Benevolence - Associations With Stress, Mental Health, and Self-Compassion at the Workplace.

OBJECTIVE: Benevolence is an emerging concept in motivation theory and research as well as in on pro-social behavior, which has stimulated increasing interest in studying factors that impair or facilitate benevolence and effects thereof. This exploratory study examines the associations between benevolence, stress, mental health, self-compassion, and satisfaction with life in two workplace samples. METHODS: In the first study n = 522 (38% = female, median age = 42) participants answered questionnaires regarding self-reported stress symptoms (i.e., emotional exhaustion), depressive symptoms and benevolence. In the second study n = 49 (female = 96%) participants answered questionnaires regarding perceived stress, self-compassion, anxiety, depression symptoms, and benevolence. RESULTS: In study 1, measures of emotional exhaustion (r = -0.295) and depression (r = -0.190) were significantly negatively correlated with benevolence. In study 2, benevolence was significantly negatively correlated with stress (r = -0.392) and depression (r = -0.310), whereas self-compassion (0.401) was significantly positively correlated with benevolence. While correlations were in expected directions, benevolence was not significantly associated with Satisfaction with Life (r = 0.148) or anxiety (r = -0.199) in study 2. CONCLUSION: Self-assessed benevolence is associated with levels of perceived stress, exhaustion, depression, and self-compassion. Future studies are warranted on how benevolence is related to stress and mental ill health such as depression and anxiety, and if benevolence can be trained in order to decrease stress and mental ill health such as depression and anxiety in workplace settings.

Cultivating Compassion and Reducing Stress and Mental Ill-Health in Employees-A Randomized Controlled Study.

Stress and mental ill-health carry considerable costs for both individuals and organizations. Although interventions targeting compassion and self-compassion have been shown to reduce stress and benefit mental health, related research in organizational settings is limited. We investigated the effects of a 6-week psychological intervention utilizing compassion training on stress, mental health, and self-compassion. Forty-nine employees of two organizations were randomly assigned to either the intervention (n = 25) or a physical exercise control condition (n = 24). Multilevel growth models showed that stress (p = 0.04) and mental ill-health (p = 0.02) decreased over 3 months in both groups (pre-intervention to follow-up: Cohen's d = -0.46 and d = 0.33, respectively), while self-compassion only increased in the intervention group (p = 0.03, between group d = 0.53). There were no significant effects on life satisfaction in any of the groups (p > 0.53). The findings show promising results regarding the ability of compassion training within organizations to decrease stress and mental ill-health and increase self-compassion.

The effectiveness of smartphone compassion training on stress among Swedish university students: A pilot randomized trial.

OBJECTIVE: To investigate the effects of a 6-week smartphone compassion training intervention on mental health. METHOD: Fifty-seven Swedish university students (mean age = 25, SD = 5) reporting high levels of stress were randomized to compassion training (n = 23), mindfulness (n = 19), or waitlist (n = 15). RESULT: Multilevel models indicated that both compassion and mindfulness training increased self-compassion compared to the waitlist, while only compassion significantly reduced stress. Between-group effect sizes for compassion compared to waitlist were large for both self-compassion (d = 1.61) and stress (d = 0.94). Compassion and mindfulness did not differ significantly, but effect sizes were in favor of compassion. Secondary outcomes indicated positive effects on emotional awareness, while no effect was found for global psychological distress. CONCLUSIONS: Our results suggest that compassion training via a smartphone application can improve self-compassion and reduce stress among university students. Future studies in larger clinical samples are warranted.

The HPV-16 E7 oncogene sensitizes malignant cells to IFN-alpha-induced apoptosis.

Interferons (IFNs) exert antitumor effects in several human malignancies, but their mechanism of action is unclear. There is a great variability in sensitivity to IFN treatment depending on both tumor type and the individual patient. The reason for this variable sensitivity is not known. The fact that several IFN-induced anticellular effects are exerted through modulation of proto-oncogenes and tumor suppressor genes may indicate that the malignant genotype may be decisive in the cell's sensitivity to IFN. To determine if a deregulated oncogene could alter the cellular response to IFN, a mouse lymphoma cell line (J3D) was stably transfected with the viral human papillomavirus-16 (HPV-16) E7 oncogene. The E7-transfected cells and their respective mock-transfected sister clones were treated with IFN-alpha and examined for possible IFN-induced anticellular effects. We found that the E7-transfected clones were greatly sensitized to IFN-alpha-induced apoptosis compared with their mock-transfected counterparts. Induction of apoptosis in the transfected cells correlated with the ability of IFN to activate parts of the proapoptotic machinery specifically in these cells, including activation of caspases and the proapoptotic protein Bak. In summary, our data suggest that transfection of malignant cells with the E7 oncogene can sensitize them to IFN-alpha-induced apoptosis. This demonstrates that an oncogenic event may alter the cellular sensitivity to IFN and might also have implications for treatment of HPV-related diseases with IFN.

Disruption of a novel ectodermal neural cortex 1 antisense gene, ENC-1AS and identification of ENC-1 overexpression in hairy cell leukemia.

Karyotypical alteration of chromosome 5 and in particular band 5q13 is a frequent finding in hairy cell leukemia (HCL). We have previously identified a number of candidate genes localized in close proximity to a constitutional inv(5)(p13.1q13.3) breakpoint in one HCL patient. These included beta-hexosaminodase HEXB, frequently mutated in the lysosomal storage disorder Sandhoff disease. We now report that the 5q13.3 breakpoint disrupts a novel evolutionary conserved alternative isoform of HEXB. This isoform directly overlaps, in a cis-antisense fashion, exon 1 of the gene for ectodermal neuronal cortex 1 ENC-1, and was thus named ENC-1AS. ENC-1 has previously been shown to be overexpressed in several malignancies, and is believed to play a critical regulatory role in malignant transformation of various tumors. Importantly, subsequent analysis of ENC-1 in purified primary HCL tumor cells revealed a striking upregulation of ENC-1 in all 26 patients examined, compared with normal peripheral blood lymphocytes from healthy donors. Upon further analysis of the ENC-1/ENC-1AS locus, we identified a complex 5' regulatory mechanism involving an inverse expression of the ENC-1 sense and the ENC-1AS transcripts in several tissues supporting the hypothesis that expression of ENC-1AS regulates ENC-1 levels. In addition, we have also found tissue-specific methylation of a 1.2 kb segment encompassing the overlapping ENC-1/ENC-1AS 5' exons, adding to the complexity of the regulation of this locus. Altogether, these results suggest that upregulation of ENC-1 contributes to the development of HCL and provides new information on the possible dysregulation of ENC-1 including expression of a novel antisense gene, ENC-1AS.

DLEU2 encodes an antisense RNA for the putative bicistronic RFP2/LEU5 gene in humans and mouse.

Our group previously identified two novel genes, RFP2/LEU5 and DLEU2, within a 13q14.3 genomic region of loss seen in various malignancies. However, no specific inactivating mutations were found in these or other genes in the vicinity of the deletion, suggesting that a nonclassical tumor-suppressor mechanism may be involved. Here, we present data showing that the DLEU2 gene encodes a putative noncoding antisense RNA, with one exon directly overlapping the first exon of the RFP2/LEU5 gene in the opposite orientation. In addition, the RFP2/LEU5 transcript can be alternatively spliced to produce either several monocistronic transcripts or a putative bicistronic transcript encoding two separate open-reading frames, adding to the complexity of the locus. The finding that these gene structures are conserved in the mouse, including the putative bicistronic RFP2/LEU5 transcript as well as the antisense relationship with DLEU2, further underlines the significance of this unusual organization and suggests a biological function for DLEU2 in the regulation of RFP2/LEU5.

Characterization of a novel B-CLL candidate gene--DLEU7--located in the 13q14 tumor suppressor locus.

Deletion of chromosome 13q14 is the most frequent genetic aberration in B-cell chronic lymphocytic leukemia (CLL), found in more than 50% of cases, indicating that this region contains a gene(s) involved in the development of CLL. However, the pathogenic gene in the critical 13q14 region has not yet been defined. Here, we have cloned and characterized a novel gene, DLEU7, located adjacent to the consensus deleted region, and overlapping the 3' end of DLEU1 tail to tail. Human DLEU7 encodes a putative 221 amino acid protein, with significant conservation in rodents. Mutational and expression analysis in primary CLL samples failed to demonstrate any specific mutations in DLEU7, but no DLEU7 expression could be detected in CLL cells. Methylation of a CpG island in the promoter region of DLEU7 was further analyzed as a possible mechanism for the absence of DLEU7 expression, and the promoter was found to be methylated in the majority of the CLL samples investigated.

Distinct organization of the candidate tumor suppressor gene RFP2 in human and mouse: multiple mRNA isoforms in both species- and human-specific antisense transcript RFP2OS.

