👤 Hung-Chang Hung

The purpose of this study was to analyze and compare cytokine and growth factor levels in modified autologous conditioned serum (mACS) and autologous serum (AS) and to evaluate their therapeutic effects in a benzalkonium chloride (BAK)-induced murine dry eye model. Serum samples were obtained from twenty healthy volunteers and analyzed by ELISA. A dry eye model was established in twenty-four C57BL/6 mice by topical application of 0.2% BAK twice daily for seven days. The mice were evenly divided into three subgroups: saline-treated, 0.5% AS-treated, and 0.5% mACS-treated. The right eyes were treated, and the left eyes served as untreated controls. Eyeballs were harvested on days 7 and 14 for immunofluorescence staining. Results showed that neuroprotective factors (BDNF and fractalkine), pro-inflammatory cytokines (IL-1β, IL-6, MIF, TNF-α), and VEGF-A were significantly elevated in the mACS group, whereas PDGF-BB was significantly reduced. Furthermore, immunofluorescence analysis demonstrated a significantly greater recovery of central corneal nerve fibers in the mACS-treated group compared with the saline group at day 7 (p < 0.01). At day 14, the mACS-treated group continued to show a trend toward increased central corneal nerve regeneration, although this difference did not reach conventional statistical significance (p < 0.1). No significant differences were observed between the AS- and saline-treated groups. In conclusion, compared with AS, mACS demonstrates a cytokine profile suggestive of enhanced neuroprotective potential and may facilitate corneal nerve regeneration in the BAK-induced murine dry eye model. Show less

Alzheimer disease (AD) pathology may begin decades before symptoms. Genetic factors, such as APOE ε4 carrier status and polygenic risk scores (PRS), influence AD risk, but their roles in cognitive decline among Asian populations remain unclear. To evaluate whether APOE ε4 carrier status and a non-APOE polygenic risk score (PRS_ADnapoe) are associated with age-related cognitive decline in community-dwelling older adults in Taiwan. This prospective cohort study used data from 2 assessment waves of the Healthy Aging Longitudinal Study in Taiwan, spanning 2009 to 2019. Participants were aged 55 years and older and had both genetic data and Mini-Mental State Examination (MMSE) scores. Data analyses were conducted from August to December 2025. APOE ε4 carrier status (noncarrier, heterozygote, homozygote) and PRS_ADnapoe score, derived from genome-wide association summary statistics excluding APOE variants. The primary outcome was change in MMSE scores, which were assessed cross-sectionally and longitudinally, modeled with mixed-effects regression accounting for age-related effects and covariates including sex, education, smoking, and population structure. Among 4392 participants (mean [SD] age, 68.2 [7.8] years; 2359 [53.7%] women), 723 (16.5%) were APOE ε4 heterozygotes and 33 (0.8%) were APOE ε4 homozygotes. Over a mean (SD) follow-up of 6.3 (0.9) years, the mean (SD) annual MMSE decline was -0.2 (0.5). APOE ε4 carriage was associated with a significantly steeper quadratic age-associated decline in MMSE scores compared with noncarriers (estimate, -0.005; SE, 0.001; P = .001). This association was strongest among homozygotes (estimate, -0.017; SE, 0.008; P = .03), with MMSE trajectories diverging after approximately age 70 years. In contrast, PRS_ADnapoe scores were not associated with MMSE decline. Sensitivity analyses restricted to participants with 2-wave data and adjusted with inverse probability of censoring weighting confirmed these findings. In this cohort study of middle-aged and older adults in Taiwan, APOE ε4 carriage, particularly homozygosity, was associated with accelerated age-related cognitive decline detectable after age 70 years, whereas non-APOE polygenic risk was not associated with cognitive decline over the current follow-up. These results highlight the potential utility of early genetic risk awareness and support consideration of targeted preventive strategies for APOE ε4 carriers. Show less

Cardiovascular disease (CVD) risk is elevated among people living with HIV (PLWH), particularly those receiving antiretroviral therapy (ART). This study aimed to examine associations between single-nucleotide polymorphisms (SNPs) in lipoprotein-related genes and CVD risk among PLWH undergoing ART. Blood samples from 337 PLWH at Chung Shan Medical University Hospital were analyzed, including 238 individuals who switched ART and 99 who continued their regimen. Genotyping of four SNPs-namely, ATP binding cassette B1 ( The cohort was predominantly male 95.6% (322/337), with a mean age of 34.6 years. Metabolic abnormalities were common, and 16.0% (54/337) of participants on ART were classified as high-risk for CVD. Among the SNPs analyzed, SNPs in Show less

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality worldwide despite intensive lipid-lowering therapy. Residual cardiovascular risk persists even in patients achieving optimal lipoprotein-cholesterol (LDL-C) levels, indicating that additional lipid mediators contribute to disease progression. Lysophosphatidylcholine (LPC), a bioactive lysophospholipid generated from phosphatidylcholine by cytosolic or lipoprotein-associated phospholipase A₂ (PLA₂), has emerged as a critical mediator linking dyslipidemia, inflammation, and vascular injury. LPC is highly enriched in oxidized LDL (oxLDL), electronegative LDL (LDL(-)), and lipoprotein(a) [Lp(a)], all of which represent highly atherogenic lipoprotein subclasses. This review delineates the metabolic origins of LPC, its transport via LDL, VLDL, and albumin, and its accumulation within atherosclerotic plaques. LPC promotes endothelial dysfunction, monocyte recruitment, foam-cell formation, and platelet activation, collectively driving plaque development and instability. Elevated LPC levels are consistently observed in metabolic disorders such as type 2 diabetes mellitus (T2DM) and non-alcoholic steatohepatitis (NASH), both of which exacerbate ASCVD risk. Although statins, ezetimibe, and PCSK9 inhibitors effectively lower LDL-C, they do not directly target LPC or its downstream inflammatory pathways. Clinical trials of lipoprotein-associated PLA₂ inhibitors (e.g., Darapladib) failed to reduce cardiovascular events, underscoring the complexity of LPC-related signaling. Future therapeutic approaches may involve enhancing lysophospholipase A Show less

Alzheimer's disease (AD) is associated with AChE and BACE1 enzymes. Designing inhibitors for preventing these enzymes can be benefit for AD treatment. In this context, theophylline derivatives were generated to prevent the biological activity of AChE and BACE1. In particular, the potential inhibitory of these compounds was rapidly and accurately estimated Show less

Encephalocraniocutaneous lipomatosis (ECCL) is a rare somatic disorder caused by mutations in various genes of the RAS-MAPK pathway. Distinctive features of ECCL include nevus psiloliparus, scalp alopecia, ocular choristomas, and intracranial lipomas. ECCL is most commonly associated with FGFR1 and KRAS mutations. An NRAS variant causing ECCL has only been reported in the literature once. We present the case of a female infant with ECCL, harboring an NRAS somatic mutation, variant c.37G>C (p.Gly13Arg). This is the second reported case of an NRAS variant in ECCL and the first to document an associated intracranial lipoma. The report highlights the genotypic, clinical, and neuroradiological presentation of ECCL, its overlap and distinctions with other mosaic RASopathies, and reviews the recommended diagnostic approach when ECCL is suspected. Show less

Alzheimer's disease (AD) is the leading cause of dementia, characterized by the buildup of amyloid plaques and neurofibrillary tangles, which lead to neuronal damage and trigger inflammatory responses in glial cells. The fibroblast growth factor receptor 1 (FGFR1)-mediated signaling pathways support the function of damaged neurons and modulate the inflammatory response. The FGFR1 agonists, including Fibroblast growth factor 1 (FGF1) and FG loop peptide (FGL), have been implicated in multiple disease therapies. However, whether FGFR1 agonists can improve pathology and cognitive function in AD remains unknown. This study showed that administration of FGF1 and FGL to the AD mouse model reversed spatial memory impairment, enhanced neurogenesis, suppressed reactive astrogliosis, and restricted dystrophic neurites. However, only FGF1 treatment reduced the deposition of senile plaque. In microglial culture studies, FGF1 improves the phagocytosis ability of microglia, but this effect is blocked by the FGFR1-specific inhibitor. Together, our findings suggested that FGFR1 agonists alleviate pathological and cognitive impairments in the AD mouse model. Show less

