To demonstrate potent efficacy, a cancer vaccine needs to activate both innate and adaptive immune cells. Personalized cancer vaccine strategies often require the identification of patient‐specific ...neoantigens; however, the clonal and mutational heterogeneity of cancer cells presents inherent challenges. Here, extracellular nanovesicles derived from alpha‐galactosylceramide‐conjugated autologous acute myeloid leukemia (AML) cells (ECNV‐αGC) are presented as a personalized therapeutic vaccine that activates both innate and adaptive immune responses, bypassing the need to identify patient‐specific neoantigens. ECNV‐αGC vaccination directly engages with and activates both invariant natural killer T (iNKT) cells and leukemia‐specific CD8+ T cells in mice with AML, thereby promoting long‐term anti‐leukemic immune memory. ECNV‐αGC sufficiently serves as an antigen‐presenting platform that can directly activate antigen‐specific CD8+ T cells even in the absence of dendritic cells, thereby demonstrating a multifaceted cellular mechanism of immune activation. Moreover, ECNV‐αGC vaccination results in a significantly lower AML burden and higher percentage of leukemia‐free survivors among cytarabine‐treated hosts with AML. Human AML‐derived ECNV‐αGCs activate iNKT cells in both healthy individuals and patients with AML regardless of responsiveness to conventional therapies. Together, autologous AML‐derived ECNV‐αGCs may be a promising personalized therapeutic vaccine that efficiently establishes AML‐specific long‐term immunity without requiring the identification of neoantigens.
An autologous extracellular nanovesicle vaccine derived from alpha‐galactosylceramide‐conjugated acute myeloid leukemia (AML) cells directly activates both innate immune cells and AML‐specific CD8+ T cells without having to define tumor antigens. It induces strong antitumor immune memory and synergizes with chemotherapy to prevent relapse in hosts with AML. Thus, it can be developed as a platform for personalized vaccines in humans.
Targeting the stromal cell–derived factor 1α (SDF-1α)/C-X-C chemokine receptor type 4 (CXCR4) axis has been shown to be a promising therapeutic approach to overcome chemoresistance in acute myeloid ...leukemia (AML). We investigated the antileukemia efficacy of a novel peptidic CXCR4 antagonist, LY2510924, in preclinical models of AML. LY2510924 rapidly and durably blocked surface CXCR4 and inhibited stromal cell–derived factor 1 (SDF-1)α–induced chemotaxis and prosurvival signals of AML cells at nanomolar concentrations more effectively than the small-molecule CXCR4 antagonist AMD3100. In vitro, LY2510924 chiefly inhibited the proliferation of AML cells with little induction of cell death and reduced protection against chemotherapy by stromal cells. In mice with established AML, LY2510924 caused initial mobilization of leukemic cells into the circulation followed by reduction in total tumor burden. LY2510924 had antileukemia effects as monotherapy as well as in combination with chemotherapy. Gene expression profiling of AML cells isolated from LY2510924-treated mice demonstrated changes consistent with loss of SDF-1α/CXCR4 signaling and suggested reduced proliferation and induction of differentiation, which was proved by showing the attenuation of multiple prosurvival pathways such as PI3K/AKT, MAPK, and β-catenin and myeloid differentiation in vivo. Effective disruption of the SDF-1α/CXCR4 axis by LY2510924 may translate into effective antileukemia therapy in future clinical applications.
•In vitro, SDF-1α/CXCR4 inhibition by LY2510924 is potent and prolonged and inhibits proliferation and stromal chemoprotection of AML cells.•In vivo, LY2510924 mobilizes AML cells, has striking antileukemia effects as monotherapy, and strongly synergizes with chemotherapy.
Although leukemic retinopathy accounts for 80% of ocular complications in acute leukemia, its pathogenesis remains unclear. To evaluate changes in retinal and choroicapillaris and structural ...parameters in patients with acute leukemia, we analyzed the correlation between vascular perfusion metrics and laboratory parameters and assessed the changes after hematopoietic stem cell transplantation (HSCT).
Herein, 104 eyes of 52 patients aged 18 and above with acute leukemia were enrolled. 80 eyes of 40 healthy patients were recruited as control participants. All participants underwent optical coherence tomography (OCT) and OCT angiography (OCTA) at baseline.
Patients with acute leukemia had a significantly thicker ganglion cell-inner plexiform layer (GCIPL) and lower circularity index than the control participants. Post-HSCT perfusion metrics did not differ significantly, but parafoveal thickness decreased significantly. During the active phase of acute leukemia, lower platelet levels were associated with significant GCIPL thickening and increased foveal avascular zone and perimeter. D-dimer levels positively correlated with GCIPL thickness.
Patients with acute leukemia had subclinical retinal microvascular deficits on OCTA and GCIPL thickening on OCT, possibly associated with bone marrow function. GCIPL thickness may indicate acute ischemia in such patients. Further studies must elucidate their clinical and prognostic significance.
