Chromothripsis in Treatment Resistance in Multiple Myeloma

Multiple myeloma (MM) is a malignant disease caused by an abnormal proliferation of plasma cells, of which the prognostic factors include chromosomal abnormality, β-2 microglobulin, and albumin. Recently, the term chromothripsis has emerged, which is the massive but highly localized chromosomal rearrangement in response to a one-step catastrophic event. Many studies have shown an association of chromothripsis with the prognosis in several cancers; however, few studies have investigated it in MM. Here, we studied the association between chromothripsis-like patterns and treatment resistance or prognosis. First, we analyzed nine MM cell lines (U266, MM.1S, RPMI8226, KMS-11, KMS-12-BM, KMS-12-PE, KMS-28-BM, KMS-28-PE, and NCI-H929) and bone marrow samples of four patients who were diagnosed with MM by next-generation sequencing-based copy number variation analysis. The frequency of the chromothripsis-like pattern was observed in seven cell lines. We analyzed the treatment-induced chromothripsis-like patterns in KMS-12-BM and KMS-12-PE cells. As a result, breakpoints and chromothripsis-like patterns were increased after drug treatment in the relatively resistant KMS-12-BM. We further analyzed the patients’ results according to the therapeutic response, which was divided into sensitive and resistant, as suggested by the International Myeloma Working Group. The chromothripsis-like pattern was more frequently observed in the resistant group. In the sensitive group, the frequency of the chromothripsis-like pattern decreased after treatment, whereas the resistant group showed increased chromothripsis-like patterns after the treatment. These results suggest that the chromothripsis-like pattern is associated with treatment response in MM

A CRISPR screen identifies a pathway required for paraquat-induced cell death

Paraquat, a herbicide linked to Parkinson's disease, generates reactive oxygen species (ROS), which causes cell death. Because the source of paraquat-induced ROS production remains unknown, we conducted a CRISPR-based positive-selection screen to identify metabolic genes essential for paraquat-induced cell death. Our screen uncovered three genes, POR (cytochrome P450 oxidoreductase), ATP7A (copper transporter), and SLC45A4 (sucrose transporter), required for paraquat-induced cell death. Furthermore, our results revealed POR as the source of paraquat-induced ROS production. Thus, our study highlights the use of functional genomic screens for uncovering redox biology

Daily Emotional Labor, Negative Affect State, and Emotional Exhaustion: Cross-Level Moderators of Affective Commitment

Employees’ emotional-labor strategies, experienced affects, and emotional exhaustion in the workplace may vary over time within individuals, even within the same day. However, previous studies on these relationships have not highlighted their dynamic properties of these relationships. In addition, although the effects of surface and deep acting on emotional exhaustion have been investigated in emotional-labor research, empirical studies on these relationships still report mixed results. Thus, we suggest that moderators may affect the relationship between emotional labor and emotional exhaustion. Also, this study examines the relationship between emotional labor and emotional exhaustion within individuals by repeated measurements, and verifies the mediating effect of a negative affect state. Finally, our study confirms the moderating effects that affective commitment has on the relationship between emotional labor and emotional exhaustion. Data was collected from tellers who had a high degree of interaction with clients at banks based in South Korea. A total of 56 tellers participated in the survey and responded for five working days. A total of 616 data entries were collected from the 56 respondents. We used a hierarchical linear model (HLM) to examine our hypothesis. The results showed that surface-acting emotional labor increases emotional exhaustion; furthermore, the relationship between surface acting emotional labor and emotional exhaustion is mediated by a negative affect state within individuals. In addition, this study verified that affective commitment buffers the negative effects that surface acting emotional labor has on emotional exhaustion. These results suggest that emotional labor is a dynamic process within individuals, and that emotional exhaustion caused by emotional labor differs among individuals, and is dependent upon factors such as the individual’s level of affective commitment

Does National Gender Equality Matter? Gender Difference in the Relationship between Entrepreneurial Human Capital and Entrepreneurial Intention

