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Piperlongumine (PPLGM), an alkaloid isolated from the long pepper (Piper longum L.), can selectively trigger cancer cell death in colorectal cancer cells. The present study investigated whether the c-Jun NH2-terminal kinase (JNK) signaling pathway is involved in PPLGM-induced apoptosis in the human colorectal cancer HCT116 cell line. The results demonstrated that PPLGM reduced the cell viability and induced cell apoptosis in a time- and concentration-dependent manner, without a significant effect on cell cycle distribution. Meanwhile, treatment with 10 µM PPLGM resulted in JNK activation within 1 h, and a marked and sustained increase in c-Jun phosphorylation in the HCT116 cells. In addition, SP600125, a general inhibitor of JNK, inhibited PPLGM-induced apoptosis in the HCT116 cells by inhibiting PPLGM-induced c-Jun phosphorylation. Altogether, it can be concluded that the JNK signaling pathway, at least in part, is involved in PPLGM-mediated apoptosis in HCT116 cells. [ABSTRACT FROM AUTHOR]

The toxicological effects of single-walled carbon nanotubes (SWCNTs) were investigated after intratracheal instillation in male Wistar rats over a 15-day period using metabonomic analysis of ¹H (nuclear magnetic resonance) NMR spectra of blood plasma and liver tissue extracts. Concurrent liver histopathology examinations and plasma clinical chemistry analyses were also performed. Significant changes were observed in clinical chemistry features, including alkaline phosphatase, total protein, and total cholesterol, and in liver pathology, suggesting that SWCNTs clearly have hepatotoxicity in the rat. ¹H NMR spectra and pattern recognition analyses from nanomaterial-treated rats showed remarkable differences in the excretion of lactate, trimethylamine oxide, bilineurin, phosphocholine, amylaceum, and glycogen. Indications of amino acid metabolism impairment were supported by increased lactate concentrations and decreased alanine concentrations in plasma. The rise in plasma and liver tissue extract concentrations of choline and phosphocholine, together with decreased lipids and lipoproteins, after SWCNTs treatment indicated a disruption of membrane fluidity caused by lipid peroxidation. Energy, amino acid, and fat metabolism appeared to be affected by SWCNTs exposure. Clinical chemistry and metabonomic approaches clearly indicated liver injury, which might have been associated with an indirect mechanism involving nanomaterial-induced oxidative stress. . . [ABSTRACT FROM AUTHOR]

Background: Tissue factor (TF) is emphasized as the promising target in the future targeted therapy strategy for colorectal cancer (CRC). Recent evidence showed that TF expression is under the control of K-ras and p53. However, a comprehensive evaluation of TF expression, K-ras status, and p53 mutation has not been systematically analyzed. The aims of this study were to identify the percentages of positive TF in CRC patients; analyze the associations of TF expression, K-ras status, and p53 mutation; and evaluate the prognostic value of TF in CRC patients. Methods: Ninety-six CRC samples were tested for TF expression, p53 mutation, and K-ras status by semiquantitative immunohistochemistry, Western blotting analysis, direct sequencing, and real-time quantitative PCR. Associations were sought with TF expression and clinical outcomes. Results: TF expression was related to clinical stages, tumor differentiation, and tumor size. The positive proportions of TF expression on tumor cells and tumor vascular endothelial cells were 70% and 53% respectively in CRC patients. The positive proportion of TF co-expression on both cancer cells and tumor vascular endothelial cells was 40%, compared to an 83% total TF positive proportion in CRC patients. TF expression on CRC appeared to be increased with K-ras and/or p53 mutation(s). Disease-free survival and overall survival were significantly reduced in CRC patients with high TF expression. Conclusions: TF may participate in both K-ras and p53 mutations involved in colorectal carcinogenesis and could be considered as a prognostic indicator for patients CRC. [ABSTRACT FROM AUTHOR]

