Corrigendum to Acta Cryst. (2009), E65, o1824.
The title of the paper by Li, Li, Li, Zhang & Li [Acta Cryst. (2009), E65, o1824] is corrected.
The title compound, C25H19N3O2, crystallizes as discrete molecules which are well ordered through one intramolecular N—H⋯O hydrogen bond. Structural analysis indicates that the molecules exist as the amine–one form.
Background and Purpose
The Sigma-1 receptor (Sig1R) impacts on calcium ion signalling and has a plethora of ligands. This study investigated Sig1R and its ligands in relation to endogenous calcium events of endothelial cells and transient receptor potential (TRP) channels.
Intracellular calcium and patch clamp measurements were made from human saphenous vein endothelial cells and HEK 293 cells expressing exogenous human TRPC5, TRPM2 or TRPM3. Sig1R ligands were applied and short interfering RNA was used to deplete Sig1R. TRP channels tagged with fluorescent proteins were used for subcellular localization studies.
In endothelial cells, 10–100 μM of the Sig1R antagonist BD1063 inhibited sustained but not transient calcium responses evoked by histamine. The Sig1R agonist 4-IBP and related antagonist BD1047 were also inhibitory. The Sig1R agonist SKF10047 had no effect. Sustained calcium entry evoked by VEGF or hydrogen peroxide was also inhibited by BD1063, BD1047 or 4-IBP, but not SKF10047. 4-IBP, BD1047 and BD1063 inhibited TRPC5 or TRPM3, but not TRPM2. Inhibitory effects of BD1047 were rapid in onset and readily reversed on washout. SKF10047 inhibited TRPC5 but not TRPM3 or TRPM2. Depletion of Sig1R did not prevent the inhibitory actions of BD1063 or BD1047 and Sig1R did not co-localize with TRPC5 or TRPM3.
Conclusions and Implications
The data suggest that two types of Sig1R ligand (BD1047/BD1063 and 4-IBP) are inhibitors of receptor- or chemically activated calcium entry channels, acting relatively directly and independently of the Sig1R. Chemical foundations for TRP channel inhibitors are suggested.
calcium channels; cationic channels; TRP channels; endothelial cells; Sigma-1 receptor; histamine; hydrogen peroxide; vascular endothelial growth factor
Coxsackievirus A16 (CVA16) is responsible for nearly 50% of all the conﬁrmed hand, foot, and mouth disease (HFMD) cases in mainland China, sometimes it could also cause severe complications, and even death. To clarify the genetic characteristics and the epidemic patterns of CVA16 in mainland China, comprehensive bioinfomatics analyses were performed by using 35 CVA16 whole genome sequences from 1998 to 2011, 593 complete CVA16 VP1 sequences from 1981 to 2011, and prototype strains of human enterovirus species A (EV-A). Analysis on complete VP1 sequences revealed that subgenotypes B1a and B1b were prevalent strains and have been co-circulating in many Asian countries since 2000, especially in mainland China for at least 13 years. While the prevalence of subgenotype B1c (totally 20 strains) was much limited, only found in Malaysia from 2005 to 2007 and in France in 2010. Genotype B2 only caused epidemic in Japan and Malaysia from 1981 to 2000. Both subgenotypes B1a and B1b were potential recombinant viruses containing sequences from other EV-A donors in the 5’-untranslated region and P2, P3 non-structural protein encoding regions.
Understanding of plasma protein binding will provide mechanistic insights into drug interactions or unusual pharmacokinetic properties. This study investigated RO4929097 binding in plasma and its implications for the pharmacokinetics and pharmacodynamics of this compound.
RO4929097 binding to plasma proteins was determined using a validated equilibrium dialysis method. Pharmacokinetics of total and unbound RO4929097 was evaluated in eight patients with breast cancer receiving RO4929097 alone and in combination with the Hedgehog inhibitor GDC-0449. The impact of protein binding on RO4929097 pharmacodynamics was assessed using an in vitro Notch cellular assay.
