Construction of a prognostic prediction model in liver cancer based on genes involved in integrin cell surface interactions pathway by multi-omics screening.

Background: Liver cancer is a common malignant tumor with an increasing incidence in recent years. We aimed to develop a model by integrating clinical information and multi-omics profiles of genes to predict survival of patients with liver cancer. Methods: The multi-omics data were integrated to identify liver cancer survival-associated signal pathways. Then, a prognostic risk score model was established based on key genes in a specific pathway, followed by the analysis of the relationship between the risk score and clinical features as well as molecular and immunologic characterization of the key genes included in the prediction model. The function experiments were performed to further elucidate the undergoing molecular mechanism. Results: Totally, 4 pathways associated with liver cancer patients' survival were identified. In the pathway of integrin cell surface interactions, low expression of COMP and SPP1, and low CNVs level of COL4A2 and ITGAV were significantly related to prognosis. Based on above 4 genes, the risk score model for prognosis was established. Risk score, ITGAV and SPP1 were the most significantly positively related to activated dendritic cell. COL4A2 and COMP were the most significantly positively associated with Type 1 T helper cell and regulatory T cell, respectively. The nomogram (involved T stage and risk score) may better predict short-term survival. The cell assay showed that overexpression of ITGAV promoted tumorigenesis. Conclusion: The risk score model constructed with four genes (COMP, SPP1, COL4A2, and ITGAV) may be used to predict survival in liver cancer patients.

Cytokine and chemokine map of peripheral specific immune cell subsets in Parkinson's disease.

Peripheral immune cells play a vital role in the development of Parkinson's disease (PD). However, their cytokine and chemokine secretion functions remain unclear. Therefore, we aimed to explore the cytokine and chemokine secretion functions of specific immune cell subtypes in drug-naïve patients with PD at different ages of onset. We included 10 early-onset and 10 late-onset patients with PD and age-matched healthy controls (HCs). We used mass cytometry to select specific immune cell subsets and evaluate intracellular cytokine and chemokine expression. Statistical tests included t-tests, analysis of variance, bivariate correlation analysis, and linear regression analysis. Compared with HCs, patients with PD exhibited significantly decreased intracellular pro-inflammatory cytokines and chemokines in selected clusters (e.g., tumor necrosis factor (TNF)-α, interleukin (IL)-8, IL-1ß, and CC-chemokine ligand (CCL)17). Specific cytokines and cell clusters were associated with clinical symptoms. TNF-α played an important role in cognitive impairment. Intracellular TNF-α levels in the naïve CD8+ T-cell cluster C16 (CD57- naïve CD8+ T) and natural killer (NK) cell cluster C32 (CD57- CD28- NK) were negatively correlated with Montreal Cognitive Assessment scores. The C16 cluster affected cognitive function and motor symptoms. Increased TNF-α and decreased interferon-γ expression in C16 correlated with increased Unified Parkinson's Disease Rating Scale III scores in patients with PD. In summary, we developed a more detailed cytokine and chemokine map of peripheral specific CD8+ T cell and NK cell subsets, which revealed disrupted secretory function in patients with PD and provided unique clues for further mechanistic exploration.

Elevated serum anti-Saccharomyces cerevisiae antibody accompanied by gut mycobiota dysbiosis as a biomarker of diagnosis in patients with de novo Parkinson disease.

BACKGROUND AND PURPOSE: Intestinal inflammation and gut microbiota dysbiosis contribute to Parkinson disease (PD) pathogenesis, and growing evidence suggests associations between inflammatory bowel diseases (IBD) and PD. Considered as markers of chronic gastrointestinal inflammation, elevated serum anti-Saccharomyces cerevisiae antibody (ASCA) levels, against certain gut fungal components, are related to IBD, but their effect on PD is yet to be investigated. METHODS: Serum ASCA IgG and IgA levels were measured using an enzyme-linked immunosorbent assay, and the gut mycobiota communities were investigated using ITS2 sequencing and analyzed using the Qiime pipeline. RESULTS: The study included 393 subjects (148 healthy controls [HCs], 140 with PD, and 105 with essential tremor [ET]). Both serum ASCA IgG and IgA levels were significantly higher in the PD group than in the ET and HC groups. Combining serum ASCA levels and the occurrence of constipation could discriminate patients with PD from controls (area under the curve [AUC] = 0.81, 95% confidence interval [CI] = 0.76-0.86) and from patients with ET (AUC = 0.85, 95% CI = 0.79-0.89). Furthermore, the composition of the gut fungal community differed between the PD and HC groups. The relative abundances of Saccharomyces cerevisiae, Aspergillus, Candida solani, Aspergillus flavus, ASV601_Fungi, ASV866_Fungi, and ASV755_Fungi were significantly higher in the PD group, and enriched Malassezia restricta was found in the HC group. CONCLUSIONS: Our study identified elevated serum ASCA levels and enriched gut Saccharomyces cerevisiae in de novo PD.

