The microbiota of both humans and animals plays an important role in their health and the development of disease. Therefore, the bacterial flora of the conjunctiva may also be associated with some diseases. However, there are no reports on the alteration of bacterial flora in conjunctiva of diabetic rats in the literature. Therefore, we investigated the changes in bacterial flora in bulbar conjunctiva of rats with streptozotocin (STZ)-induced type I diabetes.
A high dose of STZ (60 mg/kg, i.p.) was injected into Sprague-Dawley (SD) rats to induce type I diabetes mellitus (T1DM). The diabetic rats were raised in the animal laboratory and at 8 months post-injection of STZ swab samples were taken from the bulbar conjunctiva for cultivation of aerobic bacteria. The bacterial isolates were identified by Gram staining and biochemical features. The identified bacteria from both diabetic and healthy rats were then compared.
The diabetic and healthy rats had different bacterial flora present in their bulbar conjunctiva. In total, 10 and 8 bacterial species were found in the STZ and control groups, respectively, with only three species (Enterococcus faecium, Enterococcus gallinarum and Escherichia coli) shared between the two groups. Gram-positive bacteria were common in both groups and the most abundant was Enterococcus faecium. However, after the development of T1DM, the bacterial flora in the rat bulbar conjunctiva changed considerably, with a reduced complexity evident.
STZ-induced diabetes caused alterations of bacterial flora in the bulbar conjunctiva in rats, with some bacterial species disappearing and others emerging. Our results indicate that the conjunctival bacterial flora in diabetic humans should be surveyed for potential diagnostic markers or countermeasures to prevent eye infections in T1DM patients.
Lithium-ion batteries (LIBs) are promising energy storage devices for portable electronics, electric vehicles, and power-grid applications. It is highly desirable yet challenging to develop a simple and scalable method for constructions of sustainable materials for fast and safe LIBs. Herein, we exploit a novel and scalable route to synthesize ultrathin nanobelts of anatase TiO2, which is resource abundant and is eligible for safe anodes in LIBs. The achieved ultrathin nanobelts demonstrate outstanding performances for lithium storage because of the unique nanoarchitecture and appropriate composition. Unlike conventional alkali-hydrothermal approaches to hydrogen titanates, the present room temperature alkaline-free wet chemistry strategy guarantees the ultrathin thickness for the resultant titanate nanobelts. The anatase TiO2 ultrathin nanobelts were achieved simply by a subsequent calcination in air. The synthesis route is convenient for metal decoration and also for fabricating thin films of one/three dimensional arrays on various substrates at low temperatures, in absence of any seed layers.
Hypercholesterolemia arising from abnormal lipid metabolism is one of the critical risk factors for coronary artery disease (CAD), however the roles of genetic variants in lipid metabolism-related genes on premature CAD (≤60 years old) development still require further investigation. We herein genotyped four single nucleotide polymorphisms (SNPs) in lipid metabolism-related genes (rs1132899 and rs5167 in APOC4, rs1801693 and rs7765781 in LPA), aimed to shed light on the influence of these SNPs on individual susceptibility to early-onset CAD.
Genotyping of the four SNPs (rs1132899, rs5167, rs1801693 and rs7765781) was performed in 224 premature CAD cases and 297 control subjects (≤60 years old) using polymerase chain reaction-ligation detection reaction (PCR–LDR) method. The association of these SNPs with premature CAD was performed with SPSS software.
Multivariate logistic regression analysis showed that C allele (OR = 1.50, P = 0.027) and CC genotype (OR = 2.84, P = 0.022) of APOC4 rs1132899 were associated with increased premature CAD risk, while the other three SNPs had no significant effect. Further stratified analysis uncovered a more evident association with the risk of premature CAD among male subjects (C allele, OR = 1.65, and CC genotype, OR = 3.33).
Our data provides the first evidence that APOC4 rs1132899 polymorphism was associated with an increased risk of premature CAD in Chinese subjects, and the association was more significant among male subjects.
Electronic supplementary material
The online version of this article (doi:10.1186/s12944-015-0065-7) contains supplementary material, which is available to authorized users.
APOC4; Single nucleotide polymorphism; Premature coronary artery disease; Risk
The Janus kinase-signal transducers and activators of transcription signaling pathway (JAK/STAT pathway) play an important role in proliferation of breast cancer cells. Previous data showed that inhibition of STAT3 suppresses the growth of breast cancer cells, but the associated mechanisms are not well understood. This study aims to investigate the effect and associated mechanisms of JAK/STAT pathway inhibitor AG490 on proliferation and suppression of breast cancer cells.