RO4929097 was extensively bound in human plasma, with the total binding constant of 1.0 × 106 and 1.8 × 104 L/mol for α1-acid glycoprotein (AAG) and albumin, respectively. GDC-0449 competitively inhibited RO4929097 binding to AAG. In patients, RO4929097 fraction unbound (Fu) exhibited large intra- and interindividual variability; GDC-0449 increased RO4929097 Fu by an average of 3.7-fold. Concomitant GDC-0449 significantly decreased total (but not unbound) RO4929097 exposure. RO4929097 Fu was strongly correlated with the total drug exposure. Binding to AAG abrogated RO4929097 in vitro Notch-inhibitory activity.
RO4929097 is highly bound in human plasma with high affinity to AAG. Changes in plasma protein binding caused by concomitant drug (e.g., GDC-0449) or disease states (e.g., ↑AAG level in cancer) can alter total (but not unbound) RO4929097 exposure. Unbound RO4929097 is pharmacologically active. Monitoring of unbound RO4929097 plasma concentration is recommended to avoid misleading conclusions on the basis of the total drug levels.
Transgene spreading is a major concern in cultivating genetically modified (GM) corn. Cross-pollination may cause the spread of transgenes from GM cornfields to conventional fields. Occasionally, seed lot contamination, volunteers, mixing during sowing, harvest, and trade can also lead to transgene escape. Obviously, new biological confinement technologies are highly desired to mitigate transgene spreading in addition to physical separation and isolation methods. In this study, we report the development of a built-in containment method to mitigate transgene spreading in corn. In this method, an RNAi cassette for suppressing the expression of the nicosulfuron detoxifying enzyme CYP81A9 and an expression cassette for the glyphosate tolerant 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) gene G10 were constructed and transformed into corn via Agrobacterium-mediated transformation. The GM corn plants that were generated were found to be sensitive to nicosulfuron but resistant to glyphosate, which is exactly the opposite of conventional corn. Field tests demonstrated that GM corn plants with silenced CYP81A9 could be killed by applying nicosulfuron at 40 g/ha, which is the recommended dose for weed control in cornfields. This study suggests that this built-in containment method for controlling the spread of corn transgenes is effective and easy to implement.
Background. Drug-resistant tuberculosis poses a growing challenge to global public health. However, the diversity and dynamics of the bacterial population during acquisition of drug resistance have yet to be carefully examined.
Methods. Whole-genome sequencing was performed on 7 serial Mycobacterium tuberculosis (M. tuberculosis) populations from 3 patients during different stages in the development of drug resistance. The population diversity was assessed by the number and frequencies of unfixed mutations in each sample.
Results. For each bacterial population, 8–41 unfixed mutations were monitored by the fraction of single-nucleotide polymorphisms at specific loci. Among them, as many as 4 to 5 resistance-conferring mutations were transiently detected in the same single sputum, but ultimately only a single type of mutant was fixed. In addition, we identified 14 potential compensatory mutations that occurred during or after the emergence of resistance-conferring mutations.
Conclusions. M. tuberculosis population within patients exhibited considerable genetic diversity, which underwent selections for most fit resistant mutant. These findings have important implications and emphasize the need for early diagnosis of tuberculosis to decrease the chance of evolving highly fit drug-resistant strains.
The submerged cultivating conditions for triterpenoids production from Antrodia cinnamomea were optimized using uniform design method and the one-factor-at-a-time method was adopted to investigate the effect of plants oils and glucose supply on triterpenoids production and mycelia growth. Corn starch and culturing time were identified as more significant variables for triterpenoids production. The optimal conditions for triterpenoids production was 20.0 g/L corn starch, 20.0 g/L wheat bran, 1.85 g/L MgSO4, initial pH 3 and 16 days of cultivation. In addition, investigation of plant oils and glucose supply showed that 0.3 % (v/v) olive oil supply at the beginning of fermentation stimulated mycelia growth and significantly increased triterpenoids production; 0.2 % (w/v) glucose supplement at 10th day enhanced production of triterpenoids with slight effect on biomass, which is reported for the first time. The triterpenoids production experimentally obtained under the optimal conditions was 7.23 % (w/w). The uniform design method may be used to optimize many environmental and genetic factors such as temperature and agitation that can also affect the triterpenoids production from A.cinnamomea.
