Hyperthermia Selectively Destabilizes Oncogenic Fusion Proteins.

The PML/RARα fusion protein is the oncogenic driver in acute promyelocytic leukemia (APL). Although most APL cases are cured by PML/RARα-targeting therapy, relapse and resistance can occur due to drug-resistant mutations. Here we report that thermal stress destabilizes the PML/RARα protein, including clinically identified drug-resistant mutants. AML1/ETO and TEL/AML1 oncofusions show similar heat shock susceptibility. Mechanistically, mild hyperthermia stimulates aggregation of PML/RARα in complex with nuclear receptor corepressors leading to ubiquitin-mediated degradation via the SIAH2 E3 ligase. Hyperthermia and arsenic therapy destabilize PML/RARα via distinct mechanisms and are synergistic in primary patient samples and in vivo, including three refractory APL cases. Collectively, our results suggest that by taking advantage of a biophysical vulnerability of PML/RARα, thermal therapy may improve prognosis in drug-resistant or otherwise refractory APL. These findings serve as a paradigm for therapeutic targeting of fusion oncoprotein-associated cancers by hyperthermia. SIGNIFICANCE: Hyperthermia destabilizes oncofusion proteins including PML/RARα and acts synergistically with standard arsenic therapy in relapsed and refractory APL. The results open up the possibility that heat shock sensitivity may be an easily targetable vulnerability of oncofusion-driven cancers.See related commentary by Wu et al., p. 300.

Perinatal depression: Data-driven subtypes derived from life history and mindfulness and personality.

BACKGROUND: Perinatal depression is the most prevalent mental disorder during the perinatal period, and research suggests that it presents heterogeneously. We aimed to explore how subtypes of perinatal depression present in terms of multivariate patterns of stable characteristics. METHODS: A cohort study was conducted from March 2016 to March 2018 with Chinese women in the prenatal period (n = 3186). Of the participants, 682 (21.41%) women with Edinburgh Postnatal Depression Scale scores ≥10, indicating probable depression, were included, with the remaining 2504 (78.59%) representing the control group. We assessed mood distress, cognition, life history, emotional regulation, and personality, and used latent class analysis and latent transition analysis to identify perinatal depression subtypes. Of the 682 women with probable depression, only 598 were included in the full analyses, as they completed at least 10 questionnaires. A second, non-overlapping sample and a follow-up cohort were used. RESULTS: We identified four subtypes: 1) a highly distressed type characterized by distress across all domains, high levels of rumination and neuroticism, and reduced trait mindfulness; 2) two moderately distressed types: one with high trauma and low perceived social support, and another with low trauma, high perceived social support, and expressive suppression; and 3) a slightly distressed subtype. LIMITATIONS: We only collected cost and time spent in hospital from medical records. We only had a small follow-up sample. CONCLUSIONS: This multidimensional subtyping of women with perinatal depression could help reduce the apparent heterogeneity of perinatal depression. Distinguishing the subtype characteristics facilitates identifying underlying causes of perinatal depression.

Effectiveness of two guided self-administered interventions for psychological distress among women with infertility: a three-armed, randomized controlled trial.

STUDY QUESTION: What is the effect of two guided self-administered interventions on psychological distress in women undergoing IVF or ICSI? SUMMARY ANSWER: A brief mindfulness intervention significantly reduced depression and improved sleep quality, while the gratitude journal intervention showed no significant effect on any outcome variables. WHAT IS KNOWN ALREADY: Mindfulness and gratitude journal interventions have been found to be beneficial in reducing negative affect and improving well-being. However, there are very few mental health professionals who implement such interventions in low- and middle-income countries. Therefore, two guided self-administered interventions for women with infertility were designed to help them cope with their psychological distress. STUDY DESIGN, SIZE, DURATION: A three-armed, randomized controlled trial was designed to evaluate the mindfulness and gratitude journal interventions for women undergoing IVF/ICSI. Between May 2016 and November 2017, at the reproductive center in a public hospital, 234 women were randomly assigned to the brief mindfulness group (BMG, n = 78), gratitude journal group (GJG, n = 78) or control group (CG, n = 78). The inclusion criteria were being a woman undergoing her first cycle of IVF, having at least junior middle school education and having no biological or adopted children. PARTICIPANTS/MATERIALS, SETTING, METHODS: Female infertility patients (n = 346) were approached, and 112 did not meet the inclusion criteria. All three randomized groups completed questionnaires on the day of down-regulation (T1), the day before embryo(s) transfer (T2), and 3 days before the pregnancy test (T3). The BMG completed four sessions and listened to a 20-minute audio daily, including guided mindfulness breathing and body scan. The GJG completed four sessions and wrote three gratitude journals daily. The CG received routine care. A generalized estimating equation was used in an intention-to-treat analysis. The primary outcome was depression. Secondary outcomes were anxiety, sleep quality, infertility-related stress, mindfulness and gratitude. MAIN RESULTS AND THE ROLE OF CHANCE: Participants of the BMG showed decreased depression (mean difference (MD) = -1.69, [-3.01, -0.37], d = 0.44) and improved sleep quality (MD = -1.24, [-1.95, -0.39], d = 0.43) compared to the CG, but the effect was not significant for anxiety, Fertility Problem Inventory totals, mindfulness, gratitude scores or pregnancy rates. The BMG showed a significant reduction in depression and improvement in sleep quality between T1 and T2, a continuous significant reduction between T1 and T3 and no reduction between T2 and T3. There were no significant effects on any of the variables for the GJG. LIMITATIONS, REASONS FOR CAUTION: The inclusion criteria may result in bias because some participants with low education were excluded and only women with infertility were included. A low compliance rate occurred in the gratitude journals group. Moreover, men were not included in this study. Further research should consider including spouses of the target population. WIDER IMPLICATIONS OF THE FINDINGS: The brief mindfulness intervention was beneficial in decreasing depression and improving sleep quality. Implementation of guided self-administered mindfulness could make the psychological counseling service more accessible for patients with infertility in resource-poor settings. The efficiency and feasibility of the gratitude journal intervention needs to be investigated further. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the National Social Science Foundation (17BSH054). The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: ChiCTR-IOR-16008452. TRIAL REGISTRATION DATE: 9 May 2016. DATE OF FIRST PATIENT'S ENROLMENT: 15 May 2016.