Materials and Methods:
CCK-8 assay and trypan blue exclusion assay were used to investigate the cytotoxicity of AG490 to MDA-MB-231 cells. Real-time PCR was used to detect the mRNA level of SARI (suppressor of AP-1, regulated by IFN). Western blot was used to analyze the protein levels of SARI, phospho-STAT3 and total STAT3. Luciferase reporter assay was adopted to explore the mechanism of SARI mRNA upregulation.
AG490 suppressed the proliferation of MDA-MB-231 cells in a dose-dependent manner. AG490 significantly up-regulated the mRNA and protein levels of SARI in MDA-MB-231 cells. Knockdown of SARI obviously attenuated AG490-induced growth suppression effect in MDA-MB-231 cells. Furthermore, AG490 dramatically enhanced the transcription activity of SARI promoter. But the transcription activity of truncated SARI promoter, which does not contain STAT3 binding site, cannot be activated by AG490 treatment.
We demonstrate in this study that AG490 suppresses the proliferation of MDA-MB-231 cells through transcriptional activation of SARI.
AG490; MDA-MB-231; Proliferation; SARI; STAT3
Objective. To determine whether acupuncture treatment impacts the clinical efficacy of degenerative damage of the optic nerve caused by nonarteritic anterior ischemic optic neuropathy (NAION). Methods. 69 patients (93 eyes) with NAION who had been treated by acupuncture which is performed on different acupoints related to eyes by vertical insertion or Fingernail-pressure needle insertion. The best corrected visual acuity, mean defect (MD) and mean light sensitivity (MS) of the visual field, and latency and amplitude of pattern visual evoked potential (P-VEP) were compared before and after treatment. Results. After 2, 4, and 8 weeks of treatment, the total effective rates of visual acuity improvement were 74.19%, 78.89%, and 81.71%, respectively, and the decreased MD and increased MS were both statistically significant (P < 0.01). When compared with the situation before treatment, the average latency of the P100 wave was significantly reduced (P < 0.05), and the average amplitude was improved with no statistically significant difference (P > 0.05). Conclusions. Acupuncture treatment could obviously improve the visual function of patients with NAION and be used as complementary and alternative therapy in clinic.
Objective: To systematically evaluate the efficacy and safety of radical surgery (RS) and conservative surgery (CS) in the treatment of hepatic cystic echinococcosis (HCE). Methods: We searched PubMed, Embase, MEDLINE, SCI, CNKI, CBM, and WanFang databases, and the Cochrane Library (2013, Issue 3) for references published before December 2013. Both randomized and non-randomized controlled trials of radical and conservative surgery for HCE were collected. After the literature was screened in accordance with inclusion and exclusion criteria, data were extracted and the quality of methodologies of selected references was determined independently by two evaluators. A meta-analysis was performed on eligible studies with RevMan 5.1 statistical software. Results: Five non-randomized controlled trials (1267 patients) were included in this study. Patients in the RS group had fewer postoperative complications compared with the CS group [OR = 0.42, 95% CI (0.32, 0.56), P < 0.00001], whereas there was no significant difference in rates of postoperative bile leakage between the two groups [OR = 0.22, 95% CI (0.05, 1.12), P = 0.07]. Postoperative follow-up of patients revealed a significantly lower HCE recurrence rate in the RS versus CS group [OR = 0.17, 95% CI (0.08, 0.38), P < 0.0001]. Additionally, no statistical differences in the number of days of hospitalization [MD = -2.47, 95% CI (-6.42, 1.49), P = 0.22] and perioperative mortality [OR = 0.87, 95% CI (0.27, 2.79), P = 0.82] were identified between groups. Conclusion: RS, especially total pericystectomy, has obvious advantages over CS: fewer complications, lower postoperative recurrence, and a lower incidence of biliary fistula and infection, making RS the preferred surgical method. This conclusion requires further validation with high-quality RCTs with large sample sizes. Surgical approach should be based upon comprehensive assessment of individual circumstances in HCE patients.
Hepatic cystic echinococcosis; radical surgery; conservative surgery; total pericystectomy; endocystectomy
Use of the inhibitor of ALK fusion onco-protein, crizotinib (PF02341066), has achieved impressive clinical efficacy in patients with ALK-positive non-small cell lung cancer. Nevertheless, acquired resistance to this drug occurs inevitably in approximately a year, limiting the therapeutic benefits of this novel targeted therapy. In this study, we found that autophagy was induced in crizonitib-resistant lung cancer cells and contributed to drug resistance. We observed that ALK was downregulated in the crizotinib-resistant lung cancer cell line, H3122CR-1, and this was causally associated with autophagy induction. The degree of crizotinib resistance correlated with autophagic activity. Activation of autophagy in crizotinib-resistant H3122CR-1 cells involved alteration of the Akt/mTOR signaling pathway. Furthermore, we demonstrated that chloroquine, an inhibitor of autophagy, could restore sensitivity of H3122CR-1 to crizotinib and enhance its efficacy against drug-resistant lung cancer. Thus, modulating autophagy may be worth exploring as a new strategy to overcome acquired crizonitib resistance in ALK-positive lung cancer.
crizotinib; ALK; autophagy; drug resistance; lung cancer
The malignant phenotype of glioblastoma multiforme (GBM) is believed to be largely driven by glioma stem-like cells (GSCs), and targeting GSCs is now considered a promising new approach to treatment of this devastating disease. Here, we show that SN50, a cell-permeable peptide inhibitor of NFκB, induced robust differentiation of human GSCs, causing loss of their oncogenic potential. We observed that following treatment of GSCs with SN50, their differentiated progeny cells showed significant decreases in their capability to form neuro-spheres and to invade in vitro and a reduction in their tumorigenicity in mouse xenograft models, but had increased sensitivity to the chemotherapeutic drug temozolomide and to radiation treatment. These results suggest that blocking the NFκB pathway may be explored as a useful mean to induce differentiation of GSCs, and provide another supportive evidence for the promise of differentiation therapy in treatment of malignant brain tumors.
NFκB inhibitor; SN50; brain tumor; differentiation; glioma stem cells
Studies have shown that combination anti-hypertensive therapy is superior to mono-therapy in blood pressure control and prevention of cardiovascular events. However, whether such advantage exists in the prevention of stroke in Chinese hypertensive patients remains unclear. This study aimed to compare the impact of initial combination versus mono-therapy on stroke events in a large cohort of Chinese hypertensive patients.
Methods and Results
Hypertensive patients with uncontrolled blood pressure and without a history of stroke were screened from the Shanghai Community-dwelling Hypertensive Population Follow-up Database. Based on the initial treatment, individuals were divided into an initial mono-therapy group and initial dual combination group. Patients were followed for 42 months. 32,682 and 4,926 patients were included in the initial mono- and dual-therapy group. The achieved target blood pressure control rates of mono vs. combination groups at 6, 12, 24, and 42 months of follow-up, were 59.47% vs. 60.05%, 78.23% vs. 77.06%, 85.51% vs. 84.02%, and 86.90% vs. 85.44%, respectively. Their corresponding incidence densities of stroke were 0.792 vs. 0.489, 1.49 vs. 1.15, 2.79 vs. 2.38, and 4.25 vs. 4.32 (cases per 100 person-year), respectively. The 6-month incidence of stroke in dual-therapy group was significantly lower than mono-therapy group (adjusted HR 0.64; 95% CI: 0.30-0.93). However, no significant group differences in the incidence density were observed at 12, 24, and 42 months.
Our study demonstrates that, for patients with uncontrolled hypertension, initial dual therapy is more effective in the prevention of stroke during the first 6 months of treatment, but not thereafter. Combination antihypertensive therapy may be a beneficial initial strategy for early stroke prevention.
Hypertension; stroke; mono-therapy; dual-therapy; combination-therapy
Prostate cancer is the most commonly diagnosed non-cutaneous cancer and one of the leading causes of cancer death for North American men. Whereas localized prostate cancer can be cured, there is currently no cure for metastatic prostate cancer. Here we report a novel approach that utilizes designed chimeric transcription activator-like effectors (dTALEs) to control prostate cancer metastasis. Transfection of dTALEs of DNA methyltransferase or demethylase induced artificial, yet active locus-specific CpG and subsequent histone modifications. These manipulations markedly altered expression of endogenous CRMP4, a metastasis suppressor gene. Remarkably, locus-specific CpG demethylation of the CRMP4 promoter in metastatic PC3 cells abolished metastasis, whereas locus-specific CpG methylation of the promoter in non-metastatic 22Rv1 cells induced metastasis. CRMP4-mediated metastasis suppression was found to require activation of Akt/Rac1 signaling and down-regulation of MMP-9 expression. This proof-of-concept study with dTALEs for locus-specific epigenomic manipulation validates the selected CpG methylation of CRMP4 gene as an independent biomarker for diagnosis and prognosis of prostate cancer metastasis and opens up a novel avenue for mechanistic research on cancer biology.