Background: To evaluate the objective clinical outcomes of active specific immunotherapy (ASI) in advanced colorectal cancer (advanced CRC) and suspected minimal residual colorectal cancer (suspected minimal residual CRC). Methods: A search was conducted on Medline and Pub Med from January 1998 to January 2010 for original studies on ASI in colorectal cancer (CRC). All articles included in this study were assessed with the application of predetermined selection criteria and were divided into two groups: ASI in advanced CRC and ASI in suspected minimal residual CRC. For ASI in suspected minimal residual CRC, a meta-analysis was executed with results regarding the overall survival (OS) and disease-free survival (DFS). Regarding ASI in advanced colorectal cancer, a system review was performed with clinical outcomes. Results: 1375 colorectal carcinoma patients with minimal residual disease have been enrolled in Meta-analysis. A significantly improved OS and DFS was noted for suspected minimal residual CRC patients utilizing ASI (For OS: HR = 0.76, P = 0.007; For DFS: HR = 0.76, P = 0.03). For ASI in stage II suspected minimal residual CRC, OS approached significance when compared with control (HR = 0.71, P = 0.09); however, the difference in DFS of ASI for the stage II suspected minimal residual CRC reached statistical significance (HR = 0.66, P = 0.02). For ASI in stage III suspected minimal residual CRC compared with control, The difference in both OS and DFS achieved statistical significance (For OS: HR = 0.76, P = 0.02; For DFS: HR = 0.81, P = 0.03). 656 advanced colorectal patients have been evaluated on ASI in advanced CRC. Eleven for CRs and PRs was reported, corresponding to an overall response rate of 1.68%. No serious adverse events have been observed in 2031 patients. Conclusions: It is unlikely that ASI will provide a standard complementary therapeutic approach for advanced CRC in the near future. However, the clinical responses to ASI in patients with suspected minimal residual CRC have been encouraging, and it has become clear that immunotherapy works best in situations of patients with suspected minimal residual CRC. [ABSTRACT FROM AUTHOR]

Background. Endogenous morphine-like compounds have been identified in humans and are released in response to stress. Human monocytes and granulocytes express the µ opiate receptor, µ3, which is morphine selective but opiate peptide insensitive. Recent studies have shown that CYP2D6 acts at critical steps for endogenous morphine biosynthesis. We theorized that ultrarapid (UM) CYP2D6 metabolizers may have an enhancement of their endogenous pain modulating mechanisms. Methods. After institutional review board approval, a previously developed surgical patient database was evaluated for information concerning CYP2D6 genotypes and morphine consumption. One hundred forty-two patients were found to have adequate information to be included in this current analysis. The study group was divided, based on morphine consumption, into two subgroups: low morphine consumers (LMC) (≤10 mg/4 h, N = 80) and high morphine consumers (HMC) (>10 mg/4 h, N = 62). DNA was extracted from blood in all patients and was genotyped by the Amplichip (Roche, Pleasanton, CA) to determine the specific CYP2D6 genotypes. Results. CYP2D6 UM were found to occur more frequently in the LMC group than in the HMC group (8/80 vs 0/62, P = 0.0091). No significant differences were noted for the poor, intermediate, or extensive metabolizers. Conclusions. Our current results suggest that CYP2D6 UM appear to require less morphine in the acute postoperative period compared with other CYP2D6 metabolizer groups. One possible mechanism for this observation is that CYP2D6 UM may have higher efficiency in synthesizing endogenous morphine compared with other metabolizers, thus increasing endogenous pain modulation and reducing the need for exogenous morphine. [ABSTRACT FROM AUTHOR]

To investigate the role that DC-SIGN neck-region length variation plays in HIV-1 transmission, we studied 530 HIV-1-positive and 341 HIV-1-negative individuals in China. The carrier frequency of a DC-SIGN allele with <5 repeat units in the neck-region was 0.9% in HIV-1-positive and 3.8% in HIV-1-negative individuals (P=.007), an observation suggesting that this DC-SIGN variation plays a role in HIV-1 transmission. These naturally occurring DC-SIGN neck-region variants were significantly more frequent in the Chinese population than in the US population (P<.001) and in a worldwide population (P=.006). [ABSTRACT FROM AUTHOR]

In 1716 individuals—801 human immunodeficiency virus (HIV)-1-seropositive individuals, 217 high-risk HIV-1-seronegative individuals, and 698 general HIV-1-seronegative individuals—from a Seattle cohort and a Multicenter AIDS Cohort Study cohort, the association between HIV-1 susceptibility and repeat-region polymorphisms in the gene for the dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin-related molecule (DC-SIGNR) was investigated; 16 genotypes were found in the DC-SIGNR repeat region. The DC-SIGNR homozygous 7/7 repeat was found to be associated with an increased risk of HIV-1 infection (17.5% in high-risk HIV-1-seronegative individuals vs. 28.5% in HIV-1-seropositive individuals; P = .0015), whereas the DC-SIGNR heterozygous 7/5 repeat tended to be correlated with resistance to HIV-1 infection (35.5% in high-risk HIV-1-seronegative individuals vs. 27.6% in HIV-1-seropositive individuals; P = .0291). These findings suggest that DC-SIGNR polymorphisms may influence susceptibility to HIV-1. [ABSTRACT FROM AUTHOR]