Antrodia cinnamomea; Total triterpenoids; Optimization; Uniform design
After resecting tumors confined to one femoral condyle, a unicondylar osteoarticular allograft can be used for reconstruction without sacrificing the uninvolved condyle. However, unicondylar osteoarticular allografts have been associated with a high rate of joint degeneration. We describe a unicondylar osteoallograft prosthesis composite reconstruction replacing only one side of the joint to reduce compartment degeneration and avoid contamination of the tibia, but the survival, function, and complications of a unicondylar osteoallograft prosthesis composite are unclear.
Description of Technique
We located a bone resection plane intraoperatively as planned before surgery using a computer-assisted navigation system. The tumor then was removed en bloc and the unicondylar defect filled with a size-matched allogeneic unicondyle. The allograft cartilage was removed. Thereafter, the condyle of the femoral component was resurfaced with a unicompartmental knee prosthesis to form a unicondylar osteoallograft prosthesis composite, however the tibia was left undisturbed. Navigation allowed precise apposition between the unicondylar osteoallograft prosthesis composite and host bone to ensure mechanical alignment and congruency of the joint surface before fixation with a plate.
We retrospectively reviewed 12 patients who underwent unicondylar osteoallograft prosthesis composite reconstructions after unicondylar resection for tumors. One patient died from tumor-related causes without unicondylar osteoallograft prosthesis composite failure after 18 months. We observed the survival rate of unicondylar osteoallograft prosthesis composite reconstruction and related complications. Function and radiographs also were documented according to the Musculoskeletal Tumor Society (MSTS) functional scoring system and the International Society of Limb Salvage radiographic scoring system. The minimum followup was 8 months (median, 37 months; range, 8–65 months).
At last followup, 10 of the 12 unicondylar osteoallograft prosthesis composite reconstructions were still in place. Three reconstructions failed owing to two local recurrences (both treated with amputation) and there was one infection (treated with revision and maintenance of the implant at last followup). The average MSTS functional score at last followup was 27 points and the radiographic score 91%.
Our observations suggest unicondylar osteoallograft prosthesis composite reconstruction might be a reliable technique with relatively few major complications and at least short-term maintenance of the tibial cartilage.
Level of Evidence
Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
Mesenchymal stem cells (MSCs) have been considered as ideal cells for the treatment of a variety of diseases. However, aging and spontaneous differentiation of MSCs during culture expansion dampen their effectiveness. Previous studies suggest that ex
vivo aging of MSCs is largely caused by epigenetic changes particularly a decline of histone H3 acetylation levels in promoter regions of pluripotent genes due to inappropriate growth environment.
In this study, we examined whether histone deacetylase inhibitor trichostatin A (TSA) could suppress the histone H3 deacetylation thus maintaining the primitive property of MSCs. We found that in regular adherent culture, human MSCs became flatter and larger upon successive passaging, while the expression of pluripotent genes such as Oct4, Sox2, Nanog, Rex-1, CD133 and TERT decreased markedly. Administration of low concentrations of TSA in culture significantly suppressed the morphological changes in MSCs otherwise occurred during culture expansion, increased their proliferation while retaining their cell contact growth inhibition property and multipotent differentiation ability. Moreover, TSA stabilized the expression of the above pluripotent genes and histone H3 acetylation levels in K9 and K14 in promoter regions of Oct4, Sox2 and TERT.
Our results suggest that TSA may serve as an effective culture additive to maintain the primitive feature of MSCs during culture expansion.
