Citations

Abstract Macrophage inflammatory protein (MIP-1α), a member of the CC chemokine subfamily, has been shown to attract T cells and monocytes in vitro and to be expressed at sites of inflammation. Although the in vitro activities of MIP-1α have been well documented, the in vivo biological activities of MIP-1α in humans have not been studied. To address this, we challenged human subjects by intradermal injection with up to 1000 pmol of MIP-1α and performed biopsies 2, 10, and 24 h later. Although no acute cutaneous or systemic reactions were noted, endothelial cell activation, as indicated by the expression of E-selectin, was observed. In agreement with its in vitro activity, monocyte, lymphocyte, and, to a lesser degree, eosinophil infiltration was observed, peaking at 10–24 h. Surprisingly, in contrast to its reported lack of in vitro neutrophil-stimulating activity, a rapid infiltration of neutrophils was observed in vivo. This neutrophil infiltration occurred as early as 2 h, preceding the appearance of other cells, and peaked at 10 h. Interestingly, we found that neutrophils in whole blood, but not after isolation, expressed CCR1 on their cell surface. This CCR1 was thought to be functional as assessed by neutrophil CD11b up-regulation following whole-blood MIP-1α stimulation. These studies substantiate the biological effects of MIP-1α on monocytes and lymphocytes and uncover the previously unrecognized activity of MIP-1α to induce neutrophil infiltration and endothelial cell activation, underscoring the need to evaluate chemokines in vivo in humans.

Objectives. We compared breast cancer death rates and mortality trends among American Indian/Alaska Native (AI/AN) and White women using data for which racial misclassification was minimized. Methods. We used breast cancer deaths and cases linked to Indian Health Service (IHS) data to calculate age-adjusted rates and 95% confidence intervals (CIs) by IHS-designated regions from 1990 to 2009 for AI/AN and White women; Hispanics were excluded. Mortality-to-incidence ratios (MIR) were calculated for 1999 to 2009 as a proxy for prognosis after diagnosis. Results. Overall, the breast cancer death rate was lower in AI/AN women (21.6 per 100 000) than in White women (26.5). However, rates in AI/ANs were higher than rates in Whites for ages 40 to 49 years in the Alaska region, and ages 65 years and older in the Southern Plains region. White death rates significantly decreased (annual percent change [APC] = −2.1; 95% CI = −2.3, −2.0), but regional and overall AI/AN rates were unchanged (APC = 0.9; 95% CI = 0.1, 1.7). AI/AN women had higher MIRs than White women. Conclusions. There has been no improvement in death rates among AI/AN women. Targeted screening and timely, high-quality treatment are needed to reduce mortality from breast cancer in AI/AN women.

Abstract In HIV-infected patients, concurrent infections with bacteria and viruses are known to induce HIV replication as assessed by increases in plasma HIV RNA levels. In the present study, we determined the cell surface receptor and molecular mechanisms of enterobacterial LPS-induced HIV transcription. Human dermal microvessel endothelial cells (HMEC) were transfected with an HIV-long terminal repeat (LTR)-luciferase construct and subsequently stimulated with purified bacterial LPS. Our studies demonstrate that human Toll-like receptor 4 (TLR4) mediates LPS-induced NF-κB and HIV-LTR activation in HMEC through IL-1 signaling molecules, namely myeloid differentiation protein, IL-1R-associated kinase, TNFR-associated factor, and NF-κB-inducing kinase. Cotransfection of HMEC with HIV-LTR-luciferase and TLR4 cDNA from LPS-hyporesponsive C3H/HeJ mice abrogates LPS-induced HIV transcription as does the use of dominant-negative mutants of the IL-1 signaling molecules. Transfection of HMEC with an HIV-LTR-mutant that lacks the NF-κB binding site or pretreatment of cells with chemical inhibitors of the NF-κB pathway also blocked LPS-induced HIV-LTR transactivation. These data support the conclusion that TLR4 mediates enterobacterial LPS-induced HIV transcription via IL-1 signaling molecules and NF-κB activation plays an important role in HIV-LTR transactivation.

Abstract Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-κB (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P < 2.5 × 10−5). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41–2.35; P = 4.13 × 10−6] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56–0.82; P = 2.33 × 10−5). Other associations of note included TNF receptor–associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77–0.92; P = 6.49 × 10−5) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26–0.73; P = 4.56 × 10−4). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies. Cancer Epidemiol Biomarkers Prev; 23(7); 1421–7. ©2014 AACR.