Recent evidence suggests that elevated lipoprotein(a) [Lp(a)] contributes to atherosclerotic cardiovascular disease (ASCVD). The predictive value of specific Lp(a) cutoff points of 30 mg/dL remains to be established. This study investigated the relationship between Lp(a) concentrations and cardiovascular outcomes in Taiwanese individuals, stratified by pre-existing ASCVD status. We conducted a retrospective analysis of 51,934 subjects from the Chang Gung Research Database (January 2004 to June 2019), comprising 49,363 individuals without ASCVD and 2,571 with established ASCVD. The primary outcome was major adverse cardiovascular events (MACEs), encompassing acute myocardial infarction, ischemic stroke, revascularization procedures, peripheral arterial interventions, and cardiovascular mortality. Individuals were followed until their last visit to our institutions or December 31, 2019. During a mean follow-up of 6.6 years (standard deviation: 5.0 years), the study population demonstrated a median Lp(a) of 9.6 mg/dL (interquartile range: 4.6-18.5). In ASCVD-free individuals, Lp(a) concentrations ≥30 mg/dL were associated with increased MACE risk (adjusted subdistribution hazard ratio [aSHR]: 1.24; 95% confidence interval [CI]: 1.07-1.43). Similarly, in the ASCVD cohort, elevated Lp(a) predicted higher MACE occurrence (aSHR: 1.36; 95% CI: 1.07-1.74). Restricted cubic spline analysis confirmed a progressive risk elevation beyond the 30 mg/dL threshold in both groups. Lp(a) levels ≥30 mg/dL independently predicted adverse cardiovascular outcomes, regardless of baseline ASCVD status. This threshold appears suitable for cardiovascular risk stratification in both primary and secondary prevention settings. Show less

In peripheral tissues, an endothelial cell (EC) protein, GPIHBP1, captures lipoprotein lipase (LPL) from the interstitial spaces and transports it to the capillary lumen. LPL mediates the margination of triglyceride-rich (TG-rich) lipoproteins (TRLs) along capillaries, allowing the lipolytic processing of TRLs to proceed. TRL-derived fatty acids are used for fuel in oxidative tissues or stored in adipose tissue. In mice, GPIHBP1 is absent from capillary ECs of the brain (which uses glucose for fuel); consequently, LPL and TRL margination are absent in mouse brain capillaries. However, because fatty acids were reported to play signaling roles in the brain, we hypothesized that LPL-mediated TRL processing might occur within specialized vascular beds within the central nervous system. Here, we show that GPIHBP1 is expressed in capillary ECs of human and mouse choroid plexus (ChP) and that GPIHBP1 transports LPL (produced by adjacent ChP cells) to the capillary lumen. The LPL in ChP capillaries mediates both TRL margination and processing. Intracapillary LPL and TRL margination are absent in the ChP of Gpihbp1-/- mice. GPIHBP1 expression, intracapillary LPL, and TRL margination were also observed in the median eminence and subfornical organ, circumventricular organs implicated in the regulation of food intake. Show less

The effectiveness of immune checkpoint inhibitor (ICI) therapy for hepatocellular carcinoma (HCC) is limited by treatment resistance. However, the mechanisms underlying immunotherapy resistance remain elusive. We aimed to identify the role of CT10 regulator of kinase-like (CRKL) in resistance to anti-PD-1 therapy in HCC. Gene expression in HCC specimens from 10 patients receiving anti-PD-1 therapy was identified by RNA-sequencing. A total of 404 HCC samples from tissue microarrays were analyzed by immunohistochemistry. Transgenic mice (Alb-Cre/Trp53 CRKL was identified as a candidate anti-PD-1-resistance gene using a pooled genetic screen. CRKL overexpression nullifies anti-PD-1 treatment efficacy by mobilizing tumor-associated neutrophils (TANs), which block the infiltration and function of CD8 Activation of the CRKL/β-catenin/VEGFα and CXCL1 axis is a critical obstacle to successful anti-PD-1 therapy. Therefore, CRKL inhibitors combined with anti-PD-1 could be useful for the treatment of HCC. Here, we found that CRKL was overexpressed in anti-PD-1-resistant hepatocellular carcinoma (HCC) and that CRKL upregulation promotes anti-PD-1 resistance in HCC. We identified that upregulation of the CRKL/β-catenin/VEGFα and CXCL1 axis contributes to anti-PD-1 tolerance by promoting infiltration of tumor-associated neutrophils. These findings support the strategy of bevacizumab-based immune checkpoint inhibitor combination therapy, and CRKL inhibitors combined with anti-PD-1 therapy may be developed for the treatment of HCC. Show less