Gender equality contributes to economic growth and social progress by promoting women’s social and economic participation. The national gender equality level can affect women’s education and opportunities for economic participation. In this work, we examine whether entrepreneurial human capital (entrepreneurial education and experience) affects entrepreneurial intention and whether these relationships depend on gender and a country’s gender equality level. We used Global Entrepreneurship Trend Report (GETR) data provided by the Korean Entrepreneurship Foundation. The global survey was conducted by the Korean National Statistical Office in 2016. The data were collected from 20 countries, including Korea, and contain at least 2000 individual responses from each country. We used HLM analysis with the HLM 6.0 program to examine the hypotheses. Our results show that entrepreneurship education increases entrepreneurial intention, and that the relationship is stronger among women than men. We also found that for women, the positive relationship between entrepreneurial education and entrepreneurial intention is stronger in countries with lower gender equality. As for prior entrepreneurial experience, neither gender nor national gender equality level moderated the relationship between experience and entrepreneurial intention. This study contributes to the extension of entrepreneurship theory, especially in the area of women entrepreneurship. We confirm that entrepreneurial human capital contributes to entrepreneurial intention, and that gender and national gender equality level comprise an important social context that influences the effects of education and experience on the entrepreneurial intention of women

Does National Gender Equality Matter? Gender Difference in the Relationship between Entrepreneurial Human Capital and Entrepreneurial Intention

Gender equality contributes to economic growth and social progress by promoting women’s social and economic participation. The national gender equality level can affect women’s education and opportunities for economic participation. In this work, we examine whether entrepreneurial human capital (entrepreneurial education and experience) affects entrepreneurial intention and whether these relationships depend on gender and a country’s gender equality level. We used Global Entrepreneurship Trend Report (GETR) data provided by the Korean Entrepreneurship Foundation. The global survey was conducted by the Korean National Statistical Office in 2016. The data were collected from 20 countries, including Korea, and contain at least 2000 individual responses from each country. We used HLM analysis with the HLM 6.0 program to examine the hypotheses. Our results show that entrepreneurship education increases entrepreneurial intention, and that the relationship is stronger among women than men. We also found that for women, the positive relationship between entrepreneurial education and entrepreneurial intention is stronger in countries with lower gender equality. As for prior entrepreneurial experience, neither gender nor national gender equality level moderated the relationship between experience and entrepreneurial intention. This study contributes to the extension of entrepreneurship theory, especially in the area of women entrepreneurship. We confirm that entrepreneurial human capital contributes to entrepreneurial intention, and that gender and national gender equality level comprise an important social context that influences the effects of education and experience on the entrepreneurial intention of women

Daily Emotional Labor, Negative Affect State, and Emotional Exhaustion: Cross-Level Moderators of Affective Commitment

Employees’ emotional-labor strategies, experienced affects, and emotional exhaustion in the workplace may vary over time within individuals, even within the same day. However, previous studies on these relationships have not highlighted their dynamic properties of these relationships. In addition, although the effects of surface and deep acting on emotional exhaustion have been investigated in emotional-labor research, empirical studies on these relationships still report mixed results. Thus, we suggest that moderators may affect the relationship between emotional labor and emotional exhaustion. Also, this study examines the relationship between emotional labor and emotional exhaustion within individuals by repeated measurements, and verifies the mediating effect of a negative affect state. Finally, our study confirms the moderating effects that affective commitment has on the relationship between emotional labor and emotional exhaustion. Data was collected from tellers who had a high degree of interaction with clients at banks based in South Korea. A total of 56 tellers participated in the survey and responded for five working days. A total of 616 data entries were collected from the 56 respondents. We used a hierarchical linear model (HLM) to examine our hypothesis. The results showed that surface-acting emotional labor increases emotional exhaustion; furthermore, the relationship between surface acting emotional labor and emotional exhaustion is mediated by a negative affect state within individuals. In addition, this study verified that affective commitment buffers the negative effects that surface acting emotional labor has on emotional exhaustion. These results suggest that emotional labor is a dynamic process within individuals, and that emotional exhaustion caused by emotional labor differs among individuals, and is dependent upon factors such as the individual’s level of affective commitment

Targeting actomyosin contractility suppresses malignant phenotypes of acute myeloid leukemia cells

Actomyosin-mediated contractility is required for the majority of force-driven cellular events such as cell division, adhesion, and migration. Under pathological conditions, the role of actomyosin contractility in malignant phenotypes of various solid tumors has been extensively discussed, but the pathophysiological relevance in hematopoietic malignancies has yet to be elucidated. In this study, we found enhanced actomyosin contractility in diverse acute myeloid leukemia (AML) cell lines represented by highly expressed non-muscle myosin heavy chain A (NMIIA) and increased phosphorylation of the myosin regulatory light chain. Genetic and pharmacological inhibition of actomyosin contractility induced multivalent malignancy- suppressive effects in AML cells. In this context, perturbed actomyosin contractility enhances AML cell apoptosis through cytokinesis failure and aryl hydrocarbon receptor activation. Moreover, leukemic oncogenes were downregulated by the YAP/TAZ-mediated mechanotransduction pathway. Our results provide a theoretical background for targeting actomyosin contractility to suppress the malignancy of AML cells.Y

Metabolic determinants of cellular fitness dependent on mitochondrial reactive oxygen species

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). Mitochondria-derived reactive oxygen species (mROS) are required for the survival, proliferation, and metastasis of cancer cells. The mechanism by which mitochondrial metabolism regulates mROS levels to support cancer cells is not fully understood. To address this, we conducted a metabolism-focused CRISPR-Cas9 genetic screen and uncovered that loss of genes encoding subunits of mitochondrial complex I was deleterious in the presence of the mitochondria-targeted antioxidant mito-vitamin E (MVE). Genetic or pharmacologic inhibition of mitochondrial complex I in combination with the mitochondria-targeted antioxidants, MVE or MitoTEMPO, induced a robust integrated stress response (ISR) and markedly diminished cell survival and proliferation in vitro. This was not observed following inhibition of mitochondrial complex III. Administration of MitoTEMPO in combination with the mitochondrial complex I inhibitor phenformin decreased the leukemic burden in a mouse model of T cell acute lymphoblastic leukemia. Thus, mitochondrial complex I is a dominant metabolic determinant of mROS-dependent cellular fitness

Expression of Myeloid Antigen in Neoplastic Plasma Cells Is Related to Adverse Prognosis in Patients with Multiple Myeloma

We evaluated the association between the expression of myeloid antigens on neoplastic plasma cells and patient prognosis. The expression status of CD13, CD19, CD20, CD33, CD38, CD56, and CD117 was analyzed on myeloma cells from 55 newly diagnosed patients, including 36 men (65%), of median age 61 years (range: 38–78). Analyzed clinical characteristics and laboratory parameters were as follows: serum β2-microglobulin, lactate dehydrogenase, calcium, albumin, hemoglobin, serum creatinine concentrations, bone marrow histology, and cytogenetic findings. CD13+ and CD33+ were detected in 53% and 18%, respectively. Serum calcium (P=0.049) and LDH (P=0.018) concentrations were significantly higher and morphologic subtype of immature or plasmablastic was more frequent in CD33+ than in CD33− patients (P=0.022). CD33 and CD13 expression demonstrate a potential prognostic impact and were associated with lower overall survival (OS; P=0.001 and P=0.025) in Kaplan-Meier analysis. Multivariate analysis showed that CD33 was independently prognostic of shorter progression free survival (PFS; P=0.037) and OS (P=0.001) with correction of clinical prognostic factors. This study showed that CD13 and CD33 expression associated with poor prognosis in patients with MM implicating the need of analysis of these markers in MM diagnosis