The purpose of this prospectively collected single center study cohort of MF/SS 1263 patients is to evaluate the significance of stage and risk of disease progression from initial presentation, and to examine other prognostic factors.
Patients and Methods
The prognostic variables effecting overall survival (OS) were examined in a unique prospective cohort of 1263 mycosis fungoides (MF) and Sézary Syndrome (SS) patients seen by one investigator at MD Anderson Cancer Center from 1982–2009. Kaplan and Meier estimates were used to determine median overall survival (OS), progression-free survival (PFS) and disease specific survival (DSS). Cox’s proportional hazards regression model assessed prognostic factors.
Mean age at diagnosis was 55.33 years. Early MF (Stage IA-IIA) represented 71.5% (903 of 1263) and advanced (Stage IIB–IVB), 28.5% (360 of 1263) patients. Progression to a higher stage occurred in 147 patients (11.6 %) of whom 112 (12%) were early and 35 (9.7%) advanced. Death from disease occurred in 102/1263 (8.1%) patients. Median OS was 24.44 years, PFS was 16 years, and median DSS was not reached. OS and PFS were significantly better for early stage patients with patches (T1a/T2a) than with patches/plaques (T1b/T2b). PFS analyzed in 1241 patients found only 337 (27.2%) had disease progression or had died from disease. Risk factors associated with progression or deaths were advanced age, plaque stage, LDH level, and tumor area.
Improved outcome of MF/SS, reflected by overall survival and PFS for all stages, may result from earlier diagnosis, new therapies, and aggressive treatment of infections.
Mycosis Fungoides; Sézary syndrome; prognosis; lactate dehydrogenase; overall survival
The swimming crab, Portunus trituberculatus, which is naturally distributed in the coastal waters of Asia-Pacific countries, is an important farmed species in China. Salinity is one of the most important abiotic factors that influence not only the distribution and abundance of crustaceans, it is also an important factor for artificial propagation of the crab. To better understand the interaction between salinity stress and osmoregulation, we performed a transcriptome analysis in the gills of Portunus trituberculatus challenged with salinity stress, using the Illumina Deep Sequencing technology.
We obtained 27,696,835, 28,268,353 and 33,901,271 qualified Illumina read pairs from low salinity challenged (LC), non-challenged (NC), and high salinity challenged (HC) Portunus trituberculatus cDNA libraries, respectively. The overall de novo assembly of cDNA sequence data generated 94,511 unigenes, with an average length of 644 bp. Comparative genomic analysis revealed that 1,705 genes differentially expressed in salinity stress compared to the controls, including 615 and 1,516 unigenes in NC vs LC and NC vs HC respectively. GO functional enrichment analysis results showed some differentially expressed genes were involved in crucial processes related to osmoregulation, such as ion transport processes, amino acid metabolism and synthesis processes, proteolysis process and chitin metabolic process.
This work represents the first report of the utilization of the next generation sequencing techniques for transcriptome analysis in Portunus trituberculatus and provides valuable information on salinity adaptation mechanism. Results reveal a substantial number of genes modified by salinity stress and a few important salinity acclimation pathways, which will serve as an invaluable resource for revealing the molecular basis of osmoregulation in Portunus trituberculatus. In addition, the most comprehensive sequences of transcripts reported in this study provide a rich source for identification of novel genes in the crab.
Nematode neurons generally produce graded potentials instead of action potentials (APs). It is unclear how the graded potentials control postsynaptic cells under physiological conditions. Here we show that postsynaptic currents (PSCs) frequently occur in bursts at the neuromuscular junction of C. elegans. Cholinergic bursts concur with facilitated AP firing, elevated cytosolic [Ca2+], and contraction of the muscle whereas GABA ergic bursts suppress AP firing. The bursts, distinct from artificially evoked responses, are characterized by a persistent current (the primary component of burst-associated charge transfer)and increased frequency and mean amplitude of PSC events. The persistent current of cholinergic PSC bursts is mostly mediated by levamisole-sensitive acetylcholine receptors, which correlates well with locomotory phenotypes of receptor mutants. Eliminating command interneurons abolishes the bursts whereas mutating SLO-1 K+ channel, a potent presynaptic inhibitor of exocytosis, greatly increases the mean burst duration. These observations suggest that motoneurons control muscle by producing PSC bursts.
