TM4SF1 is a molecular facilitator that distributes cargo proteins intracellularly in endothelial cells in support of blood vessel formation.

Transmembrane-4 L-six family member-1 (TM4SF1) is an atypical tetraspanin that is highly and selectively expressed in proliferating endothelial cells and plays an essential role in blood vessel development. TM4SF1 forms clusters on the cell surface called TMED (TM4SF1-enriched microdomains) and recruits other proteins that internalize along with TM4SF1 via microtubules to intracellular locations including the nucleus. We report here that tumor growth and wound healing are inhibited in Tm4sf1-heterozygous mice. Investigating the mechanisms of TM4SF1 activity, we show that 12 out of 18 signaling molecules examined are recruited to TMED on the surface of cultured human umbilical vein endothelial cells (HUVEC) and internalize along with TMED; notable among them are PLCγ and HDAC6. When TM4SF1 is knocked down in HUVEC, microtubules are heavily acetylated despite normal levels of HDAC6 protein, and, despite normal levels of VEGFR2, are unable to proliferate. Together, our studies indicate that pathological angiogenesis is inhibited when levels of TM4SF1 are reduced as in Tm4sf1-heterozygous mice; a likely mechanism is that TM4SF1 regulates the intracellular distribution of signaling molecules necessary for endothelial cell proliferation and migration.

In vivo gene delivery to immune cells.

Immune cell therapies are an emerging class of living drugs that rely on the delivery of therapeutic transgenes to enhance, modulate, or restore cell function, such as those that encode for tumor-targeting receptors or replacement proteins. However, many cellular immunotherapies are autologous treatments that are limited by high manufacturing costs, typical vein-to-vein time of 3-4 weeks, and severe immune-related adverse effects. To address these issues, different classes of gene delivery vehicles are being developed to target specific immune cell subsets in vivo to address the limitations of ex vivo manufacturing, modulate therapeutic responses in situ, and reduce on- and off-target toxicity. The success of in vivo gene delivery to immune cells - which is being tested at the preclinical and clinical stages of development for the treatment of cancer, infectious diseases, and autoimmunity - is paramount for the democratization of cellular immunotherapies.

Quantifying the Healthcare Burden of Pediatric Feeding Disorder after Congenital Heart Surgery.

OBJECTIVE: To determine the healthcare costs and use burden of pediatric feeding disorder after congenital heart surgery. STUDY DESIGN: A retrospective, population-based cohort study using claims data (2009-2018) was performed. Participants include patients aged 0-18 years who had undergone congenital heart surgery and were included in the insurance database ≥1 year after surgery. The main exposure variable was the presence of a pediatric feeding disorder, defined as a need for a feeding tube at discharge or diagnosis of dysphagia or feeding-related difficulty within the study timeframe. Main outcomes include overall and feeding-related medical care use, defined as readmissions and outpatient use, and feeding-related cost of care within 1 year of surgery. RESULTS: A total of 10 849 pediatric patients were identified, with 3347 (30.9%) presenting with pediatric feeding disorder within 1 year of surgery. Patients with pediatric feeding disorder spent a median of 12 days (IQR, 6-33 days) in the hospital, compared with 5 days (IQR, 3-8 days) in patients without (P < .001). Rate ratios for overall readmissions, feeding-related readmissions, feeding-related outpatient use, and cost of care over the first year after surgery were significantly increased at 2.9 (95% CI, 2.5-3.4), 5.1 (95% CI, 4.6-5.7), 7.7 (95% CI, 6.5-9.1), and 2.2 (95% CI, 2.0-2.3) among patients with pediatric feeding disorder as compared with those without. CONCLUSIONS: Pediatric feeding disorder after congenital heart surgery is associated with a significant healthcare burden. Multidisciplinary care for and research on this health condition is needed to identify optimal management strategies to reduce this burden and improve outcomes.

Virtual management of hypertension: lessons from the COVID-19 pandemic-International Society of Hypertension position paper endorsed by the World Hypertension League and European Society of Hypertension.

The coronavirus disease 2019 pandemic caused an unprecedented shift from in person care to delivering healthcare remotely. To limit infectious spread, patients and providers rapidly adopted distant evaluation with online or telephone-based diagnosis and management of hypertension. It is likely that virtual care of chronic diseases including hypertension will continue in some form into the future. The purpose of the International Society of Hypertension's (ISH) position paper is to provide practical guidance on the virtual management of hypertension to improve its diagnosis and blood pressure control based on the currently available evidence and international experts' opinion for nonpregnant adults. Virtual care represents the provision of healthcare services at a distance with communication conducted between healthcare providers, healthcare users and their circle of care. This statement provides consensus guidance on: selecting blood pressure monitoring devices, accurate home blood pressure assessments, delivering patient education virtually, health behavior modification, medication adjustment and long-term virtual monitoring. We further provide recommendations on modalities for the virtual assessment and management of hypertension across the spectrum of resource availability and patient ability.

Adoption of healthy lifestyles among Chinese cancer survivors during the first five years after completion of treatment.

Objectives: The number of cancer survivors is increasing as a result of advances in detection and treatment. Lifestyle is a significant modifiable factor in the development of cancer. Most studies on healthy lifestyles have been conducted in Western countries. Cultural influences on the pursuit of healthy lifestyles among Chinese cancer survivors remain largely unexplored. The objectives of this qualitative study are to explore the experiences of Chinese cancer survivors in adopting healthy lifestyles, with a focus on their goals, the challenges they face, and the influences of Chinese culture.Design: Thirty-two Chinese breast and colorectal cancer survivors in their first five years after treatment were recruited from a hospital in Hong Kong to participate in eight focus groups. Qualitative content analysis was adopted to analyse the data.Results: The adoption of a healthy lifestyle was a strategy through which the participants exercised choice to restore balance in their health after developing cancer. Diet, exercise, psychological well-being, the use of traditional Chinese medicine (TCM) and health/dietary supplements, and attending medical consultations/follow-up visits were the behaviours adopted by the participants, with the goal of improving their health, controlling their cancer and preventing relapse, and managing the residual physical symptoms of their illness. In adopting a healthy lifestyle, the participants encountered challenges such as a lack of reliable and practical instructions from healthcare professionals. Chinese cultural beliefs concerning the nature of food, TCM, minimizing social disturbances, and collaborative control influenced their lifestyle.Conclusions: The cancer survivors adopted a range of healthy lifestyles but encountered challenges. Clarifying the principles of food choice while addressing Chinese beliefs regarding therapeutic food and the use of TCM, clarifying queries about conflicting information, and developing plans according to the needs, and competing demands of survivors can facilitate collaborative control between healthcare professionals and cancer survivors.

Sarcopenia Is Associated with Mortality in Adults: A Systematic Review and Meta-Analysis.

BACKGROUND: Sarcopenia can predispose individuals to falls, fractures, hospitalization, and mortality. The prevalence of sarcopenia depends on the population studied and the definition used for the diagnosis. OBJECTIVE: This systematic review and meta-analysis aimed to investigate the association between sarcopenia and mortality and if it is dependent on the population and sarcopenia definition. METHODS: A systematic search was conducted in MEDLINE, EMBASE, and Cochrane from 1 January 2010 to 6 April 2020 for articles relating to sarcopenia and mortality. Articles were included if they met the following criteria - cohorts with a mean or median age ≥18 years and either of the following sarcopenia definitions: Asian Working Group for Sarcopenia (AWGS and AWGS2019), European Working Group on Sarcopenia in Older People (EWGSOP and EWGSOP2), Foundation for the National Institutes of Health (FNIH), International Working Group for Sarcopenia (IWGS), or Sarcopenia Definition and Outcomes Consortium (SDOC). Hazard ratios (HR) and odds ratios (OR) were pooled separately in meta-analyses using a random-effects model, stratified by population (community-dwelling adults, outpatients, inpatients, and nursing home residents). Subgroup analyses were performed for sarcopenia definition and follow-up period. RESULTS: Out of 3,025 articles, 57 articles were included in the systematic review and 56 in the meta-analysis (42,108 participants, mean age of 49.4 ± 11.7 to 86.6 ± 1.0 years, 40.3% females). Overall, sarcopenia was associated with a significantly higher risk of mortality (HR: 2.00 [95% CI: 1.71, 2.34]; OR: 2.35 [95% CI: 1.64, 3.37]), which was independent of population, sarcopenia definition, and follow-up period in subgroup analyses. CONCLUSIONS: Sarcopenia is associated with a significantly higher risk of mortality, independent of population and sarcopenia definition, which highlights the need for screening and early diagnosis in all populations.

Sarcopenia is associated with 3-month and 1-year mortality in geriatric rehabilitation inpatients: RESORT.

BACKGROUND: Sarcopenia is highly prevalent in geriatric rehabilitation patients and can worsen prognosis. This study aimed to investigate the association of sarcopenia and components of sarcopenia with 3-month and 1-year post-discharge mortality in geriatric rehabilitation inpatients. METHODS: REStORing health of acutely unwell adulTs (RESORT) is an observational, prospective longitudinal cohort of geriatric rehabilitation inpatients. Sex-stratified Cox proportional-hazards analyses were used to associate sarcopenia (and its components) at admission, by the European Working Group on Sarcopenia in Older People (EWGSOP, EWGSOP2) and the Asian Working Group for Sarcopenia 2019 (AWGS 2019), with 3-month and 1-year post-discharge all-cause mortality. RESULTS: Patients (n = 1,406) had a median interquartile ranges [IQR] age of 83.0 [77.4-88.2] years (58% females). Sarcopenia was significantly associated with 3-month and 1-year mortality in females (EWGSOP, EWGSOP2 and AWGS 2019) and males (EWGSOP2, AWGS 2019). In females, low muscle mass (EWGSOP, EWGSOP2 and AWGS 2019) was significantly associated with 3-month and 1-year mortality; low muscle strength (EWGSOP, EWGSOP2 and AWGS 2019) was significantly associated with 1-year mortality. For males, low muscle mass (EWGSOP2, AWGS 2019) was significantly associated with 3-month and 1-year mortality; low muscle strength (EWGSOP2, AWGS 2019) was significantly associated with 3-month mortality. The association between physical performance with mortality was not analysed due to less than five events (death) in patients with normal physical performance. CONCLUSIONS: Sarcopenia, low muscle mass and low muscle strength at admission are associated with a significantly higher risk of mortality post-discharge from geriatric rehabilitation, highlighting the need to measure muscle mass and strength in clinical practice.

Risk Factors of Readmissions in Geriatric Rehabilitation Patients: RESORT.

OBJECTIVE: To evaluate the risk factors associated with 30- and 90-day hospital readmissions in geriatric rehabilitation inpatients. DESIGN: Observational, prospective longitudinal inception cohort. SETTING: Tertiary hospital in Victoria, Australia. PARTICIPANTS: Geriatric rehabilitation inpatients of the REStORing Health of Acutely Unwell AdulTs (RESORT) cohort evalutated by a comprehensive geriatric assessment including potential readmission risk factors (ie, demographic, social support, lifestyle, functional performance, quality of life, morbidity, length of stay in an acute ward). Of 693 inpatients, 11 died during geriatric rehabilitation. The mean age of the remaining 682 inpatients was 82.2±7.8 years, and 56.7% were women. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Thirty- and 90-day readmissions after discharge from geriatric inpatient rehabilitation. RESULTS: The 30- and 90-day unplanned all-cause readmission rates were 11.6% and 25.2%, respectively. Risk factors for 30- and 90-day readmissions were as follows: did not receive tertiary education, lower quality of life, higher Charlson Comorbidity Index and Cumulative Illness Rating Scale (CIRS) scores, and a higher number of medications used in the univariable models. Formal care was associated with increased risk for 90-day readmissions. In multivariable models, CIRS score was a significant risk factor for 30-day readmissions, whereas high fear of falling and CIRS score were significant risk factors for 90-day readmissions. CONCLUSIONS: High fear of falling and CIRS score were independent risk factors for readmission in geriatric rehabilitation inpatients. These variables should be included in hospital readmission risk prediction model developments for geriatric rehabilitation inpatients.

Feeding outcomes after paediatric cardiothoracic surgery: a retrospective review.

BACKGROUND: Feeding difficulty is a known complication of congenital heart surgery. Despite this, there is a relative sparsity in the available data regarding risk factors, incidence, associated symptoms, and outcomes. METHODS: In this retrospective chart review, patients aged 0-18 years who underwent congenital heart surgery at a single institution between January and December, 2017 were reviewed. Patients with feeding difficulties before surgery, multiple surgeries, and potentially abnormal recurrent laryngeal nerve anatomy were excluded. Data collected included patient demographics, feeding outcomes, post-operative symptoms, flexible nasolaryngoscopy findings, and rates of readmission within a 1-year follow-up period. Multivariable regression analyses were performed to evaluate the risk of an alternative feeding plan at discharge and length of stay. RESULTS: Three-hundred and twenty-six patients met the inclusion criteria for this study. Seventy-two (22.09%) were discharged with a feeding tube and 70 (97.22%) of this subgroup were younger than 12 months at the time of surgery. Variables that increased the risk of being discharged with a feeding tube included patient age, The Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery score, procedure group, aspiration, and reflux. Speech-language pathology was the most frequently utilised consulting service for patients discharged with feeding tubes (90.28%) while other services were not frequently consulted. The median length of stay was increased from 4 to 10 days for patients who required an enteral feeding tube at discharge. DISCUSSION: Multidisciplinary management protocol and interventions should be developed and standardised to improve feeding outcomes following congenital heart surgery.

Social Isolation and Loneliness in the Hearing-Impaired Pediatric Population: A Scoping Review.

OBJECTIVE: To review existing publications in order to evaluate the effect of hearing loss on social isolation and loneliness in the pediatric population. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Review (PRISMA-ScR) guidelines were followed. Eight databases were searched. Studies were independently screened and analyzed by two reviewers. Publications were included if pediatric hearing-impaired individuals and social isolation or loneliness were studied. Discrepancies were resolved by a team of five reviewers. RESULTS: Thirty-three studies were included in this review. Sixty percent of studies (12/20) found that hearing loss was related to loneliness and 64.7% found that children with hearing loss experienced more social isolation (11/17). The Asher Loneliness and Dissatisfaction Questionnaire was commonly used to assess loneliness. No commonly used tool for assessing social isolation was found. Six articles found that school type was not associated with loneliness. Difficulty communicating was the most mentioned factor leading to loneliness and social isolation. Frequent recommendations to improve social integration included facilitating interactions with the hearing-impaired and educating the nonhearing-impaired to normalize the disability. CONCLUSION: The majority of studies found that hearing impairment results in a higher prevalence of social isolation and loneliness. However, an association cannot be definitively claimed due to the lack of uniform assessment tools. This review emphasizes the need for standardized methods to assess loneliness and social isolation and highlights methods to improve social integration for the hearing impaired. Laryngoscope, 131:1869-1875, 2021.

A Celecoxib Derivative Eradicates Antibiotic-Resistant Staphylococcus aureus and Biofilms by Targeting YidC2 Translocase.

The treatment of Staphylococcus aureus infections is impeded by the prevalence of MRSA and the formation of persisters and biofilms. Previously, we identified two celecoxib derivatives, Cpd36 and Cpd46, to eradicate MRSA and other staphylococci. Through whole-genome resequencing, we obtained several lines of evidence that these compounds might act by targeting the membrane protein translocase YidC2. Our data showed that ectopic expression of YidC2 in S. aureus decreased the bacterial susceptibility to Cpd36 and Cpd46, and that the YidC2-mediated tolerance to environmental stresses was suppressed by both compounds. Moreover, the membrane translocation of ATP synthase subunit c, a substrate of YidC2, was blocked by Cpd46, leading to a reduction in bacterial ATP production. Furthermore, we found that the thermal stability of bacterial YidC2 was enhanced, and introducing point mutations into the substrate-interacting cavity of YidC2 had a dramatic effect on Cpd36 binding via surface plasmon resonance assays. Finally, we demonstrated that these YidC2 inhibitors could effectively eradicate MRSA persisters and biofilms. Our findings highlight the potential of impeding YidC2-mediated translocation of membrane proteins as a new strategy for the treatment of bacterial infections.

The Malay version of smartphone addiction scale: Development, factor structure and validation of a short form for Malaysian adolescents.