Lung adenocarcinoma (LUAD) carries a poor prognosis at advanced stages underscoring the need to elucidate the underlying molecular mechanisms driving its pathogenesis. This study aimed to investigate the roles of eukaryotic translation initiation factor 3 subunit M ( Show less

Vascular dysfunction and capillary leak are common in critically ill COVID-19 patients, but identification of endothelial pathways involved in COVID-19 pathogenesis has been limited. Angiopoietin-like 4 (ANGPTL4) is a protein secreted in response to hypoxic and nutrient-poor conditions that has a variety of biological effects including vascular injury and capillary leak. To assess the role of ANGPTL4 in COVID-19-related outcomes. Two hundred twenty-five COVID-19 ICU patients were enrolled from April 2020 to May 2021 in a prospective, multicenter cohort study from three different medical centers, University of Washington, University of Southern California and New York University. Plasma ANGPTL4 was measured on days 1, 7, and 14 after ICU admission. We used previously published tissue proteomic data and lung single nucleus RNA (snRNA) sequencing data from specimens collected from COVID-19 patients to determine the tissues and cells that produce ANGPTL4. Higher plasma ANGPTL4 concentrations were significantly associated with worse hospital mortality (adjusted odds ratio per log ANGPTL4 is expressed in pulmonary epithelial cells and fibroblasts and is associated with clinical prognosis in critically ill COVID-19 patients. Show less

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P Show less

Compared to stage I-III gastric cancer (GC), the level of cell-free DNA (cfDNA) was significantly higher in stage IV GC. The mutation patterns of different metastatic patterns between cfDNA and tumor DNA in stage IV GC have not yet been reported. We used next-generation sequencing (NGS) to analyze cfDNA and tumor DNA in 56 stage IV GC patients. Tumor DNA and cfDNA were analyzed using a 29-gene NGS panel. In tumor samples, the most commonly mutated gene was Show less

Low levels of high density lipoprotein-cholesterol (HDL-C) are associated with an elevated risk of arteriosclerotic coronary heart disease. Heritability of HDL-C levels is high. In this research discovery study, we used whole-exome sequencing to identify damaging gene variants that may play significant roles in determining HDL-C levels. We studied 204 individuals with a mean HDL-C level of 27.8 ± 6.4 mg/dl (range: 4-36 mg/dl). Data were analyzed by statistical gene burden testing and by filtering against candidate gene lists. We found 120 occurrences of probably damaging variants (116 heterozygous; four homozygous) among 45 of 104 recognized HDL candidate genes. Those with the highest prevalence of damaging variants were ABCA1 (n = 20), STAB1 (n = 9), OSBPL1A (n = 8), CPS1 (n = 8), CD36 (n = 7), LRP1 (n = 6), ABCA8 (n = 6), GOT2 (n = 5), AMPD3 (n = 5), WWOX (n = 4), and IRS1 (n = 4). Binomial analysis for damaging missense or loss-of-function variants identified the ABCA1 and LDLR genes at genome-wide significance. In conclusion, whole-exome sequencing of individuals with low HDL-C showed the burden of damaging rare variants in the ABCA1 and LDLR genes is particularly high and revealed numerous occurrences in HDL candidate genes, including many genes identified in genome-wide association study reports. Many of these genes are involved in cancer biology, which accords with epidemiologic findings of the association of HDL deficiency with increased risk of cancer, thus presenting a new area of interest in HDL genomics. Show less

Although inflammatory mechanisms driving hepatocellular carcinoma (HCC) have been proposed, the regulators of anticancer immunity in HCC remain poorly understood. We found that IL27 receptor (IL27R) signaling promotes HCC development in vivo. High IL27EBI3 cytokine or IL27RA expression correlated with poor prognosis for patients with HCC. Loss of IL27R suppressed HCC in vivo in two different models of hepatocarcinogenesis. Mechanistically, IL27R sig-naling within the tumor microenvironment restrains the cytotoxicity of innate cytotoxic lymphocytes. IL27R ablation enhanced their accumulation and activation, whereas depletion or functional impairment of innate cytotoxic cells abrogated the effect of IL27R disruption. Pharmacologic neutralization of IL27 signaling increased infiltration of innate cytotoxic lymphocytes with upregulated cytotoxic molecules and reduced HCC development. Our data reveal an unexpected role of IL27R signaling as an immunologic checkpoint regulating innate cytotoxic lymphocytes and promoting HCC of different etiologies, thus indicating a therapeutic potential for IL27 pathway blockade in HCC. HCC, the most common form of liver cancer, is characterized by a poor survival rate and limited treatment options. The discovery of a novel IL27-dependent mechanism controlling anticancer cytotoxic immune response will pave the road for new treatment options for this devastating disease. This article is highlighted in the In This Issue feature, p. 1825. Show less

