Background and Objectives
Influenza A viruses cause highly contagious diseases in a variety of hosts, including humans and pigs. To develop a vaccine that can be broadly effective against genetically divergent strains of the virus, in this study we employed molecular breeding (DNA shuffling) technology to create a panel of chimeric HA genes.
Methods and Results
Each chimeric HA gene contained genetic elements from parental swine influenza A viruses that had a history of zoonotic transmission, and also from a 2009 pandemic virus. Each parental virus represents a major phylogenetic clade of influenza A H1N1 viruses. Nine shuffled HA constructs were initially screened for immunogenicity in mice by DNA immunization, and one chimeric HA (HA-129) was expressed on both a A/Puerto Rico/8/34 backbone with mutations associated with a live, attenuated phenotype (PR8LAIV-129) and a A/swine/Texas/4199-2/98 backbone (TX98-129). When delivered to mice, the PR8LAIV-129 induced antibodies against all four parental viruses, which was similar to the breadth of immunity observed when HA-129 was delivered as a DNA vaccine. This chimeric HA was then tested as a candidate vaccine in a nursery pig model, using inactivated TX98-129 virus as the backbone. The results demonstrate that pigs immunized with HA-129 developed antibodies against all four parental viruses, as well as additional primary swine H1N1 influenza virus field isolates.
This study established a platform for creating novel genes of influenza viruses using a molecular breeding approach, which will have important applications toward future development of broadly protective influenza virus vaccines.
The relationship between diabetes mellitus (DM) and cancer incidence has been evaluated in limited kinds of cancer. The effect of anti-diabetic therapy (ADT) on carcinogenesis among diabetic patients is also unclear.
Materials and Methods
Using population-based representative insurance claims data in Taiwan, 36,270 DM patients and 145,080 comparison subjects without DM were identified from claims from 2005 to 2010. The association between the top ten leading causes of cancer-related death in Taiwan and DM was evaluated. Whether ADT altered the risk of developing cancer was also investigated.
Incidence of cancer at any site was significantly higher in patients with DM than in those without (p<0.001). The risk of carcinogenesis imparted by DM was greatest in gastroenterological malignancies (liver, pancreas, and colorectal cancer) as well as lung, breast and oral cancer (p<0.001). Among the oral types of ADT, metformin decreased the risk of lung and liver cancer, but had less effect on reducing the risk of colorectal cancer. α-glucosidase inhibitor decreased the risk of developing liver, colorectal, and breast cancer. Apart from intermediate-acting insulin, rapid-acting, long-acting, and combination insulin treatment significantly reduced the overall cancer risk among all DM patients. In subgroup analysis, long-acting insulin treatment significantly decreased the risk of lung, liver, and colorectal cancer.
Our results supported the notion that pre-existing DM increases the incidence of gastroenterological cancer. ADT, especially metformin, α-glucosidase inhibitor, and long-acting insulin treatment, may protect patients with DM against these malignancies. It is crucial that oncologists should closely collaborate with endocrinologists to provide an optimal cancer-specific therapy and diabetic treatment to patients simultaneously with cancer and DM.
Primary hepatic sarcoma (PHS) is a rare primary liver malignancy. The histological types of PHS are diverse, and the clinical outcomes and management mainly depend on the histopathology. This study aims to evaluate the results of surgical intervention.
Between January 2003 and June 2009, 13 adult patients with pathologically proven PHS were identified by record review. The patients’ demographic profile, tumor characteristics, treatment modalities, and outcomes were reviewed and analyzed. The end of follow-up was December 2014.
Nine (69%) underwent curative liver resection and two underwent liver transplantation; the others received non-operative treatments. The pathologic findings were six (46%) angiosarcomas, four (30.7%) undifferentiated sarcomas, one (7.6%) leiomyosarcoma, one (7.6%) malignant mesenchymoma, and one (7.6%) hepatic epithelioid hemangioendothelioma. The median follow-up was 31.4 (2.8 ~ 142.5) months. The 1-, 2-, and 5-year survival of surgical patients were 72.7%, 63.6%, and 36.4%, respectively. Importantly, the 1-, 2-, and 5-year survival rates of non-angiosarcoma patients were superior to those of angiosarcoma (85.7% vs. 33.3%, 71.4% vs. 16.7%, and 57.1% vs. 0%, respectively, P = 0.023).
