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Supplementary Data from FDA Approval Summary: Belumosudil for Adult and Pediatric Patients 12 Years and Older with Chronic GvHD after Two or More Prior Lines of Systemic Therapy

On July 16, 2021, the FDA approved belumosudil, a kinase inhibitor, for adult and pediatric patients 12 years and older with chronic GvHD (cGvHD) after failure of at least two prior lines of systemic therapy. Approval was based on the results of Study KD025–213, which included 65 patients with cGvHD treated with belumosudil 200 mg daily in an open-label, single-arm cohort. Efficacy was determined by the overall response rate (ORR) through Cycle 7 Day 1, which included complete response (CR) or partial response (PR) according to the 2014 NIH consensus criteria, and durability of response. The ORR through Cycle 7 Day 1 was 75% [95% confidence interval (CI), 63–85]; 6% of patients achieved a CR, and 69% achieved a PR. The median duration of response was 1.9 months (95% CI, 1.2–2.9), and 62% (95% CI, 46–74) of responding patients remained alive without new systemic therapy for at least 12 months from response. The common adverse reactions were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, phosphate decreased, gamma-glutamyl transferase increased, lymphocytes decreased, and hypertension. Additional study is warranted to confirm safety with long-term use.

A total synthesis approach of CS-E oligosaccharides was established and a series of derivatives were synthesized. These oligosaccharides were evaluated for a glycosaminoglycan (GAG)-binding protein interaction against cytokines, midkine, and pleiotrophin, by surface-plasmon resonance (SPR) assay. The binding epitopes of oligosaccharides to midkine were mapped using a saturation transfer difference (STD) NMR technique. The groups on the reducing end contributed to binding affinity, and should not be ignored in biological assays. These findings contribute to the structure and activity relationship research and a foundation of understanding that will underpin potential future optimization of this class of oligosaccharides as pharmaceutical agents.

The predictive performance of physiologically‐based pharmacokinetics (PBPK) models for pharmacokinetics (PK) in renal impairment (RI) and hepatic impairment (HI) populations was evaluated using clinical data from 29 compounds with 106 organ impairment study arms were collected from 19 member companies of the International Consortium for Innovation and Quality in Pharmaceutical Development. Fifty RI and 56 HI study arms with varying degrees of organ insufficiency along with control populations were evaluated. For RI, the area under the curve (AUC) ratios of RI to healthy control were predicted within twofold of the observed ratios for > 90% (N = 47/50 arms). For HI, > 70% (N = 43/56 arms) of the hepatically impaired to healthy control AUC ratios were predicted within twofold. Inaccuracies, typically overestimation of AUC ratios, occurred more in moderate and severe HI. PBPK predictions can help determine the need and timing of organ impairment study. It may be suitable for predicting the impact of RI on PK of drugs predominantly cleared by metabolism with varying contribution of renal clearance. PBPK modeling may be used to support mild impairment study waivers or clinical study design.

On July 16, 2021, the FDA approved belumosudil, a kinase inhibitor, for adult and pediatric patients 12 years and older with chronic GvHD (cGvHD) after failure of at least two prior lines of systemic therapy. Approval was based on the results of Study KD025–213, which included 65 patients with cGvHD treated with belumosudil 200 mg daily in an open-label, single-arm cohort. Efficacy was determined by the overall response rate (ORR) through Cycle 7 Day 1, which included complete response (CR) or partial response (PR) according to the 2014 NIH consensus criteria, and durability of response. The ORR through Cycle 7 Day 1 was 75% [95% confidence interval (CI), 63–85]; 6% of patients achieved a CR, and 69% achieved a PR. The median duration of response was 1.9 months (95% CI, 1.2–2.9), and 62% (95% CI, 46–74) of responding patients remained alive without new systemic therapy for at least 12 months from response. The common adverse reactions were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, phosphate decreased, gamma-glutamyl transferase increased, lymphocytes decreased, and hypertension. Additional study is warranted to confirm safety with long-term use.

