bluuebunny/crossref_metadata_2025 huggingface dataset:
Carbon monoxide as an endogenous vascular modulator
Authors: Leffler Charles W. , Parfenova Helena , Jaggar Jonathan H.
Published: April 2011

Carbon monoxide (CO) is produced by heme oxygenase (HO)-catalyzed heme degradation to CO, iron, and biliverdin. HO has two active isoforms, HO-1 (inducible) and HO-2 (constitutive). HO-2, but not HO-1, is highly expressed in endothelial and smooth muscle cells and in adjacent astrocytes in the brain. HO-1 is expressed basally only in the spleen and liver but can be induced to a varying extent in most tissues. Elevating heme, protein phosphorylation, Ca2+ influx, and Ca2+/calmodulin-dependent processes increase HO-2 activity. CO dilates cerebral arterioles and may constrict or dilate skeletal muscle and renal arterioles. Selected vasodilatory stimuli, including seizures, glutamatergic stimulation, hypoxia, hypotension, and ADP, increase CO, and the inhibition of HO attenuates the dilation to these stimuli. Astrocytic HO-2-derived CO causes glutamatergic dilation of pial arterioles. CO dilates by activating smooth muscle cell large-conductance Ca2+-activated K+ (BKCa) channels. CO binds to BKCa channel-bound heme, leading to an increase in Ca2+ sparks-to-BKCa channel coupling. Also, CO may bind directly to the BKCa channel at several locations. Endothelial nitric oxide and prostacyclin interact with HO/CO in circulatory regulation. In cerebral arterioles in vivo, in contrast to dilation to acute CO, a prolonged exposure of cerebral arterioles to elevated CO produces progressive constriction by inhibiting nitric oxide synthase. The HO/CO system is highly protective to the vasculature. CO suppresses apoptosis and inhibits components of endogenous oxidant-generating pathways. Bilirubin is a potent reactive oxygen species scavenger. Still many questions remain about the physiology and biochemistry of HO/CO in the circulatory system and about the function and dysfunction of this gaseous mediator system.
Protein kinase A changes calcium sensitivity but not crossbridge kinetics in human cardiac myofibrils
Authors: Walker John S. , Walker Lori A. , Margulies Ken , Buttrick Peter , de Tombe Pieter
Published: April 2011

We investigated the effect of PKA treatment (1 U/ml) on the mechanical properties of isolated human cardiac myofibrils. PKA treatment was associated with significant incorporation of radiolabeled phosphate into several sarcomeric proteins including troponin I and myosin binding protein C and was also associated with a right shift in the tension-pCa relation (ΔpCa50= 0.2 ± 0.1). PKA treatment also caused right shifts in the pCa dependence of the rate of tension development, tension redevelopment, and the linear and exponential phases of myofibril relaxation. However, there was no change in the same measures of crossbridge turnover when expressed as a function of tension. We conclude that the changes in crossbridge kinetics as a function of calcium concentration reflect a reduced tension due to a lower calcium sensitivity and that the relationship between crossbridge kinetics and tension was unchanged, indicating no direct effect of PKA treatment on crossbridge cycling.
The effect of cardiac sympathetic denervation through bilateral stellate ganglionectomy on electrical properties of the heart
Authors: Xie Xueyi , Visweswaran Ramjay , Guzman Pilar A. , Smith Rebecca M. , Osborn John W. , Tolkacheva Elena G.
Published: April 2011

The role of the cardiac sympathetic nerve activity in various cardiac diseases is typically evaluated using β-adrenergic receptor antagonists. However, these antagonists induce global denervation effects not only in the cardiovascular system, but also in the brain and kidney. The objective of this study was to detect the electrophysiological property changes due to 8 days of cardiac sympathetic denervation and investigate the possible mechanisms underlying these changes using a more cardiac-specific bilateral stellate ganglionectomy (SGX) rat model. High-resolution optical mapping using a voltage-sensitive dye was performed in isolated Langendorff-perfused sham and SGX hearts, which were paced at progressively reduced basic cycle lengths under several different conditions: control, pretreatment with isoproterenol, and administration of atenolol and esmolol. Several electrophysiological parameters were recorded during periodic pacing and ventricular fibrillation (VF). Our results demonstrate that cardiac sympathetic denervation by bilateral SGX shortens action potential duration (APD) and flattens the APD restitution curve, but does not significantly affect spatial dispersion of APD. We found that, although the vulnerability of sham and SGX hearts to VF is similar, the dynamics of VF are different. The maximum dominant frequency is higher, and the spatial distribution of VF is more complex in the SGX heart, resulting in different mechanisms of VF. We demonstrated that β1-adrenergic receptors are downregulated in the SGX compared with sham hearts. In addition, our data suggest that the mechanism of cardiac sympathetic denervation by SGX surgery is more similar to the administration of β-blocker esmolol than atenolol.
Lack of CCR7 induces pulmonary hypertension involving perivascular leukocyte infiltration and inflammation
Authors: Larsen Karl-Otto , Yndestad Arne , Sjaastad Ivar , Løberg Else Marit , Goverud Ingeborg Løstegaard , Halvorsen Bente , Jia Jing , Andreassen Arne K. , Husberg Cathrine , Jonasson Sofia , Lipp Martin , Christensen Geir , Aukrust Pål , Skjønsberg Ole Henning
Published: April 2011