Surgical intervention provides the possibility of long-term survival from PHS. Angiosarcoma is associated with a more dismal outcome than non-angiosarcoma.
Primary hepatic sarcoma; Surgery; Angiosarcoma; Non-angiosarcoma; Outcome
Objective: To investigate the association between polymorphism of Klotho G-395A and susceptibility of coronary artery disease (CAD) in East-Asia population. Methods: A total of 6 case-control studies involving 1560 patients and 1459 controls were analyzed in the study. PubMed, Embase, CBM disc, Wanfang database were searched for published case-control studies investigating the association between Klotho G-395A and CAD that were available before Dec. 2013. Fixed or random effect models were selected for odds ratio (OR) calculation. A Meta-analysis was performed to estimate heterogeneity and the pooled odds ratio (OR) to evaluate the relationship between Klotho G-395A polymorphism and CAD. The sensitivity analysis was also assessed. Results: There was no significant heterogeneity found (dominant genetic model: P = 0.2, I2 = 30.8%). The pooled OR (95% CI) value of the frequencies of the Klotho G-395A genotype (GA + AA)/GG calculated by fixed effects mode was 1.24 (95% CI:1.06-1.45), P = 0.009. There was no significant heterogeneity among the remaining articles after using random effect model or excluding the article with the largest weight or the article with larger frequencies of the allele A, respectively. And the pooled OR (95% CI) value of the frequencies of the genotype (GA + AA)/GG were similar. Publication bias was not found by Begg’s test. Conclusion: Klotho G-395A polymorphism may be a susceptible factor of CAD in East-Asia population.
Coronary artery disease; polymorphism of klotho G-395A
Gastric cancer is one of the most common malignant diseases and has one of the highest mortality rates worldwide. Its molecular mechanisms are poorly understood. Recently, the functions of non-coding RNAs (ncRNAs) in gastric cancer have attracted wide attention. Although the expression levels of various ncRNAs are different, they may work together in a network and contribute to gastric carcinogenesis by altering the expression of oncogenes or tumor suppressor genes. They affect the cell cycle, apoptosis, motility, invasion, and metastasis. Dysregulated microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), including miR-21, miR-106, H19, and ANRIL, directly or indirectly regulate carcinogenic factors or signaling pathways such as PTEN, CDK, caspase, E-cadherin, Akt, and P53. Greater recognition of the roles of miRNAs and lncRNAs in gastric carcinogenesis can provide new insight into the mechanisms of tumor development and identify targets for anticancer drug development.
miRNAs; lncRNAs; Gastric carcinogenesis; Mechanisms
A series of 3-alkoxy-4-(4-(hexyloxy/heptyloxy) phenyl)-4H-1,2,4-triazole was synthesized. The anticonvulsant effect and neurotoxicity of the compounds were calculated with maximal electroshock (MES) test and rotarod tests with intraperitoneally injected mice. Among the synthesized compounds, compound 3-heptyloxy-4-(4-(hexyloxy) phenyl)-4H-1,2,4-triazole (5f) was the most active one and also had the lowest toxicity. In the anti-MES potency test, it showed median effective dose (ED50) of 37.3 mg/Kg, median toxicity dose (TD50) of 422.5 mg/Kg, and the protective index (PI) of 11.3 which is much greater than the reference drug carbamazepine with PI value of 6.4. As well as demonstrating the anti-MES efficacy of compound 5f, its potency against seizures induced by pentylenetetrazole, 3-mercaptopropionic acid, and bicuculline were also established, with the results suggesting that GABA-mediated mechanisms might be involved in its anticonvulsant activity, such as enhancing of GABAergic neurotransmission or activity, activate GAD or inhibit GABA-T, and GABAA-mediated mechanisms.