INTRODUCTION: This study aimed to validate the Malay version of the short form Smartphone Addiction Scale (SAS-M-SF) and to examine its psychometric properties in a cohort of pre-university adolescents. METHODS: We obtained the validity and reliability evidence for the SAS-M-SF using a group of 307 pre-university students in Universiti Putra Malaysia (UPM), Serdang, Selangor, Malaysia with a mean age of 18.4±0.2 years (70.4% female and 29.6% male). A questionnaire containing the Malay version of Smartphone Addiction Scale (SAS-M), the Malay version of the short form Smartphone Addiction Scale (SAS-M-SF), and the Malay version of the Internet Addiction Test (IAT-M) was administered on the adolescents. RESULTS: The SAS-M-SF displayed good internal consistency (Cronbach's α=0.80). Using principle component analysis, we identified a 4-factor SAS-M-SF model. A significant correlation between the SAS-M-SF and the IAT-M was found, lending support for concurrent validity. The prevalence of smartphone addiction was 54.5% based on cut-off score of ≥36 with a sensitivity of 70.2% and a specificity of 72.5%. CONCLUSIONS: The 10-item SAS-M-SF is a valid and reliable screening tool for smartphone addiction among adolescents. The scale can help clinicians or educators design appropriate intervention and prevention programs targeting smartphone addiction in adolescents at clinical or school settings.

A survey on smartphone dependence and psychological effects among undergraduate students in a Malaysian University.

OBJECTIVE: Problematic smartphone use (PSU) is the development of pathological dependence at the expense of performing activities of daily living, thus having negative health and psychological impact on the users. Previous PSU studies focused on medical students and little is known regarding its effect on students undergoing other courses. The objective of this study is to identify the pattern of smartphone usage and determine the psychological factors affecting PSU among undergraduate students in Malaysia and compare the pattern among students from different fields of study. METHOD: A prospective cross-sectional study was conducted using the validated Smartphone Addiction Scale-Malay version (SAS-M) questionnaire. One-way ANOVA was used to determine the correlation between the PSU among the students categorised by their ethnicity, hand dominance and by their field of study. MLR analysis was applied to predict PSU based on socio-demographic data, usage patterns, psychological factors and fields of study. RESULTS: A total of 1060 students completed the questionnaire. Most students had some degree of problematic usage of the smartphone. Students used smartphones predominantly to access SNAs, namely Instagram. Longer duration on the smartphone per day, younger age at first using a smartphone and underlying depression carried higher risk of developing PSU, whereas the field of study (science vs. humanities based) did not contribute to an increased risk of developing PSU. CONCLUSION: Findings from this study can help better inform university administrators about at- risk groups of undergraduate students who may benefit from targeted intervention designed to reduce their addictive behaviour patterns.

Does primary closure of direct inguinal hernia defect during laparoscopic mesh repair reduce the risk of early recurrence?

PURPOSE: Hernia recurrence is an important complication following inguinal hernia repair. Primary closure of ventral hernia defects laparoscopically has been shown to reduce the risk of recurrence and seroma formation. The results for ventral hernias may potentially be applied to direct inguinal hernias. Our aim was to evaluate the value of primary closure of direct defects during laparoscopic inguinal hernia mesh repair in reducing the incidence of early recurrence. METHODS: A retrospective, single-center cohort study was conducted on cases performed from August 2016 to February 2018. Patients with direct inguinal hernias undergoing elective laparoscopic mesh repair were included. When performed, the direct hernia defect was primarily closed with extracorporeal non-absorbable interrupted sutures followed by standard placement of a lightweight mesh covering myopectineal orifices. Early recurrence was defined as occurring within 1 year of surgery. RESULTS: A total of 75 direct inguinal hernias in 53 patients who underwent surgery and completed at least 1 year of follow-up were analyzed. The mean age of patients was 63 years (range 44-82 years); with majority of patients being male (98.1%). There were no significant differences observed between the two patient populations in terms of demographics, mean operative time and risk factors. In 9 (16.9%) patients, the direct hernias were recurrent hernias and all underwent open mesh repair during the index hernia surgery. The majority of hernia repairs (63 hernias in 45 patients, 85%) were performed via the totally extraperitoneal (TEP) approach. 19 patients (35.8%) with 28 direct inguinal hernias underwent primary closure of the direct defect prior to mesh placement; while, 34 patients (64.2%) with 47 direct hernias did not undergo primary closure. There were 3 direct hernia recurrences (6.4%) at 1 year post-operatively, and all occurred in the non-closure group. In comparison, there were no recurrences in the closure group; however, this difference was not statistically significant (p = 0.289) in our study due to the small sample size. CONCLUSION: Closure of direct inguinal hernia defects during laparoscopic mesh repair has been shown to reduce the incidence of early hernia recurrence in our retrospective study but future randomized controlled trials with large numbers would enable us to draw more robust conclusions and perhaps change the way we perform laparoscopic inguinal hernia repair.

