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The development of new treatment agents in recent decades has significantly improved the survival of patients with multiple myeloma (MM). Nonetheless, MM remains an incurable disease; therefore, novel combination therapies are required. Natural killer (NK) cells are one of the safest immunotherapeutic options. In this study, we found that the anti-myeloma activity of expanded NK cells (eNKs) was improved by daratumumab, lenalidomide, and dexamethasone (DRd) in an MM xenograft mouse model. NK cells expanded from peripheral blood mononuclear cells collected from MM patients were highly cytotoxic against DRd pretreated tumor cells in vitro. To mimic the clinical protocol, a human MM xenograft model was developed using human RPMI8226-RFP-FLuc cells in NOD/SCID IL-2Rγnull (NSG) mice. MM bearing mice were randomly divided into six groups: no treatment, eNK, Rd, Rd + eNKs, DRd, and DRd + eNKs. DRd significantly enhanced the cytotoxicity of eNKs by upregulating NK cell activation ligands and effector function. DRd in combination with eNKs significantly reduced the serum M-protein level and prolonged mouse survival. In addition, DRd significantly increased the persistence of eNK and homing to MM sites. These results show that the anti-myeloma activity of ex vivo-expanded and activated NK cells is augmented by the immunomodulatory effect of DRd in MM-bearing mice, suggesting the therapeutic potential of this combination for MM patients.

Although survival outcomes of multiple myeloma (MM) have improved with the development of new and effective agents, infection remains the major cause of morbidity and mortality. Here, we evaluated the efficacy of levofloxacin prophylaxis (in a real-world setting) during bortezomib, melphalan, and prednisone (VMP) therapy in elderly patients with newly diagnosed MM.This study retrospectively analyzed the records of patients with newly diagnosed MM treated with the VMP regimen between February 2011 and September 2020 at three institutes of the Republic of Korea.Of a total of 258 patients, 204 (79.1%) received levofloxacin prophylaxis during VMP therapy. The median number of levofloxacin prophylaxis cycles was 4 (range, 1‒9), but 10 patients did not complete the planned prophylaxis because of side effects. Sixty-six patients (25.5%) experienced severe infections during VMP therapy, most of which (74.7%) occurred within the first four cycles of VMP therapy regardless of levofloxacin prophylaxis status. Early severe infection was significantly associated with poor survival. In multivariate analysis, levofloxacin prophylaxis was significantly associated with a lower risk in early severe infection.Our findings suggest that levofloxacin prophylaxis should be considered at least during the first four cycles of VMP therapy in elderly patients with newly diagnosed MM.

Purpose: This study investigates the anti-melanogenic effects of lotus seed and seedpod extract in B16F10 murine melanoma cells, and demonstrates the possible mechanisms involved in anti-pigmentation.Methods: The lotus seed and seedpod extracts were prepared using 70% ethanol as solvent. The irritation potential of the extracts was investigated using water-soluble tetrazolium salt (WST-1)-based cytotoxicity assay and expression analysis of the pro-inflammatory cytokine IL1β in B16F10 cells and HaCaT keratinocytes, respectively. The anti-melanogenic effects of the extracts were analyzed using intracellular melanin contents and tyrosinase activity assays. The effects of the extracts on tyrosinase expression were analyzed at the mRNA and protein levels. The effects of those extracts on the stability of tyrosinase protein were analyzed by evaluating the protein level after cycloheximide treatment.Results: WST-1-based cytotoxicity assay indicated that the concentration of ≤1.0% for lotus seed and seedpod extracts did not exhibit any cytotoxicity in B16F10 cells. Also, qRT-PCR analysis showed that the expression of IL-1β mRNAs was not increased by those concentrations of the extracts in HaCaT keratinocytes. Additionally, intracellular melanin contents assay showed that those extracts significantly inhibited α-MSH-induced melanin synthesis. Furthermore, cellular tyrosinase activity was significantly inhibited by the extracts. Additional investigations revealed that tyrosinase activity reduction was independent of its mRNA expression level, but dependent on its protein expression level. These findings were further confirmed by the results of the cycloheximide experiments stating that the protein stability of tyrosinase was reduced after the treatment with those extracts.Conclusion: Lotus seed and seedpod extracts showed anti-pigmentation effects by accelerating degradation of tyrosinase protein at the post-translation level in B16F10 cells.

Combination treatment with hypomethylating agents (HMAs) and venetoclax is being used increasingly in elderly patients with acute myeloid leukemia (AML). Venetoclax with HMAs has been reported to be associated with tumor lysis syndrome (TLS) in AML patients with high leukemic burden. We present a case of an elderly AML patient with low leukemic burden who developed TLS while receiving venetoclax and azacitidine (AZA). A 74-year-old man with newly diagnosed AML with NPM1 mutation received combination therapy with venetoclax and AZA in an outpatient clinic. Within 12 hours after starting venetoclax and AZA, the patient was admitted to the emergency room with fever, general weakness, and laboratory findings consistent with TLS. Based on our results, we recommend monitoring at the start of the treatment with venetoclax and HMAs to prevent and control TLS regardless of the leukemic burden and favorable genetic risk.

The use of natural killer (NK) cells is a promising and safe immunotherapeutic approach in the field of cancer immunotherapy. However, combination treatments are required to enhance the effector functions and therapeutic efficacy of NK cells. In this study, we investigated the potential of daratumumab (Dara), bortezomib, and dexamethasone (Dvd) to augment the antitumor effects of NK cells in a multiple myeloma (MM) xenograft mouse model. NK cells were expanded and activated using the K562-OX40 ligand and membrane-bound IL-18 and IL-21 in the presence of IL-2 and IL-15 from peripheral blood mononuclear cells from MM patients. A human MM xenograft model was established using human RPMI8226-RFP-FLuc cells in NOD/SCID IL-2Rγ(null) (NSG) mice. Tumor-bearing mice were divided into six treatment groups: no treatment, expanded NK cells (eNKs), Dara, Dara + eNKs, Dvd, and Dvd + eNKs. Dvd treatment strongly enhanced the cytotoxicity of eNKs by upregulating expression of NK cell activation ligands, downregulating expression of NK cell inhibitory ligands, and promoting antibody-dependent cellular cytotoxicity. The combination of eNKs with Dvd significantly prolonged mouse survival and reduced the tumor burden and serum M-protein level. Furthermore, Dvd pretreatment significantly increased eNK persistence and homing to MM sites. Our findings suggest that Dvd treatment potentiates the antimyeloma effects of NK cells expanded and activated ex vivo by modulating immune responses in MM-bearing mice.

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.

Although team downsizing or team restructuring initiatives have frequently taken place in contemporary organizations, very little research has been conducted on the issue of team insecurity. Drawing on Kim, Shin, and Rim’s, Korean Journal of Management 25, 257–280 (2017) theoretical framework, which proposes team insecurity as a multi-level and multi-dimensional construct, this study aims to develop a scale assessing team insecurity and test its validity. Team insecurity refers to an employee’s perceptions of and affective reactions to the continuity of his or her team. The employee’s perception of team insecurity can also be shared within a team, which ultimately form an insecurity climate in the team. In Study 1, we developed a multi-dimensional scale of team insecurity, which consisted of four dimensions: (1) perceived team restructuring; (2) perceived team relative status; (3) perceived team composition; and (4) overall affective reaction. We assessed the four-factor structure of team insecurity and its discriminant validity by using a sample of 248 employees. In Study 2, we tested the predictive validity of team insecurity by using survey data from 280 employees in 75 teams. The test of the predictive validity showed that employees’ perceptions of team insecurity significantly predicted their intention to leave and alternative job search, whereas team insecurity climate significantly predicted team creativity and team organizational citizenship behavior. These findings provide initial support for the construct of team insecurity.

Maintaining the integrity of cell membranes is indispensable for cellular viability. Poloxamer 188 (P188), a poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) (PEO–PPO–PEO) triblock copolymer with a number-average molecular weight of 8700 g/mol and containing 80% by mass PEO, protects cell membranes from various external injuries and has the potential to be used as a therapeutic agent in diverse applications. The membrane protection mechanism associated with P188 is intimately connected with how this block copolymer interacts with the lipid bilayer, the main component of a cell membrane. Here, we report the distribution of P188 in a model lipid bilayer comprising 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) using neutron reflectivity (NR) and atomic force microscopy (AFM). We also investigated the association of a PEO homopolymer (PEO8.4K; M(n) = 8400 g/mol) that does not protect living cell membranes. These experiments were conducted following incubation of a 4.5 mmol/L polymer solution in a buffer that mimics physiological conditions with supported POPC bilayer membranes followed by washing with the aqueous medium. In contrast to previous reports, which dealt with P188 and PEO in salt-free solutions, both P188 and PEO8.4K penetrate into the inner portion of the lipid bilayer as revealed by NR, with approximately 30% by volume occupancy across the membrane without loss of bilayer structural integrity. These results indicate that PEO is the chemical moiety that principally drives P188 binding to bilayer membranes. No defects or phase-separated domains were observed in either P188- or PEO8.4K-incubated lipid bilayers when examined by AFM, indicating that polymer chains mingle homogeneously with lipid molecules in the bilayer. Remarkably, the breakthrough force required for penetration of the AFM tip through the bilayer membrane is unaffected by the presence of the large amount of P188 and PEO8.4K.