Different patterns of exosomal α-synuclein between Parkinson's disease and probable rapid eye movement sleep behavior disorder.

BACKGROUND AND PURPOSE: The insidious onset of Parkinson's disease (PD) makes early diagnosis difficult. Notably, idiopathic rapid eye movement sleep behavior disorder (iRBD) was reported as a prodrome of PD, which may represent a breakthrough for the early diagnosis of PD. However, currently there is no reliable biomarker for PD diagnosis. Considering that α-synuclein (α-Syn) and neuroinflammation are known to develop prior to the onset of clinical symptoms in PD, it was hypothesized that plasma total exosomal α-Syn (t-exo α-Syn), neural-derived exosomal α-Syn (n-exo α-Syn) and exosomal apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) may be potential biomarkers of PD. METHODS: In this study, 78 PD patients, 153 probable iRBD patients (pRBD) and 63 healthy controls (HCs) were recruited. α-Syn concentrations were measured using a one-step paramagnetic particle-based chemiluminescence immunoassay, and ASC levels were measured using the Ella system. RESULTS: It was found that t-exo α-Syn was significantly increased in the PD group compared to the pRBD and HC groups (p < 0.0001), whilst n-exo α-Syn levels were significantly increased in both the PD and pRBD groups compared to HCs (p < 0.0001). Furthermore, although no difference was found in ASC levels between the PD and pRBD groups, there was a positive correlation between ASC and α-Syn in exosomes. CONCLUSIONS: Our results suggest that both t-exo α-Syn and n-exo α-Syn were elevated in the PD group, whilst only n-exo α-Syn was elevated in the pRBD group. Additionally, the adaptor protein of inflammasome ASC is correlated with α-Syn and may facilitate synucleinopathy.

Associations of Body Mass Index-Metabolic Phenotypes with Cognitive Decline in Parkinson's Disease.

BACKGROUND: Growing evidence suggests important effects of body mass index (BMI) and metabolic status on neurodegenerative diseases. However, the roles of BMI and metabolic status on cognitive outcomes in Parkinson's disease (PD) may vary and are yet to be determined. METHODS: In total, 139 PD patients from the whole PD cohort in Parkinson's Progression Markers Initiative database underwent complete laboratory measurements, demographic and anthropometric parameters at baseline, and were enrolled in this study. Further, they were categorized into 4 different BMI-metabolic status phenotypes using Adult Treatment Panel-III criteria. Motor and cognition scales at baseline and longitudinal changes after a 48-month follow-up were compared among the 4 groups. Repeated-measure linear mixed models were performed to compare PD-related biomarkers among BMI-metabolic status phenotypes across time. RESULTS: We found that PD patients in the metabolically unhealthy normal weight group showed more cognitive decline in global cognition and visuospatial perception after a 48-month follow-up than those in the other 3 groups (p < 0.05). No difference was found in motor scales among different BMI-metabolic status phenotypes. Finally, compared to the metabolically healthy normal weight group, the metabolically healthy obesity group had lower CSF Aß42 and serum neurofilament levels in repeated-measure linear mixed models adjusting for age, gender, APOE e4 carrier status, and years of education (p = 0.031 and 0.046, respectively). CONCLUSION: The MUNW phenotype was associated with a rapid cognitive decline in PD.

The effect of anthocyanins supplementation on liver enzymes among patients with metabolic disorders: A systematic review and meta-analysis of randomized clinical trials.

