proteolytic cleavage of LC3 in tumor cells. Our data therefore define a key role of Nampt in MM biology, providing the basis for a novel targeted therapeutic approach.
Introduction: Numerous studies have demonstrated that abnormal levels of cholesterol are associated with a high attributable risk for the occurrence of cardiovascular disease (CVD). However, there ...has been no comprehensive study to investigate the relationship between serum cholesterol levels and cardiovascular mortality. Therefore, we conducted a systematic review and dose-response meta-analysis. Methods: A systematic literature search of key databases, including EMBASE and MEDLINE, was conducted and included all the published epidemiological studies that contained estimates of the hazard ratios (HR) of serum cholesterol of CVD mortality. Data extraction, eligibility, and assessment of the risk of bias were assessed by two reviewers independently. All published risk estimates were hazard ratios and analyzed by quantitative meta-analysis using a random-effects model and dose-response relationships of serum cholesterol with CVD mortality. Results: A total of 14 independent reports, including 1,055,309 subjects and 9457 events, were analyzed. The pooled HR (95% CI) was 1.27 (95% CI, 1.19–1.36) for total cholesterol, 1.21 (95% CI, 1.09–1.35) for low-density lipoprotein cholesterol (LDL-C), and 0.60 (95% CI, 0.50–0.72) for high-density lipoprotein cholesterol (HDL-C). We observed a linear association between serum cholesterol (TC, HDL-C) levels and CVD mortality in this meta-analysis. Conclusions: Serum total cholesterol and LDL-C level is associated with increased CVD mortality, but HDL-C level is inversely associated with CVD mortality.
Recently, fusion variants of the breast cancer anti-oestrogen-resistance 4 (BCAR4) gene were recurrently discovered in lung adenocarcinoma from the genome-wide studies. However, the functional ...characterisation of BCAR4 fusion has not been investigated.
Based on the analysis of RNA-sequencing data, we identified a fusion transcript of CD63-BCAR4 in a Korean patient with lung adenocarcinoma who did not harbour any known activating mutations in EGFR and KRAS genes. To investigate the oncogenic effect of CD63-BCAR4, in vitro and in vivo animal experiments were performed.
In vitro experiments showed strongly enhanced cell migration and proliferation by the exogenous expression of CD63-BCAR4 protein in bronchial epithelial cells. Cell migration was notably reduced after knockdown of BCAR4 fusion by small-interfering RNA. The tumorigenic and metastatic capability of the CD63-BCAR4 fusion was confirmed by using the mouse xenograft model. Fusion-overexpressed cells result in metastasis to the liver and lung as well as the primary tumours after subcutaneous injection into mice. Cyclin D1, MMP1, Slug and mesenchymal markers were significantly increased after CD63-BCAR4 overexpression in the in vitro and in vivo experiments.
Taken together, our results suggest a newly identified fusion gene, CD63-BCAR4 as a potential novel oncogene in lung adenocarcinoma.
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