PRODH safeguards human naive pluripotency by limiting mitochondrial oxidative phosphorylation and reactive oxygen species production.

Naive human embryonic stem cells (hESCs) that resemble the pre-implantation epiblasts are fueled by a combination of aerobic glycolysis and oxidative phosphorylation, but their mitochondrial regulators are poorly understood. Here we report that, proline dehydrogenase (PRODH), a mitochondria-localized proline metabolism enzyme, is dramatically upregulated in naive hESCs compared to their primed counterparts. The upregulation of PRODH is induced by a reduction in c-Myc expression that is dependent on PD0325901, a MEK inhibitor routinely present in naive hESC culture media. PRODH knockdown in naive hESCs significantly promoted mitochondrial oxidative phosphorylation (mtOXPHOS) and reactive oxygen species (ROS) production that triggered autophagy, DNA damage, and apoptosis. Remarkably, MitoQ, a mitochondria-targeted antioxidant, effectively restored the pluripotency and proliferation of PRODH-knockdown naive hESCs, indicating that PRODH maintains naive pluripotency by preventing excessive ROS production. Concomitantly, PRODH knockdown significantly slowed down the proteolytic degradation of multiple key mitochondrial electron transport chain complex proteins. Thus, we revealed a crucial role of PRODH in limiting mtOXPHOS and ROS production, and thereby safeguarding naive pluripotency of hESCs.

Application of the solution-focused brief strategies via telephone for family caregivers of persons with dementia: the Alzheimer's Association National Helpline.

OBJECTIVES: Nearly 75% of persons living with dementia (PLWD) in the US live at home and are cared for by informal family members who have limited access to supportive and accessible services, indicating an increased need for these types of services (Alzheimer's Association, 2023). The Alzheimer's Association call centers offer free telephone care consultations, but it currently remains unclear which types of brief telephone support benefit caregivers. This study compares outcomes of participants who received traditional care consultation calls via the Alzheimer's Association National Helpline with care consultation calls from Helpline staff trained in Solution-Focused Brief Strategies (SFBS), a client-centered evidence- and resource-based approach. METHOD: Sequential callers were randomly assigned to the "traditional" or "SFBS" care consultation groups and were assessed at the time of call (baseline) and post-call (T1). The outcomes of interest were general self-efficacy (GSE), self-efficacy in managing emotions (PROMIS), caregiver mastery, therapeutic alliance, and goal setting. RESULTS: Of over 500 callers, callers receiving the SFBS scored higher on therapeutic alliance and goal-setting metrics, such as greater sense of collaboration on goals (effect size = 0.280, p = 0.0005, significant with Bonferroni correction), mutual agreement with care consultant on goals (effect size = 0.418, p < 0.0001, significant with Bonferroni correction), and believing the way the problem was resolved was correct (effect size = 0.286, p = 0.0007, significant with Bonferroni correction) than those receiving the traditional care consultation. Both groups reported improvements in the PROMIS measure, but there were no differences between groups. There were no significant differences in GSE or caregiver mastery scores between groups. CONCLUSION: This study provides evidence for the effectiveness of the integration of SFBS in dementia care consultation calls as part of telephone-based supportive services for dementia caregivers.

Participants' perceptions support the coexistence of benefits and burdens of cancer clinical trial participation.

BACKGROUND: To advance oncology treatment for adults, comprehensive understanding of how and why people decide to enroll in, remain in, and withdraw from cancer clinical trials is needed. While quantitative findings provide insights into these benefits and burdens, they provide limited understanding of how adults with cancer appraise their situation and approach decisions to undertake a clinical trial. The goal of this mixed methods analysis was to conceptualize participants' assessment of benefits and burdens related to cancer clinical trial participation. MATERIALS AND METHODS: This sub-group analysis of 21 participants was part of a larger sequential, explanatory mixed methods study. We used Creamer's integrated approach to linking quantitative and qualitative data to assess convergence, with qualitative data explaining quantitative results. Participants were grouped into four categories based on quantitative benefit/burden scores and thematic analysis of their qualitative data was used to describe these categories. RESULTS: Across groups participants varied in descriptions of benefits and burdens of cancer clinical trial participation and reasons for participating. Those reporting high benefit/low burden described "seizing the opportunity to participate;" those reporting low benefit/low burden described "taking responsibility" through trial participation; those reporting low benefit/high burden described how they were "willing to endure," and those with high benefit/high burden emphasized "deciding to act." CONCLUSIONS: Participants' qualitative descriptions of benefits and burdens were more nuanced and dynamic than reflected in their quantitative ratings. Thus, current measures may be missing important concepts, such as logistic challenges of trial participation. Our results have implications for consenting procedures and decisional support guidance offered to patients and their caregivers.

Identification of VPS34-PI(3)P-FEN1-mediated DNA repair pathway as a potential drug target to overcome chemoresistance.

Intrinsic or acquired chemoresistance represents a major obstacle in cancer treatment. Multiple mechanisms can contribute to cancer cells' resistance to chemotherapy. Among them, an aberrantly strengthened DNA repair mechanism is responsible for a large proportion of drug resistance to alkylating agents and radiation therapy. In cancer cells, damping overactivated DNA repair system can overcome survival advantages conferred by chromosomal translocations or mutations and lead to cytostatic effects or cytotoxic. Therefore, selectively targeting DNA repair system in cancer cells holds promise for overcoming chemoresistance. In this study, we revealed that the endonuclease Flap Endonuclease 1 (FEN1), essential for DNA replication and repair, directly interacts with phosphatidylinositol 3-phosphate [PI(3)P], and FEN1-R378 is the primary PI(3)P-binding site. PI(3)P-binding deficient FEN1 mutant (FEN1-R378A) cells exhibited abnormal chromosomal structures and were hypersensitized to DNA damage. The PI(3)P-mediated FEN1 functionality was essential for repairing DNA damages caused by multiple mechanisms. Furthermore, VPS34, the major PI(3)P synthesizing enzyme, was negatively associated with patients' survival in various cancer types, and VPS34 inhibitors significantly sensitized chemoresistant cancer cells to genotoxic agents. These findings open up an avenue for counteracting chemoresistance by targeting VPS34-PI(3)P-mediated DNA repair pathway, and call for assessing the efficacy of this strategy in patients suffering from chemoresistance-mediated cancer recurrence in clinical trials.

Identification of a RAD51B enhancer variant for susceptibility and progression to glioma.

BACKGROUND: RAD51B plays a significant role in homologous recombination-mediated repair of DNA double-strand breaks. Many enhancer variants are involved in cancer development and progression. However, the significance of enhancer variants of RAD51B in glioma susceptibility and progression remains unclear. METHODS: A case-control study consisting of 1056 individuals was conducted to evaluate the associations of enhancer variants of RAD51B with glioma susceptibility and progression. Sequenom MassARRAY technology was used for genotyping. The function of enhancer variants was explored by biochemical assays. RESULTS: A significantly decreased risk of glioma was associated with rs6573816 GC genotype compared with rs6573816 GG genotype (OR = 0.66, 95% CI 0.45-0.97; P = 0.034). Multivariable Cox regression revealed that rs6573816 was significantly associated with glioma progression in a sex-dependent manner. Worse PFS was found in the male patients with high grade glioma carrying rs6573816 GC or CC genotype (HR = 2.28, 95% CI 1.14-4.57; P = 0.020). The rs6573816 C allele repressed enhancer activity by affecting transcription factor POU2F1 binding, which resulted in lower expression of RAD51B. Remarkably attenuated expression of RAD51B was observed following POU2F1 knockdown. Consistently, positive correlation between the expression of POU2F1 and RAD51B was found in lymphoblastic cells and glioma tissues. CONCLUSIONS: These results indicate that an enhancer variant of RAD51B rs6573816 influences enhancer activity by changing a POU2F1 binding site and confers susceptibility and progression to glioma.