The subject of this work is the development and implementation of algorithms which accelerate the simulation of early stage tumor growth models. Among the different computational approaches used for the simulation of tumor progression, discrete stochastic models (e.g., cellular automata) have been widely used to describe processes occurring at the cell and subcell scales (e.g., cell-cell interactions and signaling processes). To describe macroscopic characteristics (e.g., morphology) of growing tumors, large numbers of interacting cells must be simulated. However, the high computational demands of stochastic models make the simulation of large-scale systems impractical. Alternatively, continuum models, which can describe behavior at the tumor scale, often rely on phenomenological assumptions in place of rigorous upscaling of microscopic models. This limits their predictive power. In this work, we circumvent the derivation of closed macroscopic equations for the growing cancer cell populations; instead, we construct, based on the so-called “equation-free” framework, a computational superstructure, which wraps around the individual-based cell-level simulator and accelerates the computations required for the study of the long-time behavior of systems involving many interacting cells. The microscopic model, e.g., a cellular automaton, which simulates the evolution of cancer cell populations, is executed for relatively short time intervals, at the end of which coarse-scale information is obtained. These coarse variables evolve on slower time scales than each individual cell in the population, enabling the application of forward projection schemes, which extrapolate their values at later times. This technique is referred to as coarse projective integration. Increasing the ratio of projection times to microscopic simulator execution times enhances the computational savings. Crucial accuracy issues arising for growing tumors with radial symmetry are addressed by applying the coarse projective integration scheme in a cotraveling (cogrowing) frame. As a proof of principle, we demonstrate that the application of this scheme yields highly accurate solutions, while preserving the computational savings of coarse projective integration.
Aim. To investigate the correlation of Fuzheng-Huayu tablet (FZHY) efficacy on chronic hepatitis B caused cirrhosis (HBC) and single nucleotide polymorphisms (SNPs) of CYP1A2. Methods. After 111 cases of HBC with 69 excess, 21 deficiency-excess, and 21 deficiency ZHENGs (ZHENG, also called traditional Chinese medicine syndrome) were treated by FZHY for 6 months, clinical symptoms, Child-Pugh score, and ZHENG score were observed. Three of the SNPs in CYP1A2 gene were detected and analyzed using SNaPshot assay. Results. In ZHENG efficacy between effective and invalid groups, there was significant difference (P < 0.001). The ZHENG deficiency was significantly correlated with FZHY efficacy (P < 0.05). AA genotype of CYP1A2-G2964A was significantly different with GG genotype (P < 0.05) between CYP1A2 Genotypes and FZHY efficacy on ZHENG. More importantly, GA plus AA genotype of CYP1A2-G2964A was significantly different with deficiency ZHENG (P < 0.05) between CYP1A2 genotypes and FZHY efficacy on ZHENG. Conclusion. FZHY improved ZHENG score of HBC, and these efficacies may relate to CYP1A2-G2964A sites. It was suggested that CYP1A2-G2964A locus is probably a risk factor for ZHENG-based FZHY efficacy in HBC.
Peroxiredoxin is a superfamily of antioxidative proteins that play important roles in protecting organisms against the toxicity of reactive oxygen species. In this study, a full-length of peroxiredoxin 5 (designated EcPrx5) cDNA was cloned from the ridgetail white prawn Exopalaemon carinicauda by using rapid amplification of cDNA ends (RACE) approaches. The full-length cDNA of the EcPrx5 was of 827 bp, containing a 5′ untranslated region (UTR) of 14 bp, a 3′ UTR of 228 bp with a poly (A) tail, and an open reading frame of 585 bp encoding a polypeptide of 194 amino acids with the predicted molecular weight of 20.83 kDa and estimated isoelectric point of 7.62. BLAST analysis revealed that amino acids of EcPrx5 shared 89, 68, 66, 65, 53 and 51 % identity with that of Macrobrachium rosenbergii, Megachile rotundata, Harpegnathos saltator, Acromyrmex echinatior, Danio rerio, and Homo sapiens counterparts, respectively. The conserved Prx domain and the signature of peroxiredoxin catalytic center identified in EcPrx5 suggested that EcPrx5 belonged to the atypical 2-Cys Prx subgroup. Real time quantitative RT-PCR analysis indicated that EcPrx5 could be detected in all the tested tissues with highest expression level in hepatopancreas. As time progressed, the expression level of EcPrx5 both in hemocytes and hepatopancreas increased in the first 6 h after Vibrio anguillarum and white spot syndrome virus challenge, and showed different expression profiles. The results indicated that EcPrx5 involved in immune response against bacterial and viral infection in E. carinicauda.
