Citations

ABSTRACTThe bone marrow provides a protective environment for acute myeloid leukemia (AML) cells that often allows leukemic stem cells to survive standard chemotherapeutic regimens. Targeting these leukemic stem cells within the bone marrow is critical for preventing relapse. We recently demonstrated that SDF‐1, a chemokine abundant in the bone marrow, induces apoptosis in AML cell lines and in patient samples expressing high levels of its receptor, CXCR4. Here we show that a subset of osteoblast lineage cells within the bone marrow can protect AML cells from undergoing apoptosis in response to the SDF‐1 naturally present in that location. In co‐culture systems, osteoblasts at various stages of differentiation protected AML cell lines and patient isolates from SDF‐1‐induced apoptosis. The differentiation of the osteoblast cell lines, MC3T3 and W‐20‐17, mediated this protection via a cell contact‐independent mechanism. In contrast, bone marrow‐derived mesenchymal cells, the precursors of osteoblasts, induced apoptosis in AML cells via a CXCR4‐dependent mechanism and failed to protect AML cells from exogenously added SDF‐1. These results indicate that osteoblasts in the process of differentiation potently inhibit the SDF‐1‐driven apoptotic pathway of CXCR4‐expressing AML cells residing in the bone marrow. Drugs targeting this protective mechanism could potentially provide a new approach to treating AML by enhancing the SDF‐1‐induced apoptosis of AML cells residing within the bone marrow microenvironment. J. Cell. Biochem. 115: 1128–1137, 2014. © 2013 Wiley Periodicals, Inc.

ABSTRACTBackgroundThe objective of this study was to evaluate citalopram for executive functioning in Huntington's disease (HD).MethodsThe study was randomized, double‐blind, and placebo‐controlled. Thirty‐three adults with HD, cognitive complaints, and no depression (Hamilton Depression [HAM‐D] rating scale ≤12) were administered citalopram 20 mg or placebo (7 visits, 20 weeks), with practice and placebo run‐ins. The primary outcome was change in executive functioning.ResultsThe intent to treat analysis was controlled for practice effects, comparing visits 1 and 2 to visits 5 and 6 for citalopram versus placebo. There were no significant benefits on the executive function composite (treatment‐placebo mean difference −0.167; 95% confidence interval [CI], −0.361 to 0.028; P = .092). Citalopram participants showed improved clinician‐rated depression symptoms on the HAM‐D (t = −2.02; P = 0.05). There were no group differences on motor ratings, self‐reported executive functions, psychiatric symptoms, or functional status.ConclusionsThere was no evidence that short‐term treatment with citalopram improved executive functions in HD. Despite excluding patients with active depression, participants on citalopram showed improved mood, raising the possibility of efficacy for subsyndromal depression in HD. © 2013 International Parkinson and Movement Disorder Society

Purpose: Oxygen saturation to fraction of inspired oxygen ratio (SpO 2 /FiO 2 ) has been validated as a surrogate marker for partial pressure of oxygen to fraction of inspired oxygen ratio among mechanically ventilated patients with acute respiratory distress syndrome (ARDS). The validity of SpO 2 /FiO 2 measurements in predicting ARDS has not been studied. Recently, a Lung Injury Prediction Score (LIPS) has been developed to help identify patients at risk of developing ARDS. Methods: This was a secondary analysis of the LIPS-1 cohort. A multivariate logistic regression included all established variables for LIPS, Acute Physiology and Chronic Health Evaluation 2, age, and comorbid conditions that could affect SpO 2 /FiO 2 . The primary outcome was development of ARDS in the hospital. The secondary outcomes included hospital mortality, hospital day of ARDS development, and hospital day of death. Results: Of the 5584 patients, we evaluated all 4646 with recorded SpO 2 /FiO 2 values. Median SpO 2 /FiO 2 in those who did and did not develop ARDS was 254 (100, 438) and 452 (329, 467), respectively. There was a significant association between SpO 2 /FiO 2 and ARDS ( P ≤ .001). The SpO 2 /FiO 2 was found to be an independent predictor of ARDS in a “dose-dependent” manner; for SpO 2 /FiO 2 < 100—odds ratios (OR) 2.49 (1.69-3.64, P < .001), for SpO 2 /FiO 2 100 < 200—OR 1.75 (1.16-2.58, P = .007), and for SpO 2 /FiO 2 200 < 300—OR 1.62 (1.06-2.42, P = .025). The discriminatory characteristics of the multivariable model and SpO 2 /FiO 2 as a single variable demonstrated area under the curve (AUC) of 0.81 and AUC of 0.74, respectively. Conclusions: The SpO 2 /FiO 2 , measured within the first 6 hours after hospital admission, is an independent indicator of ARDS development among patients at risk.