Secondary-type mutations (STMs), namely SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, and STAG2, are more frequently detected in secondary acute myeloid leukemia (AML) than in de novo AML. Whether de novo AML with STMs should be differently managed is, however, unclear. In 394 patients diagnosed with de novo AML who had a normal karyotype, the genetic profiling via targeted deep sequencing of 45 genes revealed 59 patients carrying STMs (STM

Background In diffuse large B-cell lymphoma (DLBCL), bone marrow involvement (BMI) has an important clinical implication as a component of staging and International Prognostic Index. This study aimed to determine whether molecular analysis of immunoglobulin heavy chain (IgH) genes and positron emission tomography-computed tomography (PET/CT) could overcome the limitation of defining morphologic BMI by trephination biopsy and could increase the diagnostic accuracy or prognostic prediction. Methods A total of 94 de novo patients with DLBCL underwent PET/CT, polymerase chain reaction (PCR) test for detection of IgH gene rearrangement, and unilateral bone marrow (BM) trephination at diagnosis. Results A total of 9 patients (9.6%) were confirmed to present morphologic BMI (mBMI) based on trephination biopsy. On the other hand, 21 patients (22.3%) were confirmed to have IgH clonality (IgH BMI), while 16 (17.0%) were classified with BMI based on the assessment of PET/CT (PET BMI). Each IgH rearrangement PCR and PET/CT showed the high negative predictive value of detecting the BMI. However, the combined assessment of IgH rearrangement and PET/CT could increase the diagnostic accuracy and specificity with 87.2% and 97.0%, respectively. The survival outcome of patients with double positive PET BMI and IgH BMI was significantly worse than that with either single positive PET BMI or IgH BMI, and even less than patients with neither PET BMI nor IgH BMI (3-year PFS: 50.0% vs. 75.4% vs. 97.9%, P = 0.007, 3-year OS: 50.0% vs. 75.6% vs. 80.1%, P = 0.035, respectively). Conclusion This study suggests that the combined evaluation of PET/CT and IgH rearrangement could give additional information for predicting therapeutic outcomes in patients with negative morphologic BMI as an important part of the prognosis., Graphical Abstract

As the clinical management of multiple myeloma (MM) has evolved, survival of patients with MM has improved in the current decade [1]. However, this prolonged survival results in cumulative toxiciti...

Background In diffuse large B-cell lymphoma (DLBCL), bone marrow involvement (BMI) has an important clinical implication as a component of staging and International Prognostic Index (IPI). Methods This study aimed to determine whether molecular analysis of immunoglobulin heavy chain (IgH) genes and PET/CT could overcome the limitation of defining morphologic bone marrow involvement by trephination biopsy and could increase the diagnostic accuracy or prognostic prediction. 94 de novo patients with DLBCL underwent PET/CT, polymerase chain reaction (PCR) test for detection of IgH gene rearrangement, and unilateral BM trephination at diagnosis. Results 9 patients (9.6%) were confirmed to present morphologic BMI (mBMI) based on trephination biopsy. On the other hands, 21 patients (22.3%) were confirmed to have IgH clonality (IgH BMI), while 16 (17.0%) were classified with BMI based on the assessment of PET/CT (PET BMI). Each IgH rearrangement PCR and PET/CT showed the high negative predict value of detecting the BMI. However, the combined assessment of IgH rearrangement and PET/CT could increase a diagnostic accuracy and specificity with 87.2% and 97.0%, respectively. The survival outcome of patients with double positive PET BMI and IgH BMI was significantly worse than that with either single positive PET BMI or IgH BMI, and even less than patients with neither PET BMI nor IgH BMI. (3-year PFS: 50.0% vs 75.4% vs 97.9%, p = 0.007, 3-year OS: 50.0% vs 75.6% vs 80.1%, p = 0.035, respectively). Conclusion This study suggested that the combined evaluation of PET/CT and IgH rearrangement could give additional information of predicting therapeutic outcomes in patients with negative morphologic BMI as an important part of the prognosis.

