Citations

The minimum inhibitory concentrations (MIC) of penicillin and six other antimicrobials were determined for 50 clinical isolates of Bacteroides melaninogenicus . Agar dilution susceptibilities were performed using supplemented brucella blood agar and the proposed National Committee for Clinical Laboratory Standards standard method for anaerobes; results with the two methods were comparable. A penicillin concentration ≥0.8 μg/ml was needed to inhibit 56% of the isolates, whereas 100% were susceptible to 0.1 μg of clindamycin per ml. All isolates with penicillin MIC values ≥0.8 μg/ml produced β-lactamase using a slide method. A micro-iodometric assay was used to quantitate β-lactamase production in six isolates. The β-lactamase activity of B. melaninogenicus was comparable to that of a Staphylococcus aureus isolate but was not inducible, and the specific amount produced correlated only partially with penicillin MIC values. A clinical review of patients from whom the β-lactamase-producing strains of B. melaninogenicus were isolated did not suggest any increased virulence in these strains or an unexpectedly poor clinical response to appropriate therapy.

Abstract Poly (ADP-ribose) polymerase (PARP) inhibition can enhance the efficacy of temozolomide (TMZ) and has been shown to significantly prolong survival in orthotopic GBM xenografts. Here the effects of PARP inhibitor AG014699 (AG699) on the efficacy of TMZ was evaluated and corresponding pharmacokinetic and pharmacodynamic studies were performed in the MGMT methylated GBM12 primary GBM xenograft line. AG699 effectively sensitized GBM12 cells to TMZ in vitro in a neurosphere formation assay: IC50 of 1.56 M for TMZ when combined with 1 μM AG699 compared to 8.16 M TMZ when used alone). Using these same cells, orthotopic xenografts were established and mice were randomized to 3–28 day cycles of placebo or TMZ (50 mg/kg days 1–5) with or without AG699 (1 mg/kg IP days 1–5). Although this model is responsive to other TMZ/PARP inhibitor combinations, the addition of AG699 was ineffective (median survival: placebo 16 days, TMZ 68 days and TMZ/AG699 81 days, p=0.883). In contrast, AG699 significantly potentiated TMZ-induced tumor regrowth delay in a flank tumor model with GBM12 (median time for tumors to reach endpoint: placebo 32 days, TMZ 86 days and TMZ/AG699 121 days, p<0.01). To more clearly understand the discrepancy between intracranial and flank studies, drug accumulation and target inhibition were assessed. Plasma and tissue distribution studies in mice bearing GBM12 orthotopic xenografts showed that 0.5 h after AG699 treatment its level in brain and tumor xenograft was much lower compared with that in liver (see table). In an assessment of catalytic activity, PARP activity in liver was inhibited more than 95% of control at least 2 h after AG699 treatment, while it was inhibited less than 50% and 30% in orthotopic xenograft tissue and normal brain, respectively (Table). Collectively, these data support the hypothesis that the efficacy of AG699 combined with TMZ is limited in the orthotopic model due to limited drug accumulation within the brain, and the mechanisms of which are under investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A77.

Background Aprotinin is a serine protease inhibitor that reduces blood loss and transfusion requirements when administered prophylactically to cardiac surgical patients. To examine the safety and dose-related efficacy of aprotinin, a prospective, multicenter, placebo-controlled trial was conducted in patients undergoing repeat coronary artery bypass graft (CABG) surgery. Methods and Results Two hundred eighty-seven patients were randomly assigned to receive either high-dose aprotinin, low-dose aprotinin, pump-prime-only aprotinin, or placebo. Drug efficacy was determined by the reduction in donor-blood transfusion up to postoperative day 12 and in postoperative thoracic-drainage volume. The percentage of patients requiring donor–red-blood-cell (RBC) transfusions in the high- and low-dose aprotinin groups was reduced compared with the pump-prime-only and placebo groups (high-dose aprotinin, 54%; low-dose aprotinin, 46%; pump-prime only, 72%; and placebo, 75%; overall P =.001). The number of units of donor RBCs transfused was significantly lower in the aprotinin-treated patients compared with placebo (high-dose aprotinin, 1.6±0.2 U; low-dose aprotinin, 1.6±0.3 U; pump-prime-only, 2.5±0.3 U; and placebo, 3.4±0.5 U; P =.0001). There was also a significant difference in total blood-product exposures among treatment groups (high-dose aprotinin, 2.2±0.4 U; low-dose aprotinin, 3.4±0.9 U; pump-prime-only, 5.1±0.9 U; placebo, 10.3±1.4 U). There were no differences among treatment groups for the incidence of perioperative myocardial infarction (MI). Conclusions This study demonstrates that high- and low-dose aprotinin significantly reduces the requirement for donor-blood transfusion in repeat CABG patients without increasing the risk for perioperative MI.

SummaryBackgroundCoeliac disease is managed by life‐long gluten withdrawal from the diet. However, strict adherence to a gluten‐free diet is difficult and is not always effective. Novel therapeutic approaches are needed to supplement or even replace the dietary treatment.AimTo review recent advances in new therapeutic options for coeliac disease.MethodsA literature search was performed on MEDLINE, EMBASE, Web of Science, Scopus, DDW.org and ClinicalTrials.gov for English articles and abstracts. The search terms used included, but not limited to, ‘Celiac disease’, ‘new’, ‘novel’, ‘Advances’, ‘alternatives’ and ‘Drug therapy’. The cited articles were selected based on the relevancy to the review objective.ResultsSeveral new therapeutic approaches for coeliac disease are currently under development by targeting its underlying pathogenesis. Alternative therapies range from reproduction of harmless wheat strains to immunomodulatory approaches. Some of these therapies such as enzymatic cleavage of gluten and permeability inhibitors have shown promise in clinical studies.ConclusionsGluten‐free diet is still the only practical treatment for patients with coeliac disease. Novel strategies provide promise of alternative adjunctive approaches to diet restriction alone for patients with this disorder.

Abstract Background: Multiple genome-wide and candidate gene association studies have been conducted in search of common risk variants for breast cancer. Recent large meta analyses, consolidating evidence from these studies, have been consistent in highlighting the caspase-8 (CASP8) gene as important in this regard. To define a risk haplotype and map the CASP8 gene region with respect to underlying susceptibility variant/s, we screened four genes in the CASP8 region on 2q33-q34 for breast cancer risk. Methods: Two independent data sets from the United Kingdom and the United States, including 3,888 breast cancer cases and controls, were genotyped for 45 tagging single nucleotide polymorphisms (tSNP) in the expanded CASP8 region. SNP and haplotype association tests were carried out using Monte Carlo-based methods. Results: We identified a three-SNP haplotype across rs3834129, rs6723097, and rs3817578 that was significantly associated with breast cancer (P < 5 × 10−6), with a dominant risk ratio and 95% CI of 1.28 (1.21–1.35) and frequency of 0.29 in controls. Evidence for this risk haplotype was extremely consistent across the two study sites and also consistent with previous data. Conclusion: This three-SNP risk haplotype represents the best characterization so far of the chromosome upon which the susceptibility variant resides. Impact: Characterization of the risk haplotype provides a strong foundation for resequencing efforts to identify the underlying risk variant, which may prove useful for individual-level risk prediction, and provide novel insights into breast carcinogenesis. Cancer Epidemiol Biomarkers Prev; 21(1); 176–81. ©2011 AACR.

Abstract Celiac disease (CD) is frequently diagnosed in patients with type 1 diabetes (T1D), and T1D patients can exhibit Abs against tissue transglutaminase, the auto-antigen in CD. Thus, gliadin, the trigger in CD, has been suggested to have a role in T1D pathogenesis. The objective of this study was to investigate whether gliadin contributes to enteropathy and insulitis in NOD-DQ8 mice, an animal model that does not spontaneously develop T1D. Gliadin-sensitized NOD-DQ8 mice developed moderate enteropathy, intraepithelial lymphocytosis, and barrier dysfunction, but not insulitis. Administration of anti-CD25 mAbs before gliadin-sensitization induced partial depletion of CD25+Foxp3+ T cells and led to severe insulitis, but did not exacerbate mucosal dysfunction. CD4+ T cells isolated from pancreatic lymph nodes of mice that developed insulitis showed increased proliferation and proinflammatory cytokines after incubation with gliadin but not with BSA. CD4+ T cells isolated from nonsensitized controls did not response to gliadin or BSA. In conclusion, gliadin sensitization induced moderate enteropathy in NOD-DQ8 mice. However, insulitis development required gliadin-sensitization and partial systemic depletion of CD25+Foxp3+ T cells. This humanized murine model provides a mechanistic link to explain how the mucosal intolerance to a dietary protein can lead to insulitis in the presence of partial regulatory T cell deficiency.