Exposed seronegative individuals (ES) with persistent high-risk sexual behavior may be less susceptible to human immunodeficiency virus type 1 (HIV-1) infection because they carry the chemokine receptor (CR) gene alleles CCR5 open reading frame (ORF) Δ32, CCR5 promoter -2459G, or CCR20RF 64I (CCR2-64I), all of which have been found to diminish HIV-1 infectivity and/or disease progression. To investigate this, we determined the haplotypes for these three genetic loci in 93 ES and 247 low-risk control individuals. To test if protective haplotypes exert their effect by modulating CR expression, we measured the protein expression of CCR5 and CXCR4 on circulating CD4+ T cells and CD14+ monocytes in 71 ES and 92 controls. To avoid investigator bias, the analysis was performed without knowledge of each subject's risk and genotype. The CCR5 -2459G allele was significantly enriched in ES Caucasian men, who constituted the majority (84%) of the ES cohort, compared to the control Caucasian men (P = 0.02). This increase was mostly attributable to a higher frequency of the -2459 A/G versus the -2459 A/A genotype in individuals heterozygous for the Δ32 allele (P = 0.012). No protective influence of the CCR2-641 allele was observed. The haplotypes CCR50RF A32/CCR5 -2459A (in complete linkage disequilibrium) and CCR50RF wt/CCR5 -2459G had a cumulative negative effect on the expression of CCR5, since we measured significantly reduced CCR5 densities on both T-helper cells and monocytes only when both haplotypes were present. Densities of CCR5 on lymphocytes and monocytes were correlated (r = 0.59; P « 0.0001), indicating concordance of CCR5 expression patterns across different cell types. We conclude that the CCR50RF Δ32/wt-CCR5 -2459 A/G genotype combination offers an advantage in resisting sexual HIV-1 transmission and that this effect is mediated by a relative paucity of CCR5 on potential target cells of HIV-1. [ABSTRACT FROM AUTHOR]

The repeat region of DC-SIGNR (CD209L) is polymorphic on the genomic level, and, in a separate study, we observed a correlation between the DC-SIGNR genotype and HIV-1 susceptibility during sexual contact. However, previous investigations using immunohistochemistry failed to detect membrane-bound DC-SIGNR on cells in the genital and rectal mucosa. We therefore explored the presence of DC-SIGNR in these compartments with a more sensitive limiting dilution RT-PCR, which also allowed for quantification of alternatively spliced mRNA isoforms. DC-SIGN (CD209) and DC-SIGNR mRNA transcript isoforms were found in all 12 vaginal and two rectal biopsies obtained from 14 healthy individuals. For DC-SIGNR, we detected significantly more isoform than full-length transcripts (mean copy numbers/µg RNA: 602 vs 26; P=0.0009). Four mucosal samples lacked full-length DC-SIGNR transcripts entirely. Cloning and sequencing of DC-SIGNR mRNA in three additional individuals revealed a diverse repertoire of DC-SIGNR isoforms, many of which encoded for proteins predicted to be soluble and secreted. Indeed, in one vaginal sample, we detected only soluble isoforms. In conjunction with our prior observation that the DC-SIGNR genotype has an effect on HIV-1 transmission in vivo, these findings emphasize that DC-SIGNR, in addition to DC-SIGN, should be considered as a cofactor in sexual HIV-1 transmission. Soluble isoforms, in particular, may modulate the efficiency of viral transmission and dissemination.European Journal of Human Genetics (2005) 13, 707-715. doi:10.1038/sj.ejhg.5201409 Published online 6 April 2005 [ABSTRACT FROM AUTHOR]

To determine the influence of host genetics on human immunodeficiency virus (HIV) type I infection, we examined 94 repeatedly exposed seronegative (ES) individuals for polymorphisms in multiple genes and compared the results with those fur 316 HIV-1-seropositive and 425 HIV-1-seronegative individuals. The frequency of homozygous C-C the mokine receptor (CCR) 5-Δ32 was higher in ES (3.2%) than in HIV-1-seropositive individuals (0.0%; P = .012). However, the CCR5-59029A, CCR2-64I, stromal cell-derived factor (SDF)-1-3A, RANTES (regulated on activation, normally T cell-expressed and secreted)-403A, and RANTES-28G polymorphisms were not associated with resistance to HIV-1 in- fection. Furthermore, we identified novel variants in the DC-SIGN (dendritic cell specific intercellular adhesion tool ecule-3-grabbing nonintegrin) repeat region and observed that heterozygous DC-SIGN reduced the risk of HIV-1-seroposfection (3.2% in ES individuals vs. 0.0% in HIV-1-seropositive individuals; P = .011). [ABSTRACT FROM AUTHOR]

An abstract of the article "Impaired CCR7 Expression on Plasmacytoid Dendritic Cells in HIV Infected Children on HAART With Virologic Failure," by Seema Desai, Aida Chaparro, Huanliang Liu, Patrick Haslett, Gwendolyn Scot, Rajenda Pahwa, and Savita Pahwa is presented.