The chemokine receptor CCR7 regulates lymphocyte trafficking, and CCR7 deficiency induces infiltration of T and B cells adjacent to vessels in mouse lungs. Perivascular infiltration of T and B cells has also been found in human pulmonary arterial hypertension, and downregulation of the CCR7 receptor in circulating leukocytes of such patients has been observed. To investigate whether changes in the CCR7 system contribute to the pathogenesis of pulmonary hypertension, we utilized mice deficient of the CCR7 receptor. The cardiopulmonary and inflammatory responses of CCR7 depletion were evaluated in CCR7-deficient and wild-type mice. Measurements of cytokines upregulated in the animal model were also performed in patients with pulmonary hypertension and controls and in vascular smooth muscle cells. We found that mice lacking CCR7 had increased right ventricular systolic pressure, reduced pulmonary artery acceleration time, increased right ventricular/tibial length ratio, Rho kinase-mediated pulmonary vasoconstriction, and increased muscularization of distal arteries, indicating pulmonary hypertension. These mice also showed increased perivascular infiltration of leukocytes, consisting mainly of T and B cells, and increased mRNA levels of the inflammatory cytokines interleukin-12 and CX3CL1 within pulmonary tissue. Increased serum levels of interleukin-12 and CX3CL1 were also observed in patients with pulmonary hypertension, particularly in those with pulmonary hypertension associated with connective tissue disorder. In smooth muscle cells, interleukin-12 induced secretion of the angiogenic cytokine interleukin-8. We conclude that these results suggest a role for CCR7 in the development of pulmonary arterial hypertension, at least in some subgroups, possibly via pulmonary infiltration of lymphocytes and secretion of interleukin-12 and CX3CL1.
Is the cellular response to cigarette smoke predictive of the phenotypic variation of COPD?
Authors: Park Gye Young , Christman John W.
Published: April 2011

the adverse health consequences of cigarette smoking are not limited to the lung but also include effects on multiple other organ systems that are exposed directly or indirectly to the hazardous gaseous and soluble compounds generated by burning tobacco. Cigarette smoking (CS) is a risk factor for many major diseases including chronic obstructive pulmonary disease (COPD), atherosclerosis, cerebral and coronary vascular diseases, hypertension, and many types of cancer. Within the diagnosis category of COPD, it is widely recognized that there is substantial phenotypic heterogeneity with respect to both pulmonary and extrapulmonary manifestations. To understand the variability in responses to CS, it becomes essential to decipher the involved mechanisms at a cellular and molecular level that contribute to cigarette-related pathology. In this issue of the Journal, there are three papers ( 1 , 4 , 6 ) that provide insight regarding the molecular pathogenesis of CS-related COPD that could be related to phenotypic variation, by examining three classes of cell types of lung: endothelial cells, epithelial cells, and immune effector cells.
Alveolar epithelial cells express mesenchymal proteins in patients with idiopathic pulmonary fibrosis
Authors: Marmai Cecilia , Sutherland Rachel E. , Kim Kevin K. , Dolganov Gregory M. , Fang Xiaohui , Kim Sophia S. , Jiang Shuwei , Golden Jeffery A. , Hoopes Charles W. , Matthay Michael A. , Chapman Harold A. , Wolters Paul J.
Published: April 2011

Prior work has shown that transforming growth factor-β (TGF-β) can mediate transition of alveolar type II cells into mesenchymal cells in mice. Evidence this occurs in humans is limited to immunohistochemical studies colocalizing epithelial and mesenchymal proteins in sections of fibrotic lungs. To acquire further evidence that epithelial-to-mesenchymal transition occurs in the lungs of patients with idiopathic pulmonary fibrosis (IPF), we studied alveolar type II cells isolated from fibrotic and normal human lung. Unlike normal type II cells, type II cells isolated from the lungs of patients with IPF express higher levels of mRNA for the mesenchymal proteins type I collagen, α-smooth muscle actin (α-SMA), and calponin. When cultured on Matrigel/collagen, human alveolar type II cells maintain a cellular morphology consistent with epithelial cells and expression of surfactant protein C (SPC) and E-cadherin. In contrast, when cultured on fibronectin, the human type II cells flatten, spread, lose expression of pro- SPC, and increase expression of vimentin, N-cadherin, and α-SMA; markers of mesenchymal cells. Addition of a TGF-β receptor kinase inhibitor (SB431542) to cells cultured on fibronectin inhibited vimentin expression and maintained pro-SPC expression, indicating persistence of an epithelial phenotype. These data suggest that alveolar type II cells can acquire features of mesenchymal cells in IPF lungs and that TGF-β can mediate this process.
Aldehyde Dehydrogenase in Combination with CD133 Defines Angiogenic Ovarian Cancer Stem Cells That Portend Poor Patient Survival
Authors: Silva Ines A. , Bai Shoumei , McLean Karen , Yang Kun , Griffith Kent , Thomas Dafydd , Ginestier Christophe , Johnston Carolyn , Kueck Angela , Reynolds R. Kevin , Wicha Max S. , Buckanovich Ronald J.
Published: April 2011