Sulfonyl fluorides are known to inhibit esterases. Early work from our laboratory has identified hexadecyl sulfonylfluoride (AM374) as a potent in vitro and in vivo inhibitor of fatty acid amide hydrolase (FAAH). We now report on later generation sulfonyl fluoride analogs that exhibit potent and selective inhibition of FAAH. Using recombinant rat and human FAAH we show that 5-(4-hydroxyphenyl)pentanesulfonyl fluoride (AM3506) has similar inhibitory activity for both the rat and the human enzyme, while rapid dilution assays and mass spectrometry analysis suggest that the compound is a covalent modifier for FAAH and inhibits its action in an irreversible manner. Our SAR results are highlighted by molecular docking of key analogs.
Emerging evidence suggests that non-olfactory tissues and cells can express olfactory receptors (ORs), however, the exact function of ectopic OR expression remains unknown. We have previously shown in mouse models that a unique cooperation between interferon-γ (IFN-γ) and lipopolysaccharide (LPS) drives the activation of pulmonary macrophages and leads to the induction of pathogenic responses in the respiratory tract. Further, through gene array studies, we have shown that activation of macrophages by these molecules results in the selective expression of a number of ORs. In this study, we validated the expression of these ORs in mouse airway and pulmonary macrophages in response to IFN-γ and LPS (γ/LPS) stimulation, and further explored the effect of odorant stimulation on macrophage function.
OR expression in airway and pulmonary macrophages in response to IFN-γ, LPS or γ/LPS treatments was assessed by microarray and validated by q-PCR. OR expression (e.g. OR622) on macrophages was confirmed by visualization in immunofluoresence assays. Functional responses to odorants were assessed by quantifying inflammatory cytokine and chemokine expression using q-PCR and cell migration was assessed by a modified Boyden chamber migration assay. Our results demonstrate that eight ORs are expressed at basal levels in both airway and pulmonary macrophages, and that γ/LPS stimulation cooperatively increased this expression. Pulmonary macrophages exposed to the combined treatment of γ/LPS+octanal (an odorant) exhibited a 3-fold increase in MCP-1 protein production, compared to cells treated with γ/LPS alone. Supernatants from γ/LPS+octanal exposed macrophages also increased macrophage migration in vitro.
Eight different ORs are expressed at basal levels in pulmonary macrophages and expression is upregulated by the synergistic action of γ/LPS. Octanal stimulation further increased MCP-1 production and the motility of macrophages. Our results suggest that ORs may mediate macrophage function by regulating MCP-1 production and cell migration.
AIM: To investigate the pathogenesis of biliary casts after liver transplantation relative to their morphology and biochemical markers.
METHODS: The microstructure of biliary casts was assessed using scanning electron microscopy and Hematoxylin and eosin staining assessed their histology. The expression levels of CD3, CD5, CD34, CD68 and CD79a in these biliary casts were evaluated immunohistochemically.
RESULTS: Biliary casts differed widely in their microstructure, with some containing blood vessels positive for CD34 and collagen fibers with positive Masson staining. Large numbers of neutrophils and other inflammatory cells were present, but only on the edge of the biliary casts; although the boundaries were clear without crossover. None of the biliary casts contained T-lymphocytes, B-lymphocytes, macrophages and other inflammatory cells.
CONCLUSION: The microcostructure of biliary casts differed. Bacteria and acute rejection are not clearly related to their formation.