Exopalaemon carinicauda; Peroxiredoxin 5 (Prx5); Gene cloning; Expression
In order to clarify the controversies of hardening mechanism for TiN/SiNx-based nanocomposite films, the microstructure and hardness for TiN/SiNx and TiAlN/SiNx nanocomposite films with different Si content were studied. With the increase of Si content, the crystallization degree for two series of films firstly increases and then decreases. The microstructural observations suggest that when SiNx interfacial phase reaches to a proper thickness, it can be crystallized between adjacent TiN or TiAlN nanocrystallites, which can coordinate misorientations between nanocrystallites and grow coherently with them, resulting in blocking of the dislocation motions and hardening of the film. The microstructure of TiN/SiNx-based nanocomposite film can be characterized as the nanocomposite structure with TiN-based nanocrystallites surrounded by crystallized SiNx interfacial phase, which can be denoted by nc-TiN/c-SiNx model ('c’ before SiNx means crystallized) and well explain the coexistence between nanocomposite structure and columnar growth structure within the TiN/SiNx-based film.
TiN/SiNx film; Nanocomposite; Hardening mechanism; Microstructure
Both physical activity and inflammation are important in the pathophysiology of metabolic syndrome (MetS). Our study aim is to explore their associations in an elderly male (≥ 65 years old) cohort.
We enrolled 309 elderly male residents (mean age: 74.4 ± 6.0 years) in a remote southern Taiwan community. The physical activity was recorded by a standard questionnaire. A high-sensitivity C-reactive protein (hsCRP) level > 3.0 mg/L indicated a high inflammatory status.
The total prevalence rate of MetS was 27.8% in this male geriatric cohort. Median hsCRP levels were significantly higher in the MetS group (1.60 ± 0.7 vs. 1.0 ± 0.3 mg/L, p < 0.01), and the risk of elevated hsCRP increased with escalating MetS components (p for trend < 0.001). The non-MetS group had higher amount of median weekly physical activity (183.1 ± 19.0 vs. 173.5 ± 10.6 MET-hr/week, p = 0.029), which was also higher among those with lower hsCRP levels (186.1 ± 14.1 vs. 167.8 ± 38.5 MET-hr/week, p = 0.013). Multivariate analysis showed that higher body mass index (ORs: 1.527, 95% CI: 1.319-1.768, p < 0.01) insulin (OR: 1.128, 95% CI: 1.045-1.218, p < 0.01) and physical activity (ORs: 0.997, 95% IC: 0.994-0.999, p < 0.05) were independent predictors of MetS, but not hsCRP level (p > 0.05).
Reduced physical activity was one major pathophysiological MetS factor in our Asian geriatric participants.
Metabolic syndrome; Inflammation; Physical activity; Geriatric
Genetic variants may influence microRNA-target interaction through modulate their binding affinity, creating or destroying miRNA-binding sites. SET8, a member of the SET domain-containing methyltransferase, has been implicated in a variety array of biological processes.
Using Taqman assay, we genotyped a polymorphism rs16917496 T>C within the miR-502 binding site in the 3′-untranslated region of the SET8 gene in 576 non-small cell lung cancer (NSCLC) patients. Functions of rs16917496 were investigated using luciferase activity assay and validated by immunostaining.
Log-rank test and cox regression indicated that the CC genotype was associated with a longer survival and a reduced risk of death for NSCLC [58.0 vs. 41.0 months, P = 0.031; hazard ratio = 0.44, 95% confidential interval: 0.26–0.74]. Further stepwise regression analysis suggested rs16917496 was an independently favorable factor for prognosis and the protective effect more prominent in never smokers, patients without diabetes and patients who received chemotherapy. A significant interaction was observed between rs16917496 and smoking status in relation to NSCLC survival (P<0.001). Luciferase activity assay showed a lower expression level for C allele as compared with T allele, and the miR-502 had an effect on modulation of SET8 gene in vitro. The CC genotype was associated with reduced SET8 protein expression based on immunostaining of 192 NSCLC tissue sample (P = 0.007). Lower levels of SET8 were associated with a non-significantly longer survival (55.0 vs. 43.1 months).
Our data suggested that the rs16917496 T>C located at miR-502 binding site contributes to NSCLC survival by altering SET8 expression through modulating miRNA-target interaction.