In the present study, we describe the human and mouse RFP2 gene structure, multiple RFP2 mRNA isoforms in the two species that have different 5' UTRs and a human-specific antisense transcript RFP2OS. Since the human RFP2 5' UTR is not conserved in mouse, these findings might indicate a different regulation of RFP2 in the two species. The predicted human and mouse RFP2 proteins are shown to contain a tripartite RING finger-B-box-coiled-coil domain (RBCC), also known as a TRIM domain, and therefore belong to a subgroup of RING finger proteins that are often involved in developmental and tumorigenic processes. Because homozygous deletions of chromosomal region 13q14.3 are found in a number of malignancies, including chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), we suggest that RFP2 might be involved in tumor development. This study provides necessary information for evaluation of the role of RFP2 in malignant transformation and other biological processes.

Effects of interferon-alpha on cell cycle regulatory proteins in leukemic cells.

One prominent activity of Interferons (IFNs) is their ability to induce cell cycle arrest, and this effect has furthermore been proposed to be of major importance in mediating the clinical antitumor activity of IFNs. In several IFN sensitive established cell lines, a rapid upregulation of the cyclin dependent kinase inhibitor p21 occurs following IFN-alpha treatment, and is thought to play a major role as an effector for this phenomenon by triggering further events. The aim of this study was to investigate how these previous findings in established cells lines correlate with clinical material. We therefore, analyzed how IFN-alpha influences the cell cycle distribution, by analysis of cellular DNA content, and the level of various cell cycle regulatory proteins by Western blot analysis, in primary leukemic cells. In 5 of 10 examined acute myeloid leukemia samples and in 1 of 6 chronic lymphocytic leukemia sample a clear increase in p21 protein levels was detected following treatment with IFN-alpha, while p21 protein levels were unaffected by IFN treatment in any of the examined acute lymphoblastic leukemia samples. In our total material consisting of 21 patient samples all other cell cycle regulatory proteins studied (p27, Cyclin E, Cdk2), were largely unaffected by IFN treatment. These results confirm that IFN-alpha can act as a potent regulator of Cdk-inhibitor expression, and that the induction of p21 seems to be a primary event in IFN-alpha mediated cell cycle regulation.

Mechanisms of Interferon-alpha induced apoptosis in malignant cells.

Interferon alpha (IFNalpha) has been used in the treatment of several types of cancer for almost 30 years, yet the mechanism(s) responsible for its anti-tumoral action remains unknown. A variety of cellular responses, including inhibition of cell growth and induction of apoptosis are induced by IFNs, and apoptotic induction by this cytokine has been proposed to be of importance for both its anti-tumoral in addition to its anti-viral responses. The aim of the present study was to delineate the pathways activated during IFNalpha-induced apoptosis in malignant cell lines. We found that apoptosis induced by IFNalpha was associated with activation of caspases-1, -2, -3, -8 and -9 and that this activation was a critical event. Caspase-3 activation was dependent on activity of caspases-8 and -9, moreover, activation of caspase-8 seems to be the upstream event in IFNalpha-induced caspase cascade. We also found loss of mitochondrial membrane potential as well as release of cytochrome c post IFN-treatment, clearly implicating the involvement of mitochondria in IFN-mediated apoptosis. Furthermore, IFNalpha-induced apoptosis was found to be independent on interactions between the Fas-receptor and its ligand. These studies form the basis for further investigations aiming to improve IFN therapy and the development of future strategies to overcome the IFN resistance observed in some malignancies.

Interferon-alpha inhibits Stat5 DNA-binding in IL-2 stimulated primary T-lymphocytes.

It has previously been shown that IFN-alpha is a potent inhibitor of IL-2 induced proliferation in primary T-lymphocytes, by selectively abrogating the downstream effects of IL-2 on the core cell cycle machinery regulating the G1/S transition. Theoretically this could be mediated through cross-talk between the signalling cascades activated by these cytokines, as several signalling components are known to be shared. IL-2 activates multiple signalling pathways that are important for T-cell proliferation and differentiation. In the present study, the effects of IFN-alpha on IL-2 signal transduction was investigated. The IFN-alpha induced inhibition of IL-2 induced proliferation in activated T-lymphocytes, was associated with a suppressed Jak3 protein expression as well as an inhibited prolonged Stat5 DNA binding, and a partially reduced expression of the Stat5 inducible gene IL-2R alpha. Our results provide a possible molecular link between the prominent antiproliferative effects of IFN-alpha on IL-2 induced T-cell proliferation and the signal transduction pathways emerging from the IL-2 receptor.