Targeting YAP Degradation by a Novel 1,2,4-Oxadiazole Derivative via Restoration of the Function of the Hippo Pathway.

Recent evidence has linked the dysregulation of the Hippo pathway to tumorigenesis and cancer progression due to its pivotal role in regulating the stability of the oncoprotein YAP. Based on an unexpected finding from the SAR study of a recently reported oxadiazole-based EGFR/c-Met dual inhibitor (compound 1), we identified a closely related derivative, compound 2, which exhibited cogent antitumor activities while devoid of compound 1's ability to promote EGFR/c-Met degradation. Compound 2 acted, in part, by facilitating YAP degradation through activation of its upstream kinase LATS1. However, it did not alter the phosphorylation status of MST1/2, a LATS1 kinase, suggesting an alternative mechanism for LATS1 activation. Orally administered compound 2 was effective in suppressing MDA-MB-231 xenograft tumor growth while exhibiting a satisfactory safety profile. From a therapeutic perspective, compound 2 might help foster new therapeutic strategies for cancer treatment by restoring the Hippo pathway regulatory function to facilitate YAP degradation.

Development of Novel Irreversible Pyruvate Kinase M2 Inhibitors.

As cancer cells undergo metabolic reprogramming in the course of tumorigenesis, targeting energy metabolism represents a promising strategy in cancer therapy. Among various metabolic enzymes examined, pyruvate kinase M2 type (PKM2) has received much attention in light of its multifaceted function in promoting tumor growth and progression. In this study, we reported the development of a novel irreversible inhibitor of PKM2, compound 1, that exhibits a differential tumor-suppressive effect among an array of cancer cell lines. We further used a clickable activity-based protein profiling (ABPP) probe and SILAC coupled with LC-MS/MS to identify the Cys-317 and Cys-326 residues of PKM2 as the covalent binding sites. Equally important, compound 1 at 10 mg/kg was effective in suppressing xenograft tumor growth in nude mice without causing acute toxicity by targeting both metabolic and oncogenic functions. Together, these data suggest its translational potential to foster new strategies for cancer therapy.

1,2,4-Oxadiazole derivatives targeting EGFR and c-Met degradation in TKI resistant NSCLC.

Development of small-molecule agents with the ability to facilitate oncoprotein degradation has emerged as a promising strategy for cancer therapy. Since EGFR and c-Met are both implicated in oncogenesis and tumor progression, we initiated a screening program by using an in-house library to identify agents capable of inducing the concomitant suppression of EGFR and c-Met expression, which led to the identification of compound 1, a 1,2,4-oxadiazole derivative. Based on the scaffold of 1, we developed a series of derivatives to assess their efficacies in facilitating the downregulation of EGFR and c-Met, among which compound 48 represented the optimal agent. 48 showed equipotent antiproliferative activity against a panel of five NSCLC cell lines with different EGFR mutational status (IC50 = 0.2-0.6 µM), while the same panel exhibited differential sensitivity to different EGFR kinase inhibitors tested. Cell cycle analysis indicated that the antiproliferative activity of 48 was associated with its ability to cause G2/M arrest and, to a lesser extent, apoptosis. Western blot and RT-PCR analyses revealed that 48 facilitated the downregulation of EGFR and c-Met at the protein level. In vivo data showed that oral administration of 48 was effective in suppressing gefitinib-resistant H1975 xenograft tumor growth in nude mice, and at a suboptimal dose, could sensitize H1975 tumors to gefitinib. Based on these findings, 48 represents a promising candidate for further development to target EGFR TKI-resistant NSCLC via dual inhibition of EGFR and c-Met oncoproteins.

The role of social network, social support, religiosity and depression among elderly Malaysians who had experienced major life events.

