Citations

ABSTRACT Patients recruited in virus-based cancer clinical trials and immunocompromised individuals in need of vaccination would profit from viral strains with defined attenuation mechanisms. We generated measles virus (MV) strains defective for the expression of either the V protein, a modulator of the innate immune response, or the C protein, which has multiple functions. The virulence of these strains was compared with that of the parental wild-type MV in a natural host, Macaca mulatta . Skin rash, viremia, and the strength of the innate and adaptive immune responses were characterized in groups of six animals. Replication of V- or C-protein-defective viruses was short-lived and reached lower levels in peripheral blood mononuclear cells and lymphatic organs compared to the wild-type virus; none of the mutants reverted to the wild type. The neutralizing antibody titers and MV-specific T-cell responses were equivalent in monkeys infected with the viral strains tested, documenting strong adaptive immune responses. In contrast, the inflammatory response was better controlled by wild-type MV, as revealed by inhibition of interleukin-6 and tumor necrosis factor alpha transcription. The interferon response was also better controlled by the wild-type virus than by the defective viruses. Since V- and C-defective MVs induce strong adaptive immune responses while spreading less efficiently, they may be developed as vaccines for immunocompromised individuals. Moreover, MV unable to interact with single innate immunity proteins may be developed for preferential replication in tumors with specific contexts of vulnerability.

Three non-destructive testing techniques are developed and investigated to determine the Young’s modulus of elasticity of the trachea and the results are compared with the standard uniaxial state of stress method. These techniques are based on: (1) simulating the trachea as a pressurized vessel and deducing a special relationship between the pressure and the radial strain; (2) using two hydrophones and determining the variation in acoustic transmittance caused by the presence of the trachea in a propagation path within a water-bath; (3) considering the trachea as a thin cylindrical shell and determining the resonance radial vibration response. Discussion is presented to identify the “pros” and “cons” of each technique and final practical recommendations are made.

Abstract Investment analysts are a growing presence at the Annual Meeting of the American Society of Hematology (ASH), and financial professionals frequently contact ASH members for information and perspective on drugs, devices, and scientific developments. Recent incidents have raised concerns about consulting relationships between physicians and the investment industry; the appropriate role of medical societies in influencing these relationships is unclear. In this essay, I summarize the current situation, discuss potential risks and benefits from interactions between physicians and investment analysts, and outline issues that all individuals involved in investment industry consulting should consider. I also propose changes in ASH policy that may help safeguard public trust as well as preserve the access of clinicians and scientists to clinically relevant data presented at the Annual Meeting.

Prior studies have suggested the possibility of immune-mediated death of xenogeneic hepatocytes in a bioartificial liver (BAL) during hemoperfusion. This study was designed to elucidate how immunity may cause death of xenogeneic hepatocytes in the BAL. Healthy dogs were treated with a BAL containing hollow fiber membranes with large pores (200 nm) or small pores (400 kDa). The immune response of recipient dogs to BAL therapy was monitored over 3 h of treatment. We observed significantly greater loss of viability of hepatocytes in the 200 nm group compared with the 400 kDa group (p < 0.001). Low viability after treatment with the large pore membrane was associated with positive staining for dog IgG, dog IgM, and dog complement on dead hepatocytes. Significant levels of dog antibody were detected in samples of BAL medium from the 200 nm group. These canine antibodies were cytotoxic to porcine hepatocytes. In contrast, medium from the 400 kDa group contained only trace levels of dog IgG and were noncytotoxic. We conclude that antibody-mediated cytotoxicity contributed to the death of hepatocytes during treatment with a xenogeneic BAL. Immune-mediated death of hepatocytes was reduced by increasing selectivity of the BAL membrane.

Abstract We have previously shown T-cell–mediated rejection of the neu-overexpressing mammary carcinoma cells (MMC) in wild-type FVB mice. However, following rejection of primary tumors, a fraction of animals experienced a recurrence of a neu antigen-negative variant (ANV) of MMC (tumor evasion model) after a long latency period. In the present study, we determined that T cells derived from wild-type FVB mice can specifically recognize MMC by secreting IFN-γ and can induce apoptosis of MMC in vitro. Neu transgenic (FVBN202) mice develop spontaneous tumors and cannot reject it (tumor tolerance model). To dissect the mechanisms associated with rejection or tolerance of MMC tumors, we compared transcriptional patterns within the tumor microenvironment of MMC undergoing rejection with those that resisted it either because of tumor evasion/antigen loss recurrence (ANV tumors) or because of intrinsic tolerance mechanisms displayed by the transgenic mice. Gene profiling confirmed that immune rejection is primarily mediated through activation of IFN-stimulated genes and T-cell effector mechanisms. The tumor evasion model showed combined activation of Th1 and Th2 with a deviation toward Th2 and humoral immune responses that failed to achieve rejection likely because of lack of target antigen. Interestingly, the tumor tolerance model instead displayed immune suppression pathways through activation of regulatory mechanisms that included in particular the overexpression of interleukin-10 (IL-10), IL-10 receptor, and suppressor of cytokine signaling (SOCS)-1 and SOCS-3. These data provide a road map for the identification of novel biomarkers of immune responsiveness in clinical trials. [Cancer Res 2008;68(7):2436–46]

Abstract Large germline deletions within the mismatch repair gene MSH2 account for a significant proportion (up to 20%) of all deleterious mutations of this gene which are associated with Lynch syndrome. An exons 1 to 6 deletion of MSH2, originally reported in nine families, has been associated with a founding event within the United States, which genealogic studies had previously dated to 1727, and the number of present day carriers was estimated to be 18,981. Here, we report the development of a robust multiplex PCR which has assisted in the detection of 32 new families who carry the MSH2 American Founder Mutation (AFM). By offering testing to family members, 126 carriers of the AFM have been identified. Extensive genealogic studies have connected 27 of the 41 AFM families into seven extended pedigrees. These extended families have been traced back to around the 18th century without any evidence of further convergence between them. Characterization of the genomic sequence flanking the deletion and the identification of a common disease haplotype of between 0.6 and 2.3 Mb in all probands provides evidence for a common ancestor between these extended families. The DMLE+2.2 software predicts an age of ∼500 years (95% confidence interval, 425–625) for this mutation. Taken together, these data are suggestive of an earlier founding event than was first thought, which likely occurred in a European or a Native American population. The consequences of this finding would be that the AFM is significantly more frequent in the United States than was previously predicted. [Cancer Res 2008;68(7):2145–53]

Abstract Antigenically distinct tumor variants can emerge in response to selective pressures inherent to host-tumor interactions. The development of successful immunotherapeutic strategies can be limited by these disparate antigenic profiles. Using the immunomodulator B7-DC XAb to activate cytolytic T cells specific for tumor-associated antigens, we found that the specificity of immune responses elicited by live tumors are distinct from the specificity of the responses elicited by soluble proteins derived from the same tumors. Remarkably, whereas the induced antitumor immunity generated against live variants of the B16 melanoma and EL4 thymic lymphoma tumors were highly specific for the original tumor variant used in the challenge, immunity generated using soluble proteins derived from tumor lysates was broadly reactive, recognizing the challenge tumor, as well as antigenically distinct variants. The antigens detected using live tumor and tumor lysate vaccines could be distinguished biochemically, demonstrating that they are structurally distinct. We show that vaccines using antigens present in tumor cell lysates induce protective immunity with strong memory against distantly related tumor variants. The existence of a class of antigens shared among tumor variants provides an attractive target for vaccine development. [Cancer Res 2008;68(7):2471–8]

Abstract Dysfunction in enzymes involved in one-carbon (1-C) metabolism can lead to increased chromosomal strand breaking and abnormal methylation patterns, which are both associated with cancer risk. Availability of 1-C units may modify risk. We investigated the association of single-nucleotide polymorphisms (SNP) in 21 genes in the 1-C transfer pathway among 829 Caucasian cases with primary epithelial ovarian cancer and 941 frequency-matched unaffected controls enrolled at Mayo Clinic (Rochester, MN) and Duke University (Durham, NC) and examined risk modification by multivitamin supplement use. Multivariable-adjusted SNP-specific logistic regression and haplotype analyses were done for 180 SNPs and false positive report probabilities (FPRP) were calculated. Each copy of the minor allele in SHMT1 intron 5 A&gt;G (rs9909104) was associated with epithelial ovarian cancer [odds ratio (OR), 1.2; 95% confidence interval (95% CI), 1.0–1.4; P trend = 0.02; FPRP = 0.16] and a 5-SNP SHMT1 haplotype was associated with decreased risk (P = 0.01; FPRP = 0.09). Three SNPs in DNMT3A were associated with risk among multivitamin supplement users: 3′ untranslated region (UTR) C&gt;G (rs13420827: OR, 0.8; 95% CI, 0.6–1.0; P interaction = 0.006; FPRP = 0.54), intron 6 G&gt;A (rs11887120: OR, 0.8; 95% CI, 0.7–1.0; P interaction = 0.007; FPRP = 0.57), and intron 22 A&gt;T (rs11695471: OR, 1.2; 95% CI, 1.0–1.5; P interaction = 0.01; FPRP = 0.66). These data extend previous findings from other cancers of a role for SHMT1 in ovarian cancer, and provide evidence that SNPs in methylation and DNA synthesis reactions are associated with risk of ovarian cancer. Interventions with modifiable factors such as multivitamin intake may reduce risk. [Cancer Res 2008;68(7):2498–506]