Background South Korea has been experiencing a third wave of coronavirus disease 2019 (COVID-19) since mid-November 2020. Our hospital in Gwangju metropolitan city experienced a healthcare-associated COVID-19 outbreak early in the third wave. The first confirmed COVID-19 patient was a symptomatic neurosurgery resident with high mobility throughout the hospital. We analyzed the transmission routes of nosocomial COVID-19 and discussed infection control strategies. Methods We retrospectively analyzed the severe acute respiratory syndrome coronavirus 2 reverse transcription-polymerase chain reaction (RT-PCR) testing results according to time point and evaluated transmission routes. Results Since COVID-19 was first confirmed in a healthcare worker (HCW) on 11/13/2020, we performed RT-PCR tests for all patients and caregivers and four complete enumeration surveys for all HCWs. We detected three clusters of nosocomial spread and several sporadic cases. The first cluster originated from the community outbreak spot, where an asymptomatic HCW visited, which led to a total of 22 cases. The second cluster, which included patient-to-patient transmission, originated from a COVID-19 positive caregiver before diagnosis and the third cluster involved a radiologist and a banker. We took measures to isolate Building 1 of the hospital for 17 days and controlled the outbreak during a period of increasing community COVID-19 prevalence. Universal screening of all inpatients upon admission and resident caregivers was made mandatory and hospital-related employees are now screened monthly. Conclusion Infection control strategies to prevent the nosocomial transmission of emerging infectious diseases must correspond with community disease prevalence. Our data reinforce the importance of multi-time point surveillance of asymptomatic HCWs and routine surveillance of patients and caregivers during an epidemic., Graphical Abstract

An online survey was conducted to explore how Instagram users’ selfie-posting behavior affects their self-esteem and body dissatisfaction. Female college students from South Korea (N = 321) participated in the survey. Results showed that Instagram users’ selfie-posting was positively related to their self-esteem. Moreover, Instagram users’ self-esteem mediated the relationship between their selfie-posting behavior and body dissatisfaction. Findings showed that Instagram users’ selfie-posting behavior may positively influence their self-esteem, which may consequently contribute to reducing their body dissatisfaction. Such an indirect effect of selfie-posting was moderated by Instagram users’ levels of the need for popularity. The indirect influence of selfie-posting on body dissatisfaction through self-esteem was only significant among those with low or moderate levels of the need for popularity. This suggests that those with lower levels of the need for popularity can benefit more from posting their selfies. These findings advance the emerging literature on the effects of selfie-posting by providing a moderated mediation model of selfie-posting and body image concerns.

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

Until recently, research disclosing the specific antecedents that induce proactive job crafting activities has been relatively lacking. Particularly, despite theoretical studies that imply the importance of work meaningfulness as a critical motivational factor for positive workplace behaviors, previous research has not observed this firsthand. Therefore, for the first time, the present study empirically assesses work meaningfulness as a key element in prompting job crafting, an individually induced job redesign strategy. The purpose of the present study is to explain the respective original job crafting concepts (i.e., task, cognitive, and relational crafting) by employing a job demands-resources (JD-R) approach, which integrates the original job crafting dimensions and JD-R-based classification of job crafting. Additionally, the present study examines boundary conditions centered on social and job resources that may further stimulate job crafting. It was posited, based upon three three-way interaction models, that social identification (i.e., social resource) and task interdependence (i.e., job resource) are moderators that strengthen the relationship between work meaningfulness and each of the respective job crafting activities. Analyzing survey data from 195 individuals in 25 organizations from private and public sectors, the results indicated that task and relational crafting were both highest when work meaningfulness, task interdependence, and social identification were all high, thus partly supporting the proposed research hypotheses.

Poloxamer 188 (P188), a poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) triblock copolymer, protects cell membranes against various external stresses whereas polyethylene oxide (PEO; 8,600 g/mol) homopolymer lacks protection efficacy. As part of a comprehensive effort to elucidate the protection mechanism, we used surface plasmon resonance (SPR) to obtain direct evidence of binding of the polymers onto supported lipid bilayers. Binding kinetics and coverage of the P188 and PEO were examined and compared. Most notably, the PEO exhibited comparable membrane association to that of the P188, evidenced by comparable association rate constants and coverage. This result highlights the need for additional mechanistic understanding beyond simple membrane association to explain the differential efficacy of P188 in therapeutic applications.

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.