Biliary cast; Biliary cast syndrome; Liver transplantation; Blood vessels; Acute rejection
Deqi sensation is believed to be important in clinical efficacy according to TCM theory. The measuring method of Deqi sensation has significant implications for the result of research trials. This study makes an investigation on acupuncture-experienced patients and expert acupuncturists in China and aims to find out the patient's needling sensations and acupuncturist's sensations which can be acceptable as descriptors of Deqi sensation, so as to provide foundation for more systematic and sensitive quantitative evaluation method of Deqi sensation. Results of this survey indicated that the Deqi sensation noted by both patient and acupuncturist is equally important to the treatment efficacy. It is found that there are some differences between the patients' real-life experience and the acupuncturists' expectations on patients' Deqi sensation. The “dull pain,” “aching,” “sore,” “numb,” “distended,” “heavy,” “electric,” “throbbing,” “warmness,” “coolness,” “spreading,” and “radiating” can be considered as the main manifestations of Deqi sensations. The acupuncturists believed that Deqi sensations were mainly “pulling,” “tight,” and “throbbing.” We suggest developing a questionnaire measuring the Deqi sensations which includes both the sensations of the patient and acupuncturist, and this would be very important and necessary for a better understanding of the relationship between Deqi sensation and acupuncture effects in future studies.
CyberKnife (CK) is a novel stereotactic radiosurgery system for treating tumors in any part of the body. It is a non-invasive or minimally invasive tumor treatment modality that can deliver high doses of spatially precise radiation and minimize exposure to neighboring healthy tissues or vital organs. The purpose of this study was to investigate the safety and efficacy of CK in the treatment of adrenal tumors.
Methods and Results
We performed a retrospective analysis of 26 patients with adrenal tumors who had been treated with CK in the radiotherapy center of our hospital between March 2009 and March 2012. Eight patients had primary adrenal tumors and 18 patients had metastatic adrenal tumors. In addition to CK, 4 patients received chemotherapy and 2 patients received immunotherapy. The average tumor volume was 72.1 cm3 and the prescribed radiation dosage ranged from 30 to 50 Gy and was fractionated 3 to 5 times with a 58% to 80% isodose line. Abdominal CT was performed between 1 to 3 months after the CK treatment to evaluate the short-term efficacy with follow-up examinations once every 3 months. Three patients had complete remission, 12 patients had partial remission, 5 patients had stable disease, and 6 patients had progressive illness. The effective rate of pain relief was 93.8% and the disease control rate was 77% with a median overall survival of 17 months and a median progression-free survival of 14 months. Treatment Related toxicity was well-tolerated, but preventative measure need to be taken for radiation enteritis.
CK is safe and effective for treating adrenal tumors with few adverse reactions. Nonetheless, its long-term effects requires further follow-up.
Compared with invasive breast cancer, breast cancer in situ (BCIS) is seldom life threatening. However, an increasing incidence has been observed in recent years over the world. The purpose of our study is to investigate the epidemiological, clinical and pathological profiles of BCIS in Chinese women from 1999-2008.
Four thousand and two hundred-eleven female breast cancer (BC) patients were enrolled in this hospital-based nation-wide and multi-center retrospective study. Patients were randomly selected from seven hospitals in seven representative geographical regions of China between 1999 and 2008. The epidemiological, clinical and pathological data were collected based on the designed case report form (CRF).
There were one hundred and forty-three BCIS cases in four thousand and two hundred-eleven BC patients (3.4%). The mean age at diagnosis was 48.3 years and BCIS peaked in age group 40-49 yrs (39.9%). The most common subtype was ductal carcinoma in situ (DCIS) (88.0%). 53.8% were positive for estrogen receptor (ER). Human epidermal growth factor receptor 2 (HER2) positive status was observed in 23.8% of patients. All patients underwent surgeries and 14.7% of them had breast conservation therapies (BCT) (21/143), but 41.9% accepted chemotherapy (64/143). Much less patients underwent radiotherapy (16.0%, 23/143) and among patients who had BCT, 67% accepted radiotherapy (14/21). Endocrine therapy was taken in 44.1% patients (63/143).
The younger age of BCIS among Chinese women than Western countries and increasing number of cases pose a great challenge. BCT and endocrine therapy are under great needs.
