To evaluate the predictive validity of sarcopenia defined by the Foundation for the National Institutes of Health (FNIH) Sarcopenia Project among Asian older adults. Data of the I-Lan Longitudinal Aging Study were obtained for analysis. Overall, 1,839 community-dwelling people aged 50 years and older, capable of completing a 6-m walk, with life expectancy of more than 6 months, and not institutionalized at time of data collection were enrolled for study. Data for subjects aged 65 years and older were obtained for study. The outcome measures were all-cause mortality and a composite adverse outcome which includes hospitalizations, emergency department visits, institutionalization, and falls. Data of 728 eligible elderly participants (73.4 ± 5.4 years; 52.9% males) were analyzed. The prevalence of FNIH-diagnosed sarcopenia was 9.5%: 11.9% males; 6.7% females. Participants having FNIH-defined sarcopenia were considerably older, frailer, more obese, with poorer physical performance than nonsarcopenic subjects (All p < .001); during mean follow-up of 32.9 ± 8.8 months, they also had 3.8 times higher risk of dying, independent of age, sex, multimorbidity, cognitive function, and nutritional status (hazard ratio = 3.8; 95% confidence interval = 1.26–11.45; p = .018). Moreover, sarcopenia defined by grip strength-BMI ratio (WeakBMI) showed stronger association with composite adverse outcomes than traditional handgrip strength (hazard ratio = 1.99; 95% confidence interval = 1.01–3.93; p = .047 vs hazard ratio = 1.80; 95% confidence interval = 0.89–3.62; p = .102 in fully-adjusted model). Among community-dwelling older people in Taiwan, participants with FNIH-defined sarcopenia had a significantly greater risk of all-cause mortality and composite falls, emergency department visits, institutionalization, and hospitalization.
Sarcopenia, a well-known geriatric syndrome, is defined as the age-related loss of muscle mass plus declined muscle function (muscle strength and/or physical performance). Sarcopenia is associated with a number of adverse outcomes, including poor quality of life, falls, disability, and mortality. The clinical impact of sarcopenia on older people will escalate along with the rapid growth of elderly population in Asia. Moreover, the differences of ethnic backgrounds between Asian people and Westerners have trigger the need for specific diagnostic criteria for Asian populations. After the publication of Asian Working Group for Sarcopenia consensus, sarcopenia has gained even more extensive research attention in Asia. In general, the reported prevalence of sarcopenia in Asia was lower than Western countries, ranging from 2.5% to 45.7%. Asian people tend to have lower muscle mass, weaker grip strength, slower gait speed, and higher body fat mass with central distribution. Compared to Western populations, the rate of age-related muscle mass decline in older Asian people remain relatively unchanged, but the decline rate in muscle strength or physical performance was more significant along with aging. With aging, Asian people presented with greater increase in fat mass and higher prevalence of central obesity, especially in women. Due to the great impact of sarcopenia, a life course program for good nutrition and physical activities would be of great benefit. However, various research challenges remain to be resolved in the future and more outcome-based trials are needed to formulate the most optimal strategy for sarcopenia in Asia.
Background PPARγ and RBP4 are known to regulate lipid and glucose metabolism and insulin resistance. The influences of PPARγ (C1431T and Pro12Ala) and RBP4 (−803GA) polymorphisms on metabolic syndrome in HIV-infected patients receiving anti-retroviral therapy were examined in this study. Materials and Methods A cross-sectional study of HIV-1 infected adults with antiretroviral therapy for more than one year in the National Cheng Kung University Hospital was conducted. The gene polymorphisms were determined by quantitative PCR. Results Ninety-one patients were included in the study. Eighty-two (90.1%) patients were males with a mean age of 44.4 years. For the C1431T polymorphism in PPARγ, while patients with the T allele (48.4%) had trends toward lower rate of hypertriglyceridemia, the borderline significance together with insignificant power did not support the protective effect of the T allele against development of hypertriglyceridemia. For the Pro12Ala polymorphism in PPARγ, although patients with the Pro/Ala genotype (8.8%) had a higher level of serum LDL (138.0 vs. 111.5 mg/dl, P = 0.04) and trends toward higher rates of hypercholesterolemia and serum LDL>110 mg/dl, these variables were found to be independent of the Pro/Ala genotype in the multivariate analysis. For the −803GA polymorphism in RBP4, patients with the A allele (23.1%) more often had insulin resistance (HOMA>3.8; 33.3 vs. 8.7%, P = 0.01) and more often received anti-hypoglycemic drugs (14.3 vs. 1.4%, P = 0.04). The detrimental effect of the A allele in RBP4 −803GA polymorphism on development of insulin resistance was supported by the multivariate analysis adjusting for covariates. Conclusion The impacts of PPARγ C1431T and Pro12Ala polymorphisms on metabolism in HIV-infected patients are not significant. RBP4 −803GA polymorphism has increased risk of insulin resistance in HIV-infected patients with anti-retroviral therapy.
Clostridium difficile infection (CDI) is known to be associated with prior exposure to many classes of antibiotics. Standard therapy for CDI (i.e., metronidazole and vancomycin) is associated with high recurrence rates. Although tetracycline derivatives such as tetracycline, doxycycline or tigecycline are not the standard therapeutic choices for CDI, they may serve as an alternative or a component of combination therapy. Previous tetracycline or doxycycline usage had been shown to have less association with CDI development. Tigecycline, a broad-spectrum glycylcycline with potency against many gram-positive or gram-negative pathogens, had been successfully used to treat severe or refractory CDI. The in vitro susceptibility of C. difficile clinical isolates to tigecycline in many studies showed low minimal inhibitory concentrations. Tigecycline can suppress in vitro toxin production in both historical and hypervirulent C. difficile strains and reduce spore production in a dose-dependent manner. Tetracycline compounds such as doxycycline, minocycline, and tigecycline possess anti-inflammatory properties that are independent of their antibiotic activity and may contribute to their therapeutic effect for CDI. Although clinical data are limited, doxycycline is less likely to induce CDI, and tigecycline can be considered one of the therapeutic choices for severe or refractory CDI.
The decline of new HIV acquisitions in Taiwan can be attributed to a combination of rapidly increasing antiretroviral therapy (ART) coverage, the successful implementation of HIV self-testing and the uptake of pre-exposure prophylaxis (PrEP) [1]. With regard to HIV prevention, the key population in Taiwan, gay and bisexual men and other men who have sex with men (GBMSM), has faced new challenges in the past decade from two major issues, the first of which is chemsex behaviour, a form of sexualized use of drugs, such as methamphetamine, gamma hydroxybutyrate/gamma butyrolactone (GHB/GBL) and mephedrone, and needed harm reduction strategies [2]. The second issue is the relative centralization of the service delivery for PrEP medications, which persistently hinders the scale-up of efforts at PrEP. A model for the provision of integrated sexual health services, the Healing, Empowerment, Recovery of Chemsex (HERO) Health Center, was established in Taiwan in 2017 by a non-governmental organization (NGO) with a decade-long relationship with the local Lesbian, Gay, Bisexual, and Transgender (LGBT) community. HERO works from a regional hospital where it served as a one-stop healthcare centre integrating services for chemsex care, mental healthcare and PrEP/PEP (post-exposure prophylaxis) [3]. In May 2022, HERO transitioned from the original model to a new social enterprise model and was renamed HÉROS. It now functions independently in an urban neighbourhood that allows easy access to GBMSM, people who engage in chemsex, people with HIV and the general population. It incorporates a pharmacy, a clinic and a community health centre, offering a one-stop, person-centred destination providing comprehensive care, and preventive treatments through the provision of differentiated and simplified PrEP [4]. HÉROS provides a series of integrated mental health services for people who engage in chemsex, including a psychiatric outpatient clinic, individual psychological counselling and various support groups, including chemsex recovery groups. There are three major types of groups led by clinical psychologists geared towards the specific needs of people at the different stages of the recovery journey. First is the early relapse prevention group which is aimed at individuals who have the intention to reduce their use of chemsex. During sessions, the issues dealt with include identifying high-risk contexts and cravings, and developing coping skills. The second group follows a 12-step programme targeted at chemsex users who are at the action stage—those managing their chemsex behaviour with the help of coping mechanisms, but remain vulnerable to relapse. Finally, the interpersonal skills group focuses on discussions of intimacy among clients who have achieved maintenance of their chemsex behaviour by mastering certain coping mechanisms. The interventions employed with this group explore the past negative experiences of these men that are associated with emotional regulation and attachment style [5]. Among GBMSM who engaged in chemsex at HERO, 23% had been members of a recovery group and 17% had visited a mental health clinic at HERO [6]. A high frequency of substance use and living with HIV were significantly associated with being members of a chemsex recovery group, but age, income, education and employment status were not. After less than 1 year since it moved into the community in 2022 (May 2022–March 2023), HÉROS clinic has received 1576 clients contributing 3600 visits. The majority were visits to the internal medicine clinic (74%). Regarding the HIV-related services provided at HÉROS, 19 people received PEP, 167 were living with HIV and 61 people received ART at HÉROS clinic when others chose to go to other clinics or hospitals. Additionally, 115 people received PrEP, 69 of whom were able to take advantage of a