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Several preclinical studies demonstrate that antitumor efficacy of programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade can be improved by combination with other checkpoint inhibitors. Lymphocyte-activation gene 3 (LAG-3) is an inhibitory checkpoint receptor involved in T cell exhaustion and tumor immune escape. Here, we describe ABL501, a bispecific antibody targeting LAG-3 and PD-L1 in modulating immune cell responses against tumors. ABL501 that efficiently inhibits both LAG-3 and PD-L1 pathways enhances the activation of effector CD4

The application of patient-specific instrumentation (PSI) for reverse total shoulder replacement has been rapidly increasing, which could reduce errors in implant positioning. Although PSI theoretically holds promise, evidence of the accuracy and reliability of PSI in shoulder replacement surgery is limited.Thirty-nine shoulders that underwent reverse total shoulder arthroplasty were included in this study and categorized into two groups: the conventional (n = 20) and PSI (n = 19) groups. Screw (length and angle) and baseplate (version, inclination, translation, and rotation) positioning were calculated based on postoperative computed tomography images using a three-dimensional measurement tool. The difference between the values of the preoperative target and postoperative measurement was calculated to evaluate the reproducibility of preoperative planning. Screw involvement in the suprascapular and spinoglenoid notches was assessed. Thus, the correlation between the position of the baseplate and the screws was assessed.The mean differences between the planned length and angle (anteroposterior and superoinferior angles) and postoperative measurement in the PSI group were significantly smaller than those in the conventional group. Similarly, the mean difference in baseplate rotation between the planned and postoperative measurements in the PSI group was significantly lower than that in the conventional group (4.5° vs 10.6°; P .001). The spinoglenoid notch was involved in 10 cases in the conventional group and 2 cases in the PSI group, and this difference was significant (P = .014). Overall, the mean difference between the preoperative and postoperative version, inferior inclination, and rotation values for the baseplate position was significantly correlated with the values for screw position (length and angle).PSI improves the reproducibility of preoperative planning for baseplate and screw positioning and reduces the risk of neurovascular injury in reverse total shoulder arthroplasty.

The gut microbiome influences cancer development and the efficacy and safety of chemotherapy, but little is known about its effects on lymphoma. We obtained stool samples from treatment-naïve, newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL) (n = 189). We first performed 16S ribosomal RNA gene sequencing (n = 158) and then conducted whole-genome shotgun sequencing (n = 106) with additional samples. We compared the microbiome data from these patients with those of healthy controls and assessed whether microbiome characteristics were associated with treatment outcomes. The alpha diversity was significantly lower in patients with DLBCL than in healthy controls (P < 0.001), and the microbial composition differed significantly between the groups (P < 0.001). The abundance of Enterobacteriaceae family belonging to the Proteobacteria phylum was markedly higher in patients than in healthy controls. Functional analysis of the microbiome revealed an association with opportunistic pathogenesis through type 1 pili, biofilm formation, and antibiotics resistance. Enterobacteriaceae members were significantly enriched in patients who experienced febrile neutropenia and in those who experienced relapse or progression (P < 0.001). Interestingly, greater abundance of Enterobacteriaceae correlated with shorter progression-free survival (P = 0.007). The cytokine profiles of patients whose microbiome was enriched with Enterobacteriaceae were significantly associated with interleukin 6 (P = 0.035) and interferon-g (P = 0.045) levels. In summary, patients with DLBCL exhibited gut microbial dysbiosis. The abundance of Enterobacteriaceae correlated with treatment outcomes and febrile neutropenia. Further study is required to elucidate the origin and role of gut dysbiosis in DLBCL.