Markers that reliably identify cancer stem cells (CSC) in ovarian cancer could assist prognosis and improve strategies for therapy. CD133 is a reported marker of ovarian CSC. Aldehyde dehydrogenase (ALDH) activity is a reported CSC marker in several solid tumors, but it has not been studied in ovarian CSC. Here we report that dual positivity of CD133 and ALDH defines a compelling marker set in ovarian CSC. All human ovarian tumors and cell lines displayed ALDH activity. ALDH+ cells isolated from ovarian cancer cell lines were chemoresistant and preferentially grew tumors, compared with ALDH− cells, validating ALDH as a marker of ovarian CSC in cell lines. Notably, as few as 1,000 ALDH+ cells isolated directly from CD133− human ovarian tumors were sufficient to generate tumors in immunocompromised mice, whereas 50,000 ALDH− cells were unable to initiate tumors. Using ALDH in combination with CD133 to analyze ovarian cancer cell lines, we observed even greater growth in the ALDH+CD133+ cells compared with ALDH+CD133− cells, suggesting a further enrichment of ovarian CSC in ALDH+CD133+ cells. Strikingly, as few as 11 ALDH+CD133+ cells isolated directly from human tumors were sufficient to initiate tumors in mice. Like other CSC, ovarian CSC exhibited increased angiogenic capacity compared with bulk tumor cells. Finally, the presence of ALDH+CD133+ cells in debulked primary tumor specimens correlated with reduced disease-free and overall survival in ovarian cancer patients. Taken together, our findings define ALDH and CD133 as a functionally significant set of markers to identify ovarian CSCs. Cancer Res; 71(11); 3991–4001. ©2011 AACR.
Comparison of Neuropathy-Inducing Effects of Eribulin Mesylate, Paclitaxel, and Ixabepilone in Mice
Authors: Wozniak Krystyna M. , Nomoto Kenichi , Lapidus Rena G. , Wu Ying , Carozzi Valentina , Cavaletti Guido , Hayakawa Kazuhiro , Hosokawa Satoru , Towle Murray J. , Littlefield Bruce A. , Slusher Barbara S.
Published: April 2011

Chemotherapy-induced neurotoxicity is a significant problem associated with successful treatment of many cancers. Tubulin is a well-established target of antineoplastic therapy; however, tubulin-targeting agents, such as paclitaxel and the newer epothilones, induce significant neurotoxicity. Eribulin mesylate, a novel microtubule-targeting analogue of the marine natural product halichondrin B, has recently shown antineoplastic activity, with relatively low incidence and severity of neuropathy, in metastatic breast cancer patients. The mechanism of chemotherapy-induced neuropathy is not well understood. One of the main underlying reasons is incomplete characterization of pathology of peripheral nerves from treated subjects, either from patients or preclinically from animals. The current study was conducted to directly compare, in mice, the neuropathy-inducing propensity of three drugs: paclitaxel, ixabepilone, and eribulin mesylate. Because these drugs have different potencies and pharmacokinetics, we compared them on the basis of a maximum tolerated dose (MTD). Effects of each drug on caudal and digital nerve conduction velocity, nerve amplitude, and sciatic nerve and dorsal root ganglion morphology at 0.25 × MTD, 0.5 × MTD, 0.75 × MTD, and MTD were compared. Paclitaxel and ixabepilone, at their respective MTDs, produced significant deficits in caudal nerve conduction velocity, caudal amplitude and digital nerve amplitudes, as well as moderate to severe degenerative pathologic changes in dorsal root ganglia and sciatic nerve. In contrast, eribulin mesylate produced no significant deleterious effects on any nerve conduction parameter measured and caused milder, less frequent effects on morphology. Overall, our findings indicate that eribulin mesylate induces less neuropathy in mice than paclitaxel or ixabepilone at equivalent MTD-based doses. Cancer Res; 71(11); 3952–62. ©2011 AACR.
Genome-Wide “Pleiotropy Scan” Identifies HNF1A Region as a Novel Pancreatic Cancer Susceptibility Locus
Authors: Pierce Brandon L. , Ahsan Habibul
Published: April 2011

In genome-wide association (GWA) studies, hundreds of thousands of single-nucleotide polymorphisms (SNP) are tested for association with a disease trait. Typically, GWA studies give equal consideration to all SNPs tested, regardless of existing knowledge of an SNP's functionality or biological plausibility of association. Because many tests are conducted, very low statistical significance thresholds (P < 5 × 10−8) are required to identify true associations with confidence. By restricting GWA analyses to SNPs with enhanced prior probabilities of association, we can reduce the number of tests conducted and relax the required significance threshold, increasing power to detect association. In this analysis of existing GWA data on pancreatic cancer cases (n = 1,736) and controls (n = 1,802) of European descent (the PanScan study), we conduct a GWA scan restricted to SNPs that have been reported to associate with human phenotypes in previous GWA studies (with P < 5 × 10−8). Using this method, we drastically reduce the number of tests conducted (from ∼550,000 to 1,087) and test only SNPs that are known to be (or tag) variants that influence human biological processes. Of the 1,087 SNPs tested, the strongest association observed was for HNF1A SNP rs7310409 (P = 3 × 10−5; PBonferroni = 0.03), an SNP known to associate with circulating C-reactive protein. This association was replicated in an independent sample of 1,094 cases and 1,165 controls (P = 0.02), producing a highly significant association in the combined data sets (P = 2 × 10−6; PBonferroni = 0.002). The HNF1A region also harbors variants that influence several human traits, including maturity-onset diabetes of the young, type 2 diabetes, low-density lipoprotein cholesterol, and N-glycan levels. This novel “pleiotropy scan” method may be useful for identifying susceptibility loci for other cancer phenotypes. Cancer Res; 71(13); 4352–8. ©2011 AACR.
Overcoming Trastuzumab Resistance in Breast Cancer by Targeting Dysregulated Glucose Metabolism
Authors: Zhao Yuhua , Liu Hao , Liu Zixing , Ding Yan , LeDoux Susan P. , Wilson Glenn L. , Voellmy Richard , Lin Yifeng , Lin Wensheng , Nahta Rita , Liu Bolin , Fodstad Oystein , Chen Jieqing , Wu Yun , Price Janet E. , Tan Ming
Published: April 2011

Trastuzumab shows remarkable efficacy in treatment of ErbB2-positive breast cancers when used alone or in combination with other chemotherapeutics. However, acquired resistance develops in most treated patients, necessitating alternate treatment strategies. Increased aerobic glycolysis is a hallmark of cancer and inhibition of glycolysis may offer a promising strategy to preferentially kill cancer cells. In this study, we investigated the antitumor effects of trastuzumab in combination with glycolysis inhibitors in ErbB2-positive breast cancer. We found that trastuzumab inhibits glycolysis via downregulation of heat shock factor 1 (HSF1) and lactate dehydrogenase A (LDH-A) in ErbB2-positive cancer cells, resulting in tumor growth inhibition. Moreover, increased glycolysis via HSF1 and LDH-A contributes to trastuzumab resistance. Importantly, we found that combining trastuzumab with glycolysis inhibition synergistically inhibited trastuzumab-sensitive and -resistant breast cancers in vitro and in vivo, due to more efficient inhibition of glycolysis. Taken together, our findings show how glycolysis inhibition can dramatically enhance the therapeutic efficacy of trastuzumab in ErbB2-positive breast cancers, potentially useful as a strategy to overcome trastuzumab resistance. Cancer Res; 71(13); 4585–97. ©2011 AACR.
Formation of the eIF4F Translation–Initiation Complex Determines Sensitivity to Anticancer Drugs Targeting the EGFR and HER2 Receptors
Authors: Zindy Pierre , Bergé Yann , Allal Ben , Filleron Thomas , Pierredon Sandra , Cammas Anne , Beck Samantha , Mhamdi Loubna , Fan Li , Favre Gilles , Delord Jean-Pierre , Roché Henri , Dalenc Florence , Lacroix-Triki Magali , Vagner Stéphan
Published: April 2011

Elucidating how cancer cells respond to antagonists of HER receptor family members is critical to understanding mechanisms of therapeutic resistance that arise in patients. In large part, resistance to such agents appears to arise from deregulation of the phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR pathway. mTOR-dependent phosphorylation of the translation repressor 4E-BP1 leads to its dissociation from eIF4E, thereby causing an increase in the formation of the eIF4F complex, which also comprises eIF4G and eIF4A. In this study, we show that trastuzumab, cetuximab, and erlotinib all decrease the formation of the eIF4F complex in breast, colon, and head and neck cancer cells, respectively. Ectopic expression of eIF4E restores the trastuzumab-dependent defect in eIF4F formation, renders cells resistant to the trastuzumab-mediated decrease in cell proliferation, and rescues breast cancer xenografts from inhibition by trastuzumab. In breast tumor specimens, the level of eIF4E expression is associated with the therapeutic response to a trastuzumab-based regimen. Together, our findings suggest that formation of the eIF4F complex may be a critical determinant of the response to anticancer drugs that target HER2 and epidermal growth factor receptor. Cancer Res; 71(12); 4068–73. ©2011 AACR.
New Strategies in Barrett's Esophagus: Integrating Clonal Evolutionary Theory with Clinical Management
Authors: Reid Brian J. , Kostadinov Rumen , Maley Carlo C.
Published: April 2011

Barrett's esophagus is a condition in which the normal stratified squamous epithelium of the distal esophagus is replaced by intestinal metaplasia. For more than three decades, the prevailing clinical paradigm has been that Barrett's esophagus is a complication of symptomatic reflux disease that predisposes to esophageal adenocarcinoma. However, no clinical strategy for cancer prevention or early detection based on this paradigm has been proven to reduce esophageal adenocarcinoma mortality in a randomized clinical trial in part because only about 5% to 10% of individuals with Barrett's esophagus develop esophageal adenocarcinoma. Recent research indicates that Barrett's metaplasia is an adaptation for mucosal defense in response to chronic reflux in most individuals. The risk of progressing to esophageal adenocarcinoma is determined by development of genomic instability and dynamic clonal evolution in the distal esophagus modulated by host and environmental risk and protective factors, including inherited genotype. The challenge for investigators of Barrett's esophagus lies in integrating knowledge about genomic instability and clonal evolution into clinical management to increase the lifespan and quality of life of individuals with this condition. Clin Cancer Res; 17(11); 3512–9. ©2011 AACR.
Relationship between Single Nucleotide Polymorphisms and Haplotypes in DPYD and Toxicity and Efficacy of Capecitabine in Advanced Colorectal Cancer
Authors: Deenen Maarten J. , Tol Jolien , Burylo Artur M , Doodeman Valerie D. , de Boer Anthonius , Vincent Andrew , Guchelaar Henk-Jan , Smits Paul H.M. , Beijnen Jos H. , Punt Cornelis J.A. , Schellens Jan H.M. , Cats Annemieke
Published: April 2011

Purpose: To explore the effect of dihydropyrimidine dehydrogenase (DPD) single nucleotide polymorphisms (SNP) and haplotypes on outcome of capecitabine.

