Deregulated JNK signaling enhances apoptosis during hyperthermia.

PURPOSE: c-Jun N-terminal kinases (JNKs) comprise a subfamily of mitogen-activated protein kinases (MAPKs). The JNK group is known to be activated by a variety of stimuli. However, the molecular mechanism underlying heat-induced JNK activation is largely unknown. The aim of this study was to clarify how JNK activity is stimulated by heat. METHODS AND MATERIALS: The expression levels of various MAPK members in HeLa cells, with or without hyperthermia treatment, were evaluated via western blotting. The kinase activity of MAPK members was assessed through in vitro kinase assays. Cell death was assessed in the absence or presence of siRNAs targeting MAPK-related members. RESULTS: Hyperthermia decreased the levels of MAP3Ks, such as ASK1 and MLK3 which are JNK kinase kinase members, but not those of the downstream MAP2K/SEK1 and MAPK/JNK. Despite the reduced or transient phosphorylation of ASK1, MLK3, or SEK1, downstream JNK was phosphorylated in a temperature-dependent manner. In vitro kinase assays demonstrated that heat did not directly stimulate SEK1 or JNK. However, the expression levels of DUSP16, a JNK phosphatase, were decreased upon hyperthermia treatment. DUSP16 knockdown enhanced the heat-induced activation of ASK1-SEK1-JNK pathway and apoptosis. CONCLUSION: JNK was activated in a temperature-dependent manner despite reduced or transient phosphorylation of the upstream MAP3K and MAP2K. Hyperthermia-induced degradation of DUSP16 may induce activation of the ASK1-SEK1-JNK pathway and subsequent apoptosis.

Cryo-EM structures of RAD51 assembled on nucleosomes containing a DSB site.

RAD51 is the central eukaryotic recombinase required for meiotic recombination and mitotic repair of double-strand DNA breaks (DSBs)1,2. However, the mechanism by which RAD51 functions at DSB sites in chromatin has remained elusive. Here we report the cryo-electron microscopy structures of human RAD51-nucleosome complexes, in which RAD51 forms ring and filament conformations. In the ring forms, the N-terminal lobe domains (NLDs) of RAD51 protomers are aligned on the outside of the RAD51 ring, and directly bind to the nucleosomal DNA. The nucleosomal linker DNA that contains the DSB site is recognized by the L1 and L2 loops-active centres that face the central hole of the RAD51 ring. In the filament form, the nucleosomal DNA is peeled by the RAD51 filament extension, and the NLDs of RAD51 protomers proximal to the nucleosome bind to the remaining nucleosomal DNA and histones. Mutations that affect nucleosome-binding residues of the RAD51 NLD decrease nucleosome binding, but barely affect DNA binding in vitro. Consistently, yeast Rad51 mutants with the corresponding mutations are substantially defective in DNA repair in vivo. These results reveal an unexpected function of the RAD51 NLD, and explain the mechanism by which RAD51 associates with nucleosomes, recognizes DSBs and forms the active filament in chromatin.

Effectiveness of a web-based learning program for promoting local healthcare planning competencies.

OBJECTIVE: To determine the effectiveness of a web-based educational program regarding local healthcare planning by public health nurses (PHNs) in Japan. DESIGN: A single-blind randomized controlled trial. SAMPLE: Full-time PHNs working for local governments across Japan. MEASUREMENTS: The primary outcome was nurses' self-perception of competencies in public health policy. The secondary outcome was self-perception of knowledge, skills, and perspectives regarding local healthcare planning. We analyzed intergroup differences using the intention-to-treat principle and the Mann-Whitney U-test. INTERVENTION: The intervention group received six web-based learning modules including substantial knowledge and skills regarding local healthcare planning based on the analysis, design, development, implementation, and evaluation model and adult learning theory. RESULTS: Totally, 273 PHNs registered, and 38 were excluded without completing the baseline survey; 235 were randomly allocated to either the intervention (n = 118) or control (n = 117) groups. Sixty-four participants in the intervention group completed the program. Over 70% of the participants lacked opportunities to learn about local healthcare planning. The intervention group showed significant improvement in self-perception of competencies, knowledge, and skills regarding local healthcare planning, except for items related to evaluation. CONCLUSIONS: The web-based learning program effectively improved participants' self-perception of competencies in local healthcare planning.

New Web-Based System for Recording Public Health Nursing Practices and Determining Best Practices: Protocol of an Exploratory Sequential Design.

BACKGROUND: Digitalization and information and communication technology (ICT) promote effective, efficient individual and community care. Clinical terminology or taxonomy and its framework visualize individual patients' and nursing interventions' classifications to improve their outcomes and care quality. Public health nurses (PHNs) provide lifelong individual care and community-based activities while developing projects to promote community health. The linkage between these practices and clinical assessment remains tacit. Owing to Japan's lagging digitalization, supervisory PHNs face difficulties in monitoring each department's activities and staff members' performances and competencies. Randomly selected prefectural or municipal PHNs collect data on daily activities and required hours every 3 years. No study has adopted these data for public health nursing care management. PHNs need ICTs to manage their work and improve care quality; it may help identify health needs and suggest best public health nursing practices. OBJECTIVE: We aim to develop and validate an electronic recording and management system for evaluating different public health nursing practice needs, including individual care, community-based activities, and project development, and for determining their best practices. METHODS: We used a 2-phase exploratory sequential design (in Japan) comprising 2 phases. In phase 1, we developed the system's architectural framework and a hypothetical algorithm to determine the need for practice review through a literature review and a panel discussion. We designed a cloud-based practice recording system, including a daily record system and a termly review system. The panels included 3 supervisors who were prior PHNs at the prefectural or municipal government, and 1 was the executive director of the Japanese Nursing Association. The panels agreed that the draft architectural framework and hypothetical algorithm were reasonable. The system was not linked to electronic nursing records to protect patient privacy. Phase 2 validated each item through interviews with supervisory PHNs using a web-based meeting system. A nationwide survey was distributed to supervisory and midcareer PHNs across local governments. RESULTS: This study was funded in March 2022 and approved by all ethics review boards from July to September and November 2022. Data collection was completed in January 2023. Five PHNs participated in the interviews. In the nationwide survey, responses were obtained from 177 local governments of supervisory PHNs and 196 midcareer ones. CONCLUSIONS: This study will reveal PHNs' tacit knowledge about their practices, assess needs for different approaches, and determine best practices. Additionally, this study will promote ICT-based practices in public health nursing. The system will enable PHNs to record their daily activities and share them with their supervisors to reflect on and improve their performance, and the quality of care to promote health equity in community settings. The system will support supervisory PHNs in creating performance benchmarks for their staff and departments to promote evidence-based human resource development and management. TRIAL REGISTRATION: UMIN-ICDR UMIN000049411; https://tinyurl.com/yfvxscfm. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/45342.

Meiotic chromosome organization and its role in recombination and cancer.

Chromosomes adopt specific conformations to regulate various cellular processes. A well-documented chromosome configuration is the highly compacted chromosome structure during metaphase. More regional chromatin conformations have also been reported, including topologically associated domains encompassing mega-bases of DNA and local chromatin loops formed by kilo-bases of DNA. In this review, we discuss the changes in chromatin conformation taking place between somatic and meiotic cells, with a special focus on the establishment of a proteinaceous structure, called the chromosome axis, at the beginning of meiosis. The chromosome axis is essential to support key meiotic processes such as chromosome pairing, homologous recombination, and balanced chromosome segregation to transition from a diploid to a haploid stage. We review the role of the chromosome axis in meiotic chromatin organization and provide a detailed description of its protein composition. We also review the conserved and distinct roles between species of axis proteins in meiotic recombination, which is a major factor contributing to the creation of genetic diversity and genome evolution. Finally, we discuss situations where the chromosome axis is deregulated and evaluate the effects on genome integrity and the consequences from protein deregulation in meiocytes exposed to heat stress, and aberrant expression of genes encoding axis proteins in mammalian somatic cells associated with certain types of cancers.

Association between public health nurses' involvement in local healthcare planning and the corresponding off-the-job training.

OBJECTIVE: This study investigated the association between receiving off-the-job training and the involvement of public health nurses in local healthcare planning. DESIGN: A nationwide, cross-sectional study design. METHODS: We sent self-report questionnaires to 2,185 public health nurses with experience in developing local healthcare plans in Japan since 2013 and collected information related to three main categories: demographic data, involvement in local healthcare planning and strategies for healthcare planning. RESULTS: We received 1,281 responses (return rate of 58.6%), of which 231 did not meet the inclusion criteria. Thus, we analysed 1,050 valid responses. Among the 1,050 respondents, 496 (47.2%) had received off-the-job training in healthcare planning. A subsequent logistic regression analysis revealed that the following factors were associated with this achievement: holding a managerial position, receiving healthcare planning education at the undergraduate level, having mentors regarding the promotion of it, partially conducting cross-sectional coordination and conducting groupwork with community-dwelling residents.

Infection control measures promoted by the public health center for "housing for the elderly" facilities during norovirus cluster outbreaks.

Objective: "Housing for the elderly" is a type of facility where a few healthcare staff and care workers provide long-term care to residents. This study aimed to explore the infection control measures promoted by the public health centers (PHC) when a cluster of norovirus cases occurred in this type of facility. Materials and Methods: This study involved a prefectural office in Japan and collected the records of PHC surveys/instructions of norovirus cluster cases that occurred in "housing for the elderly" facilities between 2017 and 2019. The records provided information about the case characteristics (cluster periods and number of infected individuals) and instructions for infection control by the PHC. We tabulated the case characteristics and performed a descriptive qualitative analysis to extract the instructions from the PHC. Results: Twelve clusters of cases were included in the study. Approximately 16% of the residents and care workers in each facility were infected, and it took an average of 23 days from the start of the outbreak to the end. Nine categories of PHC instructions emerged after the data analysis. "Collaboration with community healthcare workers" included instructions by the PHC to share information with external physicians and home-visiting nurses. In "precautions when caring for elderly residents with functional decline", the procedure for changing diapers and infection control measures considering the behavior of residents with dementia were advised. If the contents of the infection control manuals were deemed to be inadequate, an "improvement of the infection control manuals" was instructed. Conclusion: To implement effective infection control by care workers at "housing for the elderly" facilities, the PHC should promote the involvement of community physicians and nurses and advise on clear procedures based on residents' functional decline.

[Public health nurses' activities during normal times and factors associated with their promotion of residents' mutual support during disasters].

Objective　To clarify the actual state of activities conducted by public health nurses (PHNs) during normal times and assess factors related to the implementation of such activities for the promotion of residents' mutual support during disasters, across different municipalities in Japan.Methods　We conducted a nationwide cross-sectional self-report questionnaire survey of PHNs in 1,463 municipalities. The questionnaires included descriptions of municipalities, activities related to disaster prevention and the rationale for them, and the details of activities that were being conducted to promote residents' mutual support in times of disaster. We conducted multiple logistic analyses to examine the associated factors.Results　We analyzed 535 responses (valid response rate of 36.6%). The proportion of municipalities in which oriented district activity systems and oriented business activity systems were used jointly by PHNs was 81.7%. The proportion of municipalities in which PHNs participated in the formulation of regional disaster prevention plans was 31.6%. "Individual support" would be implemented for persons requiring support in evacuation activities in 41.7% of municipalities; "cooperative support for community organizations," in 34.8%; and other "activities for the purpose of residents' mutual support," in 29.9%. Reasons for not implementing such measures included "outside the division of duties" and "having no contact with residents' organizations." Logistic regression analyses showed that the oriented district activity system, participation of PHNs in the formulation of regional disaster prevention plans, and preparation of an activity manual on disaster countermeasures for PHNs were significantly associated with the performance of activities during normal times for promotion of residents' mutual support during disasters.Conclusion　Our findings clarified that the PHNs' activities during normal times for the promotion of residents' mutual support during disasters were not carried out sufficiently. It is important to review activities according to the district, to ensure supervisory PHNs play a greater role, to provide external support to municipalities for the participation of PHNs in the formulation of regional disaster prevention plans, and to prepare an activity manual on disaster countermeasures for PHNs.

Feasibility of an educational program for public health nurses to promote local healthcare planning: protocol for a pilot randomized controlled trial.

BACKGROUND: Promoting of local healthcare planning is crucial for assisting public health nurses in improving community health inequities. However, there is no effective educational program for developing relevant skills and knowledge among these nurses. Therefore, this study aims to assess the feasibility of a newly developed web-based self-learning program to promote the involvement of public health nurses in the local healthcare planning process. METHODS: A pilot randomized control trial randomly allocated eligible public health nurses to intervention and control wait-list groups [1:1]. The former will be exposed to six web-based learning modules from July to October 2021. After collecting post-test data, the wait-list group will be exposed to the same modules to ensure learning equity. The primary outcome will be evaluated by implementing a validated and standardized scale designed to measure public health policy competencies at the baseline and post-intervention, while secondary outcome will be measured on an action scale to demonstrate the necessity of healthcare activities. The third outcome will be the knowledge and skills related to local healthcare planning by public health nurses. The participants will provide feedback through free descriptions on the trial feasibility and a web-based self-learning program to identify improvement points for continual refinement. DISCUSSION: The results will provide suggestions in preparation for a future definitive randomized controlled trial. This will provide preliminary data for an intervention aimed at improving relevant competencies among public health nurses who are tasked with resolving health inequities in their respective communities through local health planning. TRIAL REGISTRATION: The protocol for this study was registered with the University Hospital Medical Information Network Clinical Trials Registry and approved by the International Committee of Medical Journal Editors (No. UMIN000043628 , March 23, 2021).

[Factors associated with community collaboration in the implementation phase of the local health-care, medical, and welfare plan].

Objective　The aim of this study was to elucidate the status of health-care, medical, and welfare planning (hereafter, "planning")-in which public health nurses (PHNs) had participated-and the factors associated with community collaboration in the implementation phase. Additionally, suggestions regarding health activities that would contribute to improving the entire community's health level were obtained.Methods　The Plan-Do-Check-Act (PDCA) cycle was the conceptual framework for this study, and the focus was the implementation phase of the plan (i.e., corresponding to the "Do" phase). Survey items were part of the "Plan" phase and identified the extent to which PHNs collaborated with community-dwellers in implementation, their demographics, their participation in the planning process, organizational factors, and the strategies used in the planning phase. The participants were full-time PHNs working in local governments who had participated in the planning process since 2013 (when the guidelines for PHNs' practices were published). A nationwide, cross-sectional survey was conducted in Japan with 2,185 PHNs from 220 regions (36 prefectures, 41 cities with public health centers, and 153 municipalities) who expressed the willingness to participate in this study. A binomial logistic regression analysis was conducted to examine the association between community collaboration and the independent variables.Results　A total of 1,281 answers (a 58.6% response rate) were received. Ultimately, 1,028 (a 47.0% valid response rate) were analyzed; exclusions were 203 for no experience in health care planning since 2013 and 50 with missing values. There were 125 (12.2%) PHNs who answered that they "did not collaborate with the community-dwellers at all," 293 (28.5%) who answered that they "did not collaborate with them much," 482 (46.9%) who replied that they "collaborated with them a little," and 128 (12.4%) who responded that they "collaborated with them a lot." The binomial logistic regression analysis showed that the following were associated with PHNs' collaboration with the community: being in a managerial position, having experience developing a health promotion plan, conducting a questionnaire survey or group work, as well as participating in municipal health planning committees with community-dwellers, utilizing research evidence, identifying target groups, and managing the plan's progress.Conclusion　From the planning phase, PHNs must collaborate with community residents and reflect their voices so that the formulated plan will help resolve medium to long-term issues in the community related to health and life.

Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia.

Blast crisis (BC) predicts dismal outcomes in patients with chronic myeloid leukaemia (CML). Although additional genetic alterations play a central role in BC, the landscape and prognostic impact of these alterations remain elusive. Here, we comprehensively investigate genetic abnormalities in 136 BC and 148 chronic phase (CP) samples obtained from 216 CML patients using exome and targeted sequencing. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients, including the RUNX1-ETS2 fusion and NBEAL2 mutations. The number of genetic alterations increase during the transition from CP to BC, which is markedly suppressed by tyrosine kinase inhibitors (TKIs). The lineage of the BC and prior use of TKIs correlate with distinct molecular profiles. Notably, genetic alterations, rather than clinical variables, contribute to a better prediction of BC prognosis. In conclusion, genetic abnormalities can help predict clinical outcomes and can guide clinical decisions in CML.

