ATR phosphorylates DHX9 at serine 321 to suppress R-loop accumulation upon genotoxic stress.

Aberrant DNA/RNA hybrids (R-loops) formed during transcription and replication disturbances pose threats to genome stability. DHX9 is an RNA helicase involved in R-loop resolution, but how DHX9 is regulated in response to genotoxic stress remains unclear. Here we report that DHX9 is phosphorylated at S321 and S688, with S321 phosphorylation primarily induced by ATR after DNA damage. Phosphorylation of DHX9 at S321 promotes its interaction with γH2AX, BRCA1 and RPA, and is required for its association with R-loops under genotoxic stress. Inhibition of ATR or expression of the non-phosphorylatable DHX9S321A prevents DHX9 from interacting with RPA and R-loops, leading to the accumulation of stress-induced R-loops. Furthermore, depletion of RPA reduces the association between DHX9 and γH2AX, and in vitro binding analysis confirms a direct interaction between DHX9 and RPA. Notably, cells with the non-phosphorylatable DHX9S321A variant exhibit hypersensitivity to genotoxic stress, while those expressing the phosphomimetic DHX9S321D variant prevent R-loop accumulation and display resistance to DNA damage agents. In summary, we uncover a new mechanism by which ATR directly regulates DHX9 through phosphorylation to eliminate stress-induced R-loops.

Development and psychometric properties of a friendly dietary function assessment scale for home-dwelling people with dementia.

BACKGROUND: Mealtime difficulties related to cognitive functioning negatively impact a patient's life during the various stages of dementia, and they typically cause a burden and stress on family caregivers. Most people with dementia live at home alone or are cared for by informal caregivers, typically their spouses or other family members. However, no suitable screening tools for home-dwelling patients with dementia have been developed, nor have measurements focused on executive and self-eating functions. This study aimed to develop and evaluate the psychometric properties of the Dietary Function Assessment Scale (DFAS) for community-dwelling persons with dementia. METHODS: A mixed-method design was used to develop the instrument. Methods included a comprehensive literature review to identify the item pool and an expert panel to assess the initial item pool. We performed convenience sampling of 190 home-dwelling people with dementia for psychometrical evaluation. The psychometric properties tests included item and factor analyses, criterion-related validity testing, internal consistency reliability testing, and defining the optimal cut-off values. The study was conducted from 2018 to 2019. RESULTS: Items were generated based on an extensive literature review and pre-existing scales related to mealtime and executive functions in persons with dementia. The S-CVI/Ave of the DFAS was 0.89. A Principal Component factor analysis demonstrated seven items, with a two-factor structure accounting for 56.94% of the total variance. The two extracted factors were Self-eating ability and Dietary executive function. The confirmatory factor analysis indicated a good model fit. The criterion-related validity was adequate (r = -0.528, p < 0.01). The reliability of Cronbach's alpha internal consistency was 0.74, and McDonald's Omega coefficient was 0.80; the optimal cut-off value of 13 points with an AUC of 0.74 was established to determine poor dietary functioning in persons with dementia. CONCLUSION: The DFAS was simple, user-friendly, and a valid and reliable instrument to assess dietary functioning in community-dwelling persons with dementia. This short scale can be helpful for caretakers, who can use it to identify the dietary needs of home-dwelling persons with dementia and improve their care and eating experience.

[Getting Lost in People With Dementia: A Scoping Review].

BACKGROUND: Many people with dementia suffer from getting lost, which not only impacts their daily lives but also affects their caregivers and the general public. The concept of getting lost in dementia has not been clarified in the literature. PURPOSE: This scoping review was designed to provide a deeper understanding of the overall phenomenon of getting lost in people with dementia, with the results intended to provide caregivers with more complete information and enlightening research and practice related to dementia getting lost. METHODS: A systematic review method was used, and articles were retrieved from electronic databases including PubMed, Embase, Airiti Library, Cochrane Library, and Gray literature. Specific keywords, MeSH terms, and Emtree terms were used to search for articles on dementia and getting lost. A total of 10,523 articles published from 2011-2020 that matched the search criteria were extracted. After screening the topics and deleting repetitions, 64 articles were selected for further analysis. These articles were classified and integrated based on the six-step literature review method proposed by Arksey and O'Malley. RESULTS: The key findings of the review included: (1) The concept of getting lost in dementia is diverse and inseparable from wandering; (2) More than half of the assessment tools related to getting lost in dementia include the concept of wandering; (3) The factors identified as affecting getting lost in dementia include the patient's personal traits, disease factors, care factors, and environmental factors; (4) Getting lost in dementia negatively affects patients as well as their caregivers and the general public; (5) Most of the articles in this review were quantitative studies and were conducted in Western countries. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: The scoping review approach may assist care providers to fully understand the phenomenon of getting lost in dementia, clarify its causes and consequences, and identify the limitations in the literature. The findings may be referenced in the creation of healthcare policies promoting related preventive measures and care plans as well as used to guide future academic research.