Experimental Design: Germline DNA was available from 568 previously untreated patients with advanced colorectal cancer participating in the CAIRO2 trial, assigned to capecitabine, oxaliplatin, and bevacizumab ± cetuximab. The coding region of dihydropyrimidine dehydrogenase gene (DPYD) was sequenced in 45 cases with grade 3 or more capecitabine-related toxicity and in 100 randomly selected controls (cohort). Most discriminating (P < 0.1) or frequently occurring (>1%) nonsynonymous SNPs were analyzed in all 568 patients. SNPs and haplotypes were associated with toxicity, capecitabine dose modifications, and survival.

Results: A total of 29 SNPs were detected in the case–cohort analysis, of which 8 were analyzed in all 568 patients. Of the patients polymorphic for DPYD IVS14+1G>A, 2846A>T, and 1236G>A, 71% (5 of 7), 63% (5 of 8), and 50% (14 of 28) developed grade 3 to 4 diarrhea, respectively, compared with 24% in the overall population. All patients polymorphic for IVS14+1G>A developed any grade 3 to 4 toxicity, including one possibly capecitabine-related death. Because of toxicity, a mean capecitabine dose reduction of 50% was applied in IVS14+1G>A and 25% in 2846A>T variant allele carriers. Patients were categorized into six haplotype groups: one predicted for reduced (10%), and two for increased risks (41% and 33%) for severe diarrhea. Individual SNPs were not associated with overall survival, whereas one haplotype was associated with overall survival [HR (95% CI) = 0.57 (0.35–0.95)].

Conclusions: DPYD IVS14+1G>A and 2846A>T predict for severe toxicity to capecitabine, for which patients require dose reductions. Haplotypes assist in selecting patients at risk for toxicity to capecitabine. Clin Cancer Res; 17(10); 3455–68. ©2011 AACR.
Extrahepatic Cancer Suppresses Nuclear Receptor–Regulated Drug Metabolism
Authors: Kacevska Marina , Downes Michael R. , Sharma Rohini , Evans Ronald M. , Clarke Stephen J. , Liddle Christopher , Robertson Graham R.
Published: April 2011

Purpose: To determine the mechanisms by which tumors situated in extrahepatic sites can cause profound changes in hepatic drug clearance, contributing to altered drug response and chemotherapy resistance.

Experimental Design: We studied in wild-type or transgenic CYP3A4 reporter mice implanted with the murine Engelbreth–Holm–Swarm sarcoma changes in nuclear receptor and hepatic transcription factor expression and/or function, particularly related to CYP3A gene regulation.

Results: Repression of hepatic CYP3A induction was dramatic and associated with reduced levels of C/EBPβ isoforms, impaired pregnane X receptor, and constitutive androstane receptor function. Unexpectedly, extrahepatic tumors strongly reduced nuclear accumulation of retinoid X receptor alpha (RXRα) in hepatocytes, providing a potential explanation for impaired function of nuclear receptors that rely on RXRα dimerization. Profiling revealed 38 nuclear receptors were expressed in liver with 14 showing between 1.5- and four-fold reduction in expression in livers of tumor-bearing animals, including Car, Trβ, Lxrβ, Pparα, Errα/β, Reverbα/β, and Shp. Altered Pparα and γ induction of target genes provided additional evidence of perturbed hepatic metabolic control elicited by extrahepatic tumors.

Conclusions: Extrahepatic malignancy can affect hepatic drug metabolism by nuclear receptor relocalization and decreased receptor expression and function. These findings could aid the design of intervention strategies to normalize drug clearance and metabolic pathways in cancer patients at risk of chemotherapy-induced toxicity or cancer cachexia. Clin Cancer Res; 17(10); 3170–80. ©2011 AACR.
Durable Complete Responses in Heavily Pretreated Patients with Metastatic Melanoma Using T-Cell Transfer Immunotherapy
Authors: Rosenberg Steven A. , Yang James C. , Sherry Richard M. , Kammula Udai S. , Hughes Marybeth S. , Phan Giao Q. , Citrin Deborah E. , Restifo Nicholas P. , Robbins Paul F. , Wunderlich John R. , Morton Kathleen E. , Laurencot Carolyn M. , Steinberg Seth M. , White Donald E. , Dudley Mark E.
Published: April 2011

Purpose: Most treatments for patients with metastatic melanoma have a low rate of complete regression and thus overall survival in these patients is poor. We investigated the ability of adoptive cell transfer utilizing autologous tumor-infiltrating lymphocytes (TIL) to mediate durable complete regressions in heavily pretreated patients with metastatic melanoma.

Experimental Design: Ninety-three patients with measurable metastatic melanoma were treated with the adoptive transfer of autologous TILs administered in conjunction with interleukin-2 following a lymphodepleting preparative regimen on three sequential clinical trials. Ninety-five percent of these patients had progressive disease following a prior systemic treatment. Median potential follow-up was 62 months.

Results: Objective response rates by Response Evaluation Criteria in Solid Tumors (RECIST) in the 3 trials using lymphodepleting preparative regimens (chemotherapy alone or with 2 or 12 Gy irradiation) were 49%, 52%, and 72%, respectively. Twenty of the 93 patients (22%) achieved a complete tumor regression, and 19 have ongoing complete regressions beyond 3 years. The actuarial 3- and 5-year survival rates for the entire group were 36% and 29%, respectively, but for the 20 complete responders were 100% and 93%. The likelihood of achieving a complete response was similar regardless of prior therapy. Factors associated with objective response included longer telomeres of the infused cells, the number of CD8+CD27+ cells infused, and the persistence of the infused cells in the circulation at 1 month (all P2 < 0.001).