Update of humanized animal disease models in studying Graft-versus-host disease.

Graft-versus-host disease (GVHD) is a severe adverse effect that results from bone marrow or peripheral blood cells transplantation and has a high rate of mortality. About 50% of the patients are accompanied with acute Graft-versus-Host Disease (aGVHD) after bone marrow cell transplantation and need systematic treatment. It has an important clinical significance to evaluate the prevention and treatment effects of GVHD. The stable and reliable approaches of humanized animal models are crucial for advancing on the study the biology of GVHD. Relative models transplanting the human immune cells into the mouse body can trigger immunoreaction similar to the humans. As it is a disease triggered by human immune cells, any intervention research prior to clinical treatment has more clinical interrelations compared with the general animal models. In this review, we update the current understanding on humanized animal disease models on studying Graft-versus-host disease and expect to provide more theoretical basis to further study on Graft-versus-host disease.

Brief psychological intervention in patients with cervical cancer: A randomized controlled trial.

OBJECTIVES: The diagnosis and treatment of cancer is considered a major life stress that has potential effects on one's psychological well-being. This study investigated the possible benefits of a brief psychological intervention based on gratitude and mindfulness for positive and negative affect in patients with cervical cancer and explored the potentially mediating role of rumination and reappraisal. METHODS: A randomized controlled trial was conducted in 3 public hospitals in China between April 2014 and December 2014. One-hundred twenty postoperative cervical cancer patients were randomly assigned into an intervention group or a wait-list control group. Participants completed self-report measures of positive and negative affect, rumination, and reappraisal before and after the 4-week intervention or waiting period. The outcome effects of the intervention were analyzed by generalized estimating equations (GEE). Mediation analyses were performed using a nonparametric bootstrapping procedure. RESULTS: GEE results indicated significant Time × Group interaction effects on positive affect (B = 1.60, χ2 = 25.90, p < .001), negative affect (B = -2.13, χ2 = 28.02, p < .001), rumination (B = -2.48, χ2 = 6.48, p = .011), and reappraisal (B = 3.28, χ2 = 41.17, p < .001) for the intervention. The effect of the intervention on positive and negative affect was mediated by changes in rumination and reappraisal respectively. CONCLUSIONS: The brief psychological intervention improved positive affect and reappraisal and reduced negative affect and rumination in women with cervical cancer. Findings support the beneficial effects for implementing this brief psychological intervention in oncology. (PsycINFO Database Record

Attitudes of midwives towards perinatal bereavement in Hong Kong.

OBJECTIVE: to explore attitudes towards perinatal bereavement care among midwives working in Hong Kong through examination of relationships between attitudes towards bereavement support, need for bereavement education and appropriate hospital policy. DESIGN: a descriptive correlational survey. SETTING: the obstetric and gynaecology units at two hospitals. INSTRUMENT: a structured self-report questionnaire on attitudes towards perinatal bereavement support; required support and education needs for midwives on bereavement care. PARTICIPANTS: 154 out of 202 midwives (76.2% response rate) working at the two units. FINDINGS: two-step cluster analysis yielded two clusters. Cluster 1 consisted of 91 (59.1%) midwives and cluster 2 consisted of 63 (40.9%) midwives. Cluster 2 midwives were younger, had less obstetric and gynaecology experience, junior ranking and less post-qualification education than cluster 1 midwives. Cluster 1 midwives had additional personal grieving experiences and experience of caring for grieving parents. Attitudes towards bereavement care were positively correlated with educational needs (r(s)=0.55, p< 0.001) and hospital policy support (r(s)=0.50, p< 0.001). CONCLUSIONS: Hong Kong midwives require increased bereavement care knowledge and experience, improved communication skills, and greater hospital and team member support. Findings may be used to improve support of midwives, to ensure sensitive bereavement care in perinatal settings and to reflect training needs in the midwifery education curricula. Study findings highlight the universality of grief for a lost baby, irrespective of cultural differences in approaching emotional topics. This study may help midwives internationally to gain a broader perspective in this area.