Aim: Chondroitin sulfate (CS) is a class of highly sulfated polysaccharides that possess many important biological functions. The heterogeneity of CS limits pharmacological research and leads to ambiguous mechanisms. Thus, glycomimetics are demanded as replacement of natural polysaccharides to explore important biological processes. Results & methodology: Here the preparation of CS glycodendrimers is reported as well as their use as CS mimetics to regulate the NF-κB pathway. Multivalent presentation of sugar epitopes on appropriate dendrimer scaffolds increased the suppression of the NF-κB pathway. The interaction between CS-E molecules and TNF-α was examined by nuclear magnetic resonance technology. Conclusion: Overall, the glycodendrimer reported here may be potentially employed as molecular tool to investigate the biological functions of CS.

Aim: To evaluate the effect of SLCO1B1 genetic variants on grazoprevir pharmacokinetics and efficacy. Methods: A retrospective analysis of 1578 hepatitis C virus-infected participants from ten Phase II/III clinical trials. Results: Relative to noncarriers of the risk allele, geometric mean ratios (95% CI) of grazoprevir area under curve (AUC)0–24 were: rs4149056 (risk allele C), one copy, 1.13 (1.06–1.21), two copies, 1.43 (1.16–1.77); and rs11045819 (risk allele A), one copy, 0.93 (0.87–1.00); two copies, 0.78 (0.61–1.00). The rs2306283 variant was not associated with grazoprevir exposure. None of the SLCO1B1 variants were associated with sustained virologic response. Conclusion: Genetic variants in SLCO1B1 were associated with modest changes in grazoprevir pharmacokinetics, but not with meaningful differences in efficacy.

Irrigation regimes should be chosen to maximize crop yield and water use efficiency. To realize high yield and efficient water use with the appropriate furrow irrigation regime, the effects of two regimes (alternate furrow irrigation and conventional furrow irrigation) and three lower soil moisture limits (60, 70, and 80%) were studied on winter wheat yield and water consumption using a multi-level fuzzy comprehensive evaluation method. The results show that under the two regimes, alternate furrow irrigation and conventional furrow irrigation, when the lower limit of the soil moisture is 70%, the harvest index (0.45 and 0.39, respectively) and crop water productivity of winter wheat (1.86 and 1.90 kg m−3, respectively) are highest. The comprehensive fuzzy evaluation model considers multiple measures, including yield, harvest indices, irrigation volume, total water consumption, and crop water productivity – the index values are highest at the 70% condition, which are 0.3468 and 0.3432, respectively. Therefore, it can be concluded that a moderate water deficit is conducive to saving water resources and improving water use efficiency. In conclusion, a multi-level and multi-factor indices system of furrow irrigation regime was constructed based on ensuring winter wheat production. Conventional furrow irrigation is recommended in areas with sufficient irrigation water, while alternating furrow irrigation, which can reduce the total amount of irrigation required, is suitable for areas with water shortages.

SREBP cleavage-activating protein (SCAP) plays a vital role in the modulation of cholesterol homeostasis, and cholesterol dysregulation is tightly associated with coronary artery disease (CAD). To investigate the correlation of the genetic polymorphism of SCAP with CAD, we conducted a case-control study of 528 CAD patients (case group) and 483 age- and sex- matched subjects from whom CAD was excluded (control group). Three tagSNPs (rs147215799, rs17079634 and rs59586735) in SCAP gene were genotyped in all participants, the genotype and allele frequencies of which were compared between two groups to determine their associations with CAD. We found rs17079634 showed significant difference in genotype distribution between the case and control group (P=0.016). The difference was most prominent in a dominant model (TT vs. CT + CC, P=0.004). After adjustment for confounding factors, the difference remained statistically significant (OR =1.363, 95% confidence interval [CI]:1.022~1.818, P=0.035). Whereas no significant associations of the other two SNPs with CAD were observed (P=0.393 for rs147215799 and 0.303 for rs59586735, respectively）. We drew conclusion that the SCAP genetic polymorphism rs17079634 was associated with CAD.

Background Coronary artery disease (CAD) is the leading cause of death worldwide. In this study, we aimed to explore whether some genetic variants of the human IDOL gene were associated with CAD among Chinese population in Xinjiang. Methods We designed two independent case–control studies. The first one included in the Han population (448 CAD patients and 343 controls), and the second one is the Uygur population (304 CAD patients and 318 controls). We genotyped three SNPs (rs2072783, rs2205796, and rs909562) of the IDOL gene. Results Our results revealed that, in the Han female subjects, for rs2205796, the distribution of alleles, dominant model (TT vs. GG + GT) and the additive model (GG + TT vs. GT) showed significant differences between CAD patients and the control subjects (P = 0.048, P = 0.014, and P = 0.032, respectively). Conclusions The rs2205796 polymorphism of the IDOL gene is associated with CAD in the Chinese Han female population in Xinjiang, China.

Background: Coronary artery disease (CAD) is a complex, multifactorial disease and the underlying pathogenesis is unclear. It is essential to improve our understanding of the aetiology and pathogenesis of CAD for developing effective methods of early diagnosis and treatment.Results: We recruited 190 participants including normal coronary artery (n = 49), stable coronary artery disease (n = 93) and acute myocardial infarction patients (n = 48). We combined metagenomics (16S rRNA sequencing and gut microbiome whole-genome sequencing) and multi-type metabolomics (serum, faeces and urine) analyses to determine the correlations among metabolites, the microbiota and clinical indexes to identify biomarkers of CAD. Compared with the faecal metabolites, serum and urine metabolites exhibited strong correlation with clinical indexes. Comparing the three types of metabolome, we discovered that the faecal and urine metabolome was more suitable than the serum metabolome for correlation analysis with the microbiota. Furthermore, we found that the serum and urine metabolome was more suitable than the faecal metabolome for correlation analysis with the clinical indexes. We constructed, for the first time, the relationship networks among the microbiota, metabolites and pathways. Through the relationship network analysis, we identified some important differential metabolites and delineated how these metabolites are related to the differentially abundant microbes.Conclusions: In our research, we used metagenome and multi-type metabolome profiling based on hundreds of samples to figure out the correlations among metabolites, microbiota and clinical indexes. In addition, we firstly constructed the relationship networks of microbiota, metabolites and pathways. We believe our findings can help the researchers to further understand the pathogenesis of CAD.

OBJECTIVE: To develop an effective, low-cost, single-visit cervical screening strategy incorporating a modified Pap test and visual inspection with acetic acid and Lugol's iodine for low-income settings. METHODS: We conducted a prospective cohort trial. Two low-income Muslim Uyghur communities in China's far western Kashi Prefecture served as pilot and validation study sites, respectively, and 4,049 women (aged 30-59 years) were screened. The conventional Pap test was modified using a cotton swab to collect cervical cells without scraping the cervix using an Ayre spatula, allowing visual inspection with acetic acid (and visual inspection with Lugol's iodine if visual inspection with acetic acid was negative) to be performed in a single visit. Results from both tests were available within 1-2 hours. Women positive for either or both underwent same-day biopsy that was shipped by a courier service to a central pathology laboratory. RESULTS: Single-visit screening incorporating both a modified Pap test and visual inspection achieved a sensitivity of 96.0% (95% CI 91.6-100), which was superior to Pap testing (76%, 95% CI 66.3-85.7; P

Hyperlipidemia is one of the main causes of obesity, type 2 diabetes mellitus (T2DM), and atherosclerosis. The adenosine derivative, 2′,3′,5′-triacetyl-N6-(3-hydroxylaniline) adenosine (IMM-H007) is an effective lipid-lowering compound that has important implications for the development of lipid-lowering drugs. Metabolomic analysis based on 1H NMR was used to monitor dynamic changes in diverse biological media including serum, liver, urine, and feces in response to high-fat diet (HFD) and IMM-H007 treatments. Ultraperformance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) and gas chromatography (GC) analyses were performed to quantify the bile acids and fatty acids in the liver and feces. Fecal microbiome profiling was performed using Illumina sequencing of the 16S rRNA (16S rRNA) gene. IMM-H007 improved the metabolism of carbohydrate, ketone bodies, fatty acids, amino acids, and bile acids in hyperlipidemic hamsters. The correlation between metabolite changes was explored in different biolog...