Trop-2 is a transmembrane glycoprotein upregulated in several human carcinomas, including prostate cancer (PrCa). Trop-2 has been suggested to regulate cell-cell adhesion, given its high homology with the other member of the Trop family, Trop-1/EpCAM, and its ability to bind the tight junction proteins claudin-1 and claudin-7. However, a role for Trop-2 in cell adhesion to the extracellular matrix has never been postulated.
Here, we show for the first time that Trop-2's expression in PrCa cells correlates with their aggressiveness. Using either shRNA-mediated silencing of Trop-2 in cells that endogenously express it, or ectopic expression of Trop-2 in cells that do not express it, we show that Trop-2 inhibits PrCa cell adhesion to fibronectin (FN). In contrast, expression of another transmembrane receptor, αvβ5 integrin, does not affect cell adhesion to this ligand. We find that Trop-2 does not modulate either protein or activation levels of the prominent FN receptors, β1 integrins; however, it promotes β1 association with the adaptor molecule RACK1, and causes significant redistribution of RACK1 to the cell membrane. As a result of Trop-2 expression, we also observe activation of Src and FAK, known to occur upon β1-RACK1 interaction. These enhanced Src and FAK activities are not mediated by changes in either the activity of IGF-IR, which is known to bind RACK1, or IGF-IR's ability to associate with β1 integrins.
In summary, our data demonstrate that the transmembrane receptor Trop-2 is a regulator of PrCa cell adhesion to FN through the β1 integrin-RACK1-Src-FAK signaling axis.
Src; Focal adhesion kinase; Insulin-like Growth Factor I Receptor
There is an accumulating body of evidence indicating a strong association between inflammation and the pathogenesis of atrial fibrillation (AF). Interleukin-6 (IL-6) is a pleiotropic cytokine, functions as a mediator of inflammatory response, and has both proinflammatory and anti-inflammatory properties. The aim of the present study was to investigate the association of the −634C/G polymorphism of the IL-6 gene with AF in elderly Han Chinese patients with essential hypertension (EH). A total of 169 elderly patients with EH were eligible for this study. Patients with AF (n=75) were allocated to the AF group, and 94 subjects without AF to the control group. The polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) technique was used to assess the genotype frequencies. The distribution of the IL-6 −634C/G genotypes (CC, CG, and GG) was 67.02%, 30.85%, and 2.13% in the controls, and 50.67%, 40.00%, and 9.33% in AF subjects, respectively (P=0.0312). The frequency of the G allele in the AF group was significantly higher than that in the control group (29.33% vs. 17.55%, P=0.0103). Compared with the CC and CG genotypes, the GG homozygote had a 4.7353-fold increased risk of AF [95% confidence interval (CI)=0.9537–23.5116, P=0.0382]. These findings suggest that the IL-6 −634C/G polymorphism is associated with AF, and the G allele has increased risk of AF in elderly Han Chinese patients with EH.
Because of rapidly increasing market demand and rising cost pressure, the innovator of etanercept (Enbrel®) will inevitably face competition from biosimilar versions of the product. In this study, to elucidate the differences between the reference etanercept and its biosimilars, we characterized and compared the quality attributes of two commercially available, biosimilar TNF receptor 2-Fc fusion protein products. Biosimilar 1 showed high similarity to Enbrel® in critical quality attributes including peptide mapping, intact mass, charge variant, purity, glycosylation and bioactivity. In contrast, the intact mass and MS/MS analysis of biosimilar 2 revealed a mass difference indicative of a two amino acid residue variance in the heavy chain (Fc) sequences. Comprehensive glycosylation profiling confirmed that biosimilar 2 has significantly low sialylated N-oligosaccharides. Biosimilar 2 also displayed significant differences in charge attributes compared with the reference product. Interestingly, biosimilar 2 exhibited similar affinity and bioactivity levels compared with the reference product despite the obvious difference in primary structure and partial physiochemical properties. For a biosimilar development program, comparative analytical data can influence decisions about the type and amount of animal and clinical data needed to demonstrate biosimilarity. Because of the limited clinical experience with biosimilars at the time of their approval, a thorough knowledge surrounding biosimilars and a case-by-case approach are needed to ensure the appropriate use of these products.
