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According to current dogma, chondrocytes and osteoblasts are considered independent lineages derived from a common osteochondroprogenitor. In endochondral bone formation, chondrocytes undergo a series of differentiation steps to form the growth plate, and it generally is accepted that death is the ultimate fate of terminally differentiated hypertrophic chondrocytes (HCs). Osteoblasts, accompanying vascular invasion, lay down endochondral bone to replace cartilage. However, whether an HC can become an osteoblast and contribute to the full osteogenic lineage has been the subject of a century-long debate. Here we use a cell-specific tamoxifen-inducible genetic recombination approach to track the fate of murine HCs and show that they can survive the cartilage-to-bone transition and become osteogenic cells in fetal and postnatal endochondral bones and persist into adulthood. This discovery of a chondrocyte-to-osteoblast lineage continuum revises concepts of the ontogeny of osteoblasts, with implications for the control of bone homeostasis and the interpretation of the underlying pathological bases of bone disorders.

The present study explored the potential causal link between ischemia-driven cyclooxygenase-2 (COX-2) expression and enhanced apoptosis during myocardial ischemia/reperfusion (I/R) by using H9C2 cardiomyocytes and primary rat cardiomyocytes subjected to hypoxia/reoxygenation (H/R). The results showed that H/R resulted in higher COX-2 expression than that of controls, which was prevented by pretreatment with Helenalin (NFκB specific inhibitor). Furthermore, pretreatment with NS398 (COX-2 specific inhibitor) significantly attenuated H/R-induced cell injury [lower lactate dehydrogenase (LDH) leakage and enhanced cell viability] and apoptosis (higher Bcl2 expression and lower level of cleaved caspases-3 and TUNEL-positive cells) in cardiomyocytes. The amelioration of posthypoxic apoptotic cell death was paralleled by significant attenuation of H/R-induced increases in proinflammatory cytokines [interleukin 6 (IL6) and tumor necrosis factor (TNFα)] and reactive oxygen species (ROS) production and by higher protein expression of phosphorylated Akt and inducible nitric oxide synthase (iNOS) and enhanced nitric oxide production. Moreover, the application of LY294002 (Akt-specific inhibitor) or 1400W (iNOS-selective inhibitor) cancelled the cellular protective effects of NS398. Findings from the current study suggest that activation of NFκB during cardiomyocyte H/R induces the expression of COX-2 and that higher COX-2 expression during H/R exacerbates cardiomyocyte H/R injury via mechanisms that involve cross talks among inflammation, ROS, and Akt/iNOS/NO signaling.

Prostaglandin E2 (PGE2) is an endogenous lipid mediator, produced from the metabolism of arachidonic acids, upon the sequential actions of phospholipase A2, cyclooxygenases, and prostaglandin E synthases. The various biological functions governed by PGE2 are mediated through its four distinct prostaglandin E receptors (EPs), designated as EP1, EP2, EP3, and EP4, among which the EP4 receptor is the one most widely distributed in the heart. The availability of global or cardiac-specific EP4 knockout mice and the development of selective EP4 agonists/antagonists have provided substantial evidence to support the role of EP4 receptor in the heart. However, like any good drama, activation of PGE2-EP4 signaling exerts both protective and detrimental effects in the ischemic heart disease. Thus, the primary object of this review is to provide a comprehensive overview of the current progress of the PGE2-EP4 signaling in ischemic heart diseases, including cardiac hypertrophy and myocardial ischemia/reperfusion injury. A better understanding of PGE2-EP4 signaling should promote the development of more effective therapeutic approaches to treat the ischemic heart diseases without triggering unwanted side effects.

