Creative Arts Therapy for Healthcare Professionals Is Associated With Long-Term Improvements in Psychological Distress.

OBJECTIVE: Burnout in healthcare professionals (HCPs) is a pressing issue in healthcare. We report the long-term impact of our previous creative arts therapy (CAT) intervention for reducing psychological distress in HCPs. METHODS: Healthcare professionals were randomized to CAT intervention or control group. The CAT group completed surveys evaluating symptoms of psychological distress at 4 months, 8 months, and 1 year postintervention, whereas the control group completed surveys at the 1-year mark. RESULTS: The CAT group demonstrated sustained improvement in distress scores for anxiety, depression, and affect at 4 and 8 months postintervention. At the 12-month mark, the CAT group exhibited improvements in anxiety, depression, and affect compared with the control group. CONCLUSION: Creative arts therapy has lasting benefits for HCPs. Long-term follow-ups are crucial for assessing sustainability, and further investigation should focus on disseminating and implementing CAT programs for HCPs.

Reversible intracellular acidification and depletion of NTPs provide a potential physiological origin for centuries of dormancy in an Antarctic freshwater copepod.

A great diversity of crustacean zooplankton found in inland and coastal waters produce embryos that settle into bottom sediments to form an egg bank. Embryos from these banks can remain dormant for centuries, creating a reservoir of genetic diversity. A large body of literature describes the ecological and evolutionary importance of zooplankton egg banks. However, literature on the physiological traits behind dormancy in crustacean zooplankton are limited. Most data on the physiology of dormancy comes from research on one species of anostracan, the brine shrimp, Artemia franciscana. Anoxia-induced dormancy in this species is facilitated by a profound and reversible acidification of the intracellular space. This acidification is accompanied by a reversible depletion of adenosine triphosphate (ATP). The present study demonstrates that acidification of the intracellular space also occurs in concert with a depletion of nucleoside triphosphates (NTPs) in the Antarctic copepod, Boeckella poppei. Like A. franciscana, the depletion of NTPs and acidification are rapidly reversed during aerobic recovery in B. poppei. These data provide the first comparative evidence that extreme dormancy under anoxia in crustacean zooplankton is associated with intracellular acidification and an ability to recover from the depletion of ATP.

Simultaneous Targeting of DNA Polymerase Theta and PARP1 or RAD52 Triggers Dual Synthetic Lethality in Homologous Recombination-Deficient Leukemia Cells.

DNA polymerase theta (Polθ, encoded by POLQ gene) plays an essential role in Polθ-mediated end-joining (TMEJ) of DNA double-strand breaks (DSB). Inhibition of Polθ is synthetic lethal in homologous recombination (HR)-deficient tumor cells. However, DSBs can be also repaired by PARP1 and RAD52-mediated mechanisms. Because leukemia cells accumulate spontaneous DSBs, we tested if simultaneous targeting of Polθ and PARP1 or RAD52 enhance the synthetic lethal effect in HR-deficient leukemia cells. Transformation potential of the oncogenes inducing BRCA1/2-deficiency (BCR-ABL1 and AML1-ETO) was severely limited in Polq-/-;Parp1-/- and Polq-/-;Rad52-/- cells when compared with single knockouts, which was associated with accumulation of DSBs. Small-molecule inhibitor of Polθ (Polθi) when combined with PARP or RAD52 inhibitors (PARPi, RAD52i) caused accumulation of DSBs and exerted increased effect against HR-deficient leukemia and myeloproliferative neoplasm cells. IMPLICATIONS: In conclusion, we show that PARPi or RAD52i might improve therapeutic effect of Polθi against HR-deficient leukemias.

Haploinsufficiency of ZNF251 causes DNA-PKcs-dependent resistance to PARP inhibitors in BRCA1-mutated cancer cells.