prostate cancer; metastasis; transcription activator-like effectors (TALEs); CRMP4; epigenetic manipulation
Systemic administration of chemotherapy for cancer often faces drug resistance, limiting its applications in cancer therapy. In this study, we developed a simple multifunctional nanocarrier based on polyethylenimine (PEI) to codeliver doxorubicin (DOX) and BCL2 small interfering RNA (siRNA) for overcoming multidrug resistance (MDR) and enhancing apoptosis in MCF-7/Adr cancer cells by combining chemotherapy and RNA interference (RNAi) therapy. The low-molecular-weight branch PEI was used to conjugate hydroxypropyl-β-cyclodextrin (HP-β-CD) and folic acid (FA), forming the codelivery nanocarrier (FA-HP-β-CD-PEI) to encapsulate DOX with the cavity HP-β-CD and bind siRNA with the positive charge of PEI for tumor-targeting codelivering drugs. The drug-loaded nanocomplexes (FA-HP-β-CD-PEI/DOX/siRNA) showed uniform size distribution, high cellular uptake, and significant gene suppression of BCL2, displaying the potential of overcoming MDR for enhancing the effect of anticancer drugs. Furthermore, the nanocomplexes achieved significant cell apoptosis through a mechanism of downregulating the antiapoptotic protein BCL2, resulted in improving therapeutic efficacy of the coadministered DOX by tumor targeting and RNA interference. Our study indicated that combined RNAi therapy and chemotherapy using our functional codelivery nanocarrier could overcome MDR and enhance apoptosis in MDR cancer cells for a potential application in treating MDR cancers.
tumor targeting; codelivery; doxorubicin; BCL2 siRNA; overcome multidrug resistance
Glioblastoma (GBM) is a highly angiogenic malignancy that is resistant to standard therapy; neo-formed vessels of this aggressive malignancy are thought to arise by sprouting of pre-existing brain capillaries. However, the conventional anti-angiogenic therapy, which seemed promising initially, shows transitory and incomplete efficacy. The discovery of vasculogenic mimicry (VM) has offered a new horizon for understanding tumor vascularization. VM is a tumor cell-constituted, matrix-embedded fluid-conducting meshwork that is independent of endothelial cells and is positively correlated with poor prognosis. Therefore, a better understanding of GBM vasculature is needed to optimize anti-angiogenic therapy. This review focuses on the signaling molecules and cascades involved in VM in relation to ongoing glioma research, as well as the clinical translational advances in GBM that have been offered by the development of optimized anti-angiogenesis treatment modalities.
Vasculogenic mimicry (VM); Glioblastoma (GBM); Angiogenesis; Cell signaling
Soluble Aβ oligomers contribute importantly to synaptotoxicity in Alzheimer's disease, but their dynamics in vivo remain unclear. Here, we found that soluble Aβ oligomers were sequestered from brain interstitial fluid onto brain membranes much more rapidly than non-toxic monomers and were recovered in part as bound to GM1 ganglioside on membranes. Aβ oligomers bound strongly to GM1 ganglioside, and blocking the sialic acid residue on GM1 decreased oligomer-mediated LTP impairment in mouse hippocampal slices. In a hAPP transgenic mouse model, substantial levels of GM1-bound Aβ42 were recovered from brain membrane fractions. We also detected GM1-bound Aβ in human CSF, and its levels correlated with Aβ42, suggesting its potential as a biomarker of Aβ-related membrane dysfunction. Together, these findings highlight a novel mechanism whereby hydrophobic Aβ oligomers become sequestered onto GM1 ganglioside and presumably other lipids on neuronal membranes, where they may induce progressive functional and structural changes.