C. elegans body-wall muscle cells are electrically coupled through gap junctions. Previous studies suggest that UNC-9 is an important, but not the only, innexin mediating the electrical coupling. Here we analyzed junctional current (Ij) for mutants of additional innexins to identify the remaining innexin(s) important to the coupling. The results suggest that a total of six innexins contribute to the coupling, including UNC-9, INX-1, INX-10, INX-11, INX-16, and INX-18. The Ij deficiency in each mutant was rescued completely by expressing the corresponding wild-type innexin specifically in muscle, suggesting that the innexins function cell-autonomously. Comparisons of Ij between various single, double, and triple mutants suggest that the six innexins probably form two distinct populations of gap junctions with one population consisting of UNC-9 and INX-18 and the other consisting of the remaining four innexins. Consistent with their roles in muscle electrical coupling, five of the six innexins showed punctate localization at muscle intercellular junctions when expressed as GFP- or epitope-tagged proteins, and muscle expression was detected for four of them when assessed by expressing GFP under the control of innexin promoters. The results may serve as a solid foundation for further explorations of structural and functional properties of gap junctions in C. elegans body-wall muscle.
The pharmacokinetics of intravenous anidulafungin in adult intensive care unit (ICU) patients were assessed in this study and compared with historical data from a general patient population and healthy subjects. Intensive plasma sampling was performed over a dosing interval at steady state from 21 ICU patients with candidemia/invasive candidiasis. All patients received the recommended dosing regimen (a 200-mg loading dose on day 1, followed by a daily 100-mg maintenance dose), except for a 54-year-old 240-kg female patient (who received a daily 150-mg maintenance dose instead). Plasma samples were assayed for anidulafungin using a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters in ICU patients were calculated by a noncompartmental method. With the exclusion of the 240-kg patient, the median (minimum, maximum) age, weight, and body mass index (BMI) of 20 ICU patients were 57 (39, 78) years, 65 (48, 106) kg, and 23.3 (16.2, 33.8) kg/m2, respectively. The average anidulafungin area under the curve over the 24-hour dosing interval (AUC0-24), maximum concentration (Cmax), and clearance (CL) in 20 ICU patients were 92.7 mg · h/liter, 7.7 mg/liter, and 1.3 liters/h, respectively. The exposure in the 240-kg patient at a daily 150-mg dose was within the range observed in ICU patients overall. The average AUC0-24 and Cmax in the general patient population and healthy subjects were 110.3 and 105.9 mg · h/liter and 7.2 and 7.0 mg/liter, respectively. The pharmacokinetics of anidulafungin in ICU patients appeared to be comparable to those in the general patient population and healthy subjects at the same dosing regimen.
Evidence about the efficacy and safety of statin treatment in high-risk patients with hypercholesterolemia is available for some populations, but not for ethnic Chinese. To test the hypothesis that treatment with pitavastatin (2 mg/day) is not inferior to treatment with atorvastatin (10 mg/day) for reducing low-density lipoprotein cholesterol (LDL-C), a 12-week multicenter collaborative randomized parallel-group comparative study of high-risk ethnic Chinese patients with hypercholesterolemia was conducted in Taiwan. In addition, the effects on other lipid parameters, inflammatory markers, insulin-resistance-associated biomarkers and safety were evaluated.
Methods and Results
Between July 2011 and April 2012, 251 patients were screened, 225 (mean age: 58.7 ± 8.6; women 38.2% [86/225]) were randomized and treated with pitavastatin (n = 112) or atorvastatin (n = 113) for 12 weeks. Baseline characteristics in both groups were similar, but after 12 weeks of treatment, LDL-C levels were significantly lower: pitavastatin group = −35.0 ± 14.1% and atorvastatin group = −38.4 ± 12.8% (both: p < 0.001). For the subgroup with diabetes mellitus (DM) (n = 125), LDL-C levels (−37.1 ± 12.9% vs. −38.0 ± 13.1%, p = 0.62) were similarly lowered after either pitavastatin (n = 63) or atorvastatin (n = 62) treatment. Triglycerides, non-high density lipoprotein cholesterol, and apoprotein B were similarly and significantly lower in both treatment groups. In non-lipid profiles, HOMA-IR and insulin levels were higher to a similar degree in both statin groups. Hemoglobin A1C was significantly (p = 0.001) higher in the atorvastatin group but not in the pitavastatin group. Both statins were well tolerated, and both groups had a similar low incidence of treatment-emergent adverse events.
Both pitavastatin (2 mg/day) and atorvastatin (10 mg/day) were well tolerated, lowered LDL-C, and improved the lipid profile to a comparable degree in high-risk Taiwanese patients with hypercholesterolemia.
