C-reactive protein (CRP) is a heritable biomarker of systemic inflammation and a predictor of cardiovascular disease (CVD). Large-scale genetic association studies for CRP have largely focused on individuals of European descent. We sought to uncover novel genetic variants for CRP in a multi-ethnic sample using the ITMAT Broad-CARe (IBC) array, a custom 50,000 SNP gene-centric array having dense coverage of over 2,000 candidate CVD genes. We performed analyses on 7570 African Americans (AA) from the Candidate gene Association Resource (CARe) study and race-combined meta-analyses that included 29,939 additional individuals of European descent from CARe, the Women’s Health Initiative (WHI) and KORA studies. We observed array-wide significance (p<2.2×10−6) for four loci in AA, three of which have been reported previously in individuals of European descent (IL6R, p=2.0×10−6; CRP, p=4.2×10−71; APOE, p=1.6×10−6). The fourth significant locus, CD36 (p=1.6×10−6), was observed at a functional variant (rs3211938) that is extremely rare in individuals of European descent. We replicated the CD36 finding (p=1.8×10−5) in an independent sample of 8041 AA women from WHI; a meta-analysis combining the CARe and WHI AA results at rs3211938 reached genome-wide significance (p=1.5×10−10). In the race-combined meta-analyses, 13 loci reached significance, including ten (CRP, TOMM40/APOE/APOC1, HNF1A, LEPR, GCKR, IL6R, IL1RN, NLRP3, HNF4A and BAZ1B/BCL7B) previously associated with CRP, and one (ARNTL) previously reported to be nominally associated with CRP. Two novel loci were also detected (RPS6KB1, p=2.0×10−6; CD36, p=1.4×10−6). These results highlight both shared and unique genetic risk factors for CRP in AA compared to populations of European descent.
C-reactive protein; Inflammation; Multi-ethnic; Candidate gene
To develop novel anti-ischemic stroke agents with better therapeutic efficacy and bioavailability, we designed and synthesized a series of 3-alkyl-2,3-dihydro-1H-isoindol-1-ones compounds (3a–i) derivatives, one of which (3d) exhibited the strongest inhibitory activity for the adenosine diphosphate-induced and arachidonic acid-induced platelet aggregation. This activity is superior to that of 3-n-butylphthalide and comparable with aspirin and edaravone. Meanwhile, 3d not only exhibited a potent activity in scavenging free radicals and improving the survival of HT22 cells against the reactive oxygen species-mediated cytotoxicity in vitro but also significantly attenuated the ischemia/reperfusion-induced oxidative stress in ischemic rat brains. Results from transient middle cerebral artery occlusion and permanent middle cerebral artery occlusion model, indicated that 3d could significantly reduce infarct size, improve neurobehavioral deficits, and prominently decrease attenuation of cerebral damage. Most importantly, 3d possessed a very high absolute bioavailability and was rapidly distributed in brain tissue to keep high plasma drug concentration for the treatment of ischemic strokes. In conclusion, our findings suggest that 3-alkyl-2,3-dihydro-1H-isoindol-1-ones, a novel series of compounds, might be candidate drugs for the treatment of acute ischemic strokes, and 3d may be a promising therapeutic agent for the primary and secondary prevention of ischemic stroke.
stroke; platelet aggregation; ischemia/reperfusion; middle cerebral artery occlusion; 3-alkyl-2,3-dihydro-1H-isoindol-1-ones
A number of epidemiologic studies examining the relationship between body mass index (BMI) and the future occurrence of Parkinson’s disease (PD) reported largely inconsistent findings. We conducted a dose-response meta-analysis of prospective studies to clarify this association.
Eligible prospective studies were identified by a search of PubMed and by checking the references of related publications. The generalized least squares trend estimation was employed to compute study-specific relative risks (RR) and 95% confidence intervals (CI) for an increase in BMI of 5 kg/m2, and the random-effects model was used to compute summary RR and 95% CI.
A total of 10 prospective studies were included in the final analysis. An increase in BMI of 5 kg/m2 was not associated with PD risk, with a summary RR of 1.00 (95% CI = 0.89-1.12). Results of subgroup analysis found similar results except for a week positive association in studies that adjusted for alcohol consumption (RR = 1.13, 95% CI = 0.99-1.29), and a week inverse association in studies that did not (RR = 0.90, 95% CI = 0.78-1.04). In a separate meta-analysis, no significant association between overweight (25 kg/m2 ≤ BMI ≤29.9 kg/m2), obesity (BMI≥30 kg/m2) or excess weight (BMI≥25 kg/m2) and PD risk was observed.
This meta-analysis does not support the notion that higher BMI materially increases PD risk. However, a week positive BMI-PD association that may be masked by confounders still cannot be excluded, and future prospective studies with a good control for potential confounding factors are needed.
Coxsackievirus A4 (CV-A4) is classified as human enterovirus A according to its serotype. CV-A4, an etiological agent of hand, foot, and mouth disease, affects children worldwide and can circulate in closed environments such as schools and hospitals for long periods.
An outbreak of febrile illness at a nursery school in Beijing, China, was confirmed to be caused by CV-A4. Phylogenetic analysis of the complete genome of the isolated strain showed that the virus belongs to the same cluster as the predominant CV-A4 strain in China. This outbreak was controlled by effective measures.
The early identification of the pathogen and timely intervention may be the most critical factors in controlling an outbreak caused by CV-A4 in a preschool.
Coxsackievirus A4; Outbreak; Preschool; Prevention; Control
The Centre for the AIDS Programme of Research in South Africa 004 (CAPRISA 004) study demonstrated that vaginally applied tenofovir gel is a promising intervention for protecting women from sexually acquiring human immunodeficiency virus (HIV). However, the potential for emergence of tenofovir resistance remains a concern in women who seroconvert while using the gel despite the lack of plasma virus resistance as assessed by population sequencing during the trial. We applied highly sensitive polymerase chain reaction–based assays to screen for tenofovir resistance in plasma and vaginal swab specimens. The absence of mutation detection suggested little immediate risk of tenofovir-resistant HIV-1 emergence and forward transmission in settings in which gel users are closely monitored for HIV seroconversion.
Vaginal microbicide; HIV prevention; pre-exposure prophylaxis; tenofovir gel; topical PrEP
The influence of catechol-o-methyltransferase (COMT) Val158Met on brain activation and functional connectivity has been widely reported. However, voxel-wise effects of this genotype on resting-state brain networks remain unclear. Here, we used resting-state fMRI and eigenvector centrality to examine the effects of COMT Val158Met genotypes on the connection patterns of the brain network and working memory (WM) in healthy, young Val/Val and Met carrier subjects. There were significant differences in the performance level on the 2-back WM task between the different COMT genotypes: Val/Val individuals exhibited a higher correct rate compared to the Met carriers. A two-sample t test was used to examine the differences in the eigenvector centrality maps, using age and gender as covariates of no interest, between the Val/Val and Met carriers. We found that the Val/Val individuals exhibited significantly higher eigenvector centrality compared to the Met carriers in the left parahippocampal cortex. Furthermore, a significantly positive correlation between the mean eigenvector centrality of the significant cluster and the correct rate of the 2-back WM task was observed. By using a voxel-wise data-driven method, our findings may provide plausible implications regarding individual differences in the genetic contribution of COMT Val158Met to the brain network and cognition.
The genetic diversity, evolution, distribution, and taxonomy of some coronaviruses dominant in birds other than chickens remain enigmatic. In this study we sequenced the genome of a newly identified coronavirus dominant in ducks (DdCoV), and performed a large-scale surveillance of coronaviruses in chickens and ducks using a conserved RT-PCR assay. The viral genome harbors a tandem repeat which is rare in vertebrate RNA viruses. The repeat is homologous to some proteins of various cellular organisms, but its origin remains unknown. Many substitutions, insertions, deletions, and some frameshifts and recombination events have occurred in the genome of the DdCoV, as compared with the coronavirus dominant in chickens (CdCoV). The distances between DdCoV and CdCoV are large enough to separate them into different species within the genus Gammacoronavirus. Our surveillance demonstrated that DdCoVs and CdCoVs belong to different lineages and occupy different ecological niches, further supporting that they should be classified into different species. Our surveillance also demonstrated that DdCoVs and CdCoVs are prevalent in live poultry markets in some regions of China. In conclusion, this study shed novel insight into the genetic diversity, evolution, distribution, and taxonomy of the coronaviruses circulating in chickens and ducks.
Heparanase is an endo-β-glucuronidase that specifically cleaves heparan sulfate proteoglycans in the extracellular matrix. Expression of this enzyme is increased in several pathological conditions including inflammation. We have investigated the role of heparanase in pulmonary inflammation in the context of allergic and non-allergic pulmonary cell recruitment using heparanase knockout (Hpa-/-) mice as a model. Following local delivery of LPS or zymosan, no significant difference was found in the recruitment of neutrophils to the lung between Hpa-/- and wild type (WT) control. Similarly neutrophil recruitment was not inhibited in WT mice treated with a heparanase inhibitor. However, in allergic inflammatory models, Hpa-/- mice displayed a significantly reduced eosinophil (but not neutrophil) recruitment to the airways and this was also associated with a reduction in allergen-induced bronchial hyperresponsiveness, indicating that heparanase expression is associated with allergic reactions. This was further demonstrated by pharmacological treatment with a heparanase inhibitor in the WT allergic mice. Examination of lung specimens from patients with different severity of chronic obstructive pulmonary disease (COPD) found increased heparanase expression. Thus, it is established that heparanase contributes to allergen-induced eosinophil recruitment to the lung and could provide a novel therapeutic target for the development of anti-inflammatory drugs for the treatment of asthma and other allergic diseases.
Pericardial calcification is detrimental to the long-term durability of valvuloplasty. However, whether calcification susceptibility differs between heterologous and autologous pericardium is unclear. In this study, we compared the progression of calcification in vivo between autologous and heterologous pericardium.
We randomly divided 28 rabbits into 4 equal groups. Resected rabbit pericardium served as autologous pericardium, and commercial bovine pericardium served as heterologous pericardium. We subcutaneously embedded one of each pericardial patch in the abdominal walls of 21 of the rabbits. The 7 control rabbits (group A) received no implants. The embedded samples were removed at 2 months in group B, at 4 months in group C, and at 6 months in group D. Each collected sample was divided into 2 parts, one for calcium-content measurement by means of atomic-absorption spectroscopy, and one for morphologic and histopathologic examinations.
When compared with the autologous pericardium, calcium levels in the heterologous pericardium were higher in groups B, C, and D (P <0.0001, P <0.0002, and P <0.0006, respectively). As embedding time increased, calcium levels in the heterologous pericardium increased faster than those in the autologous, especially in group D. Disorganized arrangements of collagenous fibers, marked calculus, and ossification were seen in the heterologous pericardium. Inflammatory cells—mainly lymphocytes and small numbers of macrophages—infiltrated the heterologous pericardium.
The autologous pericardium showed a stronger ability to resist calcification. Our results indicate that autologous pericardium might be a relatively better choice for valvuloplasty.
Aortic valve/pathology/surgery; calcinosis/pathology/prevention & control; disease models, animal; pericardium/pathology/transplantation; rabbits; reconstructive surgical procedures/methods; time factors; transplantation, autologous; transplantation, heterologous
Oxidative stress has been known to be involved in pathogenesis of dry eye disease. However, few studies have comprehensively investigated the relationship between hyperosmolarity and oxidative damage in human ocular surface. This study was to explore whether and how hyperosmolarity induces oxidative stress markers in primary human corneal epithelial cells (HCECs). Primary HCECs were established from donor limbal explants. The hyperosmolarity model was made in HCECs cultured in isosmolar (312 mOsM) or hyperosmotic (350, 400, 450 mOsM) media. Production of reactive oxygen species (ROS), oxidative damage markers, oxygenases and anti-oxidative enzymes were analyzed by DCFDA kit, RT-qPCR, immunofluorescent and immunohistochemical staining and Western blotting. Compared to isosmolar medium, ROS production significantly increased at time- and osmolarity-dependent manner in HCECs exposed to media with increasing osmolarities (350–450 mOsM). Hyperosmolarity significantly induced oxidative damage markers in cell membrane with increased toxic products of lipid peroxidation, 4–hydroxynonenal (4-HNE) and malondialdehyde (MDA), and in nuclear and mitochondria DNA with increased aconitase-2 and 8-OHdG. Hyperosmotic stress also increased the mRNA expression and protein production of heme oxygenase-1 (HMOX1) and cyclooxygenase-2 (COX2), but reduced the levels of antioxidant enzymes, superoxide dismutase-1 (SOD1), and glutathione peroxidase-1 (GPX1). In conclusion, our comprehensive findings demonstrate that hyperosmolarity induces oxidative stress in HCECs by stimulating ROS production and disrupting the balance of oxygenases and antioxidant enzymes, which in turn cause cell damage with increased oxidative markers in membrane lipid peroxidation and mitochondrial DNA damage.
The mouse is an organism that is widely used as a mammalian model for studying human physiology or disease, and the development of immunodeficient mice has provided a valuable tool for basic and applied human disease research. Following the development of large-scale mouse knockout programs and genome-editing tools, it has become increasingly efficient to generate genetically modified mouse strains with immunodeficiency. However, due to the lack of a standardized system for evaluating the immuno-capacity that prevents tumor progression in mice, an objective choice of the appropriate immunodeficient mouse strains to be used for tumor engrafting experiments is difficult.
In this study, we developed a tumor engraftment index (TEI) to quantify the immunodeficiency response to hematologic malignant cells and solid tumor cells of six immunodeficient mouse strains and C57BL/6 wild-type mouse (WT).
Mice with a more severely impaired immune system attained a higher TEI score. We then validated that the NOD-scid-IL2Rg−/− (NSI) mice, which had the highest TEI score, were more suitable for xenograft and allograft experiments using multiple functional assays.
The TEI score was effectively able to reflect the immunodeficiency of a mouse strain.
Electronic supplementary material
The online version of this article (doi:10.1186/s13045-015-0156-y) contains supplementary material, which is available to authorized users.
Immunodeficiency; Tumor; Leukemia; Xenograft; Allograft
A large number of viral and bacterial organisms are responsible for community-acquired pneumonia (CAP) which contributes to substantial burden on health management. A new resequencing microarray (RPM-IVDC1) associated with targeted multiplex PCR was recently developed and validated for multiple respiratory viruses detection and discrimination. In this study, we evaluated the capability of RPM-IVDC1 for simultaneous identification of multiple viral and bacterial organisms. The nasopharyngeal aspirates (NPAs) of 110 consecutive CAP patients, aged from 1 month to 96 years old, were collected from five distinct general hospitals in Beijing during 1-year period. The samples were subjected to the RPM-IVDC1 established protocol as compared to a real-time PCR (qRT-PCR), which was used as standard. The results of virus detection were consistent with those previously described. A total of 37 of Streptococcus pneumoniae, 14 of Haemophilus influenzae, 10 of Mycoplasma pneumoniae, two of Klebsiella pneumoniae and one of Moraxella catarrhalis were detected by RPM-IVDC1. The sensitivities and specificities were compared with those of qRT-PCR for S. pneumoniae (100, 100%, respectively), H. influenzae (92.3, 97.9%, respectively), M. pneumoniae (69.2, 99.0%, respectively), K. pneumoniae (100, 100%, respectively), and M. catarrhalis (100, 100%, respectively). Additional 22 of Streptococcus spp., 24 of Haemophilus spp. and 16 of Neisseria spp. were identified. In addition, methicillin-resistant and carbapenemases allele were also found in nine of Staphylococcus spp. and one of K. pneumoniae, respectively. These results demonstrated the capability of RPM-IVDC1 for simultaneous detection of broad-spectrum respiratory pathogens in complex backgrounds and the advantage of accessing to the actual sequences, showing great potential use of epidemic outbreak investigation. The detection results should be carefully interpreted when introducing this technique in the clinical diagnostics.
