Citations

Advances in the understanding of neonatal pain have created interest in the use of medications during commonly performed procedures in the neonatal intensive care unit. A number of small studies have examined the role of sedatives, narcotics, miscellaneous anesthetics, and neuromuscular blockers in providing a more comfortable experience for the patient during nonemergent tracheal intubation. However, the most effective combination and doses of these medications is currently unknown. This review discusses the findings of selected studies that have been used to improve the intubating experience of patient and clinician.

Abstract Purpose: p27 localization and expression has prognostic and predictive value in cancer. Little is known regarding expression patterns of p27 in renal cell carcinoma (RCC) or how p27 participates in disease progression or response to therapy. Experimental Design: RCC-derived cell lines, primary tumors, and normal renal epithelial cells were analyzed for p27 expression, phosphorylation (T157 of the NLS), and subcellular localization. RCC-derived cell lines were treated with phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitors and effects on p27 localization were assessed. The potential contribution of cytoplasmic p27 to resistance to apoptosis was also evaluated. Results: p27 was elevated in tumors compared with matched controls, and cytoplasmic mislocalization of p27 was associated with increasing tumor grade. Cytoplasmic localization of p27 correlated with phosphorylation at T157, an AKT phosphorylation site in the p27 NLS. In RCC cell lines, activated PI3K/AKT signaling was accompanied by mislocalization of p27. AKT activation and phosphorylation of p27 was associated with resistance to apoptosis, and small interfering RNA knockdown of p27 or relocalization to the nucleus increased apoptosis in RCC cells. Treatment with the PI3K inhibitors LY294002 or wortmannin resulted in nuclear relocalization of p27, whereas mTOR inhibition by rapamycin did not. Conclusions: In RCC, p27 is phosphorylated at T157 of the NLS, with increasing tumor grade associated with cytoplasmic p27. PI3K inhibition (which reduces AKT activity) reduces T157 phosphorylation and induces nuclear relocalization of p27, whereas mTOR inhibition does not. Clinical testing of these findings may provide a rational approach for use of mTOR and PI3K/AKT pathway inhibitors in patients with RCC.

AbstractOver 22,000 cases of ovarian cancer were diagnosed in 2007 in the United States, but only a fraction of them can be attributed to mutations in highly penetrant genes such as BRCA1. To determine whether low-penetrance genetic variants contribute to ovarian cancer risk, we genotyped 1,536 single nucleotide polymorphisms (SNP) in several candidate gene pathways in 848 epithelial ovarian cancer cases and 798 controls in the North Carolina Ovarian Cancer Study (NCO) using a customized Illumina array. The inflammation gene interleukin-18 (IL18) showed the strongest evidence for association with epithelial ovarian cancer in a gene-by-gene analysis (P = 0.002) with a <25% chance of being a false-positive finding (q value = 0.240). Using a multivariate model search algorithm over 11 IL18 tagging SNPs, we found that the association was best modeled by rs1834481. Further, this SNP uniquely tagged a significantly associated IL18 haplotype and there was an increased risk of epithelial ovarian cancer per rs1834481 allele (odds ratio, 1.24; 95% confidence interval, 1.06-1.45). In a replication stage, 12 independent studies from the Ovarian Cancer Association Consortium (OCAC) genotyped rs1834481 in an additional 5,877 cases and 7,791 controls. The fixed effects estimate per rs1834481 allele was null (odds ratio, 0.99; 95% confidence interval, 0.94-1.05) when data from the 12 OCAC studies were combined. The effect estimate remained unchanged with the addition of the initial North Carolina Ovarian Cancer Study data. This analysis shows the importance of consortia, like the OCAC, in either confirming or refuting the validity of putative findings in studies with smaller sample sizes. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3567–72)