Glioma is the most common malignancy of the central nervous system. Approximately 40 percent of intracranial tumors are diagnosed as gliomas. Difficulties in treatment are associated closely with the malignant phenotype, which is characterized by excessive proliferation, relentless invasion, and angiogenesis. Although the comprehensive treatment level of brain glioma is continuously progressing, the outcome of this malignancy has not been improved drastically. Therefore, the identification of new biomarkers for diagnosis and therapy of this malignancy is of significant scientific and clinical value. FRAT1 is a positive regulator of the Wnt/β-catenin signaling pathway and is overexpressed in many human tumors. In the present study, we investigated the expression status of FRAT1 in 68 patients with human gliomas and its correlation with the pathologic grade, proliferation, invasion, angiogenesis, and prognostic significance. These findings suggest that FRAT1 may be an important factor in the tumorigenesis and progression of glioma and could be explored as a potential biomarker for pathological diagnosis, an indicator for prognosis, and a target for biological therapy of malignancy.
A paucity of information exists on the recruitment of Asian Americans for biospecimen research. Although studies show that Chinese Americans are at high risk for hepatitis B virus (HBV) infection, little is known about their willingness to participate in HBV-related biospecimen research and how knowledge, attitudes, and cultural factors impact their willingness to participate. The study was guided by Community-Based Participatory Research principles. Data were derived from an assessment study on HBV-related biospecimen research participation among Chinese Americans in the Philadelphia region. The assessment was conducted with 415 Chinese Americans recruited from eight Chinese community-based organizations. Cultural beliefs, knowledge, and attitudes toward biospecimen research were examined for associations with their willingness to participate in biospecimen banking research. Overall, 192 (46.3%) of 415 participants who completed the assessment indicated they were willing to participate if they were invited to donate blood to be frozen and stored for future HBV biospecimen studies. Cultural variables significant in bivariate analysis included collectivism, knowledge about biospecimen research, and Yin-Yang beliefs. Fatalism and individualism were not associated with participation willingness. In multivariate analysis, age, health care attitudes, and trust were significantly associated with willingness to participate in biospecimen banking research. Asian American communities have little knowledge of biospecimen banking and will benefit from educational campaigns that emphasize collective benefits and attitudes towards and trust in the health care system. Understanding cultural factors is important for improving Chinese Americans' knowledge, awareness, and intentions of participation in biospecimen research. Similar efforts need to be undertaken to develop culturally appropriate educational intervention programs to increase participation in biospecimen research among other Asian American groups.
By measuring gene expression at an unprecedented resolution and throughput, RNA-seq has played a pivotal role in studying biological functions. Its typical application in clinical medicine is to identify the discrepancies of gene expression between two different types of cancer cells, sensitive and resistant to chemotherapeutic treatment, in a hope to predict drug response. Here we modified and used a mechanistic model to identify distinct patterns of gene expression in response of different types of breast cancer cell lines to chemotherapeutic treatment. This model was founded on a mixture likelihood of Poisson-distributed transcript read data, with each mixture component specified by the Skellam function. By estimating and comparing the amount of gene expression in each environment, the model can test how genes alter their expression in response to environment and how different genes interact with each other in the responsive process. Using the modified model, we identified the alternations of gene expression between two cell lines of breast cancer, resistant and sensitive to tamoxifen, which allows us to interpret the expression mechanism of how genes respond to metabolic differences between the two cell types. The model can have a general implication for studying the plastic pattern of gene expression across different environments measured by RNA-seq.
RNA-seq; Phenotypic plasticity; Gene-environment interaction; Clustering.
Induced plant defenses against herbivores are modulated by jasmonic acid-, salicylic acid-, and ethylene-signaling pathways. Although there is evidence that some pathogens suppress plant defenses by interfering with the crosstalk between different signaling pathways, such evidence is scarce for herbivores. Here, we demonstrate that the mealybug Phenacoccus solenopsis suppresses the induced defenses in tomato. We found that exogenous JA, but not SA, significantly decreased mealybug feeding time and reduced nymphal performance. In addition, constitutive activation of JA signaling in 35s::prosys plants reduced mealybug survival. These data indicate that the JA signaling pathway plays a key role in mediating the defense responses against P. solenopsis. We also found that mealybug feeding decreased JA production and JA-dependent defense gene expression, but increased SA accumulation and SA-dependent gene expression. In SA-deficient plants, mealybug feeding did not suppress but activated JA accumulation, indicating that the suppression of JA-regulated defenses depends on the SA signaling pathway. Mealybugs benefit from suppression of JA-regulated defenses by exhibiting enhanced nymphal performance. These findings confirm that P. solenopsis manipulates plants for its own benefits by modulating the JA-SA crosstalk and thereby suppressing induced defenses.