resequencing microarray; RPM-IVDC1; community-acquired pneumonia; multiple respiratory pathogens; detection
Nucleic acid based molecular device is a developing research field which attracts great interests in material for building machinelike nanodevices. G-quadruplex, as a new type of DNA secondary structures, can be harnessed to construct molecular device owing to its rich structural polymorphism. Herein, we developed a switching system based on G-quadruplexes and methylazacalixpyridine (MACP6). The induced circular dichroism (CD) signal of MACP6 was used to monitor the switch controlled by temperature or pH value. Furthermore, the CD titration, Job-plot, variable temperature CD and 1H-NMR experiments not only confirmed the binding mode between MACP6 and G-quadruplex, but also explained the difference switching effect of MACP6 and various G-quadruplexes. The established strategy has the potential to be used as the chiral probe for specific G-quadruplex recognition.
An improved LC-MS/MS method was developed for simultaneous determination of eleven bioactive constituents of Radix Angelicae Pubescentis and its related preparations. It was the first report on the quantification of bioactive constituents in different preparations of Radix Angelicae Pubescentis by LC-MS/MS analytical method. These samples were separated with an Agilent Zorbax Extend reversed-phase C18 column (1.8 μm, 4.6 × 100 mm) by linear gradient elution using aqueous ammonium acetate and acetonitrile as mobile phase. The flow rate was 0.3 mL min−1. The eleven bioactive constituents showed good regression (R > 0.990) within test ranges and the recoveries were in the range of 87.1–110%. The limit of detections and quantifications for most of the major constituents were less than 0.5 and 1.0 ng mL−1, respectively. All results indicated that the developed method could be readily utilized as a suitable quality control method for Radix Angelicae Pubescentis and related preparations.
Ivabradine is an inhibitor of mixed Na+-K+ current that could combine with HCN channels to reduce the transmembrane velocity of funny current (If), heart rate, and cardiac efficiency, and thus be used for the treatment of cardiovascular diseases such as chronic heart failure. As an ion channel blocker, Ivabradine is also a potential antiarrhythmic agent.
Twelve aging dogs (8–10 years old) underwent rapid atrial pacing for 2 months to induce age-related AF in this study. The dogs were randomly divided into the Ivabradine group and aging-AF group. The effects of Ivabradine on the electrophysiological parameters, including the effective refractory period (ERP) of the pulmonary veins and atrium, duration of AF, and inducing rate of AF, were investigated.
As compared to the aging-AF group, the ERPs of the left superior pulmonary vein (139.00±4.18 ms vs. 129.00±4.08 ms, P=0.005) and left auricle (135.00±3.53 ms vs. 122.00±4.47 ms, P=0.001) were significantly increased, while the duration of AF (46.60±5.07 s vs. 205.40±1.14 s, P=0.001) and inducing rate of AF (25% vs. 60%, P=0.001) were significantly decreased.
Ivabradine could effectively reduce the inducing rate of AF, and thus be used as an upstream drug for the prevention of age-related AF.
Aging; Arrhythmias, Cardiac; Atrial Fibrillation; Ivabradine
The area and elevation of the Tibetan Plateau over time has directly affected Asia’s topography, the characteristics of the Asian monsoon, and modified global climate, but in ways that are poorly understood. Charting the uplift history is crucial for understanding the mechanisms that link elevation and climate irrespective of time and place. While some palaeoelevation data are available for southern and central Tibet, clues to the uplift history of northern Tibet remain sparse and largely circumstantial. Leaf fossils are extremely rare in Tibet but here we report a newly discovered early Miocene barberry (Berberis) from Wudaoliang in the Hoh-Xil Basin in northern Tibet, at a present altitude of 4611 ± 9 m. Considering the fossil and its nearest living species probably occupied a similar or identical environmental niche, the palaeoelevation of the fossil locality, corrected for Miocene global temperature difference, is estimated to have been between 1395 and 2931 m, which means this basin has been uplifted ~2–3 km in the last 17 million years. Our findings contradict hypotheses that suggest northern Tibet had reached or exceeded its present elevation prior to the Miocene.
Objective: To explore the biological effects of ray cartilage extract (RCE) on human breast cancer cell line MCF-7 and its mechanism. Methods: MCF-7 cells were treated with RCE of different concentrations for different durations, and then MCF-7 cell proliferation was evaluated with MTT test, cell cycle was detected with flow cytometer and the protein levels of cyclin D1 and p21 were determined with Western blot. Results: MTT test indicated that MCF-7 cell proliferation was inhibited by RCE with an optimal inhibiting concentration of 10 μmol/L and an optimal action time of 48 h. Flow cytometer displayed that with the time prolongation of RCE action, the cells in S phase were significantly increased, but the cells in G2/M phase were significantly decreased; and MCF-7 apoptosis significantly increased as compared with blank control group (all P<0.05). Western blot found that with the time prolongation of RCE action, the level of cyclin D1 was significantly decreased, but the level of p21 was significantly increased as compared with blank control group (all P<0.05). Conclusion: RCE inhibits MCF-7 cell proliferation via arresting MCF-7 cell transformation from S phase to G2 phase. This may be associated with regulating the expressions of cyclin D1 and p21. RCE may be used as a drug for treatment of breast cancer in the future.
Breast cancer; ray cartilage extract; MCF-7 cell line; cyclin
Understanding urbanization and evaluating its impact are vital for formulating global sustainable development. The results obtained from evaluating the impact of urbanization, however, depend on the kind of measurement used. With the goal of increasing our understanding of the impact of urbanization, we developed direct and indirect subjective indicators to measure how people assess their living situation. The survey revealed that the projected endorsements and perceived social ambiance of people toward living in different types of settlements did not improve along with the urbanization level in China. The assessment scores from the city dwellers were not significantly different from those from the country areas and, more surprisingly, both were significantly higher than the assessment scores of the town dwellers, which we had expected to fall between the assessment scores of the country and city dwellers. Instead their scores were the lowest. We dubbed this V-shaped relationship the “town dislocation effect.” When searching for a potential explanation for this effect, we found additional town dislocation effects in social support, loss aversion, and receptivity toward genetically modified food. Further analysis showed that only social support mediated the relationship between the three tiers of settlements (cities, country areas, and towns) and the subjective indicator. The projected endorsements yielded significant subjective assessments that could enhance our understanding of Chinese urbanization. Towns posed specific problems that require special attention.
To investigate whether apolipoprotein A (apoA)-I glycation and paraoxonase (PON) activities are associated with the severity of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM).
Relative intensity of apoA-I glycation and activities of high-density lipoprotein (HDL)-associated PON1 and PON3 were determined in 205 consecutive T2DM patients with stable angina with (n = 144) or without (n = 61) significant CAD (luminal diameter stenosis ≥ 70 %). The severity of CAD was expressed by number of diseased coronary arteries, extent index, and cumulative coronary stenosis score (CCSS).
The relative intensity of apoA-I glycation was higher but the activities of HDL-associated PON1 and PON3 were lower in diabetic patients with significant CAD than in those without. The relative intensity of apoA-I glycation increased but the activities of HDL-associated PON1 and PON3 decreased stepwise from 1 - to 3 - vessel disease patients (P for trend < 0.001). After adjusting for possible confounding variables, the relative intensity of apoA-I glycation correlated positively, while the activities of HDL-associated PON1 and PON3 negatively, with extent index and CCSS, respectively. At high level of apoA-I glycation (8.70 ~ 12.50 %), low tertile of HDL-associated PON1 (7.03 ~ 38.97U/mL) and PON3 activities (7.11 ~ 22.30U/mL) was associated with a 1.97− and 2.49− fold increase of extent index and 1.73− and 2.68− fold increase of CCSS compared with high tertile of HDL-associated PON1 (57.85 ~ 154.82U/mL) and PON3 activities (39.63 ~ 124.10U/mL), respectively (all P < 0.01).
Elevated apoA-I glycation and decreased activities of HDL-associated PON1 and PON3, and their interaction are associated with the presence and severity of CAD in patients with T2DM.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-015-0221-4) contains supplementary material, which is available to authorized users.