Recent advances in enhancing stereocomplexation between poly(lactide) enantiomeric chains.

Over the past three decades, its excellent biodegradability and biocompatibility have enabled poly(lactide) (PLA) to be extensively explored as a replacement for oil-based thermoplastics in biomedical and industrial applications. However, PLA homopolymers have "facilitative" limitations such as low mechanical properties, low processing temperatures, slow recrystallization, and insufficient crystallinity, which have usually hindered commercial PLA in industrial and biomedical applications. The formation of stereo-complexation between enantiomeric poly(L-lactide) (PLLA) and poly(D-lactide) (PDLA) chains offers an effective approach to PLA-based engineering materials with improved properties. In this review, we have understandably summarized recent progress in improving the SC crystallization of PLA-based plastics into two aspects, i.e., enantiomeric PLA homopolymers, and enantiomeric PLA-based copolymers. One important point to be noted is that much emphasis is focused on improving SC crystallization by enhancing interactions in the enantiomeric PLA-based copolymers. There is an insightful discussion about the effect of enhanced SC crystallization as well as intermolecular interactions between PLLA and PDLA chains in various stereocomplexable systems. Most importantly, this review starts with the basic understanding of SC crystallization and further elaborates on the rational mechanism of enhanced SC crystallization to provide a broad idea for broadening the road toward PLA-based materials.

Development of a real-world database for asthma and COPD: The SingHealth-Duke-NUS-GSK COPD and Asthma Real-World Evidence (SDG-CARE) collaboration.

PURPOSE: The SingHealth-Duke-GlaxoSmithKline COPD and Asthma Real-world Evidence (SDG-CARE) collaboration was formed to accelerate the use of Singaporean real-world evidence in research and clinical care. A centerpiece of the collaboration was to develop a near real-time database from clinical and operational data sources to inform healthcare decision making and research studies on asthma and chronic obstructive pulmonary disease (COPD). METHODS: Our multidisciplinary team, including clinicians, epidemiologists, data scientists, medical informaticians and IT engineers, adopted the hybrid waterfall-agile project management methodology to develop the SingHealth COPD and Asthma Data Mart (SCDM). The SCDM was developed within the organizational data warehouse. It pulls and maps data from various information systems using extract, transform and load (ETL) pipelines. Robust user testing and data verification was also performed to ensure that the business requirements were met and that the ETL pipelines were valid. RESULTS: The SCDM includes 199 data elements relevant to asthma and COPD. Data verification was performed and found the SCDM to be reliable. As of December 31, 2019, the SCDM contained 36,407 unique patients with asthma and COPD across the spectrum from primary to tertiary care in our healthcare system. The database updates weekly to add new data of existing patients and to include new patients who fulfil the inclusion criteria. CONCLUSIONS: The SCDM was systematically developed and tested to support the use RWD for clinical and health services research in asthma and COPD. This can serve as a platform to provide research and operational insights to improve the care delivered to our patients.

A nomogram prediction model for treatment failure in primary membranous nephropathy.