Tumor localization in patients receiving neoadjuvant chemotherapy (NACT) is challenging because substantial therapeutic remission of the original tumor after NACT is often noted. Currently, there is no guidance device that allows for an accurate estimation of the resection range in breast-conserving surgery after NACT. To increase the accuracy of tumor resection, we used a 3-dimensional-printed breast surgical guide based on magnetic resonance imaging (MRI) in the supine position for a breast cancer patient who underwent breast-conserving surgery after NACT. Using this device, the breast tumor with apparent therapeutic changes after NACT on imaging was successfully removed with clear resection margins by identifying the original tumor site in the affected breast. Irrespective of whether the residual tumor area after NACT is well defined, it is possible to confirm and target the tumor area on pre-NACT MRI using this device.

In patients with acute myeloid leukemia (AML) consolidation treatment options are between allogeneic hematopoietic stem cell transplantation (HCT) and chemotherapy, based on disease risk at the time of initial presentation and age. Measurable residual disease (MRD) following induction chemotherapy could be incorporated as a useful parameter for treatment decisions. The present study evaluated treatment outcomes according to the next-generation sequencing (NGS)-based MRD status and the type of consolidation therapy in patients with normal karyotype (NK)-AML. By sequencing 278 paired samples collected at diagnosis and first remission (CR1), we identified 361 mutations in 124 patients at diagnosis and tracked these at CR1. After excluding mutations associated with age-related clonal hematopoiesis, 82 mutations in 50 of the 124 patients (40.3%) were detected at CR1. Survival benefit was observed in favor of allogeneic HCT over chemotherapy consolidation in the MRDpos subgroup with respect to overall survival (HR 0.294, p = 0.003), relapse-free survival (HR 0.376, p = 0.015) and cumulative incidence of relapse (HR 0.279, p = 0.004) in multivariate analysis, but not in the MRDneg subgroup. In summary, these data support allogeneic HCT in NK-AML patients with detectable MRD by NGS in CR1. Randomized clinical trials will be required to confirm this observation.

The iron-catalyzed hydrogen transfer strategy has been applied to the redox condensation of o-hydroxynitrobenzene with alcohol, leading to the formation of benzoxazole derivatives. A wide range of 2-substituted benzoxazoles were synthesized in good to excellent yields without the addition of an external redox agent. A series of control experiments provided a plausible mechanism. Furthermore, the reaction system was successfully extended to the synthesis of benzothiazoles and benzimidazoles.

Recently, with the increased frequency of disasters, the demand for measures to secure the golden hour after disasters has been increasing. Therefore, it is necessary to plan and select road infrastructures for effective disaster response. The purpose of this study was to determine emergency road networks for rapid rescue, paramedical activity, and resource transfer in the event of an earthquake in Seoul (including nearby areas). Decisions were made to select a suitable emergency road network in Seoul based on the collection and management of earthquake-related data, grid-based quantitative evaluation of factors regarding demands during disasters and provision of response resources, link-based importance evaluation and grouping analysis, and results of grid and link evaluations. Analysis was first conducted on 16 types of disaster demands, including building, facility, demographic, and response resource-provision data. An expert survey was conducted, and each factor was weighted and integrated into the grid structure for grid-based analysis. Roads and bridges that could play critical roles in an earthquake were selected and grouped in the road network for link-based analysis. The final emergency road network was chosen based on the quantitative and qualitative results from the second and third stages.