Synthesis; Triazole; Triazolone; Anticonvulsant activity; Neurotoxicity; Pentylenetetrazole; 3-Mercaptopropionic acid; Bicuculline
We present a quantitative analysis of the electron transfer between single gold nanorods and monolayer graphene under no electrical bias. Using single particle dark-field scattering and photoluminescence spectroscopy to access the homogenous linewidth, we observe broadening of the surface plasmon resonance for gold nanorods on graphene compared to nanorods on a quartz substrate. Because of the absence of spectral plasmon shifts, dielectric interactions between the gold nanorods and graphene are not important and we instead assign the plasmon damping to charge transfer between plasmon-generated hot electrons and the graphene that acts as an efficient acceptor. Analysis of the plasmon linewidth yields an average electron transfer time of 160 ± 30 fs, which is otherwise difficult to measure directly in the time domain with single particle sensitivity. In comparison to intrinsic hot electron decay and radiative relaxation, we furthermore calculate from the plasmon linewidth that charge transfer between the gold nanorods and the graphene support occurs with an efficiency of ~ 10%. Our results are important for future applications of light harvesting with metal nanoparticle plasmons and efficient hot electron acceptors as well as for understanding hot electron transfer in plasmon-assisted chemical reactions.
Plasmon damping; hot electrons; one-photon photoluminescence; single particle spectroscopy; surface plasmon resonance; graphene; plasmon linewidth
Members of the Enterovirus (poliovirus [PV], coxsackieviruses, and human rhinoviruses) and Kobuvirus (Aichi virus) genera in the Picornaviridae family rely on PI4KIIIβ (phosphatidylinositol-4-kinase IIIβ) for efficient replication. The small membrane-anchored enteroviral protein 3A recruits PI4KIIIβ to replication organelles, yet the underlying mechanism has remained elusive. Recently, it was shown that kobuviruses recruit PI4KIIIβ through interaction with ACBD3 (acyl coenzyme A [acyl-CoA]-binding protein domain 3), a novel interaction partner of PI4KIIIβ. Therefore, we investigated a possible role for ACBD3 in recruiting PI4KIIIβ to enterovirus replication organelles. Although ACBD3 interacted directly with coxsackievirus B3 (CVB3) 3A, its depletion from cells by RNA interference did not affect PI4KIIIβ recruitment to replication organelles and did not impair CVB3 RNA replication. Enterovirus 3A was previously also proposed to recruit PI4KIIIβ via GBF1/Arf1, based on the known interaction of 3A with GBF1, an important regulator of secretory pathway transport and a guanine nucleotide exchange factor (GEF) of Arf1. However, our results demonstrate that inhibition of GBF1 or Arf1 either by pharmacological inhibition or depletion with small interfering RNA (siRNA) treatment did not affect the ability of 3A to recruit PI4KIIIβ. Furthermore, we show that a 3A mutant that no longer binds GBF1 was capable of recruiting PI4KIIIβ, even in ACBD3-depleted cells. Together, our findings indicate that unlike originally envisaged, coxsackievirus recruits PI4KIIIβ to replication organelles independently of ACBD3 and GBF1/Arf1.
IMPORTANCE A hallmark of enteroviral infection is the generation of new membranous structures to support viral RNA replication. The functionality of these “replication organelles” depends on the concerted actions of both viral nonstructural proteins and co-opted host factors. It is thus essential to understand how these structures are formed and which cellular components are key players in this process. GBF1/Arf1 and ACBD3 have been proposed to contribute to the recruitment of the essential lipid-modifying enzyme PI4KIIIβ to enterovirus replication organelles. Here we show that the enterovirus CVB3 recruits PI4KIIIβ by a mechanism independent of both GBF1/Arf1 and ACBD3. This study shows that the strategy employed by coxsackievirus to recruit PI4KIIIβ to replication organelles is far more complex than initially anticipated.
Malignant glioma has extremely poor prognosis despite combination treatments with surgery, radiation, and chemotherapy. Dendritic cell (DC)-based immunotherapy may potentially serve as an adjuvant treatment of glioma, but its efficacy generally needs further improvement. Here we explored whether graphene oxide (GO) nanosheets could modulate the DC-mediated anti-glioma immune response in vitro, using the T98G human glioma cell line as the study model. Pulsing DCs with a glioma peptide antigen (Ag) generated a limited anti-glioma response compared to un-pulsed DCs. Pulsing DCs with GO alone failed to produce obvious immune modulation effects. However, stimulating DCs with a mixture of GO and Ag (GO-Ag) significantly enhanced the anti-glioma immune reaction (p < 0.05). The secretion of interferon gamma (IFN-γ) by the lymphocytes was also markedly boosted by GO-Ag. Additionally, the anti-glioma immune response induced by GO-Ag appeared to be target-specific. Furthermore, at the concentration used in this study, GO exhibited a negligible effect on the viability of the DCs. These results suggested that GO might have potential utility for boosting a DC-mediated anti-glioma immune response.
Glioma; Dendritic cell; DC; Graphene oxide; GO; Immunotherapy
In recent years, many approaches have been suggested for Internet and web streaming detection. In this paper, we propose an approach to signal waveform detection for Internet and web streaming, with novel statistical automatons. The system records network connections over a period of time to form a signal waveform and compute suspicious characteristics of the waveform. Network streaming according to these selected waveform features by our newly designed Aho-Corasick (AC) automatons can be classified. We developed two versions, that is, basic AC and advanced AC-histogram waveform automata, and conducted comprehensive experimentation. The results confirm that our approach is feasible and suitable for deployment.
During 2010 and 2011, 933 recently deceased birds, submitted as part of the dead bird surveillance program, tested positive for West Nile virus RNA at necropsy. The relative amount of RNA measured by qRT-PCR cycles ranged from 8.2 to 37.0 cycle threshold (Ct) and formed a bimodal frequency distribution, with maxima at 20 and 36 Ct and minima at 28–30 Ct. On the basis of frequency distributions among different avian species with different responses to infection following experimental inoculation, field serological data indicating survival of infection, and the discovery of persistent RNA in experimentally infected birds, dead birds collected in nature were scored as “recent” or “chronic” infections on the basis of Ct scores. The percentage of birds scored as having chronic infections was highest during late winter/spring, when all birds were after hatching year, and lowest during late summer, when enzootic transmission was typically highest as indicated by mosquito infections. Our data indicated that intervention efforts should not be based on dead birds with chronic infections unless supported by additional surveillance metrics.
Surveillance; West Nile virus; Dead birds; Chronic infections; Overwintering
The objective of this study was to investigate the effect of equine arteritis virus (EAV) on type I interferon (IFN) production. Equine endothelial cells (EECs) were infected with the virulent Bucyrus strain (VBS) of EAV and expression of IFN-β was measured at mRNA and protein levels by quantitative real-time RT-PCR and IFN bioassay using vesicular stomatitis virus expressing the green fluorescence protein (VSV-GFP), respectively. Quantitative RT-PCR results showed that IFN-β mRNA levels in EECs infected with EAV VBS were not increased compared to those in mock-infected cells. Consistent with quantitative RT-PCR, Sendai virus- (SeV-) induced type I IFN production was inhibited by EAV infection. Using an IFN-β promoter-luciferase reporter assay, we subsequently demonstrated that EAV nsps 1, 2, and 11 had the capability to inhibit type I IFN activation. Of these three nsps, nsp1 exhibited the strongest inhibitory effect. Taken together, these data demonstrate that EAV has the ability to suppress the type I IFN production in EECs and nsp1 may play a critical role to subvert the equine innate immune response.
Bronchial asthma influences some chronic diseases such as coronary heart disease, diabetes mellitus, and hypertension, but the impact of asthma on vital diseases such as chronic kidney disease is not yet verified. This study aims to clarify the association between bronchial asthma and the risk of developing chronic kidney disease.