BACKGROUND: Primary membranous nephropathy (PMN) has a heterogeneous natural course. Immunosuppressive therapy is recommended for PMN patients at moderate or high risk of renal function deterioration. Prediction models for the treatment failure of PMN have rarely been reported. METHODS: This study retrospectively studied patients diagnosed as PMN by renal biopsy at Sichuan Provincial People's Hospital from January 2017 to December 2020. Information on clinical characteristics, laboratory test results, pathological examination, and treatment was collected. The outcome was treatment failure, defined as the lack of complete or partial remission at the end of 12 months. Simple logistic regression was used to identify candidate predictive variables. Forced-entry stepwise multivariable logistic regression was used to develop the prediction model, and performance was evaluated using C-statistic, calibration plot, and decision curve analysis. Internal validation was performed by bootstrapping. RESULTS: In total, 310 patients were recruited for this study. 116 patients achieved the outcome. Forced-entry stepwise multivariable logistic regression indicated that PLA2Rab titer (OR = 1.002, 95% CI: 1.001-1.004, p = 0.003), inflammatory cells infiltration (OR = 2.753, 95% CI: 1.468-5.370, p = 0.002) and C3 deposition on immunofluorescence (OR = 0.217, 95% CI: 0.041-0.964, p = 0.049) were the three independent risk factors for treatment failure of PMN. The final prediction model had a C-statistic (95% CI) of 0.653 (0.590-0.717) and a net benefit of 23%-77%. CONCLUSIONS: PLA2R antibody, renal interstitial inflammation infiltration, and C3 deposition on immunofluorescence were the three independent risk factors for treatment failure in PMN. Our prediction model might help identify patients at risk of treatment failure; however, the performance awaits improvement.

Better caregiver mastery is associated with less anxiety in individuals with cognitive impairment.

BACKGROUND: When caregivers have a high level of caregiver mastery, their care recipients with cognitive impairment have less behavioral health problems. However, the relationship between caregiver mastery and anxiety among care recipients over time is unknown. Therefore, this study was conducted to examine that better caregiver mastery is associated with less anxiety in individuals with cognitive impairment over time. METHODS: A secondary data analysis was conducted using the Healthy Patterns Clinical Trial (NCT03682185) dataset and guided by Factors Associated with Behavioral and Psychological Symptoms of Dementia conceptual framework. This study included 154 dyads of individuals with cognitive impairment and their caregivers. Multiple linear regression analyses were performed on changes in anxiety. Model 1 included variables at the level of neurodegeneration (i.e., cognitive impairment and age). Model 2 added patient factors (i.e., sleep problems and depression) with the Model 1. Finally, Model 3 included caregiver factor (i.e., caregiver mastery) with the Model 2 to examine how changes in caregiver mastery influence changes in anxiety of care recipients. RESULTS: Model 3 was statistically significant; after controlling for variables at the level of neurodegeneration associated with cognitive impairment and patient factors, improvement of caregiver mastery over time (ß =-0.230, p = 0.015) was related to decreased anxiety over time (R2 = 0.1099). CONCLUSIONS: Caregivers with high caregiver mastery may have better knowledge on how to care for their loved ones and how to manage their neuropsychiatric symptoms. Therefore, improving the level of caregiver mastery by providing psychoeducational programs and resources that family caregivers need will help reduce the frequency of anxiety in individuals with cognitive impairment.

Understanding the mediated relationship between moral distress, depression, and suicide risk in undergraduate nursing students.

BACKGROUND: Nursing students are at higher risk for depression, suicide, and other mental health concerns as compared to the general college student population. Moral distress and other ethical issues may be a significant source of psychological harm within nursing student experiences and warrants further attention. PURPOSE: The purpose of this study was to understand the mediating effect of depression on the relationship between moral distress and suicide risk among undergraduate nursing students. METHODS: This cross-sectional analysis was derived from a larger sequential mixed methods study. The first phase was an online survey completed by a national sample of N = 679 nursing students in the United States. FINDINGS: The relationship between moral distress and suicide risk was fully mediated by depression and statistically significant at the alpha = 0.05 level. CONCLUSION: All three psychological variables (depression, moral distress, suicide risk) impact nursing students and require innovative solutions within nursing and educational programs.

New insights on growth trajectory in infants with complex congenital heart disease.

PURPOSE: We aimed to describe the weight-for-age Z-score growth trajectory (WAZ-GT) of infants with complex congenital heart disease (cCHD) after neonatal cardiac surgery in the first 4 months of life and assess potential risk factors. METHODS: We utilized data from a previously reported trial of the REACH telehealth home monitoring (NCT01941667) program which evaluated 178 infants with cCHD from 2012 to 2017. Over the first 4 months of life, weekly infant weights were converted to WAZ. WAZ-GT classes were identified using latent class growth modeling. Multinomial logistic regression models were used to examine the associations between potential risk factors and WAZ-GT classes. RESULTS: Four distinct classes of WAZ-GT were identified: maintaining WAZ > 0, 14%; stable around WAZ = 0, 35%; partially recovered, 28%; never recovered, 23%. Compared with reference group "stable around WAZ=0," we identified clinical and sociodemographic determinants of class membership for the three remaining groups. "Maintaining WAZ > 0" had greater odds of having biventricular physiology, borderline appetite, and a parent with at least a college education. "Partially recovered" had greater odds of hospital length of stay>14 days and being a single child in the household. "Never recovered" had greater odds hospital length of stay >14 and > 30 days, tube feeding at discharge, and low appetite. CONCLUSIONS: This study described distinct classes of WAZ-GT for infants with cCHD early in infancy and identified associated determinants. PRACTICE IMPLICATIONS: Findings from this study can be used in the identification of infants at risk of poor WAZ-GT and in the design of interventions to target growth in this vulnerable patient population.

Medical Complexity Mediates Healthcare Resource Use in the Socially Vulnerable.

GOAL: The objective of this retrospective, observational study was to assess the mediating effect of medical complexity on the relationship between social vulnerability and four acute care resource use outcomes-number of hospitalizations, emergency department (ED) visits, observation stays, and total visits. Such information may help healthcare managers better anticipate the effects of interventions targeted to the socially vulnerable in their patient population. METHODS: Electronic health records of 147,496 adults served by 27 primary care practices in one large health system from 2015 to 2017 were used. Descriptive statistics were applied to characterize patients and the primary care practices included in the study. Causal mediation analyses using a modified Baron and Kenny approach were performed. PRINCIPAL FINDINGS: Causal mediation analyses demonstrated that increased social vulnerability was associated with increased medical complexity (incidence rate ratio [IRR] = 1.57) and increased numbers of hospitalizations (IRR = 1.63), ED visits (IRR = 2.14), observation stays (IRR = 1.94), and total visits (IRR = 2.04). Effects remained significant, though attenuated, after adjusting for medical complexity (mediator), demographics, and medications (hospitalizations IRR = 1.44, ED visits IRR = 2.02, observation stays IRR = 1.74, total visits IRR = 1.86). Social vulnerability, given medical complexity, explained between 8% (ED visits) and 26% (hospitalizations) of the variation in outcomes. PRACTICAL APPLICATIONS: These findings reinforce the need to modify interventions for medically complex adults to address their social needs and, consequently, reduce costly health services. Health systems seeking to reduce costly care can use these results to estimate savings in the treatment of patients with high social vulnerability-before they get chronic conditions and later as they seek care.

Predictors of change over time in satisfaction with outdoor activities ratings among long-term care services and supports recipients.

OBJECTIVES: To identify predictors of change in older adults' satisfaction with outdoor activities ratings over the first two years of enrollment in long-term services and supports (LTSS). METHODS: Self-rated satisfaction with outdoor activities (not at all satisfied to extremely satisfied) was the primary outcome of this secondary data analysis. Mixed-effects linear regression modeling with a backward elimination process was used for analyses. RESULTS: In the final model (N = 453) older LTSS recipients at baseline had lower ratings of satisfaction with outdoor activities over time, whereas younger recipients had higher ratings over time. Those who moved into a residential facility at baseline had an increase in outdoor activity satisfaction ratings over time compared to older adults who received home and community-based services that had a decrease. DISCUSSION: LTSS clinicians can use these findings to support older adults with decision-making around enrollment into LTSS, address preferences, and develop person-centered care interventions for outdoor activity.

Should associating liver partition and portal vein ligation for staged hepatectomy be applied to hepatitis B virus-related hepatocellular carcinoma patients with cirrhosis? A multi-center study.

BACKGROUND: It is unclear whether associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) can be performed in hepatitis B virus-related hepatocellular carcinoma (HCC) patients with cirrhosis. We explored the efficacy of ALPPS in HCC patients. METHODS: Data of 54 patients who underwent ALPPS between August 2014 and July 2020 at three centers were collected. Adverse factors affecting their prognosis were analyzed and subsequently compared with 184 patients who underwent transcatheter arterial chemoembolization (TACE). RESULTS: Overall survival rates of the ALPPS group at 1, 3, and 5 years were 70.6%, 38.4%, and 31.7%, respectively; corresponding disease-free survival rates were 50.5%, 22.4%, and 19.2%, respectively. The ALPPS group had a significantly greater long-term survival rate than the TACE group (before propensity score matching, P < 0.001; after propensity score matching, P = 0.002). Multivariate analysis demonstrated that multifocal lesions (P = 0.018) and macroscopic vascular invasion (P = 0.001) were prognostic factors for HCC patients who underwent ALPPS. After the propensity score matching, the multifocal lesions (P = 0.031), macroscopic vascular invasion (P = 0.003), and treatment type (ALPPS/TACE) (P = 0.026) were the factors adversely affecting the prognosis of HCC patients. CONCLUSION: ALPPS was feasible in hepatitis B virus-related HCC patients with cirrhosis and resulted in better survival than TACE.

Comparative transcriptomic analysis of the different developmental stages of ovary in red swamp crayfish Procambarus clarkii.

BACKGROUND: The red swamp crayfish Procambarus clarkii is a freshwater species that possesses high adaptability, environmental tolerance, and fecundity. P. clarkii is artificially farmed on a large scale in China. However, the molecular mechanisms of ovarian development in P. clarkii remain largely unknown. In this study, we identified four stages of P. clarkii ovary development, the previtellogenic stage (stage I), early vitellogenic stage (stage II), middle vitellogenic stage (stage III), and mature stage (stage IV) and compared the transcriptomics among these four stages through next-generation sequencing (NGS). RESULTS: The total numbers of clean reads of the four stages ranged from 42,013,648 to 62,220,956. A total of 216,444 unigenes were obtained, and the GC content of most unigenes was slightly less than the AT content. Principal Component Analysis (PCA) and Anosim analysis demonstrated that the grouping of these four stages was feasible, and each stage could be distinguished from the others. In the expression pattern analysis, 2301 genes were continuously increase from stage I to stage IV, and 2660 genes were sharply decrease at stage IV compared to stages I-III. By comparing each of the stages at the same time, four clusters of differentially expressed genes (DEGs) were found to be uniquely highly expressed in stage I (136 genes), stage II (43 genes), stage III-IV (49 genes), and stage IV (22 genes), thus exhibiting developmental stage specificity. Moreover, in comparisons between adjacent stages, the number of DEGs between stage III and IV was the highest. GO enrichment analysis demonstrated that nutrient reservoir activity was highest at stage II and that this played a foreshadowing role in ovarian development, and the GO terms of cell, intracellular and organelle participated in the ovary maturation during later stages. In addition, KEGG pathway analysis revealed that the early development of the ovary was mainly associated with the PI3K-Akt signaling pathway and focal adhesion; the middle developmental period was related to apoptosis, lysine biosynthesis, and the NF-kappa B signaling pathway; the late developmental period was involved with the cell cycle and the p53 signaling pathway. CONCLUSION: These transcriptomic data provide insights into the molecular mechanisms of ovarian development in P. clarkii. The results will be helpful for improving the reproduction and development of this aquatic species.

An insertion variant of MGMT disrupts a STAT1 binding site and confers susceptibility to glioma.

BACKGROUND: O6-methylguanine-DNA methyltransferase (MGMT) is a pivotal enzyme for repairing DNA alkylation damage. Epigenetic modification of MGMT has been well known as a promising prognostic biomarker for glioma. However, the significance of genetic variations of MGMT in glioma carcinogenesis has not been fully elucidated. METHODS: The associations between expression quantitative trait loci (eQTLs) of MGMT and glioma susceptibility were evaluated in a case-control study of 1056 individuals. The function of susceptibility locus for glioma was explored with a set of biochemical assays, including luciferase reporter gene, EMSA and supershift EMSA, ChIP, and siRNA knockdown. RESULTS: We found that rs11016798 TT genotype was associated with a significantly decreased risk of glioma (OR = 0.57, 95% CI 0.39-0.85; P = 0.006). Stratification analyses indicated that the association between rs11016798 and glioma was more pronounced in males (OR = 0.62, 95% CI 0.40-0.97; P = 0.035), older subjects (OR = 0.46, 95% CI 0.27-0.80; P = 0.006), WHO grade IV glioma (OR = 0.58, 95% CI 0.35-0.96; P = 0.033), and IDH wildtype glioma (OR = 0.43, 95% CI 0.21-0.88; P = 0.022). We characterized an insertion variant rs10659396 in the upstream of MGMT as a causative variant. The risk allele rs10659396 ins allele was demonstrated to downregulate MGMT expression by disrupting a STAT1 binding site. Knockdown of STAT1 remarkably attenuated MGMT expression. Moreover, the rs10659396 allele-specific positive correlation was observed between the expression of STAT1 and MGMT in population. CONCLUSIONS: The study demonstrates that an insertion variant of MGMT rs10659396 confers susceptibility to glioma by downregulating MGMT expression through disrupting a STAT1 binding site.

A timed activity protocol to address sleep-wake disorders in home dwelling persons living with dementia: the healthy patterns clinical trial.

BACKGROUND: Sleep-wake disorders occur in most persons living with dementia and include late afternoon or evening agitation, irregular sleep-wake rhythms such as daytime hypersomnia, frequent night awakenings, and poor sleep efficiency. Sleep-wake disorders pose a great burden to family caregivers, and are the principal causes of distress, poor quality of life, and institutionalization. Regulating the sleep-wake cycle through the use of light and activity has been shown to alter core clock processes and suggests that a combination of cognitive, physical, and sensory-based activities, delivered at strategic times, may be an effective mechanism through which to reduce sleep-wake disorders. METHODS: A definitive Phase III efficacy trial of the Healthy Patterns intervention, a home-based activity intervention designed to improve sleep-wake disorders and quality of life, is being conducted using a randomized two-group parallel design of 200 people living with dementia and their caregivers (dyads). Specific components of this one-month, home-based intervention involve 4 in-home visits and includes: 1) assessing individuals' functional status and interests; 2) educating caregivers on environmental cues to promote activity and sleep; and 3) training caregivers in using timed morning, afternoon, and evening activities based on circadian needs across the day. The patient focused outcomes of interest are quality of life, measures of sleep assessed by objective and subjective indicators including actigraphy, subjective sleep quality, and the presence of neuropsychiatric symptoms. Caregiver outcomes of interest are quality of life, burden, confidence using activities, and sleep disruption. Salivary measures of cortisol and melatonin are collected to assess potential intervention mechanisms. DISCUSSION: The results from the ongoing study will provide fundamental new knowledge regarding the effects of timing activity participation based on diurnal needs and the mechanisms underlying timed interventions which can lead to a structured, replicable treatment protocol for use with this growing population of persons living with dementia. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov # NCT03682185 at https://clinicaltrials.gov/ ; Date of clinical trial registration: 24 September 2018.

Enzymatic Tailoring in Luzopeptin Biosynthesis Involves Cytochrome†P450-Mediated Carbon-Nitrogen Bond Desaturation for Hydrazone Formation.