Conclusions: Cell transfer therapy with autologous TILs can mediate durable complete responses in patients with metastatic melanoma and has similar efficacy irrespective of prior treatment. Clin Cancer Res; 17(13); 4550–7. ©2011 AACR.
Does Stage II Colorectal Cancer Need to Be Redefined?
Authors: Grothey Axel
Published: April 2011

Detection of guanylyl cyclase C mRNA in lymph nodes of resected stage II colorectal cancer is highly correlated with the risk of tumor recurrence. If validated, these results could have significant implications for the selection of patients for adjuvant therapy in this disease. Clin Cancer Res; 17(10); 3053–5. ©2011 AACR.
Of Timing and Surrogates: A Way Forward for Cancer Chemoprevention
Authors: Thompson Patricia A. , Gerner Eugene W.
Published: April 2011

Cancer chemoprevention strategies are not widely implemented in clinical practice. Targeting biomarkers in patients with elevated risk of developing cancer by means of short-term administration of certain agents may be a strategy to minimize toxicities while maintaining efficacy in clinical trials that can be completed in years rather than decades. Clin Cancer Res; 17(11); 3509–11. ©2011 AACR.
The RNA-Binding Protein HuR Promotes Glioma Growth and Treatment Resistance
Authors: Filippova Natalia , Yang Xiuhua , Wang Yimin , Gillespie G. Yancey , Langford Cathy , King Peter H. , Wheeler Crystal , Nabors L. Burt
Published: April 2011

Posttranscriptional regulation is a critical control point for the expression of genes that promote or retard tumor growth. We previously found that the mRNA-binding protein, ELAV 1 (HuR), is upregulated in primary brain tumors and stabilizes growth factor mRNAs such as VEGF and IL-8. To better understand the role of HuR in brain tumor growth, we altered levels of HuR in glioma cells by short hairpin RNA or ectopic expression and measured tumor cell phenotype using in vitro and in vivo models. In HuR-silenced cells, we found a significant decrease in anchorage-independent growth and cell proliferation with a concomitant induction of apoptosis. Using an intracranial tumor model with primary glioblastoma cells, HuR silencing produced a significant decrease in tumor volume. In contrast, overexpression of HuR produced in vitro chemoresistance to standard glioma therapies. Because bcl-2 is abundantly expressed in glioma and associated with tumor growth and survival, we determined the impact of HuR on its regulation as a molecular validation to the cellular and animal studies. Using UV cross-linking and RNA immunoprecipitation, we show that HuR bound to the 3′-untranslated region of all bcl-2 family members. Silencing of HuR led to transcript destabilization and reduced protein expression. Polysome profiling indicated loss of HuR from the translational apparatus. In summary, these findings reveal a HuR-dependent mechanism for cancer cell survival and sensitivity to chemotherapeutic drugs suggesting that HuR should be considered as a new therapeutic target. Mol Cancer Res; 9(5); 648–59. ©2011 AACR.
The S1103Y Cardiac Sodium Channel Variant Is Associated With Implantable Cardioverter-Defibrillator Events in Blacks With Heart Failure and Reduced Ejection Fraction
Authors: Sun Albert Y. , Koontz Jason I. , Shah Svati H. , Piccini Jonathan P. , Nilsson Kent R. , Craig Damian , Haynes Carol , Gregory Simon G. , Hranitzky Patrick M. , Pitt Geoffrey S.
Published: April 2011

Background—

Risk-stratifying heart failure patients for primary prevention implantable cardioverter-defibrillators (ICDs) remains a challenge, especially for blacks, who have an increased incidence of sudden cardiac death but have been underrepresented in clinical trials. We hypothesized that the S1103Y cardiac sodium channel
SCN5A
variant influences the propensity for ventricular arrhythmias in black patients with heart failure and reduced ejection fraction.

Methods and Results—

Blacks (n=112) with ejection fractions <35% receiving primary prevention ICDs were identified from the Duke Electrophysiology Genetic and Genomic Studies (EPGEN) biorepository and followed for appropriate ICD therapy (either anti tachycardia pacing or shock) for documented sustained ventricular tachycardia or fibrillation. The S1103Y variant was overrepresented in patients receiving appropriate ICD therapy compared with subjects who did not (35% versus 13%,
P
=0.03). Controlling for baseline characteristics, the adjusted hazard ratio using a Cox proportional hazard model for ICD therapy in Y1103 allele carriers was 4.33 (95% confidence interval, 1.60 to 11.73,
P
=<0.01). There was no difference in mortality between carriers and noncarriers.

Conclusions—

This is the first report that the S1103Y variant is associated with a higher incidence of ventricular arrhythmias in blacks with heart failure and reduced ejection fraction.
Mechanisms of Acute Mitral Regurgitation in Patients With Takotsubo Cardiomyopathy
Authors: Izumo Masaki , Nalawadi Smruti , Shiota Maiko , Das Jayanta , Dohad Suhail , Kuwahara Eiji , Fukuoka Yoko , Siegel Robert J. , Shiota Takahiro
Published: April 2011

Background—

Recent studies have suggested acute mitral regurgitation (MR) as a potentially serious complication of takotsubo cardiomyopathy (TTC); however, the mechanism of acute MR in TTC remains unclear. The aim of this study was to elucidate the mechanisms of acute MR in patients with TTC.