ClinicalTrials.gov NCT01386853 http://clinicaltrials.gov/ct2/show/NCT01386853?term=NCT01386853&rank=1
Carboxylic acids are an attractive biorenewable chemical in terms of their flexibility and usage as precursors for a variety of industrial chemicals. It has been demonstrated that such carboxylic acids can be fermentatively produced using engineered microbes, such as Escherichia coli and Saccharomyces cerevisiae. However, like many other attractive biorenewable fuels and chemicals, carboxylic acids become inhibitory to these microbes at concentrations below the desired yield and titer. In fact, their potency as microbial inhibitors is highlighted by the fact that many of these carboxylic acids are routinely used as food preservatives. This review highlights the current knowledge regarding the impact that saturated, straight-chain carboxylic acids, such as hexanoic, octanoic, decanoic, and lauric acids can have on E. coli and S. cerevisiae, with the goal of identifying metabolic engineering strategies to increase robustness. Key effects of these carboxylic acids include damage to the cell membrane and a decrease of the microbial internal pH. Certain changes in cell membrane properties, such as composition, fluidity, integrity, and hydrophobicity, and intracellular pH are often associated with increased tolerance. The availability of appropriate exporters, such as Pdr12, can also increase tolerance. The effect on metabolic processes, such as maintaining appropriate respiratory function, regulation of Lrp activity and inhibition of production of key metabolites such as methionine, are also considered. Understanding the mechanisms of biocatalyst inhibition by these desirable products can aid in the engineering of robust strains with improved industrial performance.
tolerance; membrane damage; transporters; acid resistance; intracellular pH; biocatalyst robustness; carboxylic acid toxicity
The present study was designed to evaluate the anti-fatigue activity and the behavioral and biochemical effects of Kai-Xin-San (KXS) extracts on fatigued rats. The rats were randomly divided into six groups: untreated control (UC), running control (RC), RC treated with 13 mg/kg/day modafinil and RC treated with KXS at dosages of 125, 250 and 500 mg/kg/day, respectively. The treatments were administered orally. Anti-fatigue activity was assessed using the treadmill running test and serum biochemical parameters were determined using an autoanalyzer and commercially available kits. Furthermore, the standardization of the KXS extracts was ensured using a high-performance liquid chromatography (HPLC)-fingerprint. The extracts were shown to increase exhaustive running time in the treadmill running test and reverse the fatigue-induced reduction in hepatic/muscle glycogen and testosterone, in addition to reducing the lactate dehydrogenase (LDH), serum urea nitrogen (SUN), blood lactic acid (BLA) and β-endorphin levels in the serum of the fatigued rats. Moreover, the extracts enhanced superoxide dismutase (SOD) activity and decreased the malondialdehyde (MDA) levels in the serum of the fatigued rats. The results of this preliminary study indicated that KXS exhibits anti-fatigue activity. This was reflected in the effects on the biochemical markers for fatigue.
anti-fatigue effect; Kai-Xin-San; treadmill running test; traditional Chinese medicinal formula
Carboxylic acids are an attractive biorenewable chemical. However, like many other fermentatively produced compounds, they are inhibitory to the biocatalyst. An understanding of the mechanism of toxicity can aid in mitigating this problem. Here, we show that hexanoic and octanoic acids are completely inhibitory to Escherichia coli MG1655 in minimal medium at a concentration of 40 mM, while decanoic acid was inhibitory at 20 mM. This growth inhibition is pH-dependent and is accompanied by a significant change in the fluorescence polarization (fluidity) and integrity. This inhibition and sensitivity to membrane fluidization, but not to damage of membrane integrity, can be at least partially mitigated during short-term adaptation to octanoic acid. This short-term adaptation was accompanied by a change in membrane lipid composition and a decrease in cell surface hydrophobicity. Specifically, the saturated/unsaturated lipid ratio decreased and the average lipid length increased. A fatty acid-producing strain exhibited an increase in membrane leakage as the product titer increased, but no change in membrane fluidity. These results highlight the importance of the cell membrane as a target for future metabolic engineering efforts for enabling resistance and tolerance of desirable biorenewable compounds, such as carboxylic acids. Knowledge of these effects can help in the engineering of robust biocatalysts for biorenewable chemicals production.
Electronic supplementary material
The online version of this article (doi:10.1007/s00253-013-5113-5) contains supplementary material, which is available to authorized users.