Luzopeptins and related decadepsipeptides are bisintercalator nonribosomal peptides featuring rare acyl-substituted tetrahydropyridazine-3-carboxylic acid (Thp) subunits that are critical to their biological activities. Herein, we reconstitute the biosynthetic tailoring pathway in luzopeptin A biosynthesis through in vivo genetic and in vitro biochemical approaches. Significantly, we revealed a multitasking cytochrome P450 enzyme that catalyzes four consecutive oxidations including the highly unusual carbon-nitrogen bond desaturation, forming the hydrazone-bearing 4-OH-Thp residues. Moreover, we identified a membrane-bound acyltransferase that likely mediates the subsequent O-acetylation extracellularly, as a potential self-protective strategy for the producer strain. Further genome mining of novel decadepsipeptides and an associated P450 enzyme have provided mechanistic insights into the P450-mediated carbon-nitrogen bond desaturation. Our results not only reveal the molecular basis of pharmacophore formation in bisintercalator decadepsipeptides, but also expand the catalytic versatility of P450 family enzymes.

Tumor-associated tissue eosinophilia predicts favorable clinical outcome in solid tumors: a meta-analysis.

BACKGROUND: Activated eosinophils have been deemed to affect carcinogenesis and tumor progression via various mechanisms in tumor microenvironment. However, the prognostic role of tumor-associated tissue eosinophilia (TATE) in human cancers remains controversial. Therefore, we conducted this meta-analysis to better comprehend the association between TATE and clinical outcomes of patients. METHODS: We searched PubMed, Embase and EBSCO to determine the researches assessing the association between TATE and overall survival (OS) and/or disease-free survival (DFS) in patients with cancer, then combined relevant data into hazard ratios (HRs) or odds ratio (OR) for OS, DFS and clinicopathological features including lymph node metastasis etc. with STATA 12.0. RESULTS: Twenty six researches with 6384 patients were included in this meta-analysis. We found that the presence of TATE was significantly associated with improved OS, but not with DFS in all types of cancers. In stratified analyses based on cancer types, pooled results manifested that the infiltration of eosinophils was remarkably associated with better OS in esophageal carcinoma and colorectal cancer. In addition, TATE significantly inversely correlated with lymph node metastasis, tumor stage and lymphatic invasion of cancer. CONCLUSION: TATE promotes survival in cancer patients, suggesting that it is a valuable prognostic biomarker and clinical application of biological response modifiers or agonists promoting TATE may be the novel therapeutic strategy for patients.

Genetic Predisposition to Glioma Mediated by a MAPKAP1 Enhancer Variant.

Mitogen-activated protein kinase-associated protein 1 (MAPKAP1) is a unique component of the mechanistic target of rapamycin (MTOR) pathway which plays a pivotal role in carcinogenesis. The role of enhancer variant in carcinogenesis receives increased attentions. However, the significance of enhancer variants of MAPKAP1 in glioma has not yet been investigated. The associations of enhancer variants of MAPKAP1 with glioma susceptibility were evaluated in a cohort of 400 glioma patients and 651 controls. The function of glioma susceptibility locus was examined by a set of biochemical assays. We found that an enhancer variant of MAPKAP1 rs473426 was associated with a significantly increased risk of glioma in a dominant manner (OR 1.53, 95% CI 1.13-2.06; P = 0.006). The association for rs1339499 located in the same enhancer approached the borderline of significance after multiple testing correction (OR 0.74, 95% CI 0.56-0.98; P = 0.037). Furthermore, cumulative associations of rs473426 and rs1339499 with glioma risk were observed (P = 0.011). Functional analyses showed that the risk allele rs473426 C downregulated the regulatory activity of enhancer by reducing the binding affinity of a transcriptional activator NFΙC, which resulted in lower gene expression both in vitro and in vivo. These results demonstrate for the first time that enhancer variant of MAPKAP1 confers susceptibility to glioma by downregulation of MAPKAP1 expression, and provide further evidence highlighting MAPKAP1 as a cancer suppressor in glioma carcinogenesis.