Perturbation of p38α MAPK as a Novel Strategy to Effectively Sensitize Chronic Myeloid Leukemia Cells to Therapeutic BCR-ABL Inhibitors.

Chronic myeloid leukemia (CML) is a hematopoietic malignancy characterized by the presence of the BCR-ABL oncogene. Therapeutic regimens with tyrosine kinase inhibitors (TKIs) specifically targeting BCR-ABL have greatly improved overall survival of CML. However, drug intolerance and related toxicity remain. Combined therapy is effective in reducing drug magnitude while increasing therapeutic efficacy and, thus, lowers undesired adverse side effects. The p38 MAPK activity is critically linked to the pathogenesis of a number of diseases including hematopoietic diseases; however, the role of each isozyme in CML and TKI-mediated effects is still elusive. In this study, we used specific gene knockdown to clearly demonstrate that the deficiency of p38α greatly enhanced the therapeutic efficacy in growth suppression and cytotoxicity of TKIs, first-generation imatinib, and second generation dasatinib by approximately 2.5-3.0-fold in BCR-ABL-positive CML-derived leukemia K562 and KMB5 cells. Knockdown of p38ß, which displays the most sequence similarity to p38α, exerted distinct and opposite effects on the TKI-mediated therapeutic efficacy. These results show the importance of isotype-specific intervention in enhancing the therapeutic efficacy of TKI. A highly specific p38α inhibitor, TAK715, also significantly enhanced the imatinib- and dasatinib-mediated therapeutic efficacy, supporting the feasibility of p38α deficiency in future clinic application. Taken together, our results demonstrated that p38α is a promising target for combined therapy with BCR-ABL-targeting tyrosine kinase inhibitors for future application to increase therapeutic efficacy.

The MKK-Dependent Phosphorylation of p38α Is Augmented by Arginine Methylation on Arg49/Arg149 during Erythroid Differentiation.

The activation of p38 mitogen-activated protein kinases (MAPKs) through a phosphorylation cascade is the canonical mode of regulation. Here, we report a novel activation mechanism for p38α. We show that Arg49 and Arg149 of p38α are methylated by protein arginine methyltransferase 1 (PRMT1). The non-methylation mutations of Lys49/Lys149 abolish the promotive effect of p38α on erythroid differentiation. MAPK kinase 3 (MKK3) is identified as the major p38α upstream kinase and MKK3-mediated activation of the R49/149K mutant p38α is greatly reduced. This is due to a profound reduction in the interaction of p38α and MKK3. PRMT1 can enhance both the methylation level of p38α and its interaction with MKK3. However, the phosphorylation of p38α by MKK3 is not a prerequisite for methylation. MAPK-activated protein kinase 2 (MAPKAPK2) is identified as a p38α downstream effector in the PRMT1-mediated promotion of erythroid differentiation. The interaction of MAPKAPK2 with p38α is also significantly reduced in the R49/149K mutant. Together, this study unveils a novel regulatory mechanism of p38α activation via protein arginine methylation on R49/R149 by PRMT1, which impacts partner interaction and thus promotes erythroid differentiation. This study provides a new insight into the complexity of the regulation of the versatile p38α signaling and suggests new directions in intervening p38α signaling.

[Factors Influencing "Face" in People With Dementia: A Systematic Review of the Literature].

BACKGROUND: Face (self-esteem) is an issue that involves socially endowed status, identity roles, and self-image management and maintenance. People with dementia and their family members often experience social isolation due to diminished self-image, which affects disease progression. Better understanding the factors that influence the self-image of people with dementia may promote the ability of caregivers to maintain self-image and promote public understanding and empathy toward people with dementia. PURPOSE: The aim of this study was to explore the factors influencing self-image in people with dementia using a systematic review of the literature. METHODS: A systematic review was used. Articles were retrieved from electronic databases including PubMed, CINAHL, Airiti Library, and Cochrane Library. The following keywords and MeSH terms were used to search for articles on dementia, face, self-esteem, respect, and self-concept. A total of 3,050 articles published prior to September 2018 that matched the search criteria were extracted. After screening the topics, deleting repetitions, and doing critical appraisals, eight articles were selected for analysis. Research quality was appraised using the Joanna Briggs Institute and the Melnyk and Fineout-Overholt for Evidence-Based Medicine Level of Evidence. RESULTS: Two themes related to the factors influencing self-image in people with dementia were extracted from the selected articles. The first theme was "loss of self-identity". As people with dementia gradually lose their cognitive function and memory ability, they are increasingly incapable of handling and managing their current role tasks. The second theme was "negative public perception". The public believes that people with dementia are at risk to others and that their behaviors are unpredictable, resulting in the deprivation of the rights to which people with dementia are entitled. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: Because of disease progression, people with dementia gradually lose their self-identity and become unable to perform their life-role tasks. This is accompanied by negative perceptions of the disease among the public, which, in turn, damages the self-image of people with dementia and their families. The results of this review may provide a reference for caregivers planning future person-centered care approaches for people with dementia. In addition, these results may help facilitate the establishment of a more friendly environment for people with dementia in both public and private spaces.

Calcium-dependent methylation by PRMT1 promotes erythroid differentiation through the p38α MAPK pathway.

Protein arginine methyltransferase 1 (PRMT1) stimulates erythroid differentiation, but the signaling events upstream are yet to be identified. Ca2+ plays crucial roles during erythroid differentiation. Here, we show that Ca2+ enhances methylation during induced erythroid differentiation and that Ca2+ directly upregulates the catalytic activity of recombinant PRMT1 by increasing Vmax toward the substrate heterogeneous nuclear ribonucleoprotein A2. We demonstrate that PRMT1 is essential and responsible for the effect of Ca2+ on differentiation. Depletion of Ca2+ suppresses PRMT1-mediated activation of p38α and p38α-stimulated differentiation. Furthermore, Ca2+ stimulates methylation of p38α by PRMT1. This study uncovers a novel regulatory mechanism for PRMT1 by Ca2+ and identifies the PRMT1/p38α axis as an intracellular mediator of Ca2+ signaling during erythroid differentiation.

Prehemodialysis arteriovenous access creation is associated with better cardiovascular outcomes in patients receiving hemodialysis: a population-based cohort study.

BACKGROUND: Cardiovascular (CV) disease contributes to nearly half of the mortalities in patients with end-stage renal disease. Patients who received prehemodialysis arteriovenous access (pre-HD AVA) creation had divergent CV outcomes. METHODS: We conducted a population-based cohort study by recruiting incident patients receiving HD from 2001 to 2012 from the Taiwan National Health Insurance Research Database. Patients' characteristics, comorbidities, and medicines were analyzed. The primary outcome of interest was major adverse cardiovascular events (MACEs), defined as hospitalization due to acute myocardial infarction, stroke, or congestive heart failure (CHF) occurring within the first year of HD. Secondary outcomes included MACE-related mortality and all-cause mortality in the same follow-up period. RESULTS: The patients in the pre-HD AVA group were younger, had a lower burden of underlying diseases, were more likely to use erythropoiesis-stimulating agents but less likely to use renin-angiotensin-aldosterone system blockers. The patients with pre-HD AVA creation had a marginally lower rate of MACEs but a significant 35% lower rate of CHF hospitalization than those without creation (adjusted hazard ratio (HR) 0.65, 95% confidence interval (CI) [0.48-0.88]). In addition, the pre-HD AVA group exhibited an insignificantly lower rate of MACE-related mortality but a significantly 52% lower rate of all-cause mortality than the non-pre-HD AVA group (adjusted HR 0.48, 95% CI [0.39-0.59]). Sensitivity analyses obtained consistent results. CONCLUSIONS: Pre-HD AVA creation is associated with a lower rate of CHF hospitalization and overall death in the first year of dialysis.

Factors affecting fistula failure in patients on chronic hemodialysis: a population-based case-control study.

BACKGROUND: With advancement of hemodialysis (HD) technique, late fistula failure (LFF) remains a problem significantly affecting life quality of patients. We attempt to identify factors affecting LFF in patients on chronic HD in Taiwan from the National Health Insurance Research Database. METHODS: This case-control study enrolled patients over 18 years old and who received regular HD for more than 3 months. LFF was defined as the first fistula failure episode beyond 3 months of chronic HD. We analyzed characteristics, comorbidities and medicine and investigated the association factors of LFF by logistic regression model. A trend test was conducted for risk in different provider levels. Sensitivity tests were conducted to test consistency. RESULTS: Of 1558 patients recruited, 772 (49.6%) were identified as LFF cases and 786 were identified as controls. The data showed that patients with diabetes mellitus (DM) had 42% increased rate of LFF. Patients receiving more than 10 HD sessions per month had a 90% increased rate of LFF; patients receiving chronic HD in private clinics had a 49% reduction rate of LFF. There were no significant differences in age, dialysis frequency, and comorbidities among different provider levels. There was a significant trend of risk reduction of the event from medical centers, regional hospitals, district hospitals, to private clinics. The sensitivity tests revealed similar results. CONCLUSIONS: The factors associated with LFF include DM and receiving more HD sessions; on the contrary, receiving HD in private clinics is associated with less risk of LFF.

[Holistic Healthcare for the Aged: Concepts and Strategies].

Advancing medical technology continues to extend the average human life span, resulting in population aging globally as well as in Taiwan. The challenges posed by aging society increase not only medical and care costs but also the burden on pension funds and the social welfare system. In addition, there is currently a desperate need for many well-trained health providers as well as a friendly and comprehensive long-term care system. However, attention should not simply focus on medical payments and long-term care, as this may prolong the length of unhealthy living years for the aged and further strain national finances. Holistic healthcare for the aged should be introduced as early as possible in order to respond effectively to global aging by assisting the aged to maintain their health, to live independently, and to extend their social functions. The purposes of this report are to: 1. analyze the demographic characteristics of Taiwanese older adults; 2. introduce the concept of holistic healthcare as advocated by the World Health Organization (WHO); 3. discuss the promotion of physical-psychological health and the development of age-friendly environments; 4. strengthen the framework of long-term care policies; and 5. recommend the development of a holistic healthcare model for the aged based on the WHO Global Strategy and Action Plan on Aging and Health, announced in 2016. We hope to facilitate active aging, successful aging, self-esteem, and a high quality of life for the elderly in Taiwan.

[Relationships between emotional distress, empowerment perception and self-care behavior and quality of life in patients with type 2 diabetes].

BACKGROUND: Diabetes mellitus is a chronic disorder prevalent worldwide that, in addition to being costly to manage, severely impacts patient quality life. Therefore, it is extremely important to understand the factors associated with quality of life in diabetic patients. PURPOSE: The purposes of this study were to investigate relationships between variables including demographics, disease characteristics, emotional distress, empowerment perception, and self-care behavior and quality of life, as well as to identify the important explanatory factors of quality of life in patients with type 2 diabetes. METHODS: This study used a design that was cross-sectional, descriptive and correlated. A total of 220 patients diagnosed with type 2 diabetes in the previous ten year period were recruited as participants in this study. Data was collected using a structured questionnaire that incorporated scales to capture demographic, disease characteristic, emotional distress, empowerment perception, self-care behavior and quality of life data. The quality of life scale measured the three domains of satisfaction, impact, and worried about the diabetes. RESULTS: Results included: (1) the standardized score of quality of life was 79.6, considered in the moderate to high range; (2) Education level, age, "diabetes shared care" participation and insulin therapy were variables with significant impact upon quality of life; (3) The more severe the emotional distress, the worse quality of life scores were in every domain; (4) The better the perception of empowerment, the better the score in the satisfaction domain; (5) The better self care behavior was, the better the score in the satisfaction domain; and (6) emotional distress was the most important explanatory factor of quality of life, accounting for 28.7%-53.8% of total variance. CONCLUSION/IMPLICATIONS FOR PRACTICE: The findings of this study suggested that health professionals should evaluate emotional distress of diabetic patients in the early stage, provide emotional support and consultation and apply empowerment strategy to promote their quality of life.

Combination of 13-cis retinoic acid and interferon-alpha in the treatment of recurrent or refractory peripheral T-cell lymphoma.

We previously reported the therapeutic efficacy of 13-cis retinoic acid (13-cRA) in some subtypes of peripheral T-cell lymphoma (PTCL). This study sought to clarify if the addition of interferon-alpha2a (IFN-alpha2a), an agent with synergistic cytotoxicity with 13-cRA in many types of malignant cells, may be more effective in the treatment of PTCL. Eligible patients has histologically proven PTCL, which was recurrent after or refractory to anthracycline-containing systemic chemotherapy. The treatment included oral administration of 13-cRA 1 mg/kg/day, divided into three doses, and intramuscular injection of IFN-alpha2a 4.5 MU/M2, three times per week. From March 1995 to July 2000, a total of 17 patients, 10 men and 7 women, with a median age of 47 years (range, 18-77 years), were recruited. The histologic diagnosis included 7 cases of unspecified PTCL, 6 cases of Ki-1 anaplastic large cell lymphoma (ALCL), 1 case of angioimmunoblastic T-cell lymphoma, and 3 cases of angiocentric nasal NK/T cell lymphoma. They received a median of 1.7 months of treatment (range, 0.4-13.3 months). One patient refused further treatment due to toxicity. The doses of 13-cRA and IFN-alpha2a had to be decreased in 7 and 7 patients, respectively. Grade III/IV hematologic and non-hematologic toxicity developed in 2 and 5 patients, respectively. There were 5 partial responses (Ki-1, 4; unspecified PTCL, 1), with a total response rate of 31.3% (95% CI, 5.7-56.8%). The median duration of response for the responders was 2.5 months (range, 0.8-7.2 months). The median overall survival for the entire group of patients was 3.6 months. In conclusion, a combination of 13-cRA and IFN-alpha2a is a useful salvage treatment for selected patients with recurrent or refractory PTCL, particularly those with the Ki-1 subtype. However, the data does not support that addition of IFN-alpha2a is superior to 13-cRA alone.