AbstractDo some patients benefit from an unrelated donor (URD) transplant because of a stronger graft-versus-leukemia (GVL) effect? We analyzed 4099 patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML) undergoing a myeloablative allogeneic hematopoietic cell transplantation (HCT) from an URD (8/8 human leukocyte antigen [HLA]–matched, n = 941) or HLA-identical sibling donor (n = 3158) between 1995 and 2004 reported to the CIBMTR. In the Cox regression model, acute and chronic GVHD were added as time-dependent variables. In multivariate analysis, URD transplant recipients had a higher risk for transplantation-related mortality (TRM; relative risk [RR], 2.76; P < .001) and relapse (RR, 1.50; P < .002) in patients with AML, but not ALL or CML. Chronic GVHD was associated with a lower relapse risk in all diagnoses. Leukemia-free survival (LFS) was decreased in patients with AML without acute GVHD receiving a URD transplant (RR, 2.02; P < .001) but was comparable to those receiving HLA-identical sibling transplants in patients with ALL and CML. In patients without GVHD, multivariate analysis showed similar risk of relapse but decreased LFS for URD transplants for all 3 diagnoses. In conclusion, risk of relapse was the same (ALL, CML) or worse (AML) in URD transplant recipients compared with HLA-identical sibling transplant recipients, suggesting a similar GVL effect.

Abstract Radiation has been shown to up-regulate gene expression from adenoviral vectors in previous studies. In the current study, we show that radiation-induced dsDNA breaks and subsequent signaling through the mitogen-activated protein kinase (MAPK) pathway are responsible, at least in part, for this enhancement of transgene expression both in vitro and in vivo. Inhibitors of ataxia-telangiectasia–mutated, poly(ADP-ribose) polymerase–mutated, and DNA-dependent protein kinase (DNA-PK)–mediated DNA repair were shown to maintain dsDNA breaks (γH2AX foci) by fluorescence-activated cell sorting and microscopy. Inhibition of DNA repair was associated with increased green fluorescent protein (GFP) expression from a replication-defective adenoviral vector (Ad-CMV-GFP). Radiation-induced up-regulation of gene expression was abrogated by inhibitors of MAPK (PD980059 and U0126) and phosphatidylinositol 3-kinase (LY294002) but not by p38 MAPK inhibition. A reporter plasmid assay in which GFP was under the transcriptional control of artificial Egr-1 or cytomegalovirus promoters showed that the DNA repair inhibitors increased GFP expression only in the context of the Egr-1 promoter. In vivo administration of a water-soluble DNA-PK inhibitor (KU0060648) was shown to maintain luciferase expression in HCT116 xenografts after intratumoral delivery of Ad-RSV-Luc. These data have important implications for therapeutic strategies involving multimodality use of radiation, targeted drugs, and adenoviral gene delivery and provide a framework for evaluating potential advantageous combinatorial effects. [Cancer Res 2008;68(23):9771–8]

Abstract Notch signaling plays a role in normal lymphocyte development and function. Activating Notch1-mutations, leading to aberrant downstream signaling, have been identified in human T-cell acute lymphoblastic leukemia (T-ALL). While this highlights the contribution of Notch signaling to T-ALL pathogenesis, the mechanisms by which Notch regulates proliferation and survival in normal and leukemic T cells are not fully understood. Our findings identify a role for Notch signaling in G1-S progression of cell cycle in T cells. Here we show that expression of the G1 proteins, cyclin D3, CDK4, and CDK6, is Notch-dependent both in vitro and in vivo, and we outline a possible mechanism for the regulated expression of cyclin D3 in activated T cells via CSL (CBF-1, mammals; suppressor of hairless, Drosophila melanogaster; Lag-1, Caenorhabditis elegans), as well as a noncanonical Notch signaling pathway. While cyclin D3 expression contributes to cell-cycle progression in Notch-dependent human T-ALL cell lines, ectopic expression of CDK4 or CDK6 together with cyclin D3 shows partial rescue from γ-secretase inhibitor (GSI)-induced G1 arrest in these cell lines. Importantly, cyclin D3 and CDK4 are highly overexpressed in Notch-dependent T-cell lymphomas, justifying the combined use of cell-cycle inhibitors and GSI in treating human T-cell malignancies.