BACKGROUND: Research has found that social network, social support and religiosity are associated with depression in elderly people. However, these predictors of depression have not been fully explored among the high risk elderly population. This study aims to examine the prevalence and factors associated with depression among Malaysian elderly subjects who had experienced major life events. METHODS: This is a cross-section study of a subsample of 594 participants from the original sample of 2322 Malaysian elderly respondents, who had experienced major life events. Information on socio-demographic, social network, social support, religiosity and depression were collected through an interviewer-administered questionnaire. A multiple linear regression analysis was used to determine the factors associated with depression among elderly who experienced major life events. RESULTS: Overall prevalence of depression among subsample of Malaysian elderly facing major life events was 9.4%. The results showed that age (p≤0.01), income (p≤0.001) and social network (p≤0.05) were significant associated with depression. In other words, with increasing age, low income as well as small social network associated with high risk of developing depression among elderly who had experienced major life events CONCLUSION: Other than age and income, social network were also associated with depression among elderly respondents who had experienced major life events. Therefore, professionals who are working with elderly with major life events should seek ways to enhance elderly networking as one of the strategies to prevent depression.

Loxapine, an antipsychotic drug, suppresses intracellular multiple-antibiotic-resistant Salmonella enterica serovar Typhimurium in macrophages.

BACKGROUND: The emergence of multiple-antibiotic-resistant (MAR) Salmonella has been a serious threat worldwide. Salmonella can invade into host cells and evade the attacks of host humoral defenses and antibiotics. Thus, a new antibacterial agent capable of inhibiting intracellular Salmonella is highly needed. METHODS: The anti-intracellular activity and cytotoxicity of drugs on intracellular bacteria and macrophages were assayed using intracellular CFU assay and MTT cell viability assay, respectively. The uptake of gentamicin into macrophage and the effect of autophagy inhibitor on loxapine's anti-intracellular Salmonella activity were assessed by using image-based high-content system. The expression of bacterial genes was measured by real-time PCR. The efflux pump activity of bacteria was measured by Hoechst accumulation assays. RESULTS: With our efforts, an antipsychotic drug, loxapine, was identified to exhibit high potency in suppressing intracellular MAR S. Typhimurium, Staphylococcus aureus, Shigella flexneri or Yersinia enterocolitica. Subsequent investigations indicated that loxapine's anti-intracellular bacteria activity was not associated with increased penetration of gentamicin into bacteria and macrophages. Loxapine didn't inhibit bacterial growth in broth at concentration up to 500 µM and has no effect on Salmonella's type III secretion system genes' expression. Blockage of autophagy also didn't reverse loxapine's anti-intracellular activity. Lastly, loxapine suppressed bacterial efflux pump activity in all bacteria tested. CONCLUSION: Altogether, our data suggested that loxapine might suppress intracellular bacteria through inhibiting of bacterial efflux pumps. In light of its unique activity, loxapine represents a promising lead compound with translational potential for the development of a new antibacterial agent against intracellular bacteria.

p21-Activated kinase 3 promotes cancer stem cell phenotypes through activating the Akt-GSK3ß-ß-catenin signaling pathway in pancreatic cancer cells.

Relative to several other p21-activated kinase (PAK) family members, the role of PAK3 in regulating cancer cell functions remains unclear. Our study obtained evidence that PAK3 regulates the Akt-GSK3ß-ß-catenin signaling by acting as Ser473-Akt kinase in several pancreatic cancer cell lines. Specifically, knockdown of PAK3 or overexpression of dominant-negative PAK3 inhibited the phosphorylation of Ser473-Akt and GSK3ß, resulting in the proteasomal degradation of ß-catenin. Conversely, overexpression of PAK3 led to activation of Akt signaling and increased ß-catenin expression. These changes, however, were not noted with the silencing and/or overexpression of PAK1, PAK2, or PAK4, which underlies the impetus of PAK3 as a key effector in governing malignant phenotypes in these pancreatic cancer cells, including cancer stem cell (CSC) expansion. Accordingly, PAK3 depletion effectively suppresses tumorsphere formation, ALDH activity, and the expression of CSC surface markers. Moreover, we used a stable knockdown clone of AsPC-1 cells to demonstrate the in vivo efficacy of PAK3 inhibition in suppressing tumorigenesis and xenograft tumor growth. Together, these findings suggest the potential role of PAK3 as a target for pancreatic cancer therapy, which warrants further investigations.