Chinese Americans are at increased risk for hepatitis B virus (HBV) infection. To reduce or eliminate disparities in HBV-related infection rates, participation in scientific investigations of HBV risk and treatment, including biospecimen sampling, is important. However, Asian Americans have low rates of participation in biospecimen research, and little is known about how educational interventions affect knowledge and participation in HBV-related biospecimen research.
Eight Chinese community-based organizations participated in a quasi-experimental, two-group design with education assessments at pre- and post-workshop and a three-month follow-up. Four sites were randomly assigned to receive the intervention (n = 175) and four sites to receive general health education (control; n = 240).
Participant knowledge about biospecimen research increased from pre- to post-education in the intervention but not in the control condition. Of intervention participants, 83.4% (146/175) donated one tube of blood for future HBV biospecimen research, and 50.9% (89/175) donated another tube of blood for HBV testing. In contrast, only 1.1% of participants in the control condition reported donating a blood sample at follow-up assessment.
The intervention program significantly increased knowledge of and participation in HBV biospecimen research among Chinese Americans. Community-based participatory research (CBPR) methods featured active support by community leaders, a culturally specific curriculum, and convenient, immediate access to blood sampling, which resulted in high donation rates.
HBV-related morbidity and mortality is an urgent problem faced by Chinese Americans. CBPR provides a model for engaging communities in early detection, vaccination, and treatment that can reduce this health threat.
biospecimen research; biobanking; Chinese Americans; Hepatitis B; cultural factors
SIRT1 exerts protective effects against endothelial cells dysfunction, inflammation and atherosclerosis, indicating an important role on myocardial infarction (MI) pathogenesis. Nonetheless, the effects of SIRT1 variants on MI risk remain poorly understood. Here we aimed to investigate the influence of SIRT1 polymorphisms on individual susceptibility to MI. Genotyping of three tagSNPs (rs7069102, rs3818292 and rs4746720) in SIRT1 gene was performed in a Chinese Han population, consisting of 287 MI cases and 654 control subjects. In a logistic regression analysis, we found that G allele of rs7069102 had increased MI risk with odds ratio (OR) of 1.57 [95% confidence interval (CI) = 1.15–2.16, Bonferroni corrected P (Pc) = 0.015] after adjustment for conventional risk factors compared to C allele. Similarly, the combined CG/GG genotypes was associated with the increased MI risk (OR = 1.64, 95% CI = 1.14–2.35, Pc = 0.021) compared to the CC genotype. Further stratified analysis revealed a more significant association with MI risk among younger subjects (≤ 55 years old). Consistent with these results, the haplotype rs7069102G-rs3818292A-rs4746720T containing the rs7069102 G allele was also associated with the increased MI risk (OR = 1.41, 95% CI = 1.09–1.84, Pc = 0.040). However, we did not detect any association of rs3818292 and rs4746720 with MI risk. Our study provides the first evidence that the tagSNP rs7069102 and haplotype rs7069102G-rs3818292A-rs4746720T in SIRT1 gene confer susceptibility to MI in the Chinese Han population.
G Protein Coupled Receptors (GPCRs) are critically regulated by β-arrestins (βarrs), which not only desensitize G protein signaling but also initiate a G protein independent wave of signaling1-5. A recent surge of structural data on a number of GPCRs, including the β2 adrenergic receptor (β2AR)-G protein complex, has provided novel insights into the structural basis of receptor activation6-11. Lacking however has been complementary information on recruitment of βarrs to activated GPCRs primarily due to challenges in obtaining stable receptor-βarr complexes for structural studies. Here, we devised a strategy for forming and purifying a functional β2AR-βarr1 complex that allowed us to visualize its architecture by single particle negative stain electron microscopy (EM) and to characterize the interactions between β2AR and βarr1 using hydrogen-deuterium exchange mass spectrometry (HDXMS) and chemical cross-linking. EM 2D averages and 3D reconstructions reveal bimodal binding of βarr1 to the β2AR, involving two separate sets of interactions, one with the phosphorylated carboxy-terminus of the receptor and the other with its seven-transmembrane core. Areas of reduced HDX together with identification of cross-linked residues suggest engagement of the finger loop of βarr1 with the seven-transmembrane core of the receptor. In contrast, focal areas of increased HDX indicate regions of increased dynamics in both N and C domains of βarr1 when coupled to the β2AR. A molecular model of the β2AR-βarr signaling complex was made by docking activated βarr1 and β2AR crystal structures into the EM map densities with constraints provided by HDXMS and cross-linking, allowing us to obtain valuable insights into the overall architecture of a receptor-arrestin complex. The dynamic and structural information presented herein provides a framework for better understanding the basis of GPCR regulation by arrestins.