Increased global connectivity has catalyzed technological development in almost all industries, in part through the facilitation of novel collaborative structures. Notably, open innovation and crowd-sourcing—of expertise and/or funding—has tremendous potential to increase the efficiency with which biomedical ecosystems interact to deliver safe, efficacious and affordable therapies to patients. Consequently, such practices offer tremendous potential in advancing development of cellular therapies. In this vein, the CASMI Translational Stem Cell Consortium (CTSCC) was formed to unite global thought-leaders, producing academically rigorous and commercially practicable solutions to a range of challenges in pluripotent stem cell translation. Critically, the CTSCC research agenda is defined through continuous consultation with its international funding and research partners. Herein, initial findings for all research focus areas are presented to inform global product development strategies, and to stimulate continued industry interaction around biomanufacturing, strategic partnerships, standards, regulation and intellectual property and clinical adoption.

ECG Lead I and Outflow Tract ArrhythmiaIntroductionOutflow tract ventricular arrhythmia (OTVA) can be complicated to target for ablation when originating from either the periaortic or pulmonary valve (PV) region. Both sites may present with a small R wave in lead V1. However, the utility of lead I in distinguishing these arrhythmia locations is unknown.Methods and ResultsThirty‐six consecutive patients (mean age 41 ± 14 years, 13 male) underwent catheter ablation for OTVA. OTVA origin was determined from intracardiac electrogram tracings and electroanatomic maps. Observers blinded to results measured QRS waveform amplitude and duration from standard 12‐lead ECG tracings. Measurements with highest diagnostic performance were modeled into an algorithm. Sites of successful ablation were anterior right ventricular outflow tract (RVOT; n = 6), posterior RVOT (n = 4), PV (n = 18), and right coronary cusp (RCC; n = 8). Highest performing surface ECG discriminators were from lead I to V1 vectors: RCC, lead I R wave ≥ 1.5 mV, and V1 R wave ≥2.0 mV (sensitivity 87%, specificity 93%); PV, V1 R wave > 0 mV, and lead I R/(R+S) ≤ 0.75 (sensitivity 78%, specificity 72%); anterior RVOT, V1 R wave = 0 mV, and lead I R/(R+S) <0.4 (sensitivity 67%, specificity 97%); posterior RVOT, V1 R wave > 0 mV, and lead I R/(R+S) > 0.75 (sensitivity 75%, specificity 84%). Sequential algorithmic application of these criteria resulted in an overall accuracy of 72% in predicting site of OTVA origin.ConclusionsA relatively large R wave in lead I is seen with RCC origin but not PV origin. A sequential algorithm has limited but potentially significant value beyond assessment of lead I in approaching OTVA.

Abstract A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76–0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75–0.95; P = 0.006). Considering a multiple-testing–corrected significance threshold of P &lt; 2.5 × 10−5, only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79–0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted. Cancer Res; 74(3); 852–61. ©2013 AACR.

ABSTRACTGenes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene‐environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P‐values = 3 × 10−07), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m2 (OR = 1.26, 95% CI 1.15–1.38) but not in women with a BMI of 30 kg/m2 or higher (OR = 0.89, 95% CI 0.72–1.11, P for interaction = 3.2 × 10−05). Our findings confirm comparable power of the recent methods for detecting G × E interaction and the utility of using G × E interaction analyses to identify new susceptibility loci.

Abstract Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70 917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46 450 breast cancer cases and 42 461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P &lt; 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P &lt; 10−4) were selected for more careful assessment by logistic regression. Under the first approach, 3277 SNPs were preselected, but an evaluation of all possible two-SNP combinations (1 d.f.) identified no interactions at P &lt; 10−8. Results from the second analytic approach were consistent with those from the first (P &gt; 10−10). In summary, we observed little evidence of two-way SNP interactions in breast cancer susceptibility, despite the large number of SNPs with potential marginal effects considered and the very large sample size. This finding may have important implications for risk prediction, simplifying the modelling required. Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome.