Discovery of novel anaplastic lymphoma kinase (ALK) and histone deacetylase (HDAC) dual inhibitors exhibiting antiproliferative activity against non-small cell lung cancer.

A series of novel benzimidazole derivatives were designed and synthesised based on the structures of reported oral available ALK inhibitor and HDAC inhibitor, pracinostat. In enzymatic assays, compound 3b, containing a 2-acyliminobenzimidazole moiety and hydroxamic acid side chain, could inhibit both ALK and HDAC6 (IC50 = 16 nM and 1.03 µM, respectively). Compound 3b also inhibited various ALK mutants known to be involved in crizotinib resistance, including mutant L1196M (IC50, 4.9 nM). Moreover, 3b inhibited the proliferation of several cancer cell lines, including ALK-addicted H2228 cells. To evaluate its potential for treating cancers in vivo, 3b was used in a human A549 xenograft model with BALB/c nude mice. At 20 mg/kg, 3b inhibited tumour growth by 85% yet had a negligible effect on mean body weight. These results suggest a attracting route for the further research and optimisation of dual ALK/HDAC inhibitors.

Protective Effects of Jujubosides on 6-OHDA-Induced Neurotoxicity in SH-SY5Y and SK-N-SH Cells.

6-hydroxydopamine (6-OHDA) is used to induce oxidative damage in neuronal cells, which can serve as an experimental model of Parkinson's disease (PD). Jujuboside A and B confer free radical scavenging effects but have never been examined for their neuroprotective effects, especially in PD; therefore, in this study, we aimed to investigate the feasibility of jujubosides as protectors of neurons against 6-OHDA and the underlying mechanisms. 6-OHDA-induced neurotoxicity in the human neuronal cell lines SH-SY5Y and SK-N-SH, was used to evaluate the protective effects of jujubosides. These findings indicated that jujuboside A and B were both capable of rescuing the 6-OHDA-induced loss of cell viability, activation of apoptosis, elevation of reactive oxygen species, and downregulation of the expression levels of superoxide dismutase, catalase, and glutathione peroxidase. In addition, jujuboside A and B can reverse a 6-OHDA-elevated Bax/Bcl-2 ratio, downregulate phosphorylated PI3K and AKT, and activate caspase-3, -7, and -9. These findings showed that jujubosides were capable of protecting both SH-SY5Y and SK-N-SH neuronal cells from 6-OHDA-induced toxicity via the rebalancing of the redox system, together with the resetting of the PI3K/AKT apoptotic signaling cascade. In conclusion, jujuboside may be a potential drug for PD prevention.

[Needs, Dilemmas, and Policy Suggestions Related to Patients With Mental Health Long-Term Care].

In Taiwan, The increase in life expectancy in Taiwan has increased the incidents of age-related problems among patients with mental illness. Therefore, the needs related to long-term care in mental health are significantly important. These needs include: (1) reducing stigmatization; (2) reducing the physical and economic burden of caregivers; (3) constructing a comprehensive, long-term care service system; and (4) developing assessment tools suitable to the long-term care of patients with mental illness. Moreover, six dilemmas in meeting long-term care needs were identified. These dilemmas include: (1) lack of a model of continuous care and of a platform for integrating hospital and community resources; (2) poor / inadequate service quality provided by certain community rehabilitation institutions; (3) the needs of patient/family centered care; (4) the persistence of stigma and misunderstanding; (5) the heavy burdens borne by family members providing long-term care; and (6) the disconnect between subsequent needs and the disability assessment system. Policy suggestions provided in this article include: (1) establish an inclusive platform for mental health long-term care information and resource integration; (2) construct long-term care centers for patients with mental health conditions; (3) train adequate manpower to provide long-term care services to these patients; and (4) promote community inclusiveness for these patients. In order to enter the era of long-term mental health care, government policy should target long-term care programs to meet the needs of patients with mental health conditions. These programs should include seamlessly integrating services into the long-term mental health care system and the care resources of community mental health, developing suitable assessment tools, establishing a multidisciplinary team of long-term care professionals to provide mental health care.

Effectiveness of a Sexual Health Care Training to Enhance Psychiatric Nurses' Knowledge, Attitude, and Self-Efficacy: A Quasi-Experimental Study in Southern Taiwan.

BACKGROUND: Sexual health is a taboo issue in some societies. Limited assessments were conducted during nursing care in mental health services. It is unknown whether psychiatric nurses' competencies would be enhanced through short training courses. OBJECTIVE: The present study employed a quasi-experimental design to evaluate the effectiveness of an 8-hour sexual health care training for psychiatric nurses to improve sexual health knowledge, attitude, and self-efficacy in a teaching psychiatric hospital in southern Taiwan. METHOD: Volunteered psychiatric nurses were randomly assigned to the experimental or control group. The 8-hour training program contained sexual health knowledge and attitudes, case discussion, role play, and sexual identity or harassment issues. Each nurse received a pretest and a posttest in the 1-month period between August and September 2019. Descriptive and multivariate statistical analyses were used to evaluate the effects. RESULTS: Among the 75 psychiatric nurses, 43 were in the control group and 32 were in the experimental group. The two groups were not significantly different in the working year, gender, education, marriage, and other psychosocial variables. After the training, the overall performance of sexual health care knowledge, attitudes, and self-efficacy of the experimental group improved significantly than the controls. CONCLUSIONS: The sexual health care training program enhanced psychiatric nurses' confidence and generally improved their sexual knowledge and attitudes. It is suggested that sexual health care needs to be highlighted during in-job training to augment the well-being and life quality of psychiatric patients.

Protective effects of valproic acid on 6-hydroxydopamine-induced neuroinjury.

Oxidative stress may play critically important roles in the etiology of Parkinson's disease (PD). 6-Hydroxydopamine (6-OHDA) is a physiological neurotoxin reported to induce oxidative-induced apoptosis of dopaminergic neurons in PD mice models. Valproic acid (VPA), a clinical mood stabilizer, is a HDAC inhibitor with neuroprotective capacities. In the study, we aim at examining the feasibility of VPA as a protector for dopaminergic neurons against damage from 6-OHDA, and the intracellular mechanisms. The 6-OHDA-induced neurotoxicity to the human dopaminergic cell line SH-SY5Y was applied for examining VPA protective effects. Pretreatment with VPA was able to improve cell viability and reduce 6-OHDA-induced reactive oxygen species. Furthermore, a significant suppression of apoptotic caspases including cleaved caspase-3, caspase-7, and caspase-9 was observed. The results also revealed VPA decreased the 6-OHDA-induced Bax/Bcl2 ratio, as measured at protein level. These novel findings indicate that VPA may be capable of protecting the SH-SY5Y dopaminergic neuronal cells from 6-OHDA-induced toxicity via the deceasing of apoptotic caspases (cleaved caspase-3, caspase-7, and caspase-9) and reducing of the Bax/Bcl2 ratio. Very possibly, VPA could serve as not only a mood stabilizer but also a potential antidote for PD prevention.

Prostanoid EP4 agonist L-902,688 activates PPARγ and attenuates pulmonary arterial hypertension.

Prostacyclin agonists that bind the prostacyclin receptor (IP) to stimulate cAMP synthesis are effective vasodilators for the treatment of idiopathic pulmonary arterial hypertension (IPAH), but this signaling may occur through nuclear peroxisome proliferator-activated receptor-γ (PPARγ). There is evidence of scant IP and PPARγ expression but stable prostanoid EP4 receptor (EP4) expression in IPAH patients. Both IP and EP4 functionally couple with stimulatory G protein (Gs), which activates signal transduction. We investigated the effect of an EP4-specific agonist on pulmonary arterial remodeling and its regulatory mechanisms in pulmonary arterial smooth muscle cells (PASMCs). Immunoblotting evealed IP, EP4, and PPARγ expression in human pulmonary arterial hypertension (PAH) and monocrotaline (MCT)-induced PAH rat lung tissue. Isolated PASMCs from MCT-induced PAH rats (MCT-PASMCs) were treated with L-902,688, a selective EP4 agonist, to investigate the anti-vascular remodeling effect. Scant expression of IP and PPARγ but stable expression of EP4 was observed in IPAH patient lung tissues and MCT-PASMCs. L-902,688 inhibited IP-insufficient MCT-PASMC proliferation and migration by activating PPARγ in a time- and dose-dependent manner, but these effects were reversed by AH-23848 (an EP4 antagonist) and H-89 [a protein kinase A (PKA) inhibitor], highlighting the crucial role of PPARγ in the activity of this EP4 agonist. L-902,688 attenuated pulmonary arterial remodeling in hypoxic PAH mice and MCT-induced PAH rats; therefore, we conclude that the selective EP4 agonist L-902,688 reverses vascular remodeling by activating PPARγ. This study identified a novel EP4-PKA-PPARγ pathway, and we propose EP4 as a potential therapeutic target for PAH.

[Care of Individuals With Bipolar Disorders].

Bipolar disorder (BD) is a severe mental illness that is characterized by chronicity, pervasive instability, and relatively high rates of recurrence and suicide. Current evidence supports that adverse circles among hereditary and genetic factors, neuroinflamation, and social rhythm constitute a crucial etiology. Pharmacological treatment is the first priority for BD patients during the acute stage. Pharmacological and psychosocial treatments should be combined during the maintenance stage in order to help patients self-manage medication, effectively control mood swings, enhance disease self-management and social functions, decrease the risks of relapse and re-hospitalization, and stabilize overall health. The present article firstly introduces the characteristics and etiological assumptions related to BD, the related evidence-based care models and their effects, and the early development of an evidence-based care model, the BalancingMySwing group, for BD patients in Taiwan. This article provides updated information to clinicians who are involved in caring for this population. Moreover, the existing data related to biological and psychosocial factors for BD in Taiwan is insufficient and developing individual-tailored psychosocial intervention is urgently needed. The authors hope that this article will elicit greater concern for this issue from policy decision-makers and healthcare providers.

[Developing and testing the validity and reliability of the Chinese version attitudes toward mental illness scale in a sample of senior high school students].

BACKGROUND: Public attitudes toward mental illness influence the success with which patients reenter the community. An attitude instrument suitable to the Chinese cultural setting with good reliability and validity is essential to examining public attitudes toward mental illness. Exploring the perspectives of adolescents is relevant because most mental illness occurs during adolescence. PURPOSE: This study developed and tested the psychometric quality of the Chinese-version Attitudes Toward Mental Illness (CAMI) scale among senior high school students. METHODS: The original AMI was translated into Chinese using a back and forth translation method and its content validity was examined. A cross-sectional survey of 479 senior high school students was conducted to assess the construct validity, cross validity, and internal consistency of the CAMI. RESULTS: The CAMI showed adequate content validity. The confirmatory factor analysis support: the appropriateness of CAMI's original two-factor structure of negative attitude and recovery outcomes after deleting items 9 and 11; the measurement of the negative perceptions of mentally ill patients and their risks to community; and the perceptions of recovery of mentally ill patients. The construct validity and cross validity are appropriate and the internal consistency of the total scale and two subscales are acceptable (Cronbach's α: .76, .75, .81). CONCLUSIONS / IMPLICATIONS FOR PRACTICE: The reliability and validity of the CAMI is appropriate for the sample of senior high students in this study. Future studies should target a broader range of people in order to establish the reliability and validity of the scale in different groups and to build up empirical knowledge on public attitudes toward mental illness. The application of this scale is expected to contribute to the development of anti-stigma interventions and to the creation of friendly communities for mentally ill patients.

Non-homologous End-joining Genotype, mRNA Expression, and DNA Repair Capacity in Childhood Acute Lymphocytic Leukemia.

BACKGROUND/AIM: The capacity for non-homologous end-joining (NHEJ) repair plays a pivotal role in maintaining genome stability and in carcinogenesis. However, there is little literature on the involvement of NHEJ-related genes in childhood acute lymphocytic leukemia (ALL). Our study aimed to elucidate the impact of polymorphisms of X-ray repair cross-complementing group 4 (XRCC4) (rs6869366, rs2075685, rs2075686, rs28360071, rs3734091, rs28360317, rs1805377), XRCC5 (rs828907, rs11685387, rs9288518), XRCC6 (rs5751129, rs2267437, rs132770, rs132774), XRCC7 rs7003908, and DNA ligase IV (LIG4) rs1805388, on the odds of childhood ALL. MATERIALS AND METHODS: Genotypes NHEJ-related genes of 266 cases and 266 controls were determined, and the genotype-phenotype correlation was investigated by examining mRNA transcript expression and the capacity for overall and precise NHEJ repair. RESULTS: The variant genotypes of XRCC4 rs3734091, rs28360071, XRCC5 rs828907, and XRCC6 rs5751129 were significantly associated with increased odds of childhood ALL. Further analysis based on susceptibility genotypes showed no significant differences in mRNA transcript expression levels among childhood ALL cases with various putative high-risk genotypes, except XRCC6 rs5751129. Moreover, the overall NHEJ repair capacity was similar among carriers of different XRCC4, XRCC5, and XRCC6 genotypes. However, it is worth noting that individuals carrying the variant C allele at XRCC6 rs5751129 exhibited lower precise NHEJ repair capacity compared to those with the wild-type T allele. CONCLUSION: Our study identified significant associations between XRCC4 rs3734091, rs28360071, XRCC5 rs828907, and XRCC6 rs5751129 genotypes and childhood ALL. Notably, lower transcriptional expression and reduced precise NHEJ repair capacity were observed in patients carrying the C allele of XRCC6 rs5751129. Further investigations are required to gain deeper insights into childhood ALL development.

Exploring the Difficulties and Strategies of Family Caregivers in Caring for Patients With Dementia in Acute Care Wards.

BACKGROUND: Providing appropriate care to patients with dementia in acute care settings can be a challenge for healthcare professionals. A key factor is working closely with family caregivers. PURPOSE: This study aims to explore the difficulties and strategies involved in caring for patients with dementia who have been admitted to an acute care ward from the perspective of family caregivers. METHODS: Exploratory research was conducted using a qualitative data collection approach. Data were collected by means of in-depth interviews carried out with participants. Semistructured interviews were conducted with nine participants. Content analysis was performed to analyze the data. RESULTS: A number of themes and subthemes were identified based on the primary research purposes. The first theme is "vicious cycle due to multiple factors," with the following subthemes: (a) communication disturbance, (b) endless worries, (c) inadequate care skills of paid caregivers, and (d) physical and psychological exhaustion. The second theme is "do everything," with the following subthemes: (a) management of the behavioral and psychological symptoms of dementia, (b) constant accompaniment of the patient, and (c) seeking sources of support. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The results may be used to help healthcare professionals better anticipate the difficulties faced by family caregivers while providing assistance to patients with dementia and understand the related strategies they use. Acute care wards should consider the specific needs of family caregivers to ensure patients with dementia receive adequate care from the relevant parties in the ecological care chain during the care process.