Anti-cancer effects of benzimidazole derivative BNZ-111 on paclitaxel-resistant ovarian cancer.

OBJECTIVE: Ovarian cancer, a leading cause of cancer-related deaths in women, remains a formidable challenge, especially in the context of platinum-resistant disease. This study investigated the potential of the benzimidazole derivative BNZ-111 as a novel treatment strategy for platinum-resistant ovarian cancer. METHODS: The human EOC cell lines A2780, HeyA8, SKOV3ip1, A2780-CP20, HeyA8-MDR, and SKOV3-TR were treated with BNZ-111, and cell proliferation, apoptosis, and cell cycle were assessed. RESULTS: It demonstrated strong cytotoxicity in both chemo-sensitive and chemo-resistant epithelial ovarian cancer cell lines, inducing apoptosis and G2/M cell cycle arrest. In vivo experiments using orthotopic and patient-derived xenograft models showed significant tumor growth inhibition without apparent toxicity to vital organs. Unlike paclitaxel, BNZ-111 proved effective in paclitaxel-resistant cells, potentially by bypassing interaction with MDR1 and modulating ß-3 tubulin expression to suppress microtubule dynamics. CONCLUSION: BNZ-111, with favorable drug-like properties, holds promise as a therapeutic option for platinum-resistant ovarian cancer, addressing a critical clinical need in gynecologic oncology.

Discovery of benzimidazole-2-amide BNZ-111 as new tubulin inhibitor.

Methyl benzimidazole-2-carbamate anthelmintics are a class of oral drugs to treat parasitic worm infections via microtubule disruption for non-systemic indications and currently in use. In order to use for anticancer treatment, the new benzimidazoles needs to improve solubility and pharmacokinetic parameters while maintaining its cellular potency as for systemic drug. Structure-activity-relationship on the benzimidazole is thoroughly examined and a novel benzimidazole-2 propionamide BNZ-111 is identified having good oral exposure and bioavailability in rat. Molecular docking study suggests BNZ-111 have a specific binding mode to the ß subunit of curved tubulin. BNZ-111 is potent to cancer cells and possesses good drug-like properties as oral drug. Especially, BNZ-111 is not a P-gp substrate and it demonstrates its efficacy over Paclitaxel-resistance tumor in vivo.

Novel allosteric glutaminase 1 inhibitors with macrocyclic structure activity relationship analysis.

Glutamine-addicted cancer metabolism is recently recognized as novel cancer target especially for KRAS and KEAP1 co-occurring mutations. Selective glutaminase1 (GLS1) inhibition was reported using BPTES which has novel mode of allosteric inhibition. However, BPTES is a highly hydrophobic and symmetric molecule with very poor solubility which results in suboptimal pharmacokinetic parameters and hinders its further development. As an ongoing effort to identify more drug-like GLS1 inhibitors via systematic structure - activity relationship (SAR) analysis of BPTES analogs, we disclose our novel macrocycles for GLS1 inhibition with conclusive SAR analysis on the core, core linker, and wing linker, respectively. Selected molecules resulted in reduction in intracellular glutamate levels in LR (LDK378-resistant) cells which is consistent to cell viability result. Finally, compounds 13 selectively reduced the growth of A549 and H460 cells which have co-occurring mutations including KRAS and KEAP1.

A mobile app to predict and manage behavioral and psychological symptoms of dementia: Development, usability, and users' acceptability.

Objective: Non-pharmacological interventions are considered the first-line treatment for behavioral and psychological symptoms of dementia (BPSD); however, traditional approaches have shown only small effect sizes. Mobile technology offers an opportunity to improve BPSD assessment and management in people living with dementia (PLWD). We aimed (1) to develop a mobile application (app) featuring a real-time BPSD diary, machine-learning-based BPSD prediction, and individualized non-pharmacological care programs, including therapeutic use of music and reminiscent content, and (2) to test its usability, acceptability, and preliminary efficacy among PLWD and caregivers. Methods: An Android-based app was developed through the following three phases: (1) needs assessment, (2) software development and initial testing with experts, and (3) beta-testing with end users who were dyads of PLWD and caregivers. The preliminary efficacy, usability, and acceptability of the app were assessed using validated BPSD questionnaires and face-to-face interviews with the dyads. Logs of the dyads' program participation (i.e., types, time, and duration), BPSD diaries, and engagement levels of PLWD were also collected through the app. Results: Five dyads created BPSD diaries (range: 22-48) over 3 weeks. Overall, the BPSD symptoms decreased after the beta-testing period. Each dyad participated in the care programs for 106-204 min, during which music alone was most frequently used. Engagement levels ranged from 3.38 to 4.94 (out of 5). Conclusions: The app was deemed usable, acceptable, and feasible for PLWD and caregivers. The upgraded app will be further tested and can be easily implemented at home or in the community.

Symptom-specific non-pharmacological interventions for behavioral and psychological symptoms of dementia: An umbrella review.

BACKGROUND: Non-pharmacological interventions are considered the first-line treatment for managing the behavioral and psychological symptoms of dementia. Given the heterogeneous characteristics of these symptoms, which vary for each individual and tend to fluctuate, a symptom-specific approach is necessary for providing individualized non-pharmacological interventions for people with dementia. However, clear guidelines regarding the appropriate types of interventions for individual symptoms or clusters of behavioral and psychological symptoms of dementia are lacking. OBJECTIVES: The aim of this umbrella review was to summarize the current evidence on non-pharmacological interventions for behavioral and psychological symptoms of dementia and provide guidance for determining the appropriate types of interventions for each behavioral and psychological symptom of dementia. DESIGN: An umbrella review of systematic reviews and/or meta-analyses. METHODS: The Cochrane methodology for umbrella reviews was employed for this review, and the review protocol was registered. PubMed, CINAHL, Embase, PsycINFO, and Cochrane databases were searched for relevant reviews using the 'population, intervention, control, and outcomes' formulation. Two reviewers independently screened the extracted articles for eligibility. The quality of each selected review was independently assessed by the two reviewers using A Measurement Tool to Assess Systematic Reviews 2. The results were narratively synthesized and categorized according to each symptom. RESULTS: Thirty-five systematic reviews, 71 % of which were also meta-analyses, were included in this review. The methodologies employed in the included reviews were significantly heterogeneous. The qualities of the reviews ranged from low to moderate. Diverse types of non-pharmacological interventions were identified in the reviews, with music therapy being the most frequently discussed. Among the various symptoms, depression was most frequently addressed, followed by overall symptoms, agitation, anxiety, sleep problems, and apathy. Music therapy was found to be effective for improving both overall and specific symptoms, including depression and anxiety. Notably, relatively weak evidence supports the effectiveness of exercise in addressing each symptom. Aromatherapy could be considered for agitation, whereas reminiscence may be effective in managing overall and specific symptoms, such as depression. CONCLUSIONS: The results showed that the evidence of symptom-specific effectiveness of non-pharmacological interventions varied across the different behavioral and psychological symptoms of dementia, highlighting the need for a symptom-specific approach in future research. Furthermore, future research is needed to facilitate the development of symptom-specific guidelines that can enhance the quality of individualized dementia care. REGISTRATION: Registered with PROSPERO (number: CRD42022340930) on November 9, 2022.

Symptom-specific non-pharmacological interventions for behavioural and psychological symptoms of dementia: protocol of an umbrella review of systematic reviews of randomised controlled trials.

INTRODUCTION: There are various non-pharmacological interventions for dementia care. However, healthcare providers continue to face challenges in determining the most suitable interventions for the behavioural and psychological symptoms of dementia (BPSD), which vary according to individuals. This umbrella review aims to identify and summarise the effective non-pharmacological interventions for each sub-symptom to provide individualised, evidence-based recommendations for clinical practice. METHODS AND ANALYSIS: This review follows the guideline of the Cochrane methodology for umbrella reviews. It focuses only on systematic reviews (SRs) with or without a meta-analysis of randomised controlled trials. Five electronic databases: PubMed, Cumulative Index to Nursing and Allied Health Literature, Embase, PsycINFO and Cochrane Database, will be searched. The screened SRs will be determined for eligibility by the PICO formulation: (Population) older adults with dementia of any type; (Intervention) all types of non-pharmacological intervention; (Comparison) usual care or other non-pharmacological intervention; and (Outcome) BPSD and its sub-symptoms. The quality of the individual SRs will be appraised using A Measurement Tool to Assess Systematic Reviews 2. The overlap of primary studies will also be considered by eliminating an old-date SR conducted by the same authors with the same interest and calculating the Corrected Covered Area. Data will be extracted according to the pre-determined formula, which will organise non-pharmacological interventions according to the sub-symptoms of BPSD and not according to the type of intervention. ETHICS AND DISSEMINATION: Since this is a review paper, ethical approval is not required. The findings of this review will be disseminated through publication in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42022340930.

The effectiveness of non-pharmacological interventions using information and communication technologies for behavioral and psychological symptoms of dementia: A systematic review and meta-analysis.

BACKGROUND: Although behavioral and psychological symptoms of dementia are a global public health challenge, non-pharmacological interventions using information and communication technologies can be an affordable, cost-effective, and innovative solution. OBJECTIVES: This study aimed to examine the effectiveness of non-pharmacological interventions using information and communication technologies on the behavioral and psychological symptoms of dementia and identify potential moderators of intervention effects. DESIGN: Systematic review and meta-analysis of randomized controlled trials. METHODS: A systematic literature review was conducted using PubMed, CINAHL, PsycINFO, Embase, and the Cochrane Library from May 2022. Randomized controlled trials that examined the effects of non-pharmacological interventions using information and communication technologies on the behavioral and psychological symptoms of dementia were included. A meta-analysis using a random-effects model was performed to calculate the pooled standardized mean differences between overall symptoms and each type of symptom. For moderator analyses, subgroup and meta-regression analyses were performed. RESULTS: Sixteen trials (15 articles) met the eligibility criteria. The interventions were grouped into activity engagement interventions using digital health that provided music and reminiscence therapy, physical exercise, social interaction interventions using social robots, and telehealth-based care aid interventions that provided coaching or counseling programs. Pooled evidence demonstrated that non-pharmacological interventions using information and communication technologies exerted a large effect on depression (SMD = -1.088, 95% CI -1.983 to -0.193, p = 0.017), a moderate effect on overall behavioral and psychological symptoms of dementia (SMD = -0.664, 95% CI -0.990 to -0.338, p < 0.001), and agitation (SMD = -0.586, 95% CI -1.130 to -0.042, p = 0.035). No effects on neuropsychiatric symptoms (SMD = -0.251, 95% CI -0.579 to 0.077, p = 0.133), anxiety (SMD = -0.541, 95% CI -1.270 to 0.188, p = 0.146), and apathy (SMD = -0.830, 95% CI -1.835 to 0.176, p = 0.106) were reported. Moderator analyses identified the mean age of the participants as a potential moderator of intervention effects. CONCLUSIONS: Evidence from this systematic review and meta-analysis suggests that non-pharmacological interventions, using information and communication technologies, were an applicable approach to managing behavioral and psychological symptoms among older adults with dementia, with moderate to large effect sizes. However, evidence on anxiety and apathy is inconclusive due to the limited number of existing randomized controlled trials. Future studies with subgroup analyses are warranted to conclude the most effective types of intervention using information and communication technologies for each type of symptom. REGISTRATION: CRD42021258498.

Perceived Work Environment, Educational Status, Staffing Levels, and Work Outcomes in Long-Term Care Settings During COVID-19.

OBJECTIVES: Coronavirus disease (COVID-19) has severely affected older residents in long-term care (LTC) settings. However, care workers' perceptions of their work environment and potential impact on their work outcomes during the pandemic is not well known. This study examined associations between care staff's perceived work environment, educational status, and facility staffing levels and work outcomes of care staff in LTC settings during the COVID-19 pandemic. DESIGN: This study employed a cross-sectional, observational, correlational design. SETTING AND PARTICIPANTS: A total of 207 care staff were conveniently recruited from 30 LTC settings in South Korea. METHODS: The perceived work environment, educational status of care staff, and facility staffing levels (ie, beds-to-registered nurse [RN] and beds-to-nursing assistant [NA] or care worker ratios), as well as their work outcomes (ie, general and COVID-19 specific outcomes) were collected using questionnaires. Multivariable binary logistic regressions were conducted, controlling for the characteristics of care staff (ie, age, sex, occupation, and career length) and facilities (ie, location, bed size, ownership, and residents' disease and care profiles). RESULTS: Approximately 45% of the participants were either NAs or care workers, and 38% were RNs. More than half (53.14%) perceived their work environment to be good. LTC staff who perceived their work environment to be poor were more likely to be dissatisfied with their work [odds ratio (OR) 20.88), experience high burnout (OR 8.63), intend to leave the facility within a year (OR 5.00), and experience increased overtime work (OR 3.58) and work-life imbalance (OR 1.93) due to COVID-19. CONCLUSIONS AND IMPLICATIONS: LTC work environments should be improved and government-led initiatives for ensuring such improvements should be implemented to enable a better response to future public health crises and maintain the quality of care for and safety of residents in LTC settings.

The effects of special nursing units in nursing homes on healthcare utilization and cost: A case-control study using propensity score matching.

BACKGROUND: Most nursing homes in South Korea lack professional nursing services, resulting in transporting residents to hospitals for mild health problems and nursing treatment needs. While the number of nursing homes has increased, the number of registered nurses working in nursing homes has declined. In 2019, the Korean Ministry of Health and Welfare and the National Health Insurance Service launched the Special Nursing Units in Nursing Homes, a pilot nurse-led model, to resolve the lack of health and nursing services in nursing homes by mandating registered nurses' minimum staffing levels and protecting their scope of practice. OBJECTIVE: This study explored the effects of the Special Nursing Units model in Nursing Homes on healthcare utilization and cost among nursing home residents. DESIGN: A comparative effectiveness research design using propensity score matching. SETTING(S): Eighteen nursing homes were selected based on the region and number of beds. PARTICIPANTS: There were 323 matched-pairs of residents from the case and control groups. METHODS: Nursing homes with more than 30 beds were recruited nationwide, with 18 nursing homes being selected based on the region and number of beds. The case group included 323 older adults receiving professional nursing services by registered nurses under the Special Nursing Units model in Nursing Homes for more than six months consecutively in 18 nursing homes between April and December 2019. We matched control participants using propensity score matching with health insurance and long-term care data. We analyzed the differences in healthcare utilization and cost changes between the case and control groups using generalized estimating equations. RESULTS: The groups were not statistically different in baseline demographic or health-related characteristics. There were 26 (8.1%) and 30 (9.3%) deaths in the case and control groups, respectively, during the six months of the model, which was not statistically different (p = .576). The case group showed statistically significant decreases in healthcare utilization and costs, including hospitalization frequency (p = .008), length of stay (p = .002), and hospitalization costs (p = .003); outpatient visit frequency (p = .003) and costs (p < .001); and home healthcare frequency (p < .001) and cost (p < .001) than the control group. CONCLUSIONS: Professional nursing services by registered nurses under the Special Nursing Units model in Nursing Homes decreased healthcare utilization and costs. A nurse-led model in nursing homes, which includes mandating the minimum staffing levels of registered nurses and protecting their scope of practice, promises to improve resident health outcomes.

Effectiveness of eHealth interventions targeted to improve medication adherence among older adults with mild cognitive impairment: a protocol for a systematic review and meta-analysis.

INTRODUCTION: Medication adherence is a vital component of successful healthcare, yet poor adherence exists, especially in older adults with mild cognitive impairment. Therefore, this study seeks to conduct a systematic review of eHealth-based interventions aimed at improving medication adherence among older adults with mild cognitive impairment. METHODS AND ANALYSIS: An open electronic database search will be conducted in PubMed, CINAHL, PsycINFO, EMBASE and Cochrane library to identify potential studies till 2022. Two authors will independently screen the titles and abstracts, after which studies that will be eligible for full-text review will be independently assessed by two reviewers for inclusion. Studies will be selected if they evaluate eHealth interventions aiming to improve medication adherence among older adults with mild cognitive impairment. Data will be analysed by using the Comprehensive Meta-Analysis software V.3 and Review Manager (RevMan) software V.5. The authors will separately analyse each outcome measure, compute intervention effects and present them as relative risks with 95% CIs for dichotomous data. Continuous data will be presented as mean differences and standardised mean differences (if required) with 95% CIs. If substantive statistical heterogeneity is identified, we will consider the use of random-effects models that can be incorporated into the statistical analysis. We envisage that this review will adduce evidence on eHealth interventions that will improve medication adherence among older adults with mild cognitive impairment. The findings can also inform health professionals and other relevant stakeholders on current eHealth-based interventions that are used to improve medication adherence among older adults with mild cognitive impairment. ETHICS AND DISSEMINATION: Ethical approval is not required for systematic reviews. Findings will be disseminated widely through peer-reviewed publication and at conferences. PROSPERO REGISTRATION NUMBER: CRD42021268665.

The Value of MicroRNAs as an Indicator of the Severity and the Acute Phase of Spinal Cord Injury.

OBJECTIVE: To assess the role of miRNA-21 and miRNA-223 in a balloon-compression model of spinal cord injury (SCI). METHODS: A total of 50 male Wistar rats (n=50) were divided into the three groups: the group A (n=15, insertion of the unflated Fogarty balloon catheter), the group B (n=15, insertion of the Fogarty balloon catheter at a volume of 20 µL) and the group C (n=15, insertion of the Fogarty balloon catheter at a volume of 50 µL). After the behavioral test, RNA isolation, microRNA expression profiling using microarrays and quantitative polymerase chain reaction, measurements were compared between the three groups. RESULTS: Despite a lack of significant differences in time-dependent changes in miRNA-21 expression levels between the three groups at 4 hours, there were significant differences in them at 1, 3, and 7 days (p<0.05). Moreover, there were significant differences in time-dependent changes in miRNA-223 expression levels between the three groups at 4 hours and 1, 3, and 7 days (p<0.05). Furthermore, miRNA-223 expression levels reached the highest at 1 day but were decreased with time thereafter in all the three groups. CONCLUSION: Expression levels of miRNA-21 and miRNA-223 might be associated with the severity and acute phase of SCI, respectively. It is mandatory, however, to analyze changes in levels of inflammatory markers and the relevant biological pathways.