Several studies suggest an important role of Acyl-CoA: cholesterol acyltransferase-1(ACAT-1) in the development of atherosclerosis. The aim of present study was to investigate whether there exists a possible correlation between genetic variations in ACAT-1 genes and coronary artery disease (CAD) risk. Four polymorphisms (rs1044925, rs11545566, rs12121758 and rs10913733) were finally selected and genotyped in 750 CAD patients and 580 health controls, using the improved multiplex ligation detection reaction (iMLDR) method. We found that the rs11545566 G allele was associated with a significantly elevated CAD risk [GG vs. AA: adjusted odds ratio (AOR) = 1.62, 95% confidence interval (CI) = 1.13-2.32, P = 0.008; GA/GG vs. AA: AOR = 1.67, 95% CI = 1.22-2.29, P = 0.001]. The rs10913733 G allele was also associated with a significantly elevated CAD risk (GG vs. TT: AOR = 1.57, 95% CI = 1.08-2.28, P = 0.018; GT/GG vs. TT: AOR = 1.39, 95% CI = 1.07-1.79, P = 0.013). Multivariate linear regression analysis showed that the rs11545566 polymorphism was independently associated with the Gensini scores (P = 0.005). The Gensini score of subjects in the variant GG genotype group and the GG/GA genotype group were higher than the score of subjects in the AA genotype group (32.49 ± 26.60 and 31.26 ± 26.96 vs. 23.45 ± 21.64; P = 0.001 and 0.002, respectively). Our results demonstrate that ACAT-1 rs1154556 and rs10913733 polymorphism are novel genetic factors in the development of CAD. Rs11545566 was also associated with the severity of CAD.

// Asiya Abudesimu 1, * , Dilare Adi 1, * , Dilixiati Siti 1, * , Xiang Xie 1 , Yi-Ning Yang 1 , Xiao-Mei Li 1 , Ying-Hong Wang 1 , Yong-Tao Wang 1 , Ya-Jie Meng 1 , Fen Liu 2 , Bang-Dang Chen 2 , Xiang Ma 1 , Zhen-Yan Fu 1 and Yi-Tong Ma 1 1 Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, PR China 2 Xinjiang Key Laboratory of Cardiovascular Disease, Clinical Medical Research Institute of First Affiliated Hospital of Xinjiang Medical University, Urumqi, PR China * These authors contributed equally to this work Correspondence to: Yi-Tong Ma, email: myt-xj@163.com, myt0991@126.com Zhen-Yan Fu, email: fuzhenyan316@126.com Xiang Ma, email: maxiangxj@163.com Keywords: SREBP family, FBXW7, coronary artery disease, case-control study Received: May 26, 2017 Accepted: September 05, 2017 Published: September 19, 2017 ABSTRACT Background: Hyperlipidemia is a major risk factor for coronary artery disease (CAD). The current study was designed to explore the possible correlation between single nucleotide polymorphisms (SNPs) in the lipid homeostasis regulatory genes F-box and WD repeat domain–containing 7 (FBXW7 ) and sterol regulatory element-binding proteins (SREBPs) with CAD among Han Chinese and Uygur Chinese populations in Xinjiang, China. Results: In the Uygur Chinese population, rs9902941 in SREBP-1 and rs10033601 in FBXW7 were found to be associated with CAD in a recessive model (TT vs. CT + CC, P = 0.032; GG vs. AG + AA, P = 0.010, respectively), and rs7288536 in SREBP-2 was found to be associated with CAD in an additive model (CT vs. CC + TT, P = 0.045). The difference was statistically significant in the Uygur Chinese population after multivariate adjustments [Odds ratio (OR) = 1.803, 95% confidence interval (CI): 1.036~3.137, P = 0.037; OR = 1.628, 95% CI: 1.080~2.454, P = 0.020; OR = 1.368; and 95% CI: 1.018~1.837, P = 0.037, respectively]. There were also significant interactions between the above-mentioned models in the Uygur Chinese population. However, these relationships were not observed before or after multivariate adjustment in the Han Chinese population. Materials and Methods: A total of 1,312 Han Chinese (650 CAD patients and 662 controls) and 834 Uygur Chinese (414 CAD patients and 420 controls) were enrolled in this case-control study. Three SNPs (rs9902941 in SREBP-1, rs7288536 in SREBP-2 and rs10033601 in FBXW7) were selected and genotyped using the improved multiplex ligase detection reaction (iMLDR) method. Conclusions: The results of this study indicate that variations in the lipid regulatory pathway genes FBXW7 and SREBPs (rs9902941 in SREBP-1, rs7288536 in SREBP-2 and rs10033601 in FBXW7) are associated with CAD in the Uygur Chinese population in Xinjiang, China.