This study was conducted to investigate the effects of physical properties of peat-based substrate mixtures partially substituted with parboiled rice hulls (PRH) on plant growth and performance. Thirteen substrate mixtures were formulated by substituting 0, 20, 30, 40, 50, 60, or 70% peat with either parboiled ground rice hulls (GRH) or whole rice hulls (WRH) (by volume) in commercial potting mix (CPM) containing 70% peat, 20% perlite, and 10% vermiculite. All substrate mixtures consisted of mainly medium-sized (2.0–0.25 mm) particles. However, regardless of the mixing ratio, GRH significantly increased the medium-sized particles especially with diameters of 2.0–0.71 mm, while WRH increased both the medium- and coarse-sized (> 2.0 mm) particles. A higher mixing ratio of PRH increased air space and decreased container capacity but to a greater extent by WRH compared to GRH. Similarly, bulk density was increased with a higher mixing ratio of both types of PRH, but to a greater degree by GRH. Total porosity of GRH-containing substrates was similar to that of CPM within the range of 30–70%. The substrate mixtures containing PRH did not have the same physical properties as the CPM at any mixing ratio, but the values of some GRH-containing mixtures were within or close to the suggested ranges for greenhouse substrates. Considering the maximum substitution of PRH for peat, the substitution with 40% GRH (GRH-40) was selected for a plant growth study in comparison to CPM. Petunia (Petunia × hybrida) ‘Easy Wave Neon Rose’ and zinnia (Zinnia elegans) ‘Benary’s Giant Golden Yellow’ were grown in pots containing CPM and GRH-40 at two irrigation levels: high (25–30%, by volume) and low (20–25%). Overall, shoot DW of both plant species was reduced in GRH-40, but root DW was maintained similar to those in CPM. The low irrigation level more significantly reduced shoot DW of petunia grown in CPM than in GRH-40, relative to their counterparts with the high irrigation level (20 and 7%, respectively); however, root growth of plant species grown in GRH-40 was either maintained or tended to be maintained even at the low irrigation level compared to their high irrigation counterparts. The water use efficiency of plants grown in GRH-40 was not significantly different from those in CPM regardless of irrigation level. These results indicate that GRH-40 provides desirable physical properties and water release characteristics, allowing more available water for plants under low irrigation levels than CPM. We concluded that substituting peat with 40% GRH in a commercial potting mix is a sustainable approach to produce petunia and zinnia.

As urbanization advances, the number of people living in high-rise buildings is gradually increasing. However, few studies on evacuation planning during emergencies (or simulations) simultaneously considering high-rise buildings and urban areas have been carried out. This study targeted Sejong city in Korea to analyze evacuation behavior in high-rise apartments and the effect of evacuation information. For the disaster situation, this study assumed a worst-case situation in which apartment residents need to quickly evacuate through apartment stairwells and pedestrian roads owing to a major disaster and unexpected accident occurrence. Analysis scenarios were divided by considering the evacuation information level: 1) starting evacuation within 15 min, 2) starting evacuation within 30 min, and 3) starting evacuation within 60 min. Also, scenario 4 is for the case that information for a new optimal shelter location was informed to evacuees, whereas scenario 5 is for the case that information for an existing optimal shelter location was informed to evacuees. The analysis results indicate the evacuation completion time is greatly reduced if high-level information is provided. The results of this study offer guidance on emergency situations using micro-simulations and the Social Force model.

PURPOSE The three-dimensional (3D) principal strain represents the major direction and magnitude of the deformation by its definition and can be measured using 3D echocardiography. We aimed to validate 3D echocardiographic left ventricular (LV) global principal strains as an assessment of LV contractility by comparison with gold standard invasive measurements. METHODS In 14 beagles, the LV pressure-volume loop was recorded to invasively measure the end-systolic pressure-volume relationship (ESPVR) and dP/dt as reference indicators representing LV contractility. The echocardiographic image was obtained simultaneously, and endocardial motions and volume changes were extracted in the form of speckle-tracking point grids to calculate strains. High or low inotropic states were induced pharmacologically by using an intravenous infusion of dobutamine and esmolol, respectively. RESULTS The direction of 3D endocardial global principal strain (GP1S) appeared to be circumferential. The dP/dt showed the highest Pearson's correlation coefficients with GP1S (r = -0.845, P < 0.001), whereas ESPVR showed the best correlation with global secondary strain (GP2S; r = -0.819, P < 0.001). In comparison with GP1S and GP2S, global circumferential (GCS) and longitudinal strains (GLS) tended to correlate less with invasive measurements, respectively. LV ejection fraction showed excellent correlations with GP1S or GCS, but the correlation with GLS was relatively weak. The correlations between invasive measurements and GP2S or GLS were strengthened when strains were corrected by the LV residual volume ratio, whereas those of GP1S or GCS were weakened after correction. CONCLUSIONS The principal direction of the LV endocardial contraction presents circumferential behavior reflecting LV volume change. The 3D principal strains derived from 3D echocardiography are reliable indicators for LV contractility and seem better than conventional strains.

DNA sequencing-based measurable residual disease (MRD) detection has shown to be clinically relevant in AML. However, the same methodology cannot be applied to fusion gene-driven subtypes of AML such as core-binding factor AML (CBF-AML). Here in this study, we evaluated the effectiveness of using DNA and RNA sequencing in MRD detection and in tracking clonal dynamics in CBF-AML. Using RNA-seq, we were able to quantify expression levels of RUNX1-RUNX1T1 and CBFB-MYH11 at diagnosis and their levels of reduction during remission (P RUNX1-RUNX1T1 as measured by RNA-seq and qPCR were highly correlated (R2 = 0.74, P RUNX1-RUNX1T1 and cKIT-D816mut at diagnosis, stratified RUNX1-RUNX1T1 AML patients into three subgroups. These three subgroups had 2-year overall survival rates at 87%, 74%, and 33% (P RUNX1-RUNX1T1 AML.

In patients with acute myeloid leukemia (AML) consolidation treatment options are between allogeneic hematopoietic stem cell transplantation (HCT) and chemotherapy, based on disease risk at the time of initial presentation and age. Measurable residual disease (MRD) following induction chemotherapy could be incorporated as a useful parameter for treatment decisions. The present study evaluated treatment outcomes according to the next-generation sequencing (NGS)-based MRD status and the type of consolidation therapy in patients with normal karyotype (NK)-AML. By sequencing 278 paired samples collected at diagnosis and first remission (CR1), we identified 361 mutations in 124 patients at diagnosis and tracked these at CR1. After excluding mutations associated with age-related clonal hematopoiesis, 82 mutations in 50 of the 124 patients (40.3%) were detected at CR1. Survival benefit was observed in favor of allogeneic HCT over chemotherapy consolidation in the MRD

Breast cancer is one of the major female health problems worldwide. Although there is growing evidence indicating that air pollution increases the risk of breast cancer, there is still inconsistency among previous studies. Unlike the previous studies those had case-control or cohort study designs, we performed a nationwide, whole-population census study. In all 252 administrative districts in South Korea, the associations between ambient NO2 and particulate matter 10 (PM10) concentration, and age-adjusted breast cancer mortality rate in females (from 2005 to 2016, Nmortality = 23,565), and incidence rate (from 2004 to 2013, Nincidence = 133,373) were investigated via multivariable beta regression. Population density, altitude, rate of higher education, smoking rate, obesity rate, parity, unemployment rate, breastfeeding rate, oral contraceptive usage rate, and Gross Regional Domestic Product per capita were considered as potential confounders. Ambient air pollutant concentrations were positively and significantly associated with the breast cancer incidence rate: per 100 ppb CO increase, Odds Ratio OR = 1.08 (95% Confidence Interval CI = 1.06–1.10), per 10 ppb NO2, OR = 1.14 (95% CI = 1.12–1.16), per 1 ppb SO2, OR = 1.04 (95% CI = 1.02–1.05), per 10 µg/m3 PM10, OR = 1.13 (95% CI = 1.09–1.17). However, no significant association between the air pollutants and the breast cancer mortality rate was observed except for PM10: per 10 µg/m3 PM10, OR = 1.05 (95% CI = 1.01–1.09).