Methods and Results—

Echocardiography was used to assess the mitral valve and left ventricular outflow tract (LVOT) pressure gradient in 47 patients with TTC confirmed by coronary angiography and left ventriculography. Mitral valve assessment included coaptation distance, tenting area at mid systole in the long-axis view, and systolic anterior motion of the mitral valve (SAM). Of the study patients, 12 (25.5%) had significant (moderate or severe) acute MR. In patients with acute MR versus those without acute MR, we found lower ejection fraction (31.3±6.2% versus 41.5±10.6%,
P
=0.001) and higher systolic pulmonary artery pressure (49.3±7.4 versus 35.5±8.9 mm Hg,
P
<0.001). Moreover, 6 of the 12 patients with acute MR had SAM, with peak LVOT pressure gradient >20 mm Hg (average peak LVOT pressure gradient, 81.3±35.8 mm Hg). The remaining 6 patients with acute MR revealed significantly greater mitral valve coaptation distance (10.9±1.6 versus 7.8±1.4 mm,
P
<0.001) and tenting area (2.1±0.4 versus 0.95±0.25 cm
2
,
P
<0.001) than those without acute MR. A multivariate analysis revealed that SAM and tenting area were independent predictors of acute MR in patients with TTC (all
P
<0.001).

Conclusions—

SAM and tethering of the mitral valve are independent mechanisms with differing pathophysiology that can lead to acute MR in patients with TTC.
Warrior Spirit: Soul Wound and Coping Among American Indians in Law Enforcement
Authors: Arndt Leah M. Rouse , Davis Amileah R.
Published: April 2011

This qualitative, exploratory study examined the role vocation played for American Indian non-Tribal law enforcement officers in adaptively coping with historical trauma, or Soul Wound. Participants’ views of career in relationship to its perceived congruence with their Nations’ warrior societies and how this vocation may facilitate or constrain the management of Soul Wound or historical trauma issues was examined. For this study, 12 participants were interviewed and data were analyzed utilizing extended case method. Results indicated 11 of the 12 participants believed their vocation was congruent with their Nations’ traditional warrior roles, particularly related to the role’s value of mentorship and modeling well-living for the community. Participants’ interests and satisfaction, as well as facilitating and constraining factors of their roles, are discussed. The authors elaborate on existing theoretical understandings of Soul Wound and coping using the results. Limitations, implications, and future directions are described.
The 2010 Leona Tyler Address: From the Homogeneous Hills of North Dakota to My Kaleidoscopic World Today
Authors: Heppner Puncky Paul
Published: April 2011

This article focuses on life career perspectives within the field of counseling psychology. The first goal is to promote reflection and discussion of counseling psychologists’ planning and decision making as it pertains to their career journey; the second goal is to promote additional discussion around implicit and explicit cultural perspectives in scholars’ research paradigms in counseling psychology. To address both goals, the author centers this article around four interrelated stories in his own career path: (a) finding passion and meaning in his research, (b) broadening his worldview, (c) the power of relationships in his adult life, and (d) growing and stretching into new professional roles. In addition, the author discusses two parallel streams: (a) the evolution of his career as well as (b) defining moments, early life experiences, serendipitous events, worldviews, decisions, and people who greatly affected the course of his career. One’s career journey is typically affected by a wide range of factors. The author concludes that given the wide range of factors that can affect individuals’ careers, including happenstance, it is virtually impossible to accurately predict one’s career journey very far into the future. Given the continued rapid expansion of the global village, there will be more demands for more forward-looking counseling psychologists to meet the increasingly complex societal needs of the future. The author believes that the inclusion of the cultural context will become increasingly important in all of the work of counseling psychologists in the coming decades and thus particularly important as scholars train the next generation of counseling psychologists.
Achieving Resource Equity Within a Single School District
Authors: Darden Edwin C. , Cavendish Elizabeth
Published: April 2011

This article examines the failure of school districts to distribute nonmoney resources—controlled primarily by the board of education—equally among students in affluent neighborhoods versus low-income areas. It is largely an urban phenomenon, although some county-wide and large suburban school systems display similar patterns. Such practices represent a failure to achieve the vision of equity championed in Brown v. Board of Education of Topeka. The main aspects of the opportunity gap addressed in this article are teacher assignment, staff-based budgeting, formal equality over equity, general education funds, parental involvement, curriculum, and building maintenance costs. These elements are widely accepted as important to learning outcomes. Inadvertent disparities in resource allocation, therefore, can foster a growing opportunity gap between well-off and impoverished students. The findings of Necochea and Cline highlight the negative effects on students of unequal resource allocation. Potential legal pathways in the form of Federal and State laws are suggested to combat the intradistrict educational inequity. The article concludes with policy solutions that school districts across the country have implemented to mitigate the harmful effects of unequal resource allocation and their straightforward attempts to erase the opportunity gap among students from different neighborhoods.
Difficulties of Alternatively Certified Teachers
Authors: Schonfeld Irvin Sam , Feinman Samantha J.
Published: April 2011

This daily diary study followed, over a 2-week period, 252 beginning New York City public school teachers. Seventy percent were alternatively certified (New York City Teaching Fellows) and the rest, traditionally certified teachers. Alternatively certified teachers were more likely to experience stressors such as violent incidents and classroom management problems. No differences were found in exposure to stressors/difficulties such as problematic adults, student learning problems, and students experiencing emotional upset. Although differences in the rates of exposure to violent stressors could be explained by other factors (e.g., working in a low-performing school and years of experience), differences in the rates of occurrence of classroom management problems could not. Nevertheless, the high absolute rates of management problems and violence in both groups of teachers were striking and need to be addressed. The authors suggest measures to be taken to address the problem of retaining talented new teachers.
A Systematic Review of Neighborhood and Institutional Relationships Related to Education
Authors: Johnson Odis
Published: April 2011