The present study aims to summarize and quantitatively examine the available evidence on the effectiveness of anthocyanin supplementation on liver enzymes among patients with metabolic disorders, by employing a systematic review and meta-analytic approach. Online databases including PubMed/Medline, Scopus, ISI Web of Science, and Cochrane Library were searched up to June 2020 for randomized controlled trials (RCTs) that examined the effect of anthocyanin supplementation on serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) among patients with metabolic disorders. To estimate the overall effect of anthocyanin supplementation, we employed the random-effects model. In total, 12 RCTs were included in the systematic review. Pooled analysis did not show any significant changes in ALT (WMD: -0.92 U/L, 95% CI: -4.19 to 2.35, p = .58; I2  = 91.3%) and AST (WMD: -1.22 U/L, 95% CI: -3.43 to 0.99, p = .28; I2  = 87.0) concentrations after supplementation with anthocyanin. The dose and duration of supplementation were the potential sources of heterogeneity among most of the trials. However, subgroup analysis showed that the effect is not statistically significant in all subgroups. Overall, in our study, anthocyanin does not have any effect on liver enzyme levels significantly. However, future high-quality studies are still needed to confirm the results.

Concurrent tuberculous transverse myelitis and asymptomatic neurosyphilis: A case report.

BACKGROUND: Tuberculous myelitis is a rare manifestation of tuberculosis (TB) that is usually caused by hematogenous spread of Mycobacterium tuberculosis (MTB). Neurosyphilis is a neurological disease that occurs when Treponema pallidum invades the brain or the spinal cord. Individually, these two diseases involving the spinal cord are rare and cases of concurrent tuberculous transverse myelitis and asymptomatic neurosyphilis have seldom been reported. CASE SUMMARY: A 56-year-old man presented with numbness and pain of both lower limbs for 2 wk and dysuria for 1 wk. Syphilis serology and cerebrospinal fluid (CSF) analysis supported the diagnosis of neurosyphilis and the patient was treated with intravenous ceftriaxone at first, but symptoms still progressed. Then, magnetic resonance images revealed multiple lesions along the cervicothoracic junction, and chest computed tomography showed a typical TB lesion. MTB DNA was detected in the CSF sample by metagenomic next-generation sequencing. Eventually the patient was diagnosed with tuberculous myelitis combined with asymptomatic neurosyphilis. Subsequently, quadruple anti-TB drug standardized therapy was empirically used and his neurological symptoms improved gradually. CONCLUSION: Patients can have coinfection with tuberculous transverse myelitis and asymptomatic neurosyphilis. Patients with neurosyphilis should be examined for other pathogens.

The effect of the PARK16 rs11240572 variant on brain structure in Parkinson's disease.

Increasing evidence suggests that genetic factors play a key role in the development of Parkinson's disease (PD). The variant rs11240572 in the PARK16 gene locus is strongly associated with PD. However, its effect on the pathogenesis of PD is yet to be clarified. The objective of the study was to explore the effect of the PARK16 rs11240572 variant on brain structure in PD patients. A total of 51 PD patients were enrolled in the study and genotyped for the rs11240572 variant. Clinical assessments and MRI scans were conducted across all participants. Voxel-based morphometry (VBM) was used to investigate gray matter volume (GMV) of the whole brain between these two groups. Correlation analysis was performed to identify the relationships between GMV and clinical features. There were 17 rs11240572-A variant carriers and 34 non-carriers, with no significant demographic differences between these two groups. Compared with non-carriers, rs11240572-A carriers showed increased GMV in the left caudate nucleus and putamen, but decreased GMV in the left superior temporal gyrus and supramarginal gyrus. In non-carriers, left basal ganglia GMV was positively correlated with UPDRS III (r = 0.365, p = 0.034) and bradykinesia (r = 0.352, p = 0.042), but negatively correlated with MMSE (r = - 0.344, p = 0.047), while in carriers negative correlation between basal ganglia GMV and MMSE was also observed (r = - 0.666, p = 0.004). Moreover, the GMV of left temporoparietal cortex was positively associated with cognitive function in both groups (carriers, r = 0.692, p = 0.002; non-carriers, r = 0.879, p < 0.001). When reducing the sample size of non-carriers to the level of the carrier sample, similar correlations were observed in both groups. Our study showed that the PARK16 rs11240572 variant affects the brain structure of patients with PD, especially in the basal ganglia and temporoparietal cortex. This indicated that this variant might play an important role in the pathogenesis of PD.

Therapeutic effects of Yiqi Huoxue prescription on diabetic nephropathy: a meta-analysis and systematic review.

BACKGROUND: Traditional Chinese medicine (TCM) has demonstrated excellent effects in treating diabetic nephropathy, and Yiqi Huoxue prescription has been widely used clinically. In the study, its effects on the kidney function and blood glucose of patients were explored. METHODS: Chinese and English databases including PubMed, Medline, Embase, and Web of Sciences were used to retrieve articles comparing the treatment of diabetic nephropathy using Yiqi Huoxue prescription on the basis of conventional Western medicine treatment (experimental group) and conventional Western medicine treatment alone (control group) published from January 2000 to December 2020. The risk of bias assessment tool of the Cochrane System Review Manual 5.2.2 and the Jadad scale were used to evaluate the quality of the included literature. The outcome indexes were extracted, and the Review Manager 5.3 software was used for meta-analysis. RESULTS: A total of 13 articles that satisfied the inclusion/exclusion criteria were included in this study. After treatment, compared to the control group, the experimental group exhibited lower urine microalbumin excretion rate (UAER) [mean difference (MD) =-33.94, 95% confidence interval (CI), -42.60 to -25.28, P<0.00001], serum creatinine (SCr) (MD =-7.43, 95% CI, -11.50 to -3.36, P=0.0004), blood urea nitrogen (BUN) (SMD =-1.23, 95% CI, -2.49 to 0.03, P=0.04), blood glucose-related indexes [fasting blood glucose (FBG)] (MD =-0.43, 95% CI, -0.87 to 0.01, P=0.03), glycosylated hemoglobin (HbA1c) (MD =-0.38, 95% CI, -0.68 to -0.08, P=0.01), blood lipid-related indexes [triglycerides (TG)] (MD =-0.44, 95% CI, -0.76 to -0.13, P=0.006), and serum total cholesterol (TC) (MD =-0.37, 95% CI, -0.57 to -0.18, P=0.0002). Furthermore, the experimental group also showed higher effectiveness rate (odds ratio =3.81, 95% CI, 2.71 to 5.35, P<0.00001) after treatment. DISCUSSION: The included literature had low bias risk. Yiqi Huoxue prescription on the basis of conventional Western medicine can significantly improve the renal function and reduce the levels of blood glucose and blood lipids of patients with diabetic nephropathy.

The effect of sedentary time on the results of exercise therapy in patients with peripheral arterial disease complicated with type 2 diabetes.

BACKGROUND: Peripheral artery disease (PAD) is a common chronic complication of type 2 diabetes (T2DM). This study sought to evaluate the effect of supervised exercise therapy (SET) on patients with PAD complicated with T2DM, and to assess the effect of changes in sedentary time on the results of SET treatment. METHODS: A total of 100 PAD patients who were treated in our hospital from January 2019 to October 2020 were included, and the age, gender, body mass index (BMI), hypertension, smoking, and ankle brachial index (ABI) were collected. The patients were required to complete SET treatment 2-3 times a week for 12 weeks. Subsequently, the objective 6-minute walk test (6MWT) and Short Physical Performance Battery (SPPB) were used to assess body function. After adjusting for other key confounding variables such as age, gender, and smoking status, linear regression analysis was used to evaluate the effects of changes in sedentary time on the total distance of the 6MWT. RESULTS: After 12 weeks of treatment, the total SPPB score of the patients increased from a baseline of 9.3±2.7 to 10.1±2.3 (P=0.025), the normal walking distance in the 6MWT increased from 108.9±26.8 to 148.9±29.5 m (P<0.001), the total walking distance increased from 322.5±93.4 to 348.5±86.1 m (P=0.042), and at the same time, the metabolic equivalent on the treadmill increased from 2.6±0.7 to 3.9±1.4 (P<0.001). Compared with the baseline data, the proportion of time that patients spent engaged in mild physical activity at 6 weeks increased by 20%±10% (P=0.003), and the average daily sedentary time decreased by 6.5±2.8 minutes (P=0.008), or by 3.1%±2.1% (P=0.04). Furthermore, compared with the baseline, the proportion of time that patients spent engaged in light and moderate physical activity at 12 weeks increased by 10%±3% (P=0.007) and 20%±10% (P=0.006), respectively, while the average sedentary time per day reduced by 6.8±3.1 minutes (P=0.03), or by 3.6%±1.8% (P=0.005). CONCLUSIONS: The reduction of sedentary time can significantly improve the effectiveness of exercise therapy in patients with PAD complicated by T2DM, and compared with patients with PAD alone, the improvement in patients complicated with T2DM is more significant.

Double-hit lymphoma (rearrangements of MYC, BCL-2) during pregnancy: A case report.