Under the guidance of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), scientists from 20 pharmaceutical companies formed a Victim Drug-Drug Interactions Working Group. This working group has conducted a review of the literature and the practices of each company on the approaches to clearance pathway identification (fCL), estimation of fractional contribution of metabolizing enzyme toward metabolism (fm), along with modeling and simulation-aided strategy in predicting the victim drug-drug interaction (DDI) liability due to modulation of drug metabolizing enzymes. Presented in this perspective are the recommendations from this working group on: 1) strategic and experimental approaches to identify fCL and fm, 2) whether those assessments may be quantitative for certain enzymes (e.g., cytochrome P450, P450, and limited uridine diphosphoglucuronosyltransferase, UGT enzymes) or qualitative (for most of other drug metabolism enzymes), and the impact due to the lack of quantitative information on the latter. Multiple decision trees are presented with stepwise approaches to identify specific enzymes that are involved in the metabolism of a given drug and to aid the prediction and risk assessment of drug as a victim in DDI. Modeling and simulation approaches are also discussed to better predict DDI risk in humans. Variability and parameter sensitivity analysis were emphasized when applying modeling and simulation to capture the differences within the population used and to characterize the parameters that have the most influence on the prediction outcome.

Disabled-2 (Dab2) is a clathrin and cargo-binding endocytic adaptor protein that plays a role in cellular trafficking of low-density lipoprotein receptor (LDLR). However, little is known about its involvement in coronary artery disease (CAD). Here, we aimed to investigate the association between Dab2 single-nucleotide polymorphisms (SNPs) and CAD in Chinese Han and Uyghur populations. We performed a case-control study in CAD group that consisted of 621 Han and 346 Uygurs, and the age and gender matched control group consisted of 611 Han and 405 Uygurs. The clinicopathological characteristics of these subjects were analyzed. Genotyping of 4 SNPs (rs1050903, rs2855512, rs11959928, and rs2255280) of the Dab2 gene was performed in all subjects with an improved multiplex ligase detection reaction method. The distribution of the genotype, dominant model (AA vs. AC + CC), as well as allele frequencies of both rs2855512 and rs2255280, was significantly different between CAD patients and control subjects in Han population but not in Uyghur population. AA genotype may be a risk factor for CAD. For Han population, statistical significant correlation between dominant model for both SNPs (AA) and CAD was found after multivariate adjustment. After multivariate adjustment in the Han population, we speculate that rs285512 A allele and rs2255280 A allele may be potentially associated with the onset of coronary heart disease. Individuals with the AA genotype had an OR of 1.44 (95% CI: 1.10–1.88, P = .01, rs2855512) and 1.41 (95% CI: 1.08–1.85, P = .01, rs2255280) for CAD compared with individuals with the AC or CC genotype, respectively. Our data indicates that the AA genotype of rs2855512 and rs2255280 in the Dab2 gene may be a genetic marker of CAD risk in Chinese Han population.

ObjectiveThe aim of this study was to explore the relationship between low-density lipoprotein cholesterol:high-density lipoprotein cholesterol (LDL-C:HDL-C) ratio and common carotid atherosclerotic plaque (CCAP) among obese adults of Uygur community in Xinjiang, China.DesignA hospital-based cross-sectional study.SettingFirst Affiliated Hospital of Xinjiang Medical University.ParticipantsA total of 1449 obese adults of Uygur population who were free of coronary artery disease were included in our study from 1 January 2014 to 31 December 2016.MethodologyLipid profiles, other routine laboratory parameters and intima-media thickness of the common carotid artery were measured in all participants. Multivariate logistic regression analysis was used to examine the association between LDL-C:HDL-C ratio and CCAP.ResultsFour hundred and fifteen (28.64%) participants had CCAP. Participants with CCAP had significantly higher LDL-C:HDL-C ratio compared with those without CCAP (3.21 [2.50, 3.88] vs 2.33 [1.95, 2.97], pConclusionCCAP is highly prevalent in Uygur obese adults. A high LDL-C:HDL-C ratio is an independent predictor of CCAP. It may help identify obese individuals who are at high risk of CCAP and who may benefit from intensive LDL-lowering therapy.

Nuclear magnetic resonance (NMR)-based metabolomics can be used directly to identify a variety of metabolites in biological fluids and tissues. Metabolite analysis is an important part of life science and metabolomics research. However, the identification of some metabolites using NMR spectroscopy remains a big challenge owing to low abundance or signal overlap. It is important to develop a method to measure these compounds accurately. Two-dimensional NMR spectroscopy, metabolite prediction software packages, and spike-in experiments with authentic standards are often used to solve these problems, but they are costly and time-consuming. In this study, methods were developed to identify metabolites in complex biological mixtures using both high-performance liquid chromatography (HPLC) and off-line microprobe NMR spectroscopy. With use of these methods, 83 and 73 metabolites were identified in Sprague Dawley rat urine and feces, respectively. Among them, 40 and 45 metabolites, respectively, could not be identified with traditional NMR methods. Our research revealed that the combination of HPLC and NMR techniques could significantly improve the accuracy of trace and overlapped metabolite identification, while offering an effective and convenient approach to identify potential biomarkers in complex biological systems. Electronic supplementary material The online version of this article (doi:10.1007/s00216-015-8556-y) contains supplementary material, which is available to authorized users.

A facility was designed to collect the primary combustion products of boron-based fuel-rich propellants under different chamber pressures. The morphology and particle size of condensed-phase products were analyzed using a laser particle size analyzer and a scanning electron microscope (SEM), and chemical analysis of condensed-phase products was carried out by X-ray diffraction (XRD), laser Raman spectrometry, wet chemical analysis and elemental analysis. In addition, organics in condensed-phase products and gaseous products were analyzed by Fourier Transform Infrared Spectrometry (FTIR) and Gas Chromatography (GC), respectively. The results show that the condensed-phase products mainly consist of B, C, B4C (or B12C2), BN, Mg, MgO, MgAl2O4, Al, Al2O3, AlCl3, NH4[Mg(H2O)6]Cl3, NH4Cl and Fe3O4; there are large amounts of boron oxide and boron carbide in the condensed-phase products, which indicates that elemental boron is highly active during the primary combustion process; a higher chamber pressure may be disadvantageous to the secondary combustion efficiency because more inactive boron carbide, graphite and h-BN (especially boron carbide) are produced.

A quantitative nuclear magnetic resonance (qNMR) method to measure the content of Orlistat in tablets was studied and found to be efficient, accurate, reliable, and simple. In this paper, phloroglucinolanhydrous and dimethylsulfoxide-d6 (DMSO-d6) served as the internal standard and solvent, respectively. The qNMR methodology, including the linearity, range, the limit of detection (LOD) and quantification (LOQ), stability, precision, and accuracy, was validated seriatim, and the results were very favorable. The content determination results of three batches of Orlistat in tablets were almost identical upon comparing the qNMR method and the high-performance liquid chromatography (HPLC) method. The recommended method authentically compensated the deficiencies of the current HPLC method for determining Orlistat content, and proved to be a method complementary to traditional analysis for the purity measurement of Orlistat in some pharmaceutical preparations.

Hydroxysafflor yellow A (HSYA) is the main active component of the Chinese herbCarthamus tinctoriusL.. Purified HSYA is used as a neuroprotective agent to prevent cerebral ischemia. Injectable safflor yellow (50 mg, containing 35 mg HSYA) is widely used to treat patients with ischemic cardiocerebrovascular disease. However, it is unknown how HSYA exerts a protective effect on cerebral ischemia at the molecular level. A systematical integrated study, including histopathological examination, neurological evaluation, blood-brain barrier (BBB), metabonomics, and the nuclear factor-κB (NF-κB) pathway, was applied to elucidate the pathophysiological mechanisms of HSYA neuroprotection at the molecular level. HSYA could travel across the BBB, significantly reducing the infarct volume and improving the neurological functions of rats with ischemia. Treatment with HSYA could lead to relative corrections of the impaired metabolic pathways through energy metabolism disruption, excitatory amino acid toxicity, oxidative stress, and membrane disruption revealed by1H NMR-based metabonomics. Meanwhile, HSYA treatment inhibits the NF-κB pathway via suppressing proinflammatory cytokine expression and p65 translocation and binding activity while upregulating an anti-inflammatory cytokine.