Next-generation sequencing (NGS) has been applied to define clinically relevant somatic mutations and classify subtypes in acute myeloid leukemia (AML). Persistent allelic burden after chemotherapy is associated with higher relapse incidence, but presence of allelic burden in AML patients after receiving allogeneic hematopoietic cell transplantation (HCT) has not been examined longitudinally. As such, we aimed to assess the feasibility of NGS in monitoring AML patients receiving HCT. Using a targeted gene panel, we performed NGS in 104 AML patients receiving HCT using samples collected at diagnosis, pre-HCT, and post-HCT at day 21 (post-HCTD21). NGS detected 256 mutations in 90 of 104 patients at diagnosis, which showed stepwise clearances after chemotherapy and HCT. In a subset of patients, mutations were still detectable pre-HCT and post-HCT. Most post-HCT mutations originate from mutations initially detected at diagnosis. Post-HCTD21 allelic burdens in relapsed patients were higher than in nonrelapsed patients. Post-HCTD21 mutations in relapsed patients all expanded at relapse. Assessment of variant allele frequency (VAF) revealed that overall VAF post-HCTD21 (VAF0.2%-post-HCTD21) is associated with an increased risk of relapse (56.2% vs 16.0% at 3 years; P < .001) and worse overall survival (OS; 36.5% vs 67.0% at 3 years; P = .006). Multivariate analyses confirmed that VAF0.2%-post-HCTD21 is an adverse prognostic factor for OS (hazard ratio [HR], 3.07; P = .003) and relapse incidence (HR, 4.75; P < .001), independent of the revised European LeukemiaNet risk groups. Overall, current study demonstrates that NGS-based posttransplant monitoring in AML patients is feasible and can distinguish high-risk patients for relapse.

As interest in elderly Acute Myeloid Leukemia (AML) patients increases, American society of hematology (ASH) 2020 guidelines for treating newly diagnosed AML in older adults suggested diverse treatment options. The guidelines suggest using monotherapy over combination of hypomethylation agent (HMAs) with other agents in newly diagnosed AML in older adults due to similar efficacy and the potential for more toxicity. HMAs alone is still used widely as an alternative treatment for patients who cannot use venetoclax due to the high cost and poor performance score. If there are early predictors of responsiveness to Decitabine mono therapy, it will be helpful to decide whether to combine Novel agents. This retrospective cohort study from a single institution aimed to evaluate the prognostic significance of Variant allele frequency (VAF) changes in elderly patients after 4 th cycle of decitabine. Total 123 patients with elderly AML were eligible. 57 patients performed follow-up bone marrow biopsy and 49 patients were available of follow up targeted NGS samples from biopsy after 4th cycle of decitabine. To clarify the immortal timed bias, landmark analyses were performed with patients (n=84) who remained at least the median time to perform follow-up bone marrow biopsy after 4th cycle of decitabine treatment. 24 patients (54.5%, 24 of 44) showed more than 50% decrease of VAF after 4 th cycle of decitabine (figure 1a). DMNT3A, TET2, IDH1, IDH2, and SETBP1 and SMC1A showed less than 50% of the decreases of VAF. Patients with DNA methylation genes showed significantly reduced VAF less than 50% (figure 1b). A significant difference of ∆VAF was observed depending on CR status (p=0.021). The survival outcome of patients who showed more than 50% decrease of initial VAF after 4th cycle of decitabine was significantly better than that that with less than 50% decrease of VAF(1-year OS VAF decrease ≥ 50% (n=23), 75.0%; VAF decrease < 50% (n=20), 38.5%; no mutation (n=12), 45.5%; not available of follow up targeted NGS sample (n=29), 16.6%; p < 0.001, figure 2a). Mutations in DNMT3A, TET2, and ASXL1 (DTA genes) were detected in samples from 19 patients at diagnosis. After the exclusion of DTA mutations, the survival outcome improved prognostic risk stratification power of NGS-based MRD assessment in AML. The survival outcome of patients who showed more than 50% decrease of initial VAF after 4th cycle of decitabine was significantly better than that that with less than 50% decrease of VAF(1-year OS VAF decrease ≥ 50% (n=24), 75.0%; VAF decrease < 50% (n=19), 35.1%; no mutation (n=12), 50.1%; not available of follow up targeted NGS sample (n=29), 16.6%; p Figure 1 Figure 1. Disclosures Kim: Bristol-Meier Squibb: Research Funding; Paladin: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.