BCR-ABL1
–positive acute leukemia can be classified into three disease categories: B-lymphoblastic leukemia (B-ALL), acute myeloid leukemia (AML), and mixed-phenotype acute leukemia (MPAL). We ...conducted an integrative analysis of RNA sequencing (RNA-seq) data obtained from 12
BCR-ABL1
–positive B-ALL, AML, and MPAL samples to evaluate its diagnostic utility. RNA-seq facilitated the identification of all p190
BCR-ABL1
with accurate splicing sites and a new gene fusion involving
MAP2K2
. Most of the clinically significant mutations were also identified including single-nucleotide variations, insertions, and deletions. In addition, RNA-seq yielded differential gene expression profile according to the disease category. Therefore, we selected 368 genes differentially expressed between AML and B-ALL and developed two differential diagnosis models based on the gene expression data using 1) scoring algorithm and 2) machine learning. Both models showed an excellent diagnostic accuracy not only for our 12
BCR-ABL1
–positive cases but also for 427 public gene expression datasets from acute leukemias regardless of specific genetic aberration. This is the first trial to develop models of differential diagnosis using RNA-seq, especially to evaluate the potential role of machine learning in identifying the disease category of acute leukemia. The integrative analysis of gene expression data by RNA-seq facilitates the accurate differential diagnosis of acute leukemia with successful detection of significant gene fusion and/or mutations, which warrants further investigation.
Abstract
Retinal vein occlusion (RVO) is associated with atherosclerotic cardiovascular risk factors; however, its association with the specific markers of subclinical atherosclerosis has not yet ...been established. To investigate this association, we compared 70 patients with RVO to 70 age- and sex-matched patients without RVO. Low-density lipoprotein cholesterol (LDL-C) levels and brachial-ankle pulse wave velocity (baPWV) were significantly higher in the RVO group than in the control group. Carotid plaques (54.3% vs. 28.6%, p = 0.004) were more frequent in the RVO group. Multivariate logistic regression analysis showed that the presence of carotid plaques (odds ratio OR: 3.15, 95% confidence interval CI 1.38–7.16, p = 0.006), as well as smoking, LDL-C level, and baPWV were associated with RVO. Additionally, a multinomial logistic regression model showed that the presence of carotid plaques (OR: 3.94, 95% CI 1.65–9.41, p = 0.002) and LDL-C level were associated with branch RVO, whereas smoking and baPWV were associated with central RVO. In conclusion, RVO was associated with subclinical atherosclerosis markers, including carotid plaques and baPWV. These results support the hypothesis that atherosclerosis contributes to the etiology of RVO and suggest the evaluation of subclinical atherosclerosis in patients with RVO.
The risk of developing tuberculosis (TB) in allogeneic hematopoietic stem cell transplantation (HSCT) recipients is expected to be relatively high in an intermediate TB burden country. This ...single-center retrospective study was conducted to investigate risk factors and the incidence of TB after allogeneic HSCT.
From January 2004 to March 2011, 845 adult patients were enrolled. Starting April 2009, patients were given isoniazid (INH) prophylaxis based on interferon-γ release assay results. The incidence of TB was analyzed before and after April 2009, and compared it with that of the general population in Korea.
TB was diagnosed in 21 (2.49%) of the 845 allogeneic HSCT patients. The median time to the development of TB was 386 days after transplantation (range, 49-886). Compared with the general population, the standardized incidence ratio of TB was 9.10 (95% CI; 5.59-14.79). Extensive chronic graft-versus-host disease (GVHD) was associated with the development of TB (P = 0.003). Acute GVHD, conditioning regimen with total body irradiation and conditioning intensity were not significantly related. INH prophylaxis did not reduce the incidence of TB (P = 0.548). Among 21 TB patients, one patient had INH prophylaxis.
Allogeneic HSCT recipients especially those who suffer from extensive chronic GVHD are at a high risk of developing TB. INH prophylaxis did not statistically change the incidence of TB, however, further well-designed prospective studies are needed.