Polycystic ovary syndrome (PCOS) is the most common gynecological endocrine disorder. The genetic background is believed to play a crucial role in the pathogenesis of PCOS. In recent years, the role of insulin receptor (INSR) polymorphisms in PCOS predisposition has attracted much attention. We performed a meta-analysis to investigate the association between the single nucleotide polymorphisms (SNPs) of INSR and PCOS. Published literature from Pubmed, Embase, and Cochrane CENTRAL was retrieved up until 7 August 2014. A total of 20 case-control studies including 23,845 controls and 17,460 PCOS cases with an average Newcastle-Ottawa quality assessment scale (NOS) score of 6.75 were analyzed. Ninety-eight SNPs distributed in 23 exons and the flanking regions of INSR were investigated, among which 17 SNPs were found to be associated with PCOS. Three SNPs detected in more than three studies were selected for further analyses. Twelve studies including 1158 controls and 1264 PCOS cases entered the analysis of rs1799817, but no significant association was found for every genotype (p > 0.05). Further subgroup stratification by ethnicity and weight did not lead to discovery of significant correlation (p > 0.05). For rs2059806, four studies including 442 controls and 524 PCOS cases were qualified for meta-analysis, and no significant association with PCOS was found for any genotype (p > 0.05). Four studies including 12,830 controls and 11,683 PCOS cases investigated the correlation between rs2059807 and PCOS, and five of the six cohorts indicated a significant impact. Our current meta-analysis suggests no significant correlation between rs1799817/rs2059806 SNPs and susceptibility of PCOS, while rs2059807 could be a promising candidate SNP that might be involved in the susceptibility of PCOS.
single nucleotide polymorphism (SNP); insulin receptor gene (INSR); polycystic ovary syndrome (PCOS); meta-analysis
A lipid emulsion composed of soybean oil (long-chain triglycerides, LCT), medium-chain triglycerides (MCT) and n-3 poly-unsaturated fatty acids (PUFAs) was evaluated for immune-modulation efficacy, safety, and tolerance in patients undergoing major surgery for gastric and colorectal cancer.
In a prospective, randomized, double-blind study, 99 patients with gastric and colorectal cancer receiving elective surgery were recruited and randomly assigned to either the study group, receiving the n-3 PUFAs enriched intravenous fat emulsion (IVFE), or the control group, receiving a lipid emulsion comprised of soybean oil and MCTs (0.8 – 1.5 g · kg-1 · day-1) as part of total parenteral nutrition (TPN) regimen from surgery (day -1) up to post-operative day 7. Safety and efficacy parameters were assessed on day -1 and post-operative visits on day 1, 3, and 7. Adverse events were documented daily and compared between the groups.
Pro-inflammatory markers, laboratory parameters, and adverse events did not differ prominently between the 2 groups, with the exception of net changes (day 7 minus day -1) of free fatty acids (FFAs), triglyceride, and high-density lipoprotein (HDL). Net decrease of FFAs was remarkably higher in the study group, while the net increase of triglyceride and decrease of HDL was significantly lower.
The n-3 PUFA-enriched IVFE showed improvements in lipid metabolism. In respect of efficacy, safety and tolerance both IVFE were comparable. In patients with severe stress, there is an inflammation-attenuating effect of n-3 PUFAs. Further, adequately powered clinical trials will be necessary to address this question in postsurgical GI cancer patients.
Lipid emulsion; n-3 fatty acids; LCT/MCT; Fish oils; Gastric cancer; Colorectal cancer
In the People’s Republic of China, both western medicine (WM) and traditional Chinese medicine (TCM) are the main treatment and rehabilitation options for cancer patients. This study aimed to explore cancer survivors’ perspectives and experience of treatment and rehabilitation, in order to promote patient-centered activities of treatment and rehabilitation.