government programme that subsidizes PrEP medication, while the other 46 people paid out of pocket. About 90% of clients receiving PrEP or ART at HÉROS are GBMSM. There are three transwomen and two transmen receiving ART, PrEP or hormone therapy at HÉROS. More than one-fifth of the 1576 clients aged more than 50 years, while 10% of individuals receiving ART at HÉROS aged more than 50 years. Vaccines were given at HÉROS to 40 people for shingles, 45 for Human papillomavirus (HPV), 27 for hepatitis B, 17 for hepatitis A, 5 for pneumococcal pneumonia and 7 for influenza. Finally, in its first year of operating independently, HÉROS has conducted more than 40 group sessions, with the participation of 70 chemsex-practicing GBMSM. GBMSM clients at HÉROS for the past year are more likely to be in the higher socio-economic status than those at HERO. People with more economic resources might be more likely to be early adopters of this new model and it will take time for the diffusion effect to spread through the social system. The transformation from HERO to HÉROS did not occur without a few glitches in response to which a number of solutions are currently being devised. In Table 1, the domains and constructs of the Consolidated Framework for Implementation Research (CFIR) are used to organize the determinants of the implementation of these solutions at HÉROS [7]. Table 1 also shows how the solutions correspond to the implementation strategies proposed by Powell et al. [8]. Efforts at community outreach based on working as an NGO since 1999 made it possible to attract members of the LGBT community and people who engage in chemsex to HÉROS. Recovery group sessions with a focus on HIV have been running since 2015 at the community health centre. The location in the midst of the community facilitates access. We provide a patient-centred approach and a one-stop integrated healthcare centre for people who engage in chemsex, including services for mental health, HIV/Sexually transmitted infections (STI) and substance use. The community-based clinical setting enables a faster response to new infections, policies and interventions, such as monkey pox vaccination and long-acting HIV treatment, compared to large hospitals. People living with HIV and those who engage in chemsex are getting older like the general population. Therefore, preparing in advance for the needs of ageing care for people living with HIV and chemsex users, is a key element in transitioning to community care. There is an urgent need for incorporating chemsex care with other age-related needs, such as long-term care, social interaction and social support, and managing poor physical health and comorbidities associated with the ageing process. We provide multifaceted, integrated services with the help of several professionals, such as clinicians, pharmacists, therapists and social workers. The majority of the healthcare workers and staff at HÉROS identify as LGBT. The employees at HÉROS are selected based on their cultural competency and trained when it is inadequate. A few major challenges stand in the way of HÉROS functioning smoothly and effectively as an integrated sexual health services centre. First, being located amid a community facilitates access to sexual health services for chemsex-practicing individuals; however, the location of HÉROS may concern its neighbours. HIV acquisition carries a stigma and discrimination against the LGBT community which is prevalent in Taiwanese society [9]. To address this, HÉROS exhibits a gender-neutral attitude and welcomes both chemsex-practicing LGBT community and non-LGBT clients from the neighbourhood. For example, we made the extra effort of approaching local opinion leaders by holding townhall meetings where we explained the services we provide. The second challenge is related to the fact that Taiwan is an ageing society. As we grow old, we all face difficulties such as receiving long-term care, engaging in social interaction, finding social support, and managing poor physical health and comorbidities associated with the ageing process. This issue is compounded by the discrimination faced by the LGBT community in Taiwan, which highlights the need to incorporate chemsex care into existing healthcare frameworks. Furthermore, these efforts must aim to stay one step ahead by implementing health promotion plans before the ageing population exceeds the healthcare capacity. With this in mind, healthcare providers at HÉROS encourage our clients to consider getting vaccinated for shingles, pneumococcal pneumonia, influenza and so on. Finally, HÉROS pharmacists play the role of allies to our gender-diverse clients by ensuring optimal health outcomes and by helping GBMSM achieve their therapeutic objectives [10]. The third sizeable obstacle of HÉROS, which may potentially jeopardize the sustainability of the social enterprise model upon which it was conceived, is the difficulty of simultaneously managing the work of multiple sectors, including a clinic, a pharmacy and a non-profit organization. HÉROS emphasizes coming up with creative, innovative and enterprising ways of solving problems resulting from chemsex behaviour. The centre maintains its financial health by providing access to traditional services (e.g. counselling, prevention, diagnosis and treatment), as well as tweaking, modifying and hybridizing existing solutions/services for the LGBT community to produce novel techniques. HÉROS focuses not only on caring for clients with various gender identities and sexual orientations, but also on offering innovative services based on integrative strategies, such as home-delivery packages and telemedicine. It is crucial to be able to identify areas for improvement in this model. HÉROS employs a broad range of operational and ideological approaches to the planning and delivery of healthcare services to members of the community. However, there is room for improvement. It is essential to regularly assess and adjust the business model in order to ensure that it continues to meet the evolving needs of the community, especially in light of changing societal and political contexts. This ongoing process of evaluation and adaptation will enable HÉROS to continue providing high-quality care and support to its clients. All authors have no competing interests to declare in relation to this work. CS, J-HH and N-YK wrote the original draft of the manuscript. N-YK, CS, A-CC and M-TW were responsible for the research design, and they led the project. Y-HW, K-WL and S-TH implemented the healthcare services. CS and N-YK revised all drafts, which were reviewed and approved by all authors. We wish to extend our heartfelt gratitude to the individuals who visited HÉROS that contributed to the research. We also thank the community leaders and Taiwan Centers for Diseases Control for their unwavering support and dedication in transitioning healthcare services to a more inclusive and community-led setting. This work received financial support from the National Science and Technology Council in Taiwan (grant numbers: 108–2636-B-006–004, 109–2636-B-006–004, 110–2636-B-006–011, 111-2321-B-006-009 and 111–2636-B-006–011), and Taiwan Centers for Disease Control (MOHW107-CDC–C-114–000107, MOHW108-CDC–C-114–000106 and MOHW112-CDC–C-114–000105).
Biomarkers that predict disease progression might assist the development of better therapeutic strategies for aggressive cancers, such as ovarian cancer. Here, we investigated the role of collagen type IV alpha 6 (COL4A6) in cell invasiveness and tumor formation and the prognostic impact of COL4A6 expression in ovarian cancer.
Methods
A2780CP70 and OVCAR8 cells transfected with a small interference RNA of COL4A6 (shCOL4A6) and A2780 and OVCAR4 cells transfected with a COL4A6 expression plasmid. Site-directed mutagenesis assay, luciferase assay, chromatin immunoprecipitation assay, invasion assay and xenograft animal study were performed in this study. COL4A6 mRNA expression levels of 160 ovarian tumors were determined by real-time RT-PCR.
Results
Small interference RNA-mediated specific reduction in COL4A6 protein levels suppressed the invasive ability and oncogenic potential of ovarian cancer cells and decreased tumor formation. A combination of experimental approaches, including real-time RT-PCR, casein zymography and chromatin immunoprecipitation assays, showed that COL4A6 knockdown attenuated discoidin domain receptors/p-DDR1 expression and suppressed binding of E2F to its putative DDR1 promoter binding site, suggesting that the E2F-DDR1 axis is upregulated by COL4A6. Pharmacological inhibition of DDR1 abrogated the COL4A6-dependent cell invasiveness. Analysis of 160 ovarian cancer patients indicated that high COL4A6 mRNA levels are associated with advanced disease stage. The 5-year recurrence-free and overall survival rates were significantly lower (p=0.001 and p=0.001, respectively) among patients with high expression levels of tissue COL4A6 mRNA compared to those with low expression.
Conclusion/Implications
COL4A6 may promote tumor aggressiveness via the E2F/DDR1 axis and that COL4A6 expression can predict clinical outcome in ovarian cancer patients.
We studied Akt inhibition using SC66 in a NOD-SCID xenograft mouse model and a panel of eight ovarian cancer cell lines. Elevated phospho-Akt levels in cancerous tissue were associated with short progression-free survival and overall survival. Cell sensitivity to SC66 was inversely correlated with phospho-Akt and COL11A1 expression levels, as well as resistance to cisplatin or paclitaxel. SC66 inhibited phosphorylation of Akt and its downstream effectors 4EBP1 and p70S6 kinase. SC66 also attenuated expression of TWIST1 and Mcl-1, factors important in cell invasiveness and anti-apoptosis, respectively. SC66-sensitized chemoresistant cells to cisplatin and paclitaxel treatment, and promoted apoptosis. In addition, SC66 inhibited COL11A1 expression via decreased binding of CCAAT/enhancer-binding protein beta (c/EBPβ), reducing chemoresistance and decreasing binding of nuclear transcription factor Y (NF-YA) to COL11A1. A mouse xenograft experiment demonstrated that SC66 treatment caused a reduction in tumor formation and enhanced the therapeutic efficacy of cisplatin. This study demonstrates the role of Akt in ovarian tumor progression and chemoresistance, and supports the application of SC66 as a therapy for ovarian cancer.
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