Germline mutations of the deubiquitinase BRCA1-associated protein 1 (BAP1) lead to the “BAP1 cancer syndrome” characterized by development of cancers. However, the role of BAP1 in hepatocellular carcinoma (HCC) is unclear. We found that BAP1 was upregulated at mRNA level in human HCCs and significantly correlated with a more aggressive tumour behaviour. Intriguingly, we observed cytoplasmic but no or minimal nuclear BAP1 in human HCC samples by immunohistochemistry. We observed that, while BAP1 protein was found mainly in the cytoplasm and less in the nuclei of HCC cell lines, BAP1 expression was predominantly nuclear in HepG2 cells, by cell fractionation and immunofluorescence analyses. Functionally, in the orthotopic liver injection mouse model, silencing the BAP1 predominant nuclear expression of HepG2 cells promoted intrahepatic tumor metastasis, with more frequent tumor microsatellite formation and venous invasion. With transcriptomic profiling, we identified RHOJ amongst the downregulated targets in HepG2 cells upon BAP1 knockdown. Subsequent overexpression of RHOJ suppressed cell migration in HCC cells, suggesting that BAP1 might upregulate RHOJ resulting in reduced cell migratory ability of HCC cells. Furthermore, we identified two transcription factors, CTCF and NRF1, which activated BAP1 transcription by binding to BAP1 promoter region. On the other hand, we uncovered that O-linked N-acetylglucosamine (GlcNAc) transferase (OGT) physically bound to BAP1 in the nucleus, resulting in diminished stability of the nuclear BAP1. Intriguingly, OGT transcription was upregulated and was also under the control of CTCF and NRF1 in human HCC, acting as a negative regulator of BAP1. To summarize, this study uncovered the underlying mechanisms of the regulation of BAP1 and that loss of the nuclear localization of BAP1 protein contributed to enhanced cell migration in vitro and more aggressive tumor behavior in human HCCs.

Background Late-life depression is common, modifiable, yet under-treated. Service silos and human resources shortage contribute to insufficient prevention and intervention. We describe an implementation research protocol of collaborative stepped care and peer support model that integrates community mental health and aged care services to address service fragmentation, using productive ageing and recovery principles to involve older people as peer supporters to address human resource issue. Methods/design This is a non-randomised controlled trial examining the effectiveness and cost-effectiveness of the “Jockey Club Holistic Support Project for Elderly Mental Wellness” (JC JoyAge) model versus care as usual (CAU) in community aged care and community mental health service units in 12 months. Older people aged 60 years and over with mild to moderate depressive symptoms or risk factors for developing depression will be included. JoyAge service users will receive group-based activities and psychoeducation, low-intensity psychotherapy, or high-intensity psychotherapy according to the stepped care protocol in addition to usual community mental health or aged care, with support from an older peer supporter. The primary clinical outcome, depressive symptoms, and secondary outcomes, self-harm risk, anxiety symptoms, and loneliness, will be measured with the Patient Health Questionnaire-9 (PHQ-9), Self-Harm Inventory, Generalized Anxiety Disorder 7-item scale (GAD-7), and UCLA Loneliness 3-item scale (UCLA-3) respectively. Cost-effectiveness analysis will assess health-related quality of life using the EQ-5D-5L and service utilisation using the Client Service Receipt Inventory (CSRI). We use multilevel linear mixed models to compare outcomes change between groups and calculate the incremental cost-effectiveness ratio in terms of quality-adjusted life years. Discussion This study will provide evidence about outcomes for older persons with mental health needs receiving collaborative stepped care service without silos and with trained young-old volunteers to support engagement, treatment, and transitions. Cost-effectiveness findings from this study will inform resource allocation in this under-treated population. Trial registration ClinicalTrials.gov NCT03593889. Registered on 20 July 2018.

Clinically significant copy-number variants (CNVs) known to cause human diseases are routinely detected by chromosomal microarray analysis (CMA). Recently, genome sequencing (GS) has been introduced for CNV analysis; however, sequencing depth (determined by sequencing read-length and read-amount) is a variable parameter across different laboratories. Variating sequencing depths affect the CNV detection resolution and also make it difficult for cross-laboratory referencing or comparison. In this study, by using data from 50 samples with high read-depth GS (30×) and the reported clinically significant CNVs, we first demonstrated the optimal read-amount and the most cost-effective read-length for CNV analysis to be 15 million reads and single-end 50 bp (equivalent to a read-depth of 0.25-fold), respectively. In addition, we showed that CNVs at mosaic levels as low as 30% are readily detected, furthermore, CNVs larger than 2.5 Mb are also detectable at mosaic levels as low as 20%. Herein, by conducting a retrospective back-to-back comparison study of low-pass GS versus routine CMA for 532 prenatal, miscarriage, and postnatal cases, the overall diagnostic yield was 22.4% (119/532) for CMA and 23.1% (123/532) for low-pass GS. Thus, the overall relative improvement of the diagnostic yield by low-pass GS versus CMA was ~ 3.4% (4/119). Identification of cryptic and clinically significant CNVs among prenatal, miscarriage, and postnatal cases demonstrated that CNV detection at higher resolutions is warranted for clinical diagnosis regardless of referral indications. Overall, our study supports low-pass GS as the first-tier genetic test for molecular cytogenetic testing.

Multiple factors, including host genetics, environmental factors, and Epstein–Barr virus (EBV) infection, contribute to nasopharyngeal carcinoma (NPC) development. To identify genetic susceptibility genes for NPC, a whole-exome sequencing (WES) study was performed in 161 NPC cases and 895 controls of Southern Chinese descent. The gene-based burden test discovered an association between macrophage- stimulating 1 receptor (MST1R) and NPC. We identified 13 independent cases carrying the MST1R pathogenic heterozygous germ-line variants, and 53.8% of these cases were diagnosed with NPC aged at or even younger than 20 y, indicating that MST1R germ-line variants are relevant to disease early-age onset (EAO) (age of ≤20 y). In total, five MST1R missense variants were found in EAO cases but were rare in controls (EAO vs. control, 17.9% vs. 1.2%, P = 7.94 × 10−12). The validation study, including 2,160 cases and 2,433 controls, showed that the MST1R variant c.G917A:p.R306H is highly associated with NPC (odds ratio of 9.0). MST1R is predominantly expressed in the tissue-resident-macrophages and is critical for innate immunity that protects organs from tissue damage and inflammation. Importantly, MST1R expression is detected in the ciliated epithelial cells in normal nasopharyngeal mucosa and plays a role in the cilia motility important for host defense. Although no somatic mutation of MST1R was identified in the sporadic NPC tumors, copy number alterations and promoter hypermethylation at MST1R were often observed. Our findings provide new insights into the pathogenesis of NPC by highlighting the involvement of the MST1R-mediated signaling pathways.

Background Chromosomal microarray (CMA) has been shown to be cost-effective over karyotyping in invasive prenatal diagnosis for pregnancies with fetal ultrasound anomalies. Yet, information regarding preceding and subsequent tests must be considered as a whole before the true cost-effectiveness can emerge. Currently in Hong Kong, karyotyping is offered free as the standard prenatal test while genome-wide array comparative genome hybridization (aCGH), a form of CMA, is self-financed. A new algorithm was proposed to use aCGH following quantitative fluorescent polymerase chain reaction (QF-PCR) as primary test instead of karyotyping. This study aims to evaluate the cost-effectiveness of the proposed algorithm versus the current algorithm for prenatal diagnosis in Hong Kong. Methods Between November 2014 and February 2016, 129 pregnant women who required invasive prenatal diagnosis at two public hospitals in Hong Kong were prospectively recruited. The proposed algorithm was performed for all participants in this demonstration study. For the cost-effectiveness analysis, cost and outcome (diagnostic rate) data were compared with that of a hypothetical scenario representing the current algorithm. Further analysis was performed to incorporate women’s willingness-to-pay for the aCGH test. Impact of government subsidies on the aCGH test was explored as a sensitivity analysis. Results The proposed algorithm dominated the current algorithm for prenatal diagnosis. Both algorithms were equally effective but the proposed algorithm was significantly cheaper ( p  ≤ 0.05). Taking into account women’s willingness-to-pay for an aCGH test, the proposed algorithm was more effective and less costly than the current algorithm. When the government subsidy reaches 100%, the maximum number of diagnoses could be made. Conclusion By switching to the proposed algorithm, cost saving can be achieved whilst maximizing the diagnostic rate for invasive prenatal diagnosis. It is recommended to implement aCGH as a primary test following QF-PCR to replace the majority of karyotyping for prenatal diagnosis in Hong Kong.

Numerous research studies have reported that COVID-19 adversely affects individual mental well-being, but studies on the effect of the pandemic on family well-being have been sparse. Given that happiness is an essential determinant of quality of life, we examined the predictors of family happiness during COVID-19 in this study based on a convenience sampling of 2,971 Hong Kong residents between April 2021 and March 2022. Results showed that those between 35 and 54 years were happier than those between 19 and 34. Family happiness correlated with age, individual happiness, family solidarity, family resources, family mental health, and the COVID-19 impact. Individual happiness and family factors also consistently predicted family happiness regardless of the severity of the pandemic. Findings suggest that individual happiness and several family factors shape family happiness. Fostering supportive measures and care within families is essential to improve family happiness.