BACKGROUND: Double-hit lymphoma is a highly aggressive B-cell lymphoma that is genetically characterized by rearrangements of MYC and BCL2 and/or BCL6. Lymphoma is often accompanied by atypical systemic symptoms similar to physiological changes during pregnancy and is often ignored. Herein, we describe a gravid patient with high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body. CASE SUMMARY: A 32-year-old female, gestational age 22+5 wk, complained of abdominal distension, chest tightness and limb weakness lasting approximately 4 wk, and ovarian tumors were found 14 d ago. Auxiliary examinations and a trimanual gynecologic examination suggested malignant ovarian tumor and frozen pelvis. Coupled with rapid progression, severe compression symptoms of hydrothorax, ascites and moderate anemia, labor was induced. Next, biopsy and imaging examinations showed high-grade B-cell lymphoma with a MYC and BCL-2 gene rearrangement involving multiple parts of the body. She was referred to the Department of Oncology and Hematology for chemotherapy. Because of multiple recurrences after complete remission, chemotherapy plans were continuously adjusted. At present, the patient remains in treatment and follow-up. CONCLUSION: The early detection and accurate diagnosis of lymphoma during pregnancy can help expedite proper multidisciplinary treatment to delay disease progression and decrease the mortality rate.

From inflammasome to Parkinson's disease: Does the NLRP3 inflammasome facilitate exosome secretion and exosomal alpha-synuclein transmission in Parkinson's disease?

A pivotal neuropathological manifestation of synucleinopathies, like Parkinson's disease (PD), is the aggregation of α-synuclein. In a recent cell-to-cell transmission model of α-synuclein, α-synuclein propagation was demonstrated to resemble that of prion proteins in the central nervous system. Furthermore, exosomes, as biomolecule carriers, have been shown to transmit α-synuclein from neuron to neuron. However, the mechanisms underlying exosomal α-synuclein transmission have not been well understood. The NLR family pyrin domain containing 3 protein (NLRP3) inflammasome activation in microglia, and the subsequent release of proinflammatory cytokines, are two crucial pathological events involved in neuroinflammation and PD progression. Research has revealed that the NLRP3 inflammasome may facilitate the secretion of extracellular vesicles, as well as exosomal transmission of proteins like aggregated α-synuclein. However, only a few reports have evaluated these pathogenic mechanisms. Herein we evaluate for the first time the current evidence for the involvement of the NLRP3 inflammasome in microvesicle generation by microglial cells, and the various mechanisms regarding the production, shedding, and content of exosomes in relation to α-synuclein transmission from neuron to neuron. Furthermore, we propose a model of microglial NLRP3 inflammasome-dependent exosome secretion and exosomal α-synuclein transmission in PD. This knowledge may lead to the identification of novel potential targets for drug development and stimulate further research in PD.

Different Perivascular Space Burdens in Idiopathic Rapid Eye Movement Sleep Behavior Disorder and Parkinson's Disease.

BACKGROUND: Excessive aggregation of α-synuclein is the key pathophysiological feature of Parkinson's disease (PD). Rapid eye movement sleep behavior disorder (RBD) is also associated with synucleinopathies and considered as a powerful predictor of PD. Growing evidence suggests the diminished clearance of α-synuclein may be partly attributable to poor interstitial fluid drainage, which can be reflected by magnetic resonance imaging (MRI)-visible enlarged perivascular space (EPVS). However, the effect of MRI-visible EPVS on iRBD and PD, and their correlation with clinical characteristics remain unclear. OBJECTIVE: To evaluate the clinical and neuroimaging significance of MRI-visible EPVS in iRBD and PD patients. METHODS: We enrolled 33 iRBD patients, 82 PD (with and without RBD) patients, and 35 healthy controls (HCs), who underwent clinical evaluation and 3.0 Tesla MRI. Two neurologists assessed MRI-visible EPVS in centrum semiovale (CSO), basal ganglia (BG), substantia nigra (SN), and brainstem (BS). Independent risk factors for iRBD and PD were investigated using multivariable logistic regression analysis. Spearman analysis was used to test the correlation of MRI-visible EPVS with clinical characteristics of patients. RESULTS: iRBD patients had significantly higher EPVS burdens (CSO, BG, SN, and BS) than PD patients. Higher CSO-EPVS and BS-EPVS burdens were independent risk factors for iRBD. Furthermore, higher CSO-EPVS and SN-EPVS burdens were positively correlated with the severity of clinical symptom in iRBD patients, and higher BG-EPVS burden was positively correlated with the severity of cognitive impairment in PD patients. CONCLUSION: iRBD and PD patients have different MRI-visible EPVS burdens, which may be related with a compensatory mechanism in glymphatic system. Lower MRI-visible EPVS burden in PD patients may be a manifestation of severe brain waste drainage dysfunction. These findings shed light on the pathophysiologic relationship between iRBD and PD with respect to neuroimaging marker of PD.