This review explores the conceptualization and measurement of neighborhood and institutional relationships related to children’s educational outcomes in neighborhood effects research. The review’s analysis first summarizes early statements about neighborhood and school relationships within the field. The analysis next situates neighborhood and institutional components within a broader ecological context, relying heavily on Bronfenbrenner’s ecosystems theory. A description of six emerging models of neighborhood and institutional relationships follows and serves to organize the 83 studies within this review. The analysis concludes with an assessment of the relative importance of neighborhoods and schools in a subset of studies that measure the effects of both. The analysis findings are contextualized with the author’s identification of the major methodological complications particular to the joint estimation of neighborhood and institutional effects.
The Developmental Model of Intercultural Sensitivity
Authors: Hernandez Frank , Kose Brad W.
Published: April 2011

Principals’ understanding and skills pertaining to diversity are important in leading diverse schools and preparing all students for a democratic and multicultural society. Although educational leadership scholars have theorized about exemplary leadership of and for diversity, a developmental perspective on principals’ diversity or cultural competence remains absent. This conceptual paper argues that the Developmental Model of Intercultural Sensitivity (DMIS) offers a powerful theory for understanding how principals may experience and interpret issues of difference and diversity in schools. After highlighting key aspects of the DMIS, hypothetical examples of principal interpretations and actions to a racial/ethnic achievement gap are provided. Finally, implications for principal preparation, practice, and research are discussed.
Understanding Institutional Change in Project-Based Organizing
Authors: Holti Richard
Published: April 2011

This article concerns what is involved in breaking out of entrenched adversarial models for running interorganizational projects within the construction sector. It presents data from two case studies that sought to establish a more collaborative project model. Drawing on literatures about institutional change and interorganizational collaboration, the analysis indicates the importance of three kinds of activities. First, it is possible to mobilize potential for change present within existing institutionalized models by selecting a kernel of participating organizations known to have the capabilities to operationalize collaboration. Second, adopting techniques for working together that make explicit the need to balance project objectives with organizational-level commercial viability leads to the enactment of routines through which a wider pool of project participants can develop a sense of competence and confidence in collaboration. Third, there is a necessity to preserve a unified system of authority within the project that ensures adherence to collaborative routines, although otherwise encouraging autonomy in decision making.
Economic Hardship and Depression across the Life Course
Authors: Levecque Katia , Van Rossem Ronan , De Boyser Katrien , Van de Velde Sarah , Bracke Piet
Published: April 2011

Previous research in the United States suggests that depression related to economic hardship decreases with age. We test whether this pattern can be generalized to other developed nations. Based on data from 23 countries in the European Social Survey (2006–2007), multilevel analyses show that the moderating role of age depends on the socio-political context. While the hardship–depression link is not significantly different across the life course in Nordic and Bismarckian regimes, the hardship–depression link increases with age in Southern and Eastern European countries and decreases with age in strength in Anglo-Saxon welfare states. Our findings suggest that welfare state regimes play a significant role in attenuating, boosting, or even reversing the health effects of social experiences such as economic hardship on aging. Health knowledge gained through research that ignores the socio-political context may be limited in terms of generalization.
Mobilizing in Borderline Citizenship Regimes: A Comparative Analysis of Undocumented Migrants’ Collective Actions
Authors: Monforte Pierre , Dufour Pascale
Published: April 2011

This article seeks to explain how and why groups and networks of undocumented migrants mobilizing in Berlin, Montréal, and Paris since the beginning of the 2000s construct different types of claims. The authors explore the relationship between undocumented migrants and state authorities at the local level through the concept of the citizenship regime and its specific application to undocumented migrants (which they describe as the “borderline citizenship regime”). Despite their common formal exclusion from citizenship, nonstatus migrants experience different degrees and forms of exclusion in their daily lives, in terms of access to certain rights and services, recognition, and belonging within the state (whether through formally or nonformally recognized means). As a result, they have an opportunity to create different, specific forms of leeway in the society in which they live. The concurrence of these different degrees of exclusion and different forms of leeway defines specific conditions of mobilization. The authors demonstrate how the content of their claims is influenced by these conditions of mobilization.
Novel instrumentation for measurement of relative intensity noise
Authors: Vaezi-Nejad SM , Cox M , Cooper N
Published: April 2011

Laser diode relative intensity noise (RIN) metrology capabilities have been developed and demonstrated, providing significantly improved sensitivity and accuracy compared with existing methods. The novel use of the demonstrated reference noise source has shown significant advantages, achieving improved sensitivity, reducing measurement accuracy as low as ±1 dB and simplifying the system calibration methodology, thus improving flexibility. Laser RINs of between 10 and 14 dB below the shot RIN have been shown (typically −170 dBm/Hz), which is a direct result of the improved system sensitivity. A neodinium yag 1319-nm ring laser provided a ‘cold’ reference source, in a similar manner to that used in RF electrical metrology. Application of the ‘flat’ low noise optical RF noise source from 10 MHz to 20 GHz has been demonstrated for the first time in optical RF metrology, providing a calculable reference traceable via the incident optical power received. Because of the simplistic nature of this approach, system calibration can be performed for each RIN measurement that is carried out, reducing measurement uncertainty associated with RF mismatch, system linearity and loss. High specification components have been assessed individually and in the combined system indicating an overall system noise figure of 2–3 dB over the 10 MHz to 20 GHz frequency range (−171 to −172 dBm), some 4–5 dB better than previously reported.