The National Health Research Institute provided a database of one million random subjects for the study. A random sample of 141 064 patients aged ≥18 years without a history of kidney disease was obtained from the database. Among them, there were 35 086 with bronchial asthma and 105 258 without asthma matched for sex and age for a ration of 1:3. After adjusting for confounding risk factors, a Cox proportional hazards model was used to compare the risk of developing chronic kidney disease during a three-year follow-up period.
Of the subjects with asthma, 2 196 (6.26%) developed chronic kidney disease compared to 4 120 (3.91%) of the control subjects. Cox proportional hazards regression analysis revealed that subjects with asthma were more likely to develop chronic kidney disease (hazard ratio [HR]: 1.56; 95% CI: 1.48-1.64; p < 0.001). After adjusting for sex, age, monthly income, urbanization level, geographic region, diabetes mellitus, hypertension, hyperlipidemia, and steroid use, the HR for asthma patients was 1.40 (95% CI: 1.33-1.48; p = 0.040). There was decreased HRs in steroid use (HR: 0.56; 95% CI: 0.62-0.61; p < 0.001) in the development of chronic kidney disease. Expectorants, bronchodilators, anti-muscarinic agents, airway smooth muscle relaxants, and leukotriene receptor antagonists may also be beneficial in attenuating the risk of chronic kidney disease.
Patients with bronchial asthma may have increased risk of developing chronic kidney disease. The use of steroids or non-steroidal drugs in the treatment of asthma may attenuate this risk.
Bronchial asthma; Chronic kidney diseases; National Health Insurance Research Dataset
Fishbones are the most commonly ingested foreign bodies that cause gastrointestinal tract penetration. However, fishbones embedded in the gastrointestinal tract that lead to foreign body granulomas that mimic submucosal tumors are rare. Herein, we describe a 56-year-old woman who presented with a 20-day-history of upper abdominal pain. Endoscopy revealed an elevated lesion in the gastric antrum. An abdominal computed tomography scan showed a mass in the gastric antrum and a linear calcified lesion in the mass. An endoscopic ultrasonography examination revealed a 3.9 cm × 2.2 cm, irregular, hypoechoic mass with indistinct margins in the muscularis propria layer. The patient was initially diagnosed as having a submucosal tumor, and subsequent surgical resection showed that the lesion was a foreign body granuloma caused by an embedded fishbone. Our case indicated that the differential diagnosis of a foreign body granuloma should be considered in cases of elevated lesions in the gastrointestinal tract.
Gastric; Foreign body granuloma; Fishbone; Endoscopic ultrasonography; Computed tomography
There is still uncertainty concerning the beneficial effects of shoe collar height for ankle sprain prevention and very few data are available in the literature regarding the effect of high-top and low-top shoes on muscle responses during landing. The purpose of this study was to quantify the effect of high-top and low-top shoes on ankle inversion kinematics and pre-landing EMG activation of ankle evertor muscles during landing on a tilted surface.
Thirteen physical education students landed on four types of surfaces wearing either high-top shoes (HS) or low-top shoes (LS). The four conditions were 15° inversion, 30° inversion, combined 25° inversion + 10° plantar flexion, and combined 25° inversion + 20° plantar flexion. Ankle inversion kinematics and EMG data of the tibialis anterior (TA), peroneus longus (PL), and peroneus brevis (PB) muscles were measured simultaneously. A 2 × 4 (shoe × surface) repeated measures ANOVA was performed to examine the effect of shoe and landing surfaces on ankle inversion and EMG responses.
No significant differences were observed between the various types of shoes in the maximum ankle inversion angle, the ankle inversion range of motion, and the maximum ankle inversion angular velocity after foot contact for all conditions. However, the onset time of TA and PB muscles was significantly later wearing HS compared to LS for the 15° inversion condition. Meanwhile, the mean amplitude of the integrated EMG from the 50 ms prior to contact (aEMGpre) of TA was significantly lower with HS compared to LS for the 15° inversion condition and the combined 25° inversion + 20° plantarflexion condition. Similarly, the aEMGpre when wearing HS compared to LS also showed a 37.2% decrease in PL and a 31.0% decrease in PB for the combined 25° inversion + 20° plantarflexion condition and the 15° inversion condition, respectively.
These findings provide preliminary evidence suggesting that wearing high-top shoes can, in certain conditions, induce a delayed pre-activation timing and decreased amplitude of evertor muscle activity, and may therefore have a detrimental effect on establishing and maintaining functional ankle joint stability.
High-top/low-top shoe; Ankle inversion; Muscle pre-activity; Tilted surface; Landing
Survivin is a member of the inhibitor-of-apoptosis proteins (IAPs) family; its overexpression has been widely demonstrated to occur in various types of cancer. Overexpression of survivin also correlates with tumor progression and induces anticancer drug resistance. Interestingly, recent studies reveal that survivin exhibits multiple pro-mitotic and anti-apoptotic functions; the differential functions of survivin seem to be caused by differential subcellular localization, phosphorylation, and acetylation of this molecule. In this review, the complex expression regulations and post-translational modifications of survivin are discussed. This review also discusses how recent discoveries improve our understanding of survivin biology and also create opportunities for developing differential-functioned survivin-targeted therapy. Databases such as PubMed, Scopus® (Elsevier, New York, NY, USA), and SciFinder® (CAS, Columbus, OH, USA) were used to search for literature in the preparation of this review.
survivin; BIRC5; IAP; XIAP; caspase-9; Samc; DIABLO
Anemone flaccida Fr. Schmidt, a family of ancient hopanoids, have been used as traditional Asian herbs for the treatments of inflammation and convulsant diseases. Previous study on HeLa cells suggested that triterpenoid saponins from Anemone flaccida Fr. Schmidt may have potential antitumor effect due to their apoptotic activities. Here, we confirmed the apoptotic activities of the following five triterpenoid saponins: glycoside St-I4a (1), glycoside St-J (2), anhuienoside E (3), hedera saponin B (4), and flaccidoside II (5) on human BEL-7402 and HepG2 hepatoma cell lines, as well as the model of HeLa cells treated with lipopolysaccharide (LPS). We found that COX-2/PGE2 signaling pathway, which plays key roles in the development of cancer, is involved in the antitumor activities of these saponins. These data provide the evidence that triterpenoid saponins can induce apoptosis via COX-2/PGE2 pathway, implying a preventive role of saponins from Anemone flaccida in tumor.
We have developed a porcine intestine epithelial cell line, designated SD-PJEC for the propagation of influenza viruses. The SD-PJEC cell line is a subclone of the IPEC-J2 cell line, which was originally derived from newborn piglet jejunum. Our results demonstrate that SD-PJEC is a cell line of epithelial origin that preferentially expresses receptors of oligosaccharides with Sia2-6Gal modification. This cell line is permissive to infection with human and swine influenza A viruses and some avian influenza viruses, but poorly support the growth of human-origin influenza B viruses. Propagation of swine-origin influenza viruses in these cells results in a rapid growth rate within the first 24 h post-infection and the titres ranged from 4 to 8 log10 TCID50 ml−1. The SD-PJEC cell line was further tested as a potential alternative cell line to Madin–Darby canine kidney (MDCK) cells in conjunction with 293T cells for rescue of swine-origin influenza viruses using the reverse genetics system. The recombinant viruses A/swine/North Carolina/18161/02 (H1N1) and A/swine/Texas/4199-2/98 (H3N2) were rescued with virus titres of 7 and 8.25 log10 TCID50 ml−1, respectively. The availability of this swine-specific cell line represents a more relevant substrate for studies and growth of swine-origin influenza viruses.
Laboratory and field research was conducted to determine if Culex tarsalis Coquillett expectorated West Nile virus (WNV) during sugar feeding and if a lure or bait station could be developed to exploit this behavior for WNV surveillance. Experimentally infected Cx. tarsalis repeatedly expectorated WNV onto filter paper strips and into vials with wicks containing sucrose that was readily detectable by a quantitative reverse transcriptase-polymerase chain reaction assay. Few females (33%, n = 27) became infected by imbibing sugar solutions spiked with high concentrations (107 plaque forming units/ml) of WNV, indicating sugar feeding stations probably would not be a source of WNV infection. In nature, sugar bait stations scented with the floral attractant phenyl acetaldehyde tracked WNV transmission activity in desert but not urban or agricultural landscapes in California. When deployed in areas of the Coachella Valley with WNV activity during the summer of 2011, 27 of 400 weekly sugar samples (6.8%) tested positive for WNV RNA by reverse transcriptase-polymerase chain reaction. Prevalence of positives varied spatially, but positive sugar stations were detected before concurrent surveillance measures of infection (mosquito pools) or transmission (sentinel chicken seroconversions). In contrast, sugar bait stations deployed in urban settings in Los Angeles or agricultural habits near Bakersfield in Kern County supporting WNV activity produced 1 of 90 and 0 of 60 positive weekly sugar samples, respectively. These results with sugar bait stations will require additional research to enhance bait attractancy and to understand the relationship between positive sugar stations and standard metrics of arbovirus surveillance.
surveillance; West Nile virus; sugar feeding; bait station; Culex tarsalis
Virus replication strongly depends on cellular factors, in particular, on host proteins. Here we report that the replication of the arteriviruses equine arteritis virus (EAV) and porcine reproductive and respiratory syndrome virus (PRRSV) is strongly affected by low-micromolar concentrations of cyclosporine A (CsA), an inhibitor of members of the cyclophilin (Cyp) family. In infected cells, the expression of a green fluorescent protein (GFP) reporter gene inserted into the PRRSV genome was inhibited with a half-maximal inhibitory concentration (IC50) of 5.2 μM, whereas the GFP expression of an EAV-GFP reporter virus was inhibited with an IC50 of 0.95 μM. Debio-064, a CsA analog that lacks its undesirable immunosuppressive properties, inhibited EAV replication with an IC50 that was 3-fold lower than that of CsA, whereas PRRSV-GFP replication was inhibited with an IC50 similar to that of CsA. The addition of 4 μM CsA after infection prevented viral RNA and protein synthesis in EAV-infected cells, and CsA treatment resulted in a 2.5- to 4-log-unit reduction of PRRSV or EAV infectious progeny. A complete block of EAV RNA synthesis was also observed in an in vitro assay using isolated viral replication structures. The small interfering RNA-mediated knockdown of Cyp family members revealed that EAV replication strongly depends on the expression of CypA but not CypB. Furthermore, upon fractionation of intracellular membranes in density gradients, CypA was found to cosediment with membranous EAV replication structures, which could be prevented by CsA treatment. This suggests that CypA is an essential component of the viral RNA-synthesizing machinery.
AIM: To analyze the clinical characteristics of small bowel tumors detected by double-balloon enteroscopy (DBE) and to evaluate the diagnostic value of DBE in tumors.
METHODS: Four hundred and forty consecutive DBE examinations were performed in 400 patients (250 males and 150 females, mean age 46.9 ± 16.3 years, range 14-86 years) between January 2007 and April 2012. Of these, 252 patients underwent the antegrade approach, and 188 patients underwent the retrograde approach. All the patients enrolled in our study were suspected of having small bowel diseases with a negative etiological diagnosis following other routine examinations, such as upper and lower gastrointestinal endoscopy and radiography tests. Data on tumors, such as clinical information, endoscopic findings and operation results, were retrospectively collected.