Poly (ADP-ribose) polymerase (PARP) inhibitors represent a promising new class of agents that have demonstrated efficacy in treating various cancers, particularly those that carry BRCA1/2 mutations. The cancer associated BRCA1/2 mutations disrupt DNA double strand break (DSB) repair by homologous recombination (HR). PARP inhibitors (PARPis) have been applied to trigger synthetic lethality in BRCA1/2-mutated cancer cells by promoting the accumulation of toxic DSBs. Unfortunately, resistance to PARPis is common and can occur through multiple mechanisms, including the restoration of HR and/or the stabilization of replication forks. To gain a better understanding of the mechanisms underlying PARPi resistance, we conducted an unbiased CRISPR-pooled genome-wide library screen to identify new genes whose deficiency confers resistance to the PARPi olaparib. Our study revealed that ZNF251, a transcription factor, is a novel gene whose haploinsufficiency confers PARPi resistance in multiple breast and ovarian cancer lines harboring BRCA1 mutations. Mechanistically, we discovered that ZNF251 haploinsufficiency leads to constitutive stimulation of DNA-PKcs-dependent non-homologous end joining (NHEJ) repair of DSBs and DNA-PKcs-mediated fork protection in BRCA1-mutated cancer cells (BRCA1mut + ZNF251KD). Moreover, we demonstrated that DNA-PKcs inhibitors can restore PARPi sensitivity in BRCA1mut + ZNF251KD cells ex vivo and in vivo. Our findings provide important insights into the mechanisms underlying PARPi resistance and highlight the unexpected role of DNA-PKcs in this phenomenon.

Evaluation of computer-based training and high-fidelity simulation to improve early recognition of sepsis on the adult general ward.

This quality improvement project involved developing, implementing and evaluating an educational intervention using computer-based training (CBT) and high-fidelity simulation (HFS) to increase knowledge, confidence and compliance of nurses identifying sepsis. A one-group pretest-posttest design was used. Participants were nurses on a general ward of an academic medical centre. Study variables were measured over three timepoints: 2 weeks before, immediately after and 90 days after implementation. Data were collected from January 30, 2018, to June 22, 2018. SQUIRE 2.0 checklist for quality improvement reporting used. Improvements in knowledge of sepsis (F(2,83)  = 18.14, p < 0.001, ηp 2  = 0.30) and confidence in early recognition of sepsis (F(2,83)  = 13.67, p < 0.001, ηp 2  = 0.25) were found. Additionally, compliance with sepsis screening improved between the preimplementation and postimplementation period (χ2  = 13.633, df = 1, p < 0.001). Overall, the nurses evaluated their experience with the CBT and HFS as strongly positive. When designing and implementing an educational intervention on sepsis, a process for follow-up which provides reinforcement should be considered to retain nurses' knowledge.

DNA polymerase θ protects leukemia cells from metabolically induced DNA damage.

Leukemia cells accumulate DNA damage, but altered DNA repair mechanisms protect them from apoptosis. We showed here that formaldehyde generated by serine/1-carbon cycle metabolism contributed to the accumulation of toxic DNA-protein crosslinks (DPCs) in leukemia cells, especially in driver clones harboring oncogenic tyrosine kinases (OTKs: FLT3(internal tandem duplication [ITD]), JAK2(V617F), BCR-ABL1). To counteract this effect, OTKs enhanced the expression of DNA polymerase theta (POLθ) via ERK1/2 serine/threonine kinase-dependent inhibition of c-CBL E3 ligase-mediated ubiquitination of POLθ and its proteasomal degradation. Overexpression of POLθ in OTK-positive cells resulted in the efficient repair of DPC-containing DNA double-strand breaks by POLθ-mediated end-joining. The transforming activities of OTKs and other leukemia-inducing oncogenes, especially of those causing the inhibition of BRCA1/2-mediated homologous recombination with and without concomitant inhibition of DNA-PK-dependent nonhomologous end-joining, was abrogated in Polq-/- murine bone marrow cells. Genetic and pharmacological targeting of POLθ polymerase and helicase activities revealed that both activities are promising targets in leukemia cells. Moreover, OTK inhibitors or DPC-inducing drug etoposide enhanced the antileukemia effect of POLθ inhibitor in vitro and in vivo. In conclusion, we demonstrated that POLθ plays an essential role in protecting leukemia cells from metabolically induced toxic DNA lesions triggered by formaldehyde, and it can be targeted to achieve a therapeutic effect.

The Effect of Creative Arts Therapy on Psychological Distress in Health Care Professionals.

BACKGROUND: Work-related psychological distress is common among health care professionals. We determined whether 4 creative arts therapy (CAT) programs were acceptable, feasible, and improved psychological distress and job turnover intention in health care professionals with burnout symptoms. METHODS: Health care professionals were enrolled during the coronavirus disease (COVID-19) pandemic from September 2020 until July 2021. Participants attended in-person weekly 90-minute group session for 12 consecutive weeks. Intervention and control subjects completed surveys before the beginning and after the end of their cohort. The study outcomes were session attendance (feasibility), program satisfaction (acceptability), and change in symptoms of anxiety, depression, burnout, posttraumatic stress disorder (PTSD), and job turnover intention. RESULTS: We randomized 165 participants into 4 CAT interventions and 1 common control group across 3 sequential cohorts. Thirty-five randomized participants dropped out before the start of the cohort, and 16 were replaced from a waiting list. Therefore, the cohort consisted of 146 participants. On average, participants were 35 years old, white (85%), and female (92%). Overall, 52% were nurses, 10% were doctors, and 16% were behavioral health specialists. Participants attended a median of 9.5 [8-11] sessions. Program satisfaction was high with a median Client Satisfaction Questionnaire (CSQ-8) score of 31 [17-32] out of a possible score of 32. Participants randomized to the intervention had improvements in anxiety (P < .0001) and depression scores (P = .0007), total posttraumatic stress disorder score (P =.0002), burnout scores (P = .001, .003, .008), and turnover intention (P = .001). CONCLUSIONS: A CAT program is feasible, acceptable, and may reduce psychological distress and turnover intention for health care professionals.

TET2 and DNMT3A Mutations Exert Divergent Effects on DNA Repair and Sensitivity of Leukemia Cells to PARP Inhibitors.

Somatic variants in TET2 and DNMT3A are founding mutations in hematological malignancies that affect the epigenetic regulation of DNA methylation. Mutations in both genes often co-occur with activating mutations in genes encoding oncogenic tyrosine kinases such as FLT3ITD, BCR-ABL1, JAK2V617F , and MPLW515L , or with mutations affecting related signaling pathways such as NRASG12D and CALRdel52 . Here, we show that TET2 and DNMT3A mutations exert divergent roles in regulating DNA repair activities in leukemia cells expressing these oncogenes. Malignant TET2-deficient cells displayed downregulation of BRCA1 and LIG4, resulting in reduced activity of BRCA1/2-mediated homologous recombination (HR) and DNA-PK-mediated non-homologous end-joining (D-NHEJ), respectively. TET2-deficient cells relied on PARP1-mediated alternative NHEJ (Alt-NHEJ) for protection from the toxic effects of spontaneous and drug-induced DNA double-strand breaks. Conversely, DNMT3A-deficient cells favored HR/D-NHEJ owing to downregulation of PARP1 and reduction of Alt-NHEJ. Consequently, malignant TET2-deficient cells were sensitive to PARP inhibitor (PARPi) treatment in vitro and in vivo, whereas DNMT3A-deficient cells were resistant. Disruption of TET2 dioxygenase activity or TET2-Wilms' tumor 1 (WT1)-binding ability was responsible for DNA repair defects and sensitivity to PARPi associated with TET2 deficiency. Moreover, mutation or deletion of WT1 mimicked the effect of TET2 mutation on DSB repair activity and sensitivity to PARPi. Collectively, these findings reveal that TET2 and WT1 mutations may serve as biomarkers of synthetic lethality triggered by PARPi, which should be explored therapeutically. SIGNIFICANCE: TET2 and DNMT3A mutations affect distinct DNA repair mechanisms and govern the differential sensitivities of oncogenic tyrosine kinase-positive malignant hematopoietic cells to PARP inhibitors.

Polθ promotes the repair of 5'-DNA-protein crosslinks by microhomology-mediated end-joining.