Abstract Breast density is a strong risk factor for breast cancer; however, no standard assessment method exists. An automated breast density method was modified and compared with a semi-automated, user-assisted thresholding method (Cumulus method) and the Breast Imaging Reporting and Data System four-category tissue composition measure for their ability to predict future breast cancer risk. The three estimation methods were evaluated in a matched breast cancer case-control (n = 372 and n = 713, respectively) study at the Mayo Clinic using digitized film mammograms. Mammograms from the craniocaudal view of the noncancerous breast were acquired on average 7 years before diagnosis. Two controls with no previous history of breast cancer from the screening practice were matched to each case on age, number of previous screening mammograms, final screening exam date, menopausal status at this date, interval between earliest and latest available mammograms, and residence. Both Pearson linear correlation (R) and Spearman rank correlation (r) coefficients were used for comparing the three methods as appropriate. Conditional logistic regression was used to estimate the risk for breast cancer (odds ratios and 95% confidence intervals) associated with the quartiles of percent breast density (automated breast density method, Cumulus method) or Breast Imaging Reporting and Data System categories. The area under the receiver operator characteristic curve was estimated and used to compare the discriminatory capabilities of each approach. The continuous measures (automated breast density method and Cumulus method) were highly correlated with each other (R = 0.70) but less with Breast Imaging Reporting and Data System (r = 0.49 for automated breast density method and r = 0.57 for Cumulus method). Risk estimates associated with the lowest to highest quartiles of automated breast density method were greater in magnitude [odds ratios: 1.0 (reference), 2.3, 3.0, 5.2; P trend &lt; 0.001] than the corresponding quartiles for the Cumulus method [odds ratios: 1.0 (reference), 1.7, 2.1, and 3.8; P trend &lt; 0.001] and Breast Imaging Reporting and Data System [odds ratios: 1.0 (reference), 1.6, 1.5, 2.6; P trend &lt; 0.001] method. However, all methods similarly discriminated between case and control status; areas under the receiver operator characteristic curve were 0.64, 0.63, and 0.61 for automated breast density method, Cumulus method, and Breast Imaging Reporting and Data System, respectively. The automated breast density method is a viable option for quantitatively assessing breast density from digitized film mammograms. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3090–7)

AbstractPurpose: Complement may play a role in the clinical response to rituximab and other monoclonal antibody–based therapies of cancer. The purpose of this study was to explore the relationship between the C1qA[276] polymorphism and the clinical response to rituximab in patients with follicular lymphoma.Experimental Design: Genotyping for C1qA[276A/G] was done in 133 subjects with follicular lymphoma treated with single-agent rituximab, and correlation with clinical response was done using Cox regression analysis.Results: Prolonged remission was observed among subjects that responded clinically to rituximab therapy and were carriers of the A allele compared with homozygous G subjects. Homozygous G subjects had a time to progression of 282 days, whereas A-allele carriers had a time to progression of 708 days [hazard ratio, (HR), 2.5; 95% confidence interval (95% CI), 2.0-3.1; P = 0.02]. Among subjects who achieved complete remission, homozygous G subjects had a time to progression of 250 days, whereas A-allele carriers had a time to progression of 1,118 days (HR, 4.5; 95% CI, 4.1-4.8, P = 0.04). The difference persisted after controlling for CD32 and CD16 polymorphisms. In patients who responded to rituximab used as first-line agent, a linear trend was observed among the C1qA[276] genotypes, with homozygous A subjects achieving complete response at a higher rate compared with heterozygous or homozygous G subjects.Conclusions: Our findings indicate that polymorphisms in the C1qA gene may affect the clinical response and duration of response to rituximab therapy of follicular lymphoma. These results could have direct implications on designing antibodies with improved efficiency and enhance our understanding of the role of complement in monoclonal antibody therapy.

Abstract Purpose: Alterations in transforming growth factor-β (TGF-β) signaling occur early during malignant transformation of renal epithelial cells and are associated with loss of type III TGF-β receptor (TβRIII) expression. We evaluated the role of TβRIII in mediation of apoptosis using in vitro cell culture and in vivo animal models of clear cell renal cell carcinoma. Experimental Design: TβR3 expression was manipulated with adenoviral gene vector delivery system in vitro and in vivo. Induction of apoptosis and signaling through the Smad and mitogen-activated protein kinase (MAPK) pathways were examined at various time points after infection. To study viral oncolysis in vivo, human renal cell carcinoma cells were implanted s.c. in the flanks of nude mice and treated with intratumoral injections of adenovirus. Results: Restoring TβRIII expression in clear cell renal cell carcinoma resulted in a marked induction of apoptosis using in vitro cell culture and in vivo animal models. The expression of the cytoplasmic domain, but not the extracellular domain, of TβRIII mimicked the induction of apoptosis by full-length TβRIII in cell culture and the growth inhibition of tumors in athymic nude mice. TβRIII-associated apoptosis was not dependent on signaling through the canonical TGF-β/Smad pathway but was mediated through p38 MAPK. Conclusion: These findings indicate a novel mechanistic antitumor function for TβRIII and further support its role as an important tumor suppressor in clear cell renal cell carcinoma.