etanercept; biosimilar; TNF receptor 2-Fc fusion protein; N-Glycosylation; sialic acid; intact mass; MS/MS; charge variant; CE-LIF
♦ Background: Since the mid-1990s, early dialysis initiation has dramatically increased in many countries. The Initiating Dialysis Early and Late (IDEAL) study demonstrated that, compared with late initiation, planned early initiation of dialysis was associated with comparable clinical outcomes and increased health care costs. Because residual renal function is a key determinant of outcome and is better preserved with peritoneal dialysis (PD), the present pre-specified subgroup analysis of the IDEAL trial examined the effects of early-compared with late-start dialysis on clinical outcomes in patients whose planned therapy at the time of randomization was PD.
♦ Methods: Adults with an estimated glomerular filtration rate (eGFR) of 10 - 15 mL/min/1.73 m2 who planned to be treated with PD were randomly allocated to commence dialysis at an eGFR of 10 - 14 mL/min/1.73 m2 (early start) or 5 - 7 mL/min/1.73 m2 (late start). The primary outcome was all-cause mortality.
♦ Results: Of the 828 IDEAL trial participants, 466 (56%) planned to commence PD and were randomized to early start (n = 233) or late start (n = 233). The median times from randomization to dialysis initiation were, respectively, 2.03 months [interquartile range (IQR):1.67 - 2.30 months] and 7.83 months (IQR: 5.83 - 8.83 months). Death occurred in 102 early-start patients and 96 late-start patients [hazard ratio: 1.04; 95% confidence interval (CI): 0.79 - 1.37]. No differences in composite cardiovascular events, composite infectious deaths, or dialysis-associated complications were observed between the groups. Peritonitis rates were 0.73 episodes (95% CI: 0.65 - 0.82 episodes) per patient-year in the early-start group and 0.69 episodes (95% CI: 0.61 - 0.78 episodes) per patient-year in the late-start group (incidence rate ratio: 1.19; 95% CI: 0.86 - 1.65; p = 0.29). The proportion of patients planning to commence PD who actually initiated dialysis with PD was higher in the early-start group (80% vs 70%, p = 0.01).
♦ Conclusion: Early initiation of dialysis in patients with stage 5 chronic kidney disease who planned to be treated with PD was associated with clinical outcomes comparable to those seen with late dialysis initiation. Compared with early-start patients, late-start patients who had chosen PD as their planned dialysis modality were less likely to commence on PD.
Dialysis timing; mortality; outcomes; peritonitis
Tick-borne encephalitis (TBE), caused by tick-borne encephalitis virus (TBEV), is an infectious disease involving the central nervous system (CNS). The pathogenesis of CNS injury has not been clearly demonstrated. Matrix metalloproteinase-9 (MMP-9) and some cytokines, such as interleukin 6 (IL-6), may play important roles in the disruption of the blood-brain barrier (BBB) and the pathogenesis of TBE.
72 cerebrospinal fluid (CSF) samples were collected from TBE patients in north eastern China. IgG levels in CSF and serum were compared and MMP-9 and IL-6 levels were evaluated by ELISA. The correlation between the elevated MMP-9 levels and IgG extravasation, disease severity, and neuroinflammation was analyzed.
Increased concentration of MMP-9 was detected in some of the CSF samples, and the elevation was found to be closely related to CSF TBEV IgG extravasation and enhancement of IL-6 expression. Moreover, elevated levels of MMP-9 were found to be correlated with IL-6 enhancement. Four of the 72 patients, the ones who died, presented with high CSF MMP-9 levels.
In TBE patients, elevated CSF MMP-9 levels were associated with brain inflammatory reaction, disruption of the blood-brain barrier, and disease severity.