Pancreas ductal adenocarcinoma (PDAC) remains a deadly malignancy with poor early diagnostic and no effective therapy. Although several proteomic studies have performed comparative analysis between normal and malignant tissues, there is a lack of clear characterization of proteins that could be of clinical value. Systemically reachable ("potentially accessible") proteins, suitable for imaging technologies and targeted therapies represent a major group of interest. The current study explores potentially accessible proteins overexpressed in PDAC, employing innovative proteomics technologies. In the discovery phase, potentially accessible proteins from fresh human normal and PDAC tissues were ex vivo biotinylated, isolated and identified using 2D-nano-HPLC-MS/MS method. The analysis revealed 422 up-regulated proteins in the tumor, of which 83 (including protein isoforms) were evaluated as potentially accessible. Eleven selected candidates were further confirmed as up-regulated using Western blot and multiple reaction monitoring protein quantification. Of these, transforming growth factor beta-induced (TGFBI), latent transforming growth factor beta binding 2 (LTBP2), and asporin (ASPN) were further investigated by employing large scale immunohistochemistry-based validations. They were found to be significantly expressed in a large group of clinical PDAC samples compared to corresponding normal and inflammatory tissues. In conclusion, TGFBI, LTBP2, and ASPN are novel, overexpressed, and potentially accessible proteins in human PDAC. They bear the potential to be of clinical value for diagnostic and therapeutic applications and merit further studies using in vivo models.

Three novel sesquinlignans, tatanans A (1), B (2), and C (3), have been isolated from the rhizomes of Acorus tatarinowii Schott. Their structures were established by spectroscopic techniques and single-crystal X-ray analysis. Tatanans A-C potently increase GK enzymatic activity with EC(1.5) values in the range of 0.16-1.85 μM. The potent GK activity and unique structural features of tatanans make them promising leads for therapeutic development of antihyperglycemic drugs.

Laropiprant is a selective antagonist of the prostaglandin D2 receptor subtype 1, and is primarily eliminated via glucuronidation with a minor contribution from oxidative metabolism via CYP3A. The effects of multiple oral doses of clarithromycin on the pharmacokinetics of laropiprant were investigated in an open-labeled, randomized, 2-period cross-over study. A single oral dose of 40 mg laropiprant was administered alone or coadministered with 500 mg clarithromycin b.i.d. on Day 5 of a 7-day clarithromycin regimen. Geometric mean ratios (90% confidence intervals) for AUC0-∞ and Cmax of laropiprant in the presence versus absence of clarithromycin were 1.39 (1.19, 1.62) and 1.46 (1.17, 1.80), respectively. No statistically significant differences were observed in Tmax (P= 0.543) or apparent terminal half-life (P= 0.502) of laropiprant, which implies that the effect of clarithromycin on laropiprant is largely a first-pass rather than a systemic effect. The results of this study suggest that laropiprant is not a sensitive CYP3A substrate, and strong CYP3A inhibitors like clarithromycin are not expected to have a clinically meaningful impact on the pharmacokinetics of laropiprant.

Disabled-2 (Dab2) is a clathrin and cargo binding endocytic adaptor protein and cell biology studies revealed that Dab2 plays a role in cellular trafficking of a number of transmembrane receptors and signaling proteins. However, little to nothing is known about its involvement or significance in

Objective: The aim of this study was to assess the association between the human CYP8A1 gene and myocardial infarction (MI) in Chinese people. Methods: 210 MI patients and 206 age-matched controls were genotyped and constructed haplotypes for 3 SNPs [3982C>T (rs5602), C1117A (rs5629), C251T (rs454-98106)] of the human CYP8A1 gene. Results: The CC genotype of rs5629 was more frequently in MI patients than in control subjects (P = .030). The frequency of the A-C-T haplotype was significantly higher in MI patients than in control subjects (P =.001). The frequency of the C-T-T haplotype was significantly lower in MI patients than in control subjects (P= .011). Conclusions: The present results indicate that MI is associated with the CC genotype of rs5629 in the human CYP8A1 gene. The A-C-T haplotype appears to be a useful genetic marker and the C-T-T haplotype might be a protective factor of MI in Chinese people.