Implications of the germline variants of DNA damage response genes detected by cancer precision medicine for radiological risk communication and cancer therapy decisions.

Large-scale cancer-associated gene testing is now being rapidly incorporated into clinical settings, and is leading to incidental identification of the germline variants present in cancer patients. Because many cancer susceptibility genes are related to DNA damage response and repair, the variants may reflect not only the susceptibility to cancer but also the genetically defined radiation sensitivity of the patients and their relatives. When the presence of a certain germline variant increases the risk for developing radiation toxicity or radiation-induced secondary cancers, it will greatly influence the clinical decision-making. In order to achieve optimal radiological risk communication and to select the best cancer management for a given patient based on information from gene testing, healthcare professionals including genetic counselors, risk communicators and clinicians need to increase their knowledge of the health effects of various genetic variants. While germline loss-of-function mutations in both of the alleles of the DNA damage response genes cause rare hereditary diseases characterized by extreme hypersensitivity to radiation, the health effects of the carriers who have germline variants in one allele of such genes would be a matter of debate, especially when the significance of the variants is currently unknown. In this review, we describe the clinical significance of the genetic variants of the important DNA damage response genes, including ATM and TP53, and discuss how we can apply current knowledge to the management of cancer patients and their relatives from a radiological point of view.

Self-reported competences of public health nurses for developing needs-oriented local healthcare plans: A nationwide cross-sectional survey.

AIM: To identify self-reported competencies of public health nurses for reflecting community healthcare needs in local healthcare plans. DESIGN: We conducted a nationwide cross-sectional survey in Japan from October 7-November 30, 2019. METHODS: We sent 2,185 self-reported questionnaires to public health nurses in Japan who had developed a local healthcare plan since 2013. Self-reported questionnaires included questions regarding demographic data and the reflection of community healthcare needs in local healthcare plans, and the involvement in local healthcare planning. RESULTS: We analysed 1,042 questionnaires: 651 (62.5%) were from public health nurses who reported that they elicited and shared community views to be reflected for purposes of local healthcare planning (the reflecting group), and 391 (37.5%) of the remaining public health nurses who reported that they did not do so (the non-reflecting group). The logistic regression analysis revealed that public health nurses in the reflecting group were more likely to be in a managerial position, have colleagues who played an active role in healthcare planning, conduct a questionnaire survey, engage in group work, participate in a municipal healthcare planning committee with community-dwelling people, and identify the opinions of the professional organizations. CONCLUSIONS: Identifying community healthcare needs through collaboration with community-dwelling people and professional organizations should be essential competencies for public health nurses (the reflecting group) in developing needs-oriented local healthcare plans. IMPACT: Identification of their related competencies for developing a needs-oriented local healthcare plan as an upstream strategy to mitigate the prevalence of health inequities in each community.

Synaptonemal complex proteins modulate the level of genome integrity in cancers.

The synaptonemal complex (SC) is a proteinaceous structure that is transiently formed during meiosis to promote homologous recombination between maternal and paternal chromosomes. As this structure is required only for meiotic recombination, the proteins constituting the complex are almost undetectable in normal somatic cells, but they can be expressed under the conditions in which the transcriptional machinery is deregulated. Accumulating evidence indicates that they are epigenetically expressed in cancers of various origin. Not surprisingly, in contrast to their meiotic roles, the somatic roles of the SC proteins remain to be investigated. However, it has recently been reported that SYCP3 and SYCE2 control DNA double-strand break repair negatively and positively, respectively, suggesting that the ectopic expression of the SC proteins in somatic cells could be associated with the maintenance of genomic instability. Thus, it is highly likely that the investigation of the somatic roles of the SC proteins would improve our understanding of the mechanisms underlying tumor development.

High-throughput functional evaluation of BRCA2 variants of unknown significance.