RESULTS: Small bowel tumors were diagnosed in 78 patients, of whom 67 were diagnosed using DBE, resulting in a diagnostic yield of 16.8% (67/400); the other 11 patients had negative DBE findings and were diagnosed through surgery or capsule endoscopy. Adenocarcinoma (29.5%, 23/78), gastrointestinal stromal tumor (24.4%, 19/78) and lymphoma (15.4%, 12/78) were the most common tumors. Among the 78 tumors, 60.3% (47/78) were located in the jejunum, and the overall number of malignant tumors was 74.4% (58/78). DBE examinations were frequently performed in patients with obscure gastrointestinal bleeding (47.4%) and abdominal pain (24.4%). The positive detection rate for DBE in the 78 patients with small bowel tumors was 85.9% (67/78), which was higher than that of a computed tomography scan (72.9%, 51/70). Based on the operation results, the accuracy rates of DBE for locating small bowel neoplasms, such as adenocarcinoma, gastrointestinal stromal tumor and lymphoma, were 94.4%, 100% and 100%, respectively. The positive biopsy rates for adenocarcinoma and lymphoma were 71.4% and 60%, respectively.
CONCLUSION: DBE is a useful diagnostic tool with high clinical practice value and should be considered the gold standard for the investigation of small bowel tumors.
Double-balloon enteroscopy; Small bowel tumors; Diagnosis; Capsule endoscopy; Endoscopic findings
To investigate the relationship of fibroblast growth factor receptor 4 (FGFR4) gene polymorphisms with the response of Chinese patients with non-small cell lung cancer (NSCLC) to chemotherapy.
A total of 629 patients with Stage III (A+B) or IV NSCLC, as well as 729 age- and gender-matched healthy controls were recruited. All the patients received platinum-based chemotherapy, and the therapeutic effects were evaluated. Three polymorphisms in the FGFR4 gene (rs351855G/A, rs145302848C/G, and rs147603016G/A) were genotyped, and the association between the 3 polymorphisms and the chemotherapy effect was analyzed using SPSS software, version 16.0.
The genotype frequencies of rs145302848C/G and rs147603016G/A were not significantly different between NSCLC patients and healthy controls on one hand, and between the responders and non-responders to the chemotherapy on the other hand. The distribution of AA genotype and A-allele of rs351855G/A was significantly lower in NSCLC patients than in healthy controls. Using patients with the GG genotype as a reference, the AA carrier had a significantly reduced risk for the development of NSCLC after normalizing to age, sex and smoking habits. In NSCLC patients, this genotype occurred more frequently in the responders to the chemotherapy than in non-responders. The chance of being a responder was significantly increased with the AA genotype as compared to G genotype. The AA genotype of rs351855G/A had a better prognosis compared with GA and GG genotype carriers: the overall survival of patients with the AA genotype of rs351855G/A was significantly longer than those with the GG+GA genotype (21.1 vs 16.5 months).
The rs351855G/A polymorphisms of FGFR4 gene can be used to predict the occurrence, chemotherapy response and prognosis of NSCLC.
non-small cell lung cancer; platinum-based chemotherapy; fibroblast growth factor receptor 4; gene polymorphism; response to chemotherapy; prognosis; Chinese population
Objective. To improve the quantitative assessment of cerebral blood volume (CBV) and flow (CBF) in the brain voxels from MR perfusion images. Materials and Methods. Normal brain parenchyma was automatically segmented with the time-to-peak criteria after cerebrospinal fluid removal and preliminary vessel voxel removal. Two scaling factors were calculated by comparing the relative CBV and CBF of the segmented normal brain parenchyma with the absolute values in the literature. Using the scaling factors, the relative values were converted to the absolute CBV and CBF. Voxels with either CBV > 8 mL/100 g or CBF > 100 mL/100 g/min were characterized as vessel voxels and were excluded from the quantitative measurements. Results. The segmented brain parenchyma with normal perfusion was consistent with the angiographic findings for each patient. We confirmed the necessity of dual thresholds including CBF and CBV for proper removal of vessel voxels. The scaling factors were 0.208 ± 0.041 for CBV, and 0.168 ± 0.037, 0.172 ± 0.037 for CBF calculated using standard and circulant singular value decomposition techniques, respectively. Conclusion. The automatic scaling and vessel removal techniques provide an alternative method for obtaining improved quantitative assessment of CBV and CBF in patients with thromboembolic cerebral arterial disease.