Anti-angiogenic therapies, such as anti-VEGF antibodies (AVAs), have shown promise in clinical settings. However, adaptive resistance to such therapies occurs frequently. We use orthotopic ovarian cancer models with AVA-adaptive resistance to investigate the underlying mechanisms. Genomic profiling of AVA-resistant tumors guides us to endothelial p130cas. We find that bevacizumab induces cleavage of VEGFR2 in endothelial cells by caspase-10 and that VEGFR2 fragments internalize into the nucleus and autophagosomes. Nuclear VEGFR2 and p130cas fragments, together with TNKS1BP1 (tankyrase-1-binding protein), initiate endothelial cell death. Blockade of autophagy in AVA-resistant endothelial cells retains VEGFR2 at the membrane with bevacizumab treatment. Targeting host p130cas with RGD (Arg-Gly-Asp)-tagged nanoparticles or genomic ablation of vascular p130cas in p130cas Show less

We previously reported on the role of pericyte-like cells as functional sentinel immune cells in lung injury. However, much about the biological role of pericytes in lung injury remains unknown. Lung pericyte-like cells are well-positioned to sense disruption to the epithelial barrier and coordinate local inflammatory responses due to their anatomic niche within the alveoli. In this report, we characterized transcriptional responses and functional changes in pericyte-like cells following activation by alveolar components from injured and uninjured lungs in a mouse model of acute lung injury (ALI). Purified pericyte-like cells from lung digests using PDGFRβ as a selection marker were expanded in culture as previously described (1). We induced sterile acute lung injury in mice with recombinant human Fas ligand (rhFasL) instillation followed by mechanical ventilation (1). We then collected bronchoalveolar lavage fluid (BALF) from injured and uninjured mice. Purified pericyte-like cells in culture were exposed to growth media only (control), BALF from uninjured mice, and BALF from injured mice for 6 and 24 hours. RNA collected from these treatment conditions were processed for RNAseq. Targets of interest identified by pathway analysis were validated using in vitro and in vivo assays. We observed robust global transcriptional changes in pericyte-like cells following treatment with uninjured and injured BALF at 6 hours, but this response persisted for 24 hours only after exposure to injured BALF. Functional enrichment analysis of pericytes treated with injured BALF revealed the activation of pro-inflammatory, cell migration, and angiogenesis-related pathways, whereas processes associated with tissue development and cell differentiation were down-regulated. We validated select upregulated targets in the inflammatory, angiogenic, and cell migratory pathways using functional biological assays in vitro and in vivo. We conclude that lung pericyte-like cells are highly responsive to alveolar compartment content from both uninjured and injured lungs, but injured BALF elicits a more sustained response. The inflammatory, angiogenic, and migratory changes exhibited by activated pericyte-like cells underscore the phenotypic plasticity of these specialized stromal cells in the setting of acute lung injury. Show less

Head and neck squamous cell carcinoma (HNSCC), which includes cancers of the oral cavity and oropharynx, is a cause of substantial global morbidity and mortality. Strategies to reduce disease burden include discovery of novel therapies and repurposing of existing drugs. Statins are commonly prescribed for lowering circulating cholesterol by inhibiting HMG-CoA reductase (HMGCR). Results from some observational studies suggest that statin use may reduce HNSCC risk. We appraised the relationship of genetically-proxied cholesterol-lowering drug targets and other circulating lipid traits with oral (OC) and oropharyngeal (OPC) cancer risk using two-sample Mendelian randomization (MR). For the primary analysis, germline genetic variants in HMGCR, NPC1L1, CETP, PCSK9 and LDLR were used to proxy the effect of low-density lipoprotein cholesterol (LDL-C) lowering therapies. In secondary analyses, variants were used to proxy circulating levels of other lipid traits in a genome-wide association study (GWAS) meta-analysis of 188,578 individuals. Both primary and secondary analyses aimed to estimate the downstream causal effect of cholesterol lowering therapies on OC and OPC risk. The second sample for MR was taken from a GWAS of 6,034 OC and OPC cases and 6,585 controls (GAME-ON). Analyses were replicated in UK Biobank, using 839 OC and OPC cases and 372,016 controls and the results of the GAME-ON and UK Biobank analyses combined in a fixed-effects meta-analysis. We found limited evidence of a causal effect of genetically-proxied LDL-C lowering using HMGCR, NPC1L1, CETP or other circulating lipid traits on either OC or OPC risk. Genetically-proxied PCSK9 inhibition equivalent to a 1 mmol/L (38.7 mg/dL) reduction in LDL-C was associated with an increased risk of OC and OPC combined (OR 1.8 95%CI 1.2, 2.8, p = 9.31 x10-05), with good concordance between GAME-ON and UK Biobank (I2 = 22%). Effects for PCSK9 appeared stronger in relation to OPC (OR 2.6 95%CI 1.4, 4.9) than OC (OR 1.4 95%CI 0.8, 2.4). LDLR variants, resulting in genetically-proxied reduction in LDL-C equivalent to a 1 mmol/L (38.7 mg/dL), reduced the risk of OC and OPC combined (OR 0.7, 95%CI 0.5, 1.0, p = 0.006). A series of pleiotropy-robust and outlier detection methods showed that pleiotropy did not bias our findings. We found limited evidence for a role of cholesterol-lowering in OC and OPC risk, suggesting previous observational results may have been confounded. There was some evidence that genetically-proxied inhibition of PCSK9 increased risk, while lipid-lowering variants in LDLR, reduced risk of combined OC and OPC. This result suggests that the mechanisms of action of PCSK9 on OC and OPC risk may be independent of its cholesterol lowering effects; however, this was not supported uniformly across all sensitivity analyses and further replication of this finding is required. Show less

Preterm birth severely threatens neonatal health and life. Although the detailed mechanism of preterm birth is not well understood, accurately predicting preterm birth can help people make preparations in advance, greatly reducing the subsequent health risk of neonates. Therefore, in this study, we aimed to identify potential protein biomarkers of preterm birth in amniotic fluid (AF). We first enrolled pregnant subjects and collected their AF samples when they underwent amniocentesis at the second trimester of gestation. After delivery, the collected AF samples were classified into a full-term birth (sample size n = 21) set or preterm birth (n = 36) set, followed by 2-D DIGE and MS/MS assays. By doing so, we identified seven potential protein biomarkers of preterm birth, three of which were further validated in all samples with ELISA, including Apolipoprotein A-IV (Apoa4), Lumican (Lum) and Kininogen-1 (Kng1). As a result, all three potential biomarkers were significantly differently expressed between preterm and full-term birth AF samples. Furthermore, without prior classification, we found that these three biomarkers were positively correlated with gestation age (correlation coefficient ranging from 0.25 to 0.38) and were able to predict the occurrence of preterm birth. In this study, by examining amniotic fluid, we identified three biomarker proteins that may facilitate the identification of preterm birth. There three proteins were never reported to be related to preterm birth. Their pathogenesis roles in preterm birth deserve further investigations by using in vitro cell model or in vivo animal model assays. Show less

CVD is the leading cause of death worldwide, and genetic investigations into the human lipidome may provide insight into CVD risk. The aim of this study was to estimate the heritability of circulating lipid species and their genetic correlation with CVD traits. Targeted lipidomic profiling was performed on 4,492 participants from the Busselton Family Heart Study to quantify the major fatty acids of 596 lipid species from 33 classes. We estimated narrow-sense heritabilities of lipid species/classes and their genetic correlations with eight CVD traits: BMI, HDL-C, LDL-C, triglycerides, total cholesterol, waist-hip ratio, systolic blood pressure, and diastolic blood pressure. We report heritabilities and genetic correlations of new lipid species/subclasses, including acylcarnitine (AC), ubiquinone, sulfatide, and oxidized cholesteryl esters. Over 99% of lipid species were significantly heritable (h Show less