A traditional distance learning system requires supervisors or teachers always available on online to facilitate and monitor a learner’s progress by answering questions and guiding users. We presents an English chat room system in which students discuss course contents and ask questions to and receive from teachers and other students. The mechanism contains an agent that detects syntax errors in sentences written by the online the user and also checks the semantics of a sentence. The agent can thus offer recommendations to the user and, then, analyze the data of the learner corpus. When users query the system, this system will attempt to find the answers from the knowledge ontology that is stored in the records of previous user comments. With the availability of automatic supervisors, messages can be monitored and syntax or semantic mistakes can be corrected to resolve learner-related problems.

A simple, rapid, accurate, and selective quantitative nuclear magnetic resonance method for the determination of tadalafil in bulk drugs and its tablets was established and evaluated. Spectra were obtained in dimethylsulfoxide-d6 using 2,4-dinitrotoluene as the internal standard. In this study, the method’s linearity, range, limit of quantification, stability, precision, and accuracy were validated. The results were consistent with those obtained from high-performance liquid chromatography analysis. Thus, the proposed method is a useful and practical tool for the determination of tadalafil in bulk drugs and its tablets.

[reaction: see text] Two new iridoid glucoside tetramers, dipsanosides A (1) and B (2), the first-reported iridoid tetramers with four glucosides, were isolated from Dipsacus asper. Their structures were determined by analysis of 1D and 2D NMR data as well as by comparison with model compounds. Their cytotoxicities were tested, but neither of them showed obvious activity.

Mobile Ad Hoc Networks (MANETs), which provide data networking without infrastructure, represent one kind of wireless networks. A MANET is a self-organizating and adaptive wireless network formed by the dynamic gathering of mobile nodes. Due to the mobility of mobile nodes, the topology of a MANET frequently changes and thus results in the disability of originally on-the-fly data transmission routes. The dynamic properties of MANETs are therefore challenging to protocol design. To cope with the intrinsic properties of MANETs, Dynamic Backup Routes Routing Protocol (DBR^2P), a backup node mechanism for quick reconnection during link failures, is proposed in this paper. DBR^2P is an on-demand routing protocol and it can set up many routes to reach a destination node in a given period. Even when a link fails, those routes from the source node to the destination node can be analyzed to obtain backup routes to sustain quick reconnection. The information of backup routes can be saved in a specific on-the-route node and enables backup routes to be found immediately in situation regarding disconnection. As a result, DBR^2P could more thoroughly improve the quality of routing protocol than those proposed in the past.

Fractionation of the ethanolic extract of the stem bark of Morus macroura resulted in the isolation of four new Diels-Alder type adducts, named guangsangons K--N (1, 2, 5, 6), together with two known compounds, mulberrofuran G (3) and K (4). Their structures were determined on the basis of spectroscopic analyses and chemical methods. Furthermore, by means of (1)H-NMR variable temperature experiments and the Cotton curves in the circular dichroism (CD) spectra, the stereochemistry of four new compounds was elucidated. The isolated new compounds showed good activity on anti-oxidant in vitro, with the inhibitory rates of MDA being from 91.8 to 100.0% at concentrations of 10(-5) mol/l.

This work presents a novel English distance learning system that was developed through multimedia database and Internet technologies called English multimedia corpus. The system includes English articles, dialogs, and videos. A student can study English writing and reading as well as view Web browser listings to connect the Corpus server. In the system, semantic query and "link grammar" are applied to construct the English multimedia corpus system. Furthermore, it promotes the query level from keyword-base and content-based query to a semantic level. The main function of this system is to query the English sentence pattern through keywords from the English multimedia corpus. The other function is to detect grammatical errors in written English. Thus, the system not only teaches English grammar, but also, due to its database, allows teachers to understand the most frequent mistakes.