MRI-visible perivascular spaces are associated with cerebrospinal fluid biomarkers in Parkinson's disease.

Perivascular spaces in the brain have been known to communicate with cerebrospinal fluid and contribute to waste clearance in animal models. In this study, we sought to determine the association between MRI-visible enlarged perivascular spaces (EPVS) and disease markers in Parkinson's disease (PD). We obtained longitudinal data from 245 patients with PD and 98 healthy controls from the Parkinson's Progression Marker Initiative. Two trained neurologists performed visual ratings on T2-weighted images to characterize EPVS in the centrum semiovale (CSO), the basal ganglia (BG) and the midbrain. We found that a greater proportion of patients with PD had low grade BG-EPVS relative to healthy controls. In patients with PD, lower grade of BG-EPVS and CSO-EPVS predicted lower CSF α-synuclein and t-tau. Lower grade of BG-EPVS were also associated with accelerated Hoehn &Yahr stage progression in patients with baseline stage 1. BG-EPVS might be a valuable predictor of disease progression.

Genetic testing of FUS, HTRA2, and TENM4 genes in Chinese patients with essential tremor.

INTRODUCTION: Essential tremor (ET) is one of the most prevalent movement disorders. The genetic etiology of ET has not been well defined although a significant proportion (≥50%) are familial cases. Linkage analysis and genome-wide association studies (GWASs) have identified several risk variants. In recent years, whole-exome sequencing of ET has revealed several specific causal variants in FUS (p.Q290X), HTRA2 (p.G399S), and TENM4 (c.4324 G>A, c.4100C>A, and c.3412G>A) genes. OBJECTIVE: To investigate the genetic contribution of these three genes to ET, the protein-coding sequences of FUS, HTRA2, and TENM4 were analyzed in a total of 238 ET patients and 272 controls from eastern China using direct Sanger sequencing. RESULTS: We identified two synonymous coding single nucleotide polymorphisms (SNPs), rs741810 and rs1052352 in FUS, and three previously reported synonymous SNPs, rs11237621, rs689369, and rs2277277 in TENM4. No nonsynonymous exonic variants were identified in these subjects. We found that the frequency of the rs1052352C allele was significantly higher (P = .001) in the ET group than in the control group. CONCLUSION: Overall, our findings suggest that rs1052352 of FUS might contribute to ET risk in Chinese population.

A Novel Mutation Of The EMD Gene In A Family With Cardiac Conduction Abnormalities And A High Incidence Of Sudden Cardiac Death.

BACKGROUND: Emery-Dreifuss muscular dystrophy, caused by mutations in genes such as emerin (EMD) or lamin A/C (LMNA), is a disorder affecting the joints, muscles, and heart, with a wide spectrum of patient phenotypes including muscle wasting and cardiac conduction defects. METHODS AND RESULTS: Here we report a multi-generation family from the Hunan Province of China. Affected family members displayed an uncommon clinical presentation of serious cardiac conduction abnormalities at an early age and a high incidence of sudden cardiac death along with mild skeletal muscular atrophy and joint contracture. Clinical analysis of affected members provided evidence of X-linked recessive inheritance. Consequently, using Sanger sequencing of X chromosome exomes, we identified a novel duplication mutation (c.405dup/p.Asp136X) in the EMD gene as the cause for the disease in this family. This variant is a novel mutation that has not been previously reported in Pubmed, Clinvar or other cases reported in the Human Gene Mutation Database. CONCLUSION: Our finding expands the mutation spectrum of Emery-Dreifuss muscular dystrophy and provides a rationale for EMD mutation testing in cases of X-linked inherited cardiac conduction disease and sudden cardiac death, even in those lacking pathognomonic neuromuscular features.

Bioaccessibility and cellular uptake of ß-carotene in emulsion-based delivery systems using scallop (Patinopecten yessoensis) gonad protein isolates: effects of carrier oil.