Membrane lipids; Escherichia coli; Bacterial inhibition; Short chain fatty acids; Membrane fluidity; Tolerance
Nanoparticles composed of galactosylated chitosan oligosaccharide (Gal-CSO) and adenosine triphosphate (ATP) were prepared for hepatocellular carcinoma cell-specific uptake, and the characteristics of Gal-CSO/ATP nanoparticles were evaluated. CSO/ATP nanoparticles were prepared as a control. The average diameter and zeta potential of Gal-CSO/ATP nanoparticles were 51.03 ± 3.26 nm and 30.50 ± 1.25 mV, respectively, suggesting suitable properties for a drug delivery system. Subsequently, the cytotoxicity of Gal-CSO/ATP nanoparticles were examined by the methyl tetrazolium (MTT) assay, and the half maximal inhibitory concentration (IC50) values were calculated with HepG2 (human hepatocellular carcinoma cell line) cells. The results showed that the cytotoxic effect of nanoparticles on HepG2 cells was low. In the meantime, it was also found that the Gal-CSO/ATP nanoparticles could be uptaken by HepG2 cells, due to expression of the asialoglycoprotein receptor (ASGP-R) on their surfaces. The presented results indicate that the Gal-CSO nanoparticles might be very attractive to be used as an intracellular drug delivery carrier for hepatocellular carcinoma cell targeting, thus warranting further in vivo or clinical investigations.
galactosylated chitosan oligosaccharide; adenosine triphosphate; nanoparticles; hepatocyte uptake; targeted drug delivery
A number of observational studies have been conducted to investigate the association of the IL-10 gene polymorphisms with systemic lupus erythematosus (SLE) susceptibility. However, their results are conflicting.
We searched published case-control studies on the IL-10 polymorphisms and SLE in PubMed, EMBASE and Chinese Biomedical Literature Database. A meta-analysis was conducted using a fixed-effect or random-effect model based on between-study heterogeneity.
A total of 42 studies with 7948 cases and 11866 controls were included in this meta-analysis. Among Caucasians, the CA27 allele of the IL10.G microsatellites (OR 2.38, 95% CI 1.01–5.62), the G allele of the IL-10 -1082G/A polymorphism (G vs. A: OR 1.21, 95% CI 1.02–1.44; GG vs. AA: OR 1.45, 95% CI 1.16–1.82; GG+GA vs. AA: OR 1.16, 95% CI 1.03–1.29) and its associated haplotype -1082G/−819C/−592C (OR 1.25, 95% CI 1.10–1.42) were associated with increased SLE susceptibility without or with unimportant between-study heterogeneity. Removing studies deviating from Hardy-Weinberg equilibrium (HWE) hardly changed these results. Among Asians, the CA21 allele of the IL-10.G microsatellites (OR 1.28, 95% CI 1.02–1.60) and the -1082G/−819C/−592C haplotype (OR 1.24, 95% CI 1.00–1.53) were associated with increased SLE susceptibility, but with substantial between-study heterogeneity or sensitive to HWE status. Removing studies deviating from HWE also produced statistically significant associations of the IL-10 -1082G/A (GG vs. AA: OR 3.21, 95% CI 1.24–8.28; GG vs. AA+GA: OR 2.85, 95% CI 1.19–6.79) and -592C/A polymorphisms (CC+CA vs. AA: OR 0.69, 95% CI 0.51–0.94) with SLE among Asians.
This meta-analysis showed that the IL10.G microsatellites, the IL-10 -1082G/A and -592C/A polymorphisms and the haplotype -1082G/−819C/−592C are associated with SLE susceptibility. Besides, this is the first time to report an association between the CA27 allele of the IL-10.G microsatellites and SLE among Caucasians. Further studies are needed to confirm these findings.
Although evidence of inflammation and fatigue has been noted in cancer survivors, whether inflammation is linked to the expression of fatigue and other symptoms arising from concurrent chemoradiation therapy (CXRT) has not been well studied. Patients undergoing CXRT for locally advanced colorectal or esophageal cancer (n = 103) reported multiple symptoms weekly via the M. D. Anderson Symptom Inventory (MDASI) from start of therapy. Serum samples were collected weekly to examine changes in inflammatory markers (interleukin [IL]-6, IL-8, IL-10, IL-1 receptor antagonist [IL-1RA], vascular endothelial growth factor [VEGF], and soluble receptor 1 for tumor necrosis factor [sTNF-R1]) via enzyme-linked immunosorbent assay. Relationships between symptom severity and inflammatory-marker concentration levels were estimated using mixed-effect regression analysis, controlled for week of therapy, age, sex, body mass index, pre-CXRT tumor stage, pre-CXRT chemotherapy, pre-CXRT statin use, and type of cancer. Fatigue was the most severe symptom over time, its development profile shared with pain, distress, drowsiness, poor appetite, and disturbed sleep. sTNF-R1 and IL-6 shared a similar pattern of symptom development, with significant increase during CXRT and decrease after completion of CXRT. Serum concentrations of sTNF-R1 were positively associated over time with the severity of fatigue (p = .00097), while sTNF-R1 and IL-6 were positively related to the severity of a component score of the six most severe symptoms (both p < .0001). This longitudinal study suggests a role for over-expressed sTNF-R1 and IL-6 in the development of fatigue and other severe sickness symptoms during CXRT in patients with colorectal or esophageal cancer.
fatigue; symptoms; sickness behavior; cytokines; cancer; inflammation; MDASI; chemoradiation
To evaluate the exposure-response relationships for efficacy and safety of intravenous anidulafungin in adult patients with fungal infections, a population pharmacokinetic-pharmacodynamic (PK-PD) analysis was performed with data from 262 patients in four phase 2/3 studies. The plasma concentration data were fitted with a previously developed population PK model. Anidulafungin exposures in patients with weight extremities (e.g., 40 kg and 150 kg) were simulated based on the final PK model. Since the patient population, disease status, and efficacy endpoints varied in these studies, the exposure-efficacy relationship was investigated separately for each study using logistic regression as appropriate. Safety data from three studies (n = 235) were pooled for analysis, and one study was excluded due to concomitant use of amphotericin B as a study treatment and different disease populations. The analysis showed that the same dosing regimen of anidulafungin can be administered to all patients regardless of body weight. Nonetheless, caution should be taken for patients with extremely high weight (e.g., >150 kg). There was a trend of positive association between anidulafungin exposure and efficacy in patients with esophageal candidiasis or invasive candidiasis, including candidemia (ICC); however, adequate characterization of the effect of anidulafungin exposure on response could not be established due to the relatively small sample size. No threshold value for exposure could be established, since patients with low exposure also achieved successful outcomes (e.g., area under the curve < 40 mg · h/liter in ICC patients). There was no association between anidulafungin exposure and the treatment-related adverse events or all-causality hepatic laboratory abnormalities.
To explore the potential mechanism of molecular hydrogen in the regulation of miRNA expression and signal-modulating activities.
Retinal microglia cells were activated by Lipopolysaccharides (LPS) and then treated with hydrogen-saturated medium or normal medium without hydrogen. qRT-PCR was used to detect the expression difference in miR-9, miR-21 and miR-199 between these two groups. Moreover, the expression of LPS-induced signaling proteins, including Myd88, IKK-β, NF-κB, and PDCD4, were detected by Western blotting.
The results demonstrated a marked down-regulation of miR-9 and miR-21 and up-regulation of miR-199 by hydrogen treatment; the expression of Myd88 and IKK-β was decreased after hydrogen treatment, whereas PDCD4 was increased, and there was no significant change in NF-κB expression.
The results in the present study indicate that miR-9, miR-199 and miR-21 play an important role in the anti-inflammatory regulation of LPS-activated microglia cells by molecular hydrogen, which will help to explain the protective mechanism of molecular hydrogen against inflammatory injury.
hydrogen; Lipopolysaccharides; miR-9; miR-21; miR-199; Toll-like receptor 4
Prodigiosins (PGs) are a family of natural red pigments with anticancer activity, and one member of the family has entered clinical phase II trials. However, the anticancer mechanisms of PGs remain largely unclear. This study was designed to investigate the molecular basis of anticancer activity of UP, a derivative of PGs, in P388 cells. By introducing pharmacological inhibitors and utilizing a variety of analytical approaches including western blotting, flow cytometry and confocal laser microscopy, we found that UP inhibited proliferation of P388 via arresting cells at G2/M phase and inducing cells apoptosis, which was related to the activation of P38, JNK rather than ERK1/2 signaling. ROS regeneration and acidification in cells appear not involved in UP induced apoptosis. Furthermore, utilizing mass spectrometry, sucrose density gradient fractionation and immunofluorescence staining, we discovered that UP was apparently located at ribosome. These results together indicate that ribosome may be the potential target of UP in cancer cells, which opened a new avenue in delineating the anticancer mechanism of PGs.
The causal genes for congenital cataract are good candidates for the genetic susceptibility for age-related cataract (ARC). The aim of this study was to investigate association between the polymorphisms in the causal genes for congenital cataract and ARC in a Chinese population. Meanwhile, we performed the replication study for previous identified risk genes for ARC.