DNA polymerase θ (Polθ) confers resistance to chemotherapy agents that cause DNA-protein crosslinks (DPCs) at double-strand breaks (DSBs), such as topoisomerase inhibitors. This suggests Polθ might facilitate DPC repair by microhomology-mediated end-joining (MMEJ). Here, we investigate Polθ repair of DSBs carrying DPCs by monitoring MMEJ in Xenopus egg extracts. MMEJ in extracts is dependent on Polθ, exhibits the MMEJ repair signature, and efficiently repairs 5' terminal DPCs independently of non-homologous end-joining and the replisome. We demonstrate that Polθ promotes the repair of 5' terminal DPCs in mammalian cells by using an MMEJ reporter and find that Polθ confers resistance to formaldehyde in addition to topoisomerase inhibitors. Dual deficiency in Polθ and tyrosyl-DNA phosphodiesterase 2 (TDP2) causes severe cellular sensitivity to etoposide, which demonstrates MMEJ as an independent DPC repair pathway. These studies recapitulate MMEJ in vitro and elucidate how Polθ confers resistance to etoposide.

The ultrastructure of resurrection: Post-diapause development in an Antarctic freshwater copepod.

The copepod, Boeckella poppei, is broadly distributed in Antarctic and subantarctic maritime lakes threatened by climate change and anthropogenic chemicals. Unfortunately, comparatively little is known about freshwater zooplankton in lakes influenced by the Southern Ocean. In order to predict the impact of climate change and chemicals on freshwater species like B. poppei, it is necessary to understand the nature of their most resilient life stages. Embryos of B. poppei survive up to two centuries in a resilient dormant state, but no published studies evaluate the encapsulating wall that protects theses embryos or their development after dormancy. This study fills that knowledge gap by using microscopy to examine development and the encapsulating wall in B. poppei embryos from Antarctica. The encapsulating wall of B. poppei is comprised of three layers that appear to be conserved among crustacean zooplankton, but emergence and hatching are uniquely delayed until the nauplius is fully formed in this species. Diapause embryos in Antarctic sediments appear to be in a partially syncytial mid-gastrula stage. The number of nuclei quadruples between the end of diapause and hatching. Approximately 75% of yolk platelets are completely consumed during the same time period. However, some yolk platelets are left completely intact at the time of hatching. Preservation of complete yolk platelets suggests an all-or-none biochemical process for activating yolk consumption that is inactivated during dormancy to preserve yolk for post-dormancy development. The implications of these and additional ultrastructural features are discussed in the context of anthropogenic influence and the natural environment.

TGFßR-SMAD3 Signaling Induces Resistance to PARP Inhibitors in the Bone Marrow Microenvironment.

Synthetic lethality triggered by PARP inhibitor (PARPi) yields promising therapeutic results. Unfortunately, tumor cells acquire PARPi resistance, which is usually associated with the restoration of homologous recombination, loss of PARP1 expression, and/or loss of DNA double-strand break (DSB) end resection regulation. Here, we identify a constitutive mechanism of resistance to PARPi. We report that the bone marrow microenvironment (BMM) facilitates DSB repair activity in leukemia cells to protect them against PARPi-mediated synthetic lethality. This effect depends on the hypoxia-induced overexpression of transforming growth factor beta receptor (TGFßR) kinase on malignant cells, which is activated by bone marrow stromal cells-derived transforming growth factor beta 1 (TGF-ß1). Genetic and/or pharmacological targeting of the TGF-ß1-TGFßR kinase axis results in the restoration of the sensitivity of malignant cells to PARPi in BMM and prolongs the survival of leukemia-bearing mice. Our finding may lead to the therapeutic application of the TGFßR inhibitor in patients receiving PARPis.

Novel allosteric PARP1 inhibitors for the treatment of BRCA-deficient leukemia.

The successful use of PARP1 inhibitors like olaparib (Loparza®) in the treatment of BRCA1/2- deficient breast cancer has provided clinical proof of concept for applying personalized medicine based on synthetic lethality to the treatment of cancer. Unfortunately, all marketed PARP1 inhibitors act by competing with the cofactor NAD+ and resistance is already developing to this anti-cancer mechanism. Allosteric PARP1 inhibitors could provide a means of overcoming this resistance. A high throughput screen performed by Tulin et al. identified 5F02 as an allosteric PARP inhibitor that acts by preventing the enzymatic activation of PARP1 by histone H4. 5F02 demonstrated anti-cancer activity in several cancer cell lines and was more potent than olaparib and synergistic with olaparib in these assays. In the present study we explored the structure-activity relationship of 5F02 by preparing analogs that possessed structural variation in four regions of the chemical scaffold. Our efforts led to lead molecule 7, which demonstrated potent anti-clonogenic activity against BRCA-deficient NALM6 leukemia cells in culture and a therapeutic index for the BRCA-deficient cells over their BRCA-proficient isogenic counterparts.

Creative Arts Therapy as a Potential Intervention to Prevent Burnout and Build Resilience in Health Care Professionals.

The delivery of health care is undergoing a rapid evolution that is dramatically changing the way health care professionals perform their job responsibilities. In this increasingly stressful work environment, professionals are experiencing alarming rates of burnout. Recent efforts to enhance wellness have been directed toward organizations. However, because of the nature of the work performed in intensive care units, interventions to develop individual resilience are also needed. Currently, medical centers are environments in which the emotional impact of work-related trauma is often minimized and rarely processed. Some individuals may struggle to describe or express the impact of those traumas. Through nonverbal interventions, creative arts therapy can help people access, explore, and share authentic emotion in visual, musical, physical, or written form. By reconstructing meaning through transformative methods, participants may confront, reflect, and better cope with traumatic experiences while catalyzing social support networks and deepening relational bonds in the workplace.

Publisher Correction: Molecular basis of microhomology-mediated end-joining by purified full-length Polθ.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Effects of an Upper-Body Training Program Involving Resistance Exercise and High-Intensity Arm Cranking on Peak Handcycling Performance and Wheelchair Propulsion Efficiency in Able-Bodied Men.

Chaikhot, D, Reed, K, Petroongrad, W, Athanasiou, F, van Kooten, D, and Hettinga, FJ. Effects of an upper-body training program involving resistance exercise and high-intensity arm cranking on peak handcycling performance and wheelchair propulsion efficiency in able-bodied men. J Strength Cond Res 34(8): 2267-2275, 2020-The aim of this study was to determine the training effects of an upper-body training program involving resistance exercise and high-intensity arm cranking on peak handcycling performance, propulsion efficiency, and biomechanical characteristics of wheelchair propulsion in able-bodied men. The training group (n = 10) received a 4-week upper-body resistance training (RT), 70% of 1 repetition maximum, 3 sets of 10 repetitions, 8 exercise stations, 2 times per week, combined with high-intensity interval training (HIIT) 2 times per week. High-intensity interval training consisted of arm-crank exercise, 7 intervals of 2 minutes at 80-90% of peak heart rate (HRpeak) with 2-minute active rest at 50-60% of HRpeak. The control group (n = 10) received no training. Both groups performed a preincremental and postincremental handcycling test until volitional exhaustion to evaluate fitness and a 4-minute submaximal wheelchair propulsion test at comfortable speed (CS), 125 and 145% of CS, to evaluate gross mechanical efficiency (GE), fraction of effective force (FEF), percentage of peak oxygen consumption (% V[Combining Dot Above]O2peak), and propulsion characteristics. Repeated-measures analysis of variance was performed (p < 0.05). Training resulted in a 28.2 ± 16.5% increase in peak power output, 13.3 ± 7.5% increase in V[Combining Dot Above]O2peak, 5.6 ± 0.9% increase in HRpeak, and 3.8 ± 1.5% decrease in HRrest. No training effects on FEF, GE, % V[Combining Dot Above]O2peak, and push characteristics were identified. In conclusion, the combined RT and arm-cranking HIIT improved fitness. However, it seems that this training did not result in improvements in propulsion efficiency and push characteristics. Additional wheelchair skill training may be needed to fully benefit from this advantage in daily life propulsion.

RAD52 as a Potential Target for Synthetic Lethality-Based Anticancer Therapies.

Alterations in DNA repair systems play a key role in the induction and progression of cancer. Tumor-specific defects in DNA repair mechanisms and activation of alternative repair routes create the opportunity to employ a phenomenon called "synthetic lethality" to eliminate cancer cells. Targeting the backup pathways may amplify endogenous and drug-induced DNA damage and lead to specific eradication of cancer cells. So far, the synthetic lethal interaction between BRCA1/2 and PARP1 has been successfully applied as an anticancer treatment. Although PARP1 constitutes a promising target in the treatment of tumors harboring deficiencies in BRCA1/2-mediated homologous recombination (HR), some tumor cells survive, resulting in disease relapse. It has been suggested that alternative RAD52-mediated HR can protect BRCA1/2-deficient cells from the accumulation of DNA damage and the synthetic lethal effect of PARPi. Thus, simultaneous inhibition of RAD52 and PARP1 might result in a robust dual synthetic lethality, effectively eradicating BRCA1/2-deficient tumor cells. In this review, we will discuss the role of RAD52 and its potential application in synthetic lethality-based anticancer therapies.

Molecular basis of microhomology-mediated end-joining by purified full-length Polθ.

DNA polymerase θ (Polθ) is a unique polymerase-helicase fusion protein that promotes microhomology-mediated end-joining (MMEJ) of DNA double-strand breaks (DSBs). How full-length human Polθ performs MMEJ at the molecular level remains unknown. Using a biochemical approach, we find that the helicase is essential for Polθ MMEJ of long ssDNA overhangs which model resected DSBs. Remarkably, Polθ MMEJ of ssDNA overhangs requires polymerase-helicase attachment, but not the disordered central domain, and occurs independently of helicase ATPase activity. Using single-particle microscopy and biophysical methods, we find that polymerase-helicase attachment promotes multimeric gel-like Polθ complexes that facilitate DNA accumulation, DNA synapsis, and MMEJ. We further find that the central domain regulates Polθ multimerization and governs its DNA substrate requirements for MMEJ. These studies identify unexpected functions for the helicase and central domain and demonstrate the importance of polymerase-helicase tethering in MMEJ and the structural organization of Polθ.

Disaster journalism: fostering citizen and community disaster mitigation, preparedness, response, recovery, and resilience across the disaster cycle.

Natural and human-caused disasters pose a significant risk to the health and well-being of people. Journalists and news organisations can fulfil multiple roles related to disasters, ranging from providing warnings, assessing disaster mitigation and preparedness, and reporting on what occurs, to aiding long-term recovery and fostering disaster resilience. This paper considers these possible functions of disaster journalism and draws on semi-structured interviews with 24 journalists in the United States to understand better their approach to the discipline. A thematic analysis was employed, which resulted in the identification of five main themes and accompanying subthemes: (i) examining disaster mitigation and preparedness; (ii) facilitating recovery; (iii) self-care and care of journalists; (iv) continued spread of social media; and (v) disaster journalism ethics. The paper concludes that disaster journalism done poorly can result in harm, but done well, it can be an essential instrument with respect to public disaster planning, management, response, and recovery.

Embryos of an Antarctic zooplankton require anoxia for dormancy, are permeable to lipophilic chemicals, and reside in sediments containing PCBs.

Zooplankton in Antarctic maritime lakes face challenges imposed by anthropogenic chemicals. Studies on temperate species suggest that lipophilic chemicals will accumulate in dormant embryos of Antarctic zooplankton and decrease hatching success, thereby threatening centuries of accumulated genetic diversity that would increase population resilience in the face of climate change. We evaluated the potential for lakes to act as sinks for legacy pollutants in the maritime Antarctic by testing sediments for polychlorinated biphenyls (PCBs) previously identified in soil, flora and fauna of lake catchments. Direct tests of embryo permeability to chemicals are confounded by potential adhesion of chemicals to the embryo surface and limited biomass available. Therefore, in order to assess the potential for lipophilic chemicals to penetrate and passively accumulate in dormant embryos of Antarctic lacustrine zooplankton, we evaluated the effect of anoxia on post-diapause development in the calanoid copepod, Boeckella poppei, and then used chemical anoxia induced by rotenone as a reporter for permeability of these embryos to moderately lipophilic chemicals. The data presented demonstrate that embryos of B. poppei from Antarctic lake sediments will passively accumulate moderately lipophilic chemicals while lying dormant in anoxic sediments. Implications for legacy POPs in sediments of Antarctic maritime lakes are discussed.