Emulsion-based delivery systems were structured by using scallop gonad protein isolates (SGPIs) as novel food-grade emulsifiers. The effects of carrier oil, including the long chain triglycerides (LCT) and medium chain triglycerides (MCT), on the bioaccessibility and cellular uptake of ß-carotene (BC) were investigated. Both LCT and MCT delivery systems remained stable at pH 7-8 but aggregated at lower pH values (3-6) according to the results of light scattering and microscopy measurements. LCT droplets fabricated within SGPIs were digested and released more slowly than MCT droplets during the simulated gastrointestinal tract digestion. The LCT emulsion showed higher BC bioaccessibility (65.5%) than the MCT emulsion (23.1%) as a result of the greater solubilization of BC in mixed micelles fabricated from long-chain fatty acids. Moreover, the LCT emulsion produced higher cellular uptake of BC as compared with the MCT emulsion in intestinal epithelial cells. These results demonstrated that SGPIs could be used as novel food-grade emulsifiers to protect lipophilic bioactive compounds in emulsion-based delivery systems, in which LCT is more suitable to encapsulate and deliver BC than MCT.

Photooxidatively crosslinked acellular tumor extracellular matrices as potential tumor engineering scaffolds.

Acellular tumor extracellular matrices (ECMs) have limitations when employed as three-dimensional (3D) scaffolds for tumor engineering. In this work, methylene blue-mediated photooxidation was used to crosslink acellular tumor ECMs. Photooxidative crosslinking greatly increased the stiffness of acellular tumor ECM scaffolds but barely altered the Amide III band of the secondary structure of polypeptides and proteins. MCF-7, HepG2 and A549 cells cultured on photooxidatively crosslinked acellular tumor ECM scaffolds exhibited greater cell number per scaffold, more IL-8 and VEGF secretion, and increase migration and invasion abilities than cells cultured on uncrosslinked acellular tumor ECM scaffolds. The three tumor cell lines cultured on the stiffer photooxidatively crosslinked acellular matrices acquire mesenchymal properties (mesenchymal shift) and dedifferentiated phenotypes. Furthermore, the malignant phenotypes induced in vitro when cultured on the crosslinked scaffold promoted the in vivo tumor growth of BALB/c nude mice. Finally, the dedifferentiated cancer cells, including MCF-7, HepG2 and A549 cells, were less sensitive to chemotherapeutics. Thus, photooxidatively crosslinked acellular tumor ECMs have potentials as 3D tumor engineering scaffolds for cancer research. STATEMENT OF SIGNIFICANCE: Natural material scaffolds have been successfully used as 3D matrices to study the in vitro tumor cell growth and mimic the in vivo tumor microenvironment. Acellular tumor ECMs are developed as 3D scaffolds for tumor engineering but have limitations in terms of elastic modulus and cell spheroid formation. Here we use methylene blue-mediated photooxidation to crosslink acellular tumor ECMs and investigate the influence of photooxidative crosslinking on structural, mechanical and biological characteristics of acellular tumor ECM scaffolds. It is the first study to evaluate the feasibility of photooxidatively crosslinked acellular tumor ECMs as 3D scaffolds for cancer research and the results are encouraging. Moreover, this study provides new research areas in regard to photodynamic therapy (PDT) for Cancer.

MircroRNA-19a promotes vascular inflammation and foam cell formation by targeting HBP-1 in atherogenesis.

Atherosclerosis, a serious threat to human cardiovascular health, involves inflammation throughout its various stages of development. MicroRNAs play an important regulatory role in macrophages that respond to inflammation, but the underlying mechanisms are largely unknown. In this work, we study the impact of miR-19a in macrophage-derived foam cell formation during atherogenesis. A microarray-based analysis of serums from patients with coronary heart disease in comparison with healthy controls reveals a significant enrichment of miR-19a in the serums of atherosclerosis patients. A higher level of miR-19a is also observed in atherosclerosis-prone ascending aortic wall tissues than in internal mammary artery amongst patients with coronary heart disease. We identify HMG-Box Transcription Factor 1 (HBP-1) as a target gene of miR-19a. HBP1 is repressor of macrophage migration inhibiting factor (MIF) and overexpression of miR-19a increases MIF expression. By administering a miR-19a antagonist to the caudal vein, we found a decrease in atherosclerotic plaques and lipids load in apoE-null mice fed with high-fat diet. These results support inhibition of miR-19a reduces inflammatory reaction and constitutes a potent therapeutic approach against atherosclerosis.