Hepatitis C virus (HCV) NS3/NS4A serine protease is essential for viral replication, which is regarded as a promising drug target for developing direct-acting anti-HCV agents. In this study, sixteen novel compounds with cell-based HCV replicon activity ranging from 3.0 to 28.2 μM (IC50) were successfully identified by means of structure-based virtual screening. Compound 5 and compound 11, with an IC50 of 3.0 μM and 5.1 μM, respectively, are the two most potent molecules with low cytotoxicity.
hepatitis C virus (HCV); NS3/NS4A serine protease; structure-based drug design (SBDD); virtual screening
Previous studies in narcolepsy, an autoimmune disorder affecting hypocretin (orexin) neurons and recently associated with H1N1 influenza, have demonstrated significant associations with five loci. Using a well-characterized Chinese cohort, we refined known associations in TRA@ and P2RY11-DNMT1 and identified new associations in the TCR beta (TRB@; rs9648789 max P = 3.7×10−9 OR 0.77), ZNF365 (rs10995245 max P = 1.2×10−11 OR 1.23), and IL10RB-IFNAR1 loci (rs2252931 max P = 2.2×10−9 OR 0.75). Variants in the Human Leukocyte Antigen (HLA)- DQ region were associated with age of onset (rs7744020 P = 7.9×10−9 beta −1.9 years) and varied significantly among cases with onset after the 2009 H1N1 influenza pandemic compared to previous years (rs9271117 P = 7.8×10−10 OR 0.57). These reflected an association of DQB1*03:01 with earlier onset and decreased DQB1*06:02 homozygosity following 2009. Our results illustrate how genetic association can change in the presence of new environmental challenges and suggest that the monitoring of genetic architecture over time may help reveal the appearance of novel triggers for autoimmune diseases.
Narcolepsy-hypocretin deficiency results from a highly specific autoimmune attack on hypocretin cells. Recent studies have established antigen presentation by specific class II proteins encoded by (HLA DQB1*06:02 and DQA1*01:02) to the cognate T cell receptor as the main disease pathway, with a role for H1N1 influenza in the triggering process. Here, we have used a large and well-characterized cohort of Chinese narcolepsy cases to examine genetic architecture not observed in European samples. We confirmed previously implicated susceptibility genes (T cell receptor alpha, P2RY11), and identify new loci (ZNF365, IL10RB-IFNAR1), most notably, variants at the beta chain of the T cell receptor. We found that one HLA variant, (DQB1*03:01), is associated with dramatically earlier disease onset (nearly 2 years). We also identified differences in HLA haplotype frequencies among cases with onset following the 2009 H1N1 influenza pandemic as compared to before the outbreak, with fewer HLA DQB1*06:02 homozygotes. This may be the first demonstration of such an effect, and suggests that the study of changes in GWAS signals over time could help identify environmental factors in other autoimmune diseases.
To design novel synthetic gene delivery system in which the carrier molecule functions dually as a carrier and a cytotoxic agent targeting dysregulated polyamine metabolism in cancer.
Bisethylnorspermine (BENSpm) lipopolyamine was synthesized and its toxicity evaluated by MTS assay in MCF-7 and MCF-10A cells. Transfection activity was determined using luciferase plasmid DNA.
Asymmetrical lipid analogue of polyamine anticancer drug BENSpm was synthesized using nucleophilic ring opening of azetidinium ion. The synthesized LipoBENSpm showed cytotoxicity comparable to that of parent BENSpm in human breast cancer cell line MCF-7 but mediated 3–4 orders magnitude higher transfection activity. Importantly, cytostatic activity of BENSpm, typically in a low µM range, falls within a relevant and typical concentration range required for efficient gene delivery.
These findings make gene delivery vectors based on BENSpm promising candidates for combination drug/gene approaches to the treatment of cancer.
drug combination; drug delivery; gene delivery; lipid; transfection