Diabetes mellitus; ApoA-I glycation; Paraoxonase; Coronary artery disease
Modified RNA molecules have recently been shown to regulate nervous system functions. This mini-review and associated mini-symposium provide an overview of the types and known functions of novel modified RNAs in the nervous system, including covalently modified RNAs, edited RNAs, and circular RNAs. We discuss basic molecular mechanisms involving RNA modifications as well as the impact of modified RNAs and their regulation on neuronal processes and disorders, including neural fate specification, intellectual disability, neurodegeneration, dopamine neuron function, and substance use disorders.
Metabolic alteration is a hallmark of cancer. Dysregulation of methionine metabolism is implicated in human liver cancer. Methionine adenosyltransferase IIα (MAT IIα) is a key enzyme in the methionine cycle, catalysing the production of S-adenosylmethionine (SAM), a key methyl donor in cellular processes, and is associated with uncontrolled cell proliferation in cancer. Here we show that P300 acetylates MAT IIα at lysine residue 81 and destabilizes MAT IIα by promoting its ubiquitylation and subsequent proteasomal degradation. Conversely, histone deacetylase-3 deacetylates and stabilizes MAT IIα by preventing its proteasomal degradation. Folate deprivation upregulates K81 acetylation and destabilizes MAT IIα to moderate cell proliferation, whereas a single mutation at K81 reverses the proliferative disadvantage of cancer cells upon folate deprivation. Moreover, MAT IIα K81 acetylation is decreased in human hepatocellular cancer. Collectively, our study reveals a novel mechanism of MAT IIα regulation by acetylation and ubiquitylation, and a direct functional link of this regulation to cancer development.
Folate plays an essential role in dividing cells and is regulated by methionine adenosyltransferase (MAT), where a switch from MAT Iα to MAT IIα expression seems to promote liver cancer progression. Here the authors demonstrate that MAT IIα stability is regulated by acetylation and this regulation is important for tumour growth.
Thyroid cancer is the most common endocrine malignancy, with an increasing prevalence worldwide. Poorly-differentiated thyroid cancer (PDTC) is relatively rare and its prognosis is poor. To date, no ideal treatment strategy is available for patients with advanced recurrent PDTC, particularly for patients in crisis. However, partial success in treating thyroid cancer has been achieved with targeted therapy, and advances made in understanding the molecular biology of the tumor. The current study describes the case of a patient diagnosed with PDTC following presentation with hoarseness, orthopnea, and a large right neck mass. A transient partial response to sunitinib malate treatment was achieved for >3 months. In addition, the current study reviewed the relevant literature and discussed the therapeutic value of sunitinib as a more favorable treatment strategy for patients with advanced recurrent PDTC compared with the currently available treatments. Successful treatment with sunitinib, as well as molecular analysis of the tumor, occurred in the present case. Sunitinib was determined to have potential in treating thyroid tumors, however, larger prospective studies are required to validate the findings of the current case study prior to the application of this agent in clinical practice.
sunitinib; thyroid carcinoma; poorly-differentiated; crisis
The Hedgehog (Hh) signaling pathway has been demonstrated to play a critical role in controlling embryonic development, tissue patterning, wound healing and a variety of cell functions. Aberrant activation of Hh signaling is implicated in the pathogenesis of many human cancers, and in angiogenesis. However, the role of this pathway in uveal melanoma (UM) carcinogenesis remains unknown. In this study, we investigated the effects of Hh inhibition using the specific Smoothened (Smo) antagonist cyclopamine to block Hh signaling in cultured human UM cell lines expressing Hh signaling components. Cyclopamine treatment effectively increased apoptosis and inhibited cell proliferation, migration, and epithelial-to-mesenchymal transition (EMT) by downregulating the Hh final arbiter glioblastoma 1 (Gli1), which regulates the transcription of target genes in the nucleus. Changes in gene and protein expression levels were detected by real-time PCR and by western blotting and immunocytochemistry, respectively. Cell cycle and apoptosis regulation induced by cyclopamine were demonstrated by flow cytometry. In addition, the migration capability of UM cells was reduced, as demonstrated by transwell migration and scratch assays. The effects of Hh inhibition on the levels of angiogenesis factors secreted by UM cells were examined by tube-formation assay. Conclusion: Blocking the Hh pathway by cyclopamine decreased cell viability, migration, EMT, and angiogenesis, increased apoptosis, and induced G1 phase cell cycle arrest in UM cells. Collectively, these results provide the first evidence of the significance of Gli1 activation downstream of Smo as a therapeutic target and the potential value of cyclopamine for the treatment of human UM.
uveal melanoma; Hedgehog signaling pathway; cell growth; cell migration; cyclopamine
Rising temperatures are severely affecting the mortality, laying performance, and meat quality of duck. Our aim was to investigate the effect of acute heat stress on the expression of heat shock proteins (HSPs: HSP90, 70, 60, 40, and 10) and inflammatory factors (nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2)) and antioxidant enzyme activity (superoxide dismutase (SOD), malondialdehybe (MDA), catalase (CAT), total antioxidant capacity (T-AOC)) in livers of ducks and to compare the thermal tolerance of Pekin and Muscovy ducks exposed to acute heat stress. Ducks were exposed to heat at 39 ± 0.5 °C for 1 h and then returned to 20 °C for 1 h followed by a 3-h recovery period. The liver and other tissues were collected from each individual for analysis. The mRNA levels of HSPs (70, 60, and 40) increased in both species, except for HSP10, which was upregulated in Muscovy ducks and had no difference in Pekin ducks after heat stress. Simultaneously, the mRNA level of HSP90 decreased in the stress group in both species. Morphological analysis indicated that heat stress induced tissue injury in both species, and the liver of Pekin ducks was severely damaged. The activities of several antioxidant enzymes increased in Muscovy duck liver, but decreased in Pekin duck. The mRNA levels of inflammatory factors were increased after heat stress in both duck species. These results suggested that heat stress could influence HSPs, inflammatory factors expression, and the activities of antioxidant enzymes. Moreover, the differential response to heat stress indicated that the Muscovy duck has a better thermal tolerance than does the Pekin duck.
Antioxidant defense system; Inflammatory injury; Heat shock proteins; Thermal sensitivities; Duck
Based on a genome-wide association study (GWAS) of testicular dysgenesis syndrome (TDS) reporting possible association with TGFBR3, we analyzed GWAS data from a larger, phenotypically restricted cryptorchidism population for potential replication of this signal.
Materials and Methods
We excluded samples based on strict quality control criteria, leaving 844 cases and 2718 controls of European ancestry that were analyzed in 2 separate groups based on genotyping platform. Analyses included genotype imputation at the TGFBR3 locus, association analysis of imputed data with correction for population substructure, subsequent meta-analysis of Group 1 and 2 data and selective genotyping of independent cases (n=330) and controls (n=324) for replication. We also measured Tgfbr3 mRNA levels and performed TGFBR3/betaglycan immunostaining in rat fetal gubernaculum.
We identified suggestive (p≤1×10−4) association of markers in/near TGFBR3 including rs9661103 (OR 1.40, 95% CI 1.20,1.64, p=2.71×10−5) and rs10782968 (OR 1.58, CI 1.26,1.98, p=9.36×10−5) in Groups 1 and 2, respectively. In subgroup analyses, we observed strongest association of rs17576372 (OR 1.42, CI 1.24,1.60; p=1.67×10−4) with proximal and rs11165059 (OR 1.32, CI 1.15,1.38; p=9.42×10−4) with distal testis position, signals in strong linkage disequilibrium with rs9661103 and rs10782968, respectively. Association of the prior GWAS signal (rs12082710) was marginal (OR 1.13, CI 0.99,1.28, p=0.09 for Group 1) and we were unable to replicate signals in our independent cohort. Tgfbr3/betaglycan was differentially expressed in wild type and cryptorchid rat fetal gubernaculum.
These data suggest complex or phenotype-specific association of cryptorchidism with TGFBR3 and the gubernaculum as a potential target of TGFβ signaling.
Cryptorchidism; genetic association studies; TGFRB3; gubernaculum