We recruited 212 sporadic Han Chinese patients with age-related cataracts (ARC) and 172 normal controls in this study. We analyzed 31 SNPs from 13 genes which mostly possible contributes the progress of ARC in a Chinese population, comprising 212 cataract patients and 172 controls. Polymorphism-spanning fragments were amplified by using the multiplex polymerase chain reaction (PCR) and genotyped using primer extension method in MassARRAY platform. Allelic and haplotypic difference in the frequencies were estimated using the SHEsis software platform. P-value was adjusted by the Bonferroni correction.
There was no difference in the frequencies of the genotype and allele of the all SNPs between the patients with ARC and the controls. In the haplotypic analysis, the haplotypes consisting of rs7154572, rs7150141 and rs12432994 in Kinesin Light Chain 1 Gene (KLC1) showed significant association with ARC (p = 0.000878). A rare haplotype CGT was more frequent in patients (p = 0.000106, and p = 0.00795 after corrected for 75 tests).
Our study provides evidence that the combined effect of three variants within the KLC1 gene may predispose to ARC, but the precise mechanism needs further investigating.
To evaluate the importance of morphology in quantifying expression after in vivo gene transfer and to compare gene expression after intra-arterial (IA) and intra-tumoral (IT) delivery of adenovirus expressing a SSTR2-based reporter gene in a large animal tumor model.
Materials and Methods
Tumor directed IA or IT delivery of adenovirus containing a human somatostatin receptor type 2A (Ad-CMV-HA-SSTR2A) gene chimera or control adenovirus (Ad-CMV-GFP) was performed in VX2 tumors growing in both rabbit thighs. Three days later, 111In-octreotide was administered intravenously after CT imaging using a clinical scanner. 111In-octreotide uptake in tumors was evaluated the following day using a clinical gamma-camera. Gene expression was normalized to tumor weight with and without necrosis. This procedure was repeated on nine additional rabbits to investigate longitudinal gene expression both 5 days and 2 weeks after adenovirus delivery. CT images were used to evaluate tumor morphology and excised tissue samples were analyzed to determine 111In-octreotide biodistribution ex vivo.
VX2 tumors infected with Ad-CMV-HA-SSTR2 had greater 111In-octreotide uptake than with control virus (P<0.05). Intra-arterial and intra-tumoral routes resulted in similar levels of gene expression. Longitudinally, expression appeared to wane at 2 weeks versus 5 days after delivery. Areas of necrosis did not demonstrate significant uptake ex vivo. Morphology identified areas of necrosis on contrast enhanced CT and upon excluding necrosis, in vivo biodistribution analysis resulted in greater percent injected dose per gram (P<0.01) and corresponded better with ex vivo biodistribution(r = 0.72, P<0.01, Coefficient of the x-variable = .72) at 2 weeks than without excluding necrosis (P<0.01).
Tumor specificity and high transgene expression can be achieved in tumors via both tumor directed intra-arterial and intra-tumoral delivery in a large animal tumor model. Using clinical machines, morphologic imaging contributes to functional imaging for quantifying SSTR2-based reporter expression in vivo.
Yi Guan Jian Decoction (YGJD), a famous Chinese prescription, has long been employed clinically to treat liver fibrosis. However, as of date, there is no report on the effects of YGJD from a metabonomic approach. In this study, a urine metabonomic method based on gas chromatography coupled with mass spectrometry (GC/MS) was employed to study the protective efficacy and metabolic profile changes caused by YGJD in carbon tetrachloride (CCl4)-induced liver fibrosis.
Urine samples from Wistar rats of three randomly divided groups (control, model, and YGJD treated) were collected at various time-points, and the metabolic profile changes were analyzed by GC/MS with principal component analysis (PCA) and partial least squares-discriminate analysis (PLS-DA). Furthermore, histopathology and biochemical examination were also carried out to ensure the success of CCl4-induced liver fibrosis model.
Urine metabolic profile studies suggested distinct clustering of the three groups, and YGJD group was much closer to the control group by showing a tendency of recovering towards the control group. Fourteen significantly changed metabolites were found, and YGJD treatment could reverse the levels of these metabolites to normal levels or close to normal levels.
The current study indicates that the YGJD has significant anti-fibrotic effects on CCl4-induced liver fibrosis in rats, which might be by regulating the dysfunction of energy metabolism, amino acid metabolism, tryptophan metabolism, cytochrome P450 metabolism, and gut microflora metabolism. The metabonomic approach can be recommended to study the pharmacological effect and mechanism of complex Chinese medicines.
Yi Guan Jian Decoction; Carbon tetrachloride; Liver fibrosis; Urine metabolic profiles; GC/MS