Obesity and related metabolic diseases show clear sex-related differences. The growing burden of these diseases calls for better understanding of the age- and sex-related metabolic consequences. High-throughput lipidomic analyses of population-based cohorts offer an opportunity to identify disease-risk-associated biomarkers and to improve our understanding of lipid metabolism and biology at a population level. Here, we comprehensively examined the relationship between lipid classes/subclasses and molecular species with age, sex, and body mass index (BMI). Furthermore, we evaluated sex specificity in the association of the plasma lipidome with age and BMI. Some 747 targeted lipid measures, representing 706 molecular lipid species across 36 classes/subclasses, were measured using a high-performance liquid chromatography coupled mass spectrometer on a total of 10,339 participants from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab), with 563 lipid species being validated externally on 4,207 participants of the Busselton Health Study (BHS). Heat maps were constructed to visualise the relative differences in lipidomic profile between men and women. Multivariable linear regression analyses, including sex-interaction terms, were performed to assess the associations of lipid species with cardiometabolic phenotypes. Associations with age and sex were found for 472 (66.9%) and 583 (82.6%) lipid species, respectively. We further demonstrated that age-associated lipidomic fingerprints differed by sex. Specific classes of ether-phospholipids and lysophospholipids (calculated as the sum composition of the species within the class) were inversely associated with age in men only. In analyses with women alone, higher triacylglycerol and lower lysoalkylphosphatidylcholine species were observed among postmenopausal women compared with premenopausal women. We also identified sex-specific associations of lipid species with obesity. Lysophospholipids were negatively associated with BMI in both sexes (with a larger effect size in men), whilst acylcarnitine species showed opposing associations based on sex (positive association in women and negative association in men). Finally, by utilising specific lipid ratios as a proxy for enzymatic activity, we identified stearoyl CoA desaturase (SCD-1), fatty acid desaturase 3 (FADS3), and plasmanylethanolamine Δ1-desaturase activities, as well as the sphingolipid metabolic pathway, as constituent perturbations of cardiometabolic phenotypes. Our analyses elucidate the effect of age and sex on lipid metabolism by offering a comprehensive view of the lipidomic profiles associated with common cardiometabolic risk factors. These findings have implications for age- and sex-dependent lipid metabolism in health and disease and suggest the need for sex stratification during lipid biomarker discovery, establishing biological reference intervals for assessment of disease risk. Show less

The discovery of effective therapeutic options for treating metastatic poorly differentiated neuroendocrine carcinoma (NEC) after prior platinum-based chemotherapy remains elusive. This study analyzed the efficacy of TLC388 (Lipotecan) Hydrochloride, a novel camptothecin analog, for pretreated patients with metastatic NEC. This single-arm, two-stage, phase II clinical trial was conducted at four community and academic centers in Taiwan. Patients aged 20 years or older with confirmed metastatic NEC and who had received prior systemic therapy with etoposide plus cisplatin were enrolled between July 2015 and May 2018. Patients received 40 mg/m Twenty-three patients with a median age of 61 (range, 44-73) years, 18 of whom were men (78%), were enrolled. Patients received a median of 2 (range, 0-6) treatment cycles. Among 20 evaluable patients, 3 patients exhibited stable disease and no patient experienced a complete or partial remission, resulting in a disease control rate of 15%. Median progression-free survival was 1.8 (95% confidence interval [CI], 0.4-15) months, and the median overall survival was 4.3 (95% CI, 1.7-15) months. The most common treatment-related hematologic adverse events at grade 3 or higher were leukopenia (22.7%), anemia (31.8%), and thrombocytopenia (18.2%). The most frequent mutated genes in 35 patients with NEC were ARSA, DPYD, HEXB, BRCA1, HPD, MYBPC3, BBS2, IL7R, HSD17B4, and PRODH. TLC388 demonstrates limited antitumor activity in metastatic NEC. ClinicalTrials.gov identifier: NCT02457273. Poorly differentiated neuroendocrine carcinomas (NECs) are rare and aggressive. Currently, effective therapeutic options for treating metastatic poorly differentiated NECs beyond platinum-based chemotherapy remain elusive. In this single-arm, multicenter, phase II study, 23 patients with NEC were enrolled and received TLC388 (Lipotecan) Hydrochloride, which is a novel camptothecin analog. The results demonstrated the disease control rate of 15%, the median progression-free survival of 1.8 (95% confidence interval [CI], 0.4-15) months, and the median overall survival of 4.3 (95% CI, 1.7-15) months. Most importantly, several novel genetic mutations and pathways were identified. These results offer the opportunity to develop future treatment strategies in this rare cancer. Show less

Obesity has become a worldwide health concern. Pharmacotherapies are now being introduced because lifestyle modifications alone are insufficient for weight management. The treatment outcomes of current approved anti-obesity agents are not satisfying due to drug-related intolerances. And so natural therapies including herbal medicines are popular alternatives for weight reduction; however, there are limited studies about their mechanism of actions. Five databases (PubMed, Scopus, Google Scholar, Science Direct, Proquest) were searched to investigate the targets and safety profiles of the current and past anti-obesity drugs that have been approved by the Food and Drug Administration (FDA) or the European Medicines Agency (EMA) as well as the commonly used off-label agents. The targets for weight-loss natural products and their principle bioactive components have also been searched. Only articles in English were included. The targets for current anti-obesity single agents include pancreatic lipase, Glucagon Like Peptide-1(GLP-1) receptor, and serotonin 2C (5-HT2C) receptor. Potential targets such as amylin, pancreatic alpha amylase, leptin receptor, melanocortin receptor 4 receptor (MC4R), Peroxisome Proliferator- Activated Receptors gamma (PPAR γ), endocannabinoid 1 (CB1) receptor and Adenosine Monophosphate (AMP)-Activated Protein Kinase (AMPK) were discussed in various studies. Natural compounds have been found to interact with targets like pancreatic lipase, pancreatic alpha amylase, AMPK and PPAR γ to achieve weight reduction. Current pharmacotherapies and natural chemical compounds do act on same targets. Further investigations on the interactions between herbal compounds and the above targets are essential for the development of novel weight-loss therapies. Show less

Dyslipidemia and insulin resistance are significant adverse outcomes of consuming high-sugar diets. Conversely, dietary fish oil (FO) reduces plasma lipids. Diet-induced dyslipidemia in a rhesus model better approximates the pathophysiology of human metabolic syndrome (MetS) than rodent models. Here, we investigated relationships between metabolic parameters and hypertriglyceridemia in rhesus macaques consuming a high-fructose diet (n = 59) and determined the effects of FO supplementation or RNA interference (RNAi) on plasma ApoC3 and triglyceride (TG) concentrations. Fructose supplementation increased body weight, fasting insulin, leptin, TGs, and large VLDL particles and reduced adiponectin concentrations (all Show less

Urothelial carcinoma (UC) carcinogenesis has been hypothesized to occur through epigenetic repression of tumor-suppressor genes (TSGs). By quantitative real-time polymerase chain reaction array, we found that one potential TSG, angiopoietin-like 4 (ANGPTL4), was expressed at very low levels in all bladder cancer cell lines we examined. Previous studies had demonstrated that ANGPTL4 is highly expressed in some cancers, but downregulated, by DNA methylation, in others. Consequently, owing to these seemingly conflicting functions in distinct cancers, the precise role of ANGPTL4 in the etiology of UC remains unclear. In this study, using methylation-specific PCR and bisulfite pyrosequencing, we show that ANGPTL4 is transcriptionally repressed by DNA methylation in UC cell lines and primary tumor samples, as compared with adjacent noncancerous bladder epithelium. Functional studies further demonstrated that ectopic expression of ANGPTL4 potently suppressed UC cell proliferation, monolayer colony formation in vitro, and invasion, migration, and xenograft formation in vivo. Surprisingly, circulating ANGPTL4 was significantly higher in plasma samples from UC patients than normal control, suggesting it might be secreted from other cell types. Interestingly, our data also indicated that exogenous cANGPTL4 could promote cell proliferation and cell migration via activation of signaling through the Erk/focal adhesion kinase axis. We further confirmed that mouse xenograft tumor growth could be promoted by administration of exogenous cANGPTL4. Finally, immunohistochemistry demonstrated that ANGPTL4 was downregulated in tumor cells but overexpressed in tumor adjacent stromal tissues of muscle-invasive UC tissue samples. In conclusion, our data support dual roles for ANGPTL4 in UC progression, either as a tumor suppressor or oncogene, in response to microenvironmental context. Show less