Heterotopic pancreas (HP) can be detected by accompanying symptoms or incidentally during gastrointestinal (GI) tract tumor resection. We compared clinicopathologic features among 165 resected HPs ...(57 gastric 35%, 56 duodenal 34%, 30 omental 18%, and 22 jejunal 13%). Symptomatic HPs (79/135 GI tract wall HPs, 59%) were larger (P=0.05), more common in younger patients and in a gastric location (both P<0.001), and more frequently associated with lymphoid cuffs (P=0.03) than incidentally found HPs. Gastric/jejunal HPs were more frequently symptomatic (P<0.001), deeply located (P=0.03), and associated with lymphoid cuffs (P=0.008) and pancreatic intraepithelial neoplasia/intraductal papillary mucinous neoplasms (PanIN/IPMN; P=0.001) than duodenal HPs. HP was frequently associated with acinar-ductal metaplasias (117/135 GI tract wall HPs, 87%) and PanINs/IPMNs (68/135, 50%); those with PanINs/IPMNs were larger (P<0.001), more frequently located in stomach (P=0.001), had deeper wall involvement (P=0.03), and more often showed infiltrative growth (P<0.001) and lymphoid cuffs (P=0.02). Four HPs containing PanINs abutted adenocarcinomas, all expressing wild-type KRAS and intact SMAD4/DPC4 expression. Thus, symptomatic HP is associated with younger age, larger size, gastric location, and lymphoid cuffs. HPs containing PanINs/IPMNs (usually low grade) are larger and more common in stomach, have deeper wall location, and show infiltrative growth and lymphoid cuffs. Adenocarcinomas are rarely observed adjacent to HPs with PanINs/IPMNs. KRAS mutational and SMAD4/DPC4 immunohistochemical studies can discriminate between adenocarcinoma derived from HP and concurrent adenocarcinoma with HP.
Escherichia coli
and
Klebsiella pneumoniae
are main pathogens in neutropenic fever even if the proportion of Gram-positive cocci is increasing. Extended-spectrum β-lactamases (ESBL)-producing ...organisms are an emerging problem in nosocomial infection. Nevertheless, until now, information about risk factors for the acquisition and clinical outcomes of bacteremia due to ESBL-producing organisms is limited in neutropenic patients. From medical records collected between January 2007 and December 2008, we identified a total of 101 consecutive patients who developed bacteremia due to
E. coli
(
n
= 87) or
K. pneumoniae
(
n
= 14). Twenty-six (26 %) cases of bacteremia were caused by ESBL-producing organisms. A hospital stay of >2 weeks during the 3 months preceding bacteremia adjusted odds ratio (OR), 5.887; 95 % confidence interval (CI), 1.572–22.041 and the use of broad-spectrum cephalosporins in the 4 weeks prior to bacteremia (adjusted OR, 6.186; 95 % CI, 1.616–23.683) were significantly related to the acquisition of ESBL. Twenty-four (92 %) of the ESBL-producing organisms were susceptible to either piperacillin–tazobactam or amikacin. Aminoglycosides (amikacin or isepamicin) were the main appropriate antimicrobial agents used against the ESBL-producing isolates during the initial empirical treatment (16/22, 73 %). However, the 30-day mortality rates for ESBL bacteremia and non-ESBL bacteremia were not significantly different (15 vs 5 %;
p
= 0.199). As alternatives to carbapenem, piperacillin–tazobactam plus amikacin or isepamicin combinations may be effective empirical therapeutic options for patients with neutropenic fever who are at high risk of developing bacteremia with ESBL-producing pathogens.
The 2007 World Economic Forum (WEF) referred to climate change as the overriding problem we face. Concerns have been raised about how global warming would accelerate future climate change and its ...consequences. Many climate change studies expect the possible occurrence of extreme high temperature, increase in heavy rains and strong typhoons in the near future. Currently, climate change scenarios are used to prepare an appropriate plan for these phenomena under climate change. The main purpose of this paper is to suggest and evaluate an operational method of assessing the potential impact of climate change on hydrologic components and water resources at the regional scale. Future runoff was simulated using high resolution Regional Circulation Model (RCM) (12.5 × 12.5 km) Representative Concentration Pathway (RCP) scenario operated by the Korea Meteorological Administration (KMA) and a semi-distribution model or SLURP (Semi-distributed Land Use-based Runoff Process). The study was carried out on the Han River including its nine dams. The study found that runoff characteristics, especially annual distribution, could change. The discharge in July tends to decrease while runoff can increase in August and September. The flow duration curve was estimated and compared with observed data and simulated daily runoff data for Paldang-dam to evaluate the effect of climate change. The analysis of the flow duration curve shows that the mean average low flow increased while the average wet and normal flow decreased under the climate change scenario.
The Korean road network has been aging rapidly. It is necessary to assess the pavement conditions of various road networks in order to come up with proper rehabilitation strategies against the aging ...road networks. Pavement management system is an essential tool for road management, and each road management organization has developed its own pavement condition index for assessing the road conditions. Nonetheless, because the pavement condition of various types of roads could not be represented by a single pavement condition index, it was difficult to comprehend the condition of the entire roads of Korea and its changing trend at a glance. Moreover, there has been a limitation on the persuasion of the justification for the use of road management and rehabilitation budget at national level to the people and the budget office of Korea. This study derived the relationship among the pavement condition indices of Korean expressways, Korean national highways, and Seoul city roads so that those pavement indices can be represented by one unified pavement condition index. A sensitivity analysis of how variables of pavement distress (roughness, rut depth, and crack ratio) influenced each of the pavement condition index was carried out. Then, correlation equations between the pavement condition indices were developed in order to represent them by a single pavement condition index (NHPCI) through a statistical analysis of the pavement condition monitoring system data over 8 years, and its application plan is proposed.
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