Numerous nontruncating missense variants of the BRCA2 gene have been identified, but there is a lack of convincing evidence, such as familial data, demonstrating their clinical relevance and they thus remain unactionable. To assess the pathogenicity of variants of unknown significance (VUSs) within BRCA2, here we develop a method, the MANO-B method, for high-throughput functional evaluation utilizing BRCA2-deficient cells and poly (ADP-ribose) polymerase (PARP) inhibitors. The estimated sensitivity and specificity of this assay compared to those of the International Agency for Research on Cancer classification system is 95% and 95% (95% confidence intervals: 77-100% and 82-99%), respectively. We classify the functional impact of 186 BRCA2 VUSs with our computational pipeline, resulting in the classification of 126 variants as normal/likely normal, 23 as intermediate, and 37 as abnormal/likely abnormal. We further describe a simplified, on-demand annotation system that could be used as a companion diagnostic for PARP inhibitors in patients with unknown BRCA2 VUSs.

Impact of web-based learning for health program planning competency, knowledge and skills among mid-level public health nurses: A randomized controlled trial.

OBJECTIVES: To evaluate the impact of web-based learning modules for health program planning competency, recognition, knowledge and skills among mid-level public health nurses (PHNs). DESIGN: Parallel-group randomized controlled trial. SAMPLE: During 2018, 244 Japanese PHNs were eligible as participants with 5-20 years experiences as a PHN were randomly allocated to the intervention (n = 121) or control group (n = 123). MEASUREMENTS: The outcome was assessed using the Competency Measurement of Creativity for PHNs (CMC) and 26 questions about recognition, knowledge, and skills for health program planning. INTERVENTIONS: Eight web-based modules. RESULTS: No significant differences in CMC scores between the control and intervention groups at base line and post-intervention. By contrast, significant differences in total score of the 26 items of knowledge and skills. In an exploratory analysis, there was a significant difference identified in CMC scores in the demographic of post graduate training in program planning at base line and post-intervention. (p = .034). CONCLUSIONS: The findings suggested that web-based learning with flexibility in terms of time and location would improve competency, skills and knowledge of health program planning among mid-level PHNs.

Effectiveness of an educational program for mid-level Japanese public health nurses to improve program planning competencies: A preliminary randomized control trial.

OBJECTIVE: To evaluate the effectiveness of an education program for mid-level Japanese public health nurses (PHNs) to improve their competencies in program planning, which will fulfill community health needs. DESIGN: Randomized control trial. SAMPLE: During 2017, 103 PHNs with 5-20 years of PHN work experience in Japan were enrolled and randomly allocated to the intervention (n = 51) or control group (n = 52). MEASUREMENTS: The primary outcome measured competency in program planning based on Competency Measurement of Creativity for PHNs (CMC), knowledge, and skills regarding program planning. INTERVENTION: Six web-based learning modules followed by two face-to-face group sessions. RESULTS: The PHN participants averaged about 12 years of experience. In the intervention group, 25 PHNs completed all modules (49.0%). Post intervention, there were no statistically significant differences among any between-group CMC scores. However, the intervention group's CMC 3 score was significantly higher than that of the control group of ≥12 years of experience. Total knowledge and skill scores also improved significantly in the intervention group compared with the control group. CONCLUSIONS: The results suggest that PHNs with ≥12 years of experience are a suitable target of this educational program, and should play a key role in program planning.

[A Case of Breast Cancer Complicated with Castleman's Disease].

The patient was a 57-year-old woman with Castleman's disease. The follow-up CT scans obtained during the treatment of Castleman's disease, detected a 15mm nodule in the right breast AC area, and the patient was diagnosed with breast cancer. Lymphadenopathy was noted on both sides of the axilla; however, it was considered to be due to Catsleman's disease. Mastectomy and sentinel lymph node biopsy were performed with preoperative diagnosis of cT1cN0M0, cStage Ⅰ. Rapid diagnosis of the sentinel lymph node during the operation showed a metastatic tumor measuring 3mm and axillary dissection was performed. However, no metastasis was found in the dissected lymph node, which was, therefore, considered as an enlargement due to Castleman's disease.