Background Patients with a sore or burning mouth associated with clinically normal oral mucosa present a difficult diagnostic challenge. Objective The objective of this study was to assess the value of patch testing in patients with burning mouth syndrome. Methods We retrospectively reviewed the results of patch testing to an oral series in patients with burning mouth syndrome seen at Mayo Clinic, Rochester, Minnesota, between January 2000 and April 2006. Results Of 195 consecutive patients with a burning or sore mouth, 75 had patch testing to an oral series, and 28 of these patients (37.3%) had allergic patch test reactions. The most common allergens were nickel sulfate hexahydrate 2.5%, balsam of Peru, and gold sodium thiosulfate 0.5%. On follow-up, 15 patients reported improvement, 4 removed or avoided the offending dental metal, and 6 avoided the dietary allergen. Thirteen patients did not improve; 6 avoided identified allergens, but without improvement; 1 removed dental metals without symptom change; and 5 avoided test-positive dietary allergens but without improvement. The remaining 7 nonresponders had nonrelevant patch test results or did not avoid allergens. Conclusions Patch testing can identify patients who may be allergic to dental metals or dietary additives and who may benefit from removal or avoidance of these.

Abstract The ability to consistently detect cell-free tumor-specific DNA in peripheral blood of patients with metastatic breast cancer provides the opportunity to detect changes in tumor burden and to monitor response to treatment. We developed cMethDNA, a quantitative multiplexed methylation-specific PCR assay for a panel of ten genes, consisting of novel and known breast cancer hypermethylated markers identified by mining our previously reported study of DNA methylation patterns in breast tissue (103 cancer, 21 normal on the Illumina HumanMethylation27 Beadchip) and then validating the 10-gene panel in The Cancer Genome Atlas project breast cancer methylome database. For cMethDNA, a fixed physiologic level (50 copies) of artificially constructed, standard nonhuman reference DNA specific for each gene is introduced in a constant volume of serum (300 μL) before purification of the DNA, facilitating a sensitive, specific, robust, and quantitative assay of tumor DNA, with broad dynamic range. Cancer-specific methylated DNA was detected in training (28 normal, 24 cancer) and test (27 normal, 33 cancer) sets of recurrent stage IV patient sera with a sensitivity of 91% and a specificity of 96% in the test set. In a pilot study, cMethDNA assay faithfully reflected patient response to chemotherapy (N = 29). A core methylation signature present in the primary breast cancer was retained in serum and metastatic tissues collected at autopsy two to 11 years after diagnosis of the disease. Together, our data suggest that the cMethDNA assay can detect advanced breast cancer, and monitor tumor burden and treatment response in women with metastatic breast cancer. Cancer Res; 74(8); 2160–70. ©2014 AACR.

BACKGROUNDTo ensure that National Institutes of Health‐funded research is relevant to the population's needs, specific emphasis on proportional representation of minority/sex groups into National Cancer Institute (NCI) cancer centers' clinical research programs is reported to the NCI.METHODSEMPaCT investigators at 5 regionally diverse comprehensive cancer centers compared data reported to the NCI for their most recent Cancer Center Support Grant competitive renewal to assess and compare the centers' catchment area designations, data definitions, data elements, collection processes, reporting, and performance regarding proportional representation of race/ethnicity and sex subsets.RESULTSCancer centers' catchment area definitions differed widely in terms of their cancer patient versus general population specificity, levels of specificity, and geographic coverage. Racial/ethnic categories were similar, yet were defined differently, across institutions. Patients' socioeconomic status and insurance status were inconsistently captured across the 5 centers.CONCLUSIONSCatchment area definitions and the collection of patient‐level demographic factors varied widely across the 5 comprehensive cancer centers. This challenged the assessment of success by cancer centers in accruing representative populations into the cancer research enterprise. Accrual of minorities was less than desired for at least 1 racial/ethnic subcategory at 4 of the 5 centers. Institutions should clearly and consistently declare their primary catchment area and the rationale and should report how race/ethnicity and sex are defined, determined, collected, and reported. More standardized, frequent, consistent collection, reporting, and review of these data are recommended, as is a commitment to collecting socioeconomic data, given that socioeconomic status is a primary driver of cancer disparities in the United States. Cancer 2014;120(7 suppl):1113–21. © 2014 American Cancer Society.