Using a qualitative research approach, 68 cancer survivors were recruited from eight community cancer rehabilitation organizations in Shanghai, People’s Republic of China. Eight focus group interviews were conducted. All these interviews were transcribed verbatim, and the data were analyzed by theme analysis.
WM was the main choice in treatment phase though study participants noted more side effects. TCM was primarily used in the recovery phase. The lack of communication between doctors and cancer patients appears to affect treatment adherence and impair the doctor–patient relationship. WM was expensive for diagnostic procedures and treatment, while the cumulative costs of frequent use of TCM in the long rehabilitation period were also high. Both treatment options created significant perceived economic burden on patients. Conflicting information about dietary supplements tended to make cancer survivors confused.
Improving the communication between doctors and cancer patients helps to ameliorate cancer patient adherence and the effect of treatments. It is essential to educate cancer patients about the effect and cost of both WM and traditional TCM. Meanwhile, marketing management and guidance to consumers regarding use of dietary supplements in the cancer rehabilitation field are also necessary.
preference; adherence; cancer survivor education; focus group interview
Gut microflora play a crucial role in the biotransformation of ginsenosides to compound K (CK), which may affect the pharmacological effects of ginseng. Prebiotics, such as NUTRIOSE, could enhance the formation and consequent absorption of CK through the modulation of gut microbial metabolic activities. In this study, the effect of a prebiotic fiber (NUTRIOSE) on the pharmacokinetics of ginsenoside CK, a bioactive metabolite of ginsenosides, and its mechanism of action were investigated.
Male Sprague–Dawley rats were given control or NUTRIOSE-containing diets (control diet + NUTRIOSE) for 2 wk, and ginseng extract or vehicle was then orally administered. Blood samples were collected to investigate the pharmacokinetics of CK using liquid chromatography–tandem mass spectrometry. Fecal activities that metabolize ginsenoside Rb1 to CK were assayed with fecal specimens or bacteria cultures.
When ginseng extract was orally administered to rats fed with 2.5%, 5%, or 10% NUTRIOSE containing diets, the maximum plasma concentration (Cmax) and area under the plasma concentration–time curve values of CK significantly increased in a NUTRIOSE content-dependent manner. NUTRIOSE intake increased glycosidase activity and CK formation in rat intestinal contents. The CK-forming activities of intestinal microbiota cultured in vitro were significantly induced by NUTRIOSE.
These results show that prebiotic diets, such as NUTRIOSE, may promote the metabolic conversion of ginsenosides to CK and the subsequent absorption of CK in the gastrointestinal tract and may potentiate the pharmacological effects of ginseng.
compound K; ginsenoside Rb; NUTRIOSE; Panax ginseng; pharmacokinetic
AIM: To assess the diagnostic value of serum interleukin-8 (IL-8) in the detection of colorectal cancer (CRC).
METHODS: An original study was conducted to explore the potential value of IL-8 in CRC diagnosis. Receiver operating characteristic (ROC) analysis was performed and the area under the curve (AUC) value was calculated. PUBMED and EMBASE were searched (to October, 2013), supplemented with manual screening for relevant publications. Meta-analysis methods were applied to pool sensitivity, specificity, positive and negative likelihood ratios, and diagnostic odds ratios and to construct a summary receiver-operating characteristic (sROC) curve. Heterogeneity across studies was checked by the I2 test and Deek’s funnel plot method was applied to test publication bias.
RESULTS: In our original study, serum IL-8 yielded an AUC of 0.742 [95%CI: 0.635-0.849]. The sensitivity and specificity were 85.42% and 54.05%, respectively, at a cut-off value of 5.39. In this meta-analysis, we included five studies with 668 CRC patients and 374 controls and one study in our own center with 48 CRC patients and 37 controls. The pooled sensitivity and specificity of IL-8 were 0.69 (95%CI: 0.42-0.87) and 0.85 (95%CI: 0.68-0.94) for CRC detection. Besides, the area under the sROC curve was 0.86 (95%CI: 0.82-0.88). Subgroup analysis suggested that there was no heterogeneity in the Asian subgroup but some in the European subgroup. In addition, no publication bias was found according to the Deek’s funnel plot asymmetry test.
CONCLUSION: Serum IL-8 is a promising biomarker for CRC detection and may become a clinically useful tool to identify high-risk patients.
Interleukin-8; Colorectal cancer; Diagnostic value; Case-control study; Meta-analysis