bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevention of Chemotherapy-Induced Anemia and Thrombocytopenia by Constant Administration of Stem Cell Factor
Authors: Bartucci Monica , Dattilo Rosanna , Martinetti Daniela , Todaro Matilde , Zapparelli Giuseppina , Di Virgilio Antonio , Biffoni Mauro , De Maria Ruggero , Zeuner Ann 
Published: August 2011

Abstract
Purpose: Chemotherapy-induced apoptosis of immature hematopoietic cells is a major cause of anemia and thrombocytopenia in cancer patients. Although hematopoietic growth factors such as erythropoietin and colony-stimulating factors cannot prevent the occurrence of drug-induced myelosuppression, stem cell factor (SCF) has been previously shown to protect immature erythroid and megakaryocytic cells in vitro from drug-induced apoptosis. However, the effect of SCF in vivo as a single myeloprotective agent has never been elucidated.
Experimental Design: The ability of SCF to prevent the occurrence of chemotherapy-induced anemia and thrombocytopenia was tested in a mouse model of cisplatin-induced myelosuppression. To highlight the importance of maintaining a continuous antiapoptotic signal in immature hematopoietic cells, we compared two treatment schedules: in the first schedule, SCF administration was interrupted during chemotherapy treatment and resumed thereafter, whereas in the second schedule, SCF was administered without interruption for 7 days, including the day of chemotherapy treatment.
Results: The administration of SCF to cisplatin-treated mice could preserve bone marrow integrity, inhibit apoptosis of erythroid and megakaryocytic precursors, prevent chemotherapy-induced anemia, and rapidly restore normal platelet production. Treatment with SCF increased the frequency of Bcl-2/Bcl-XL–positive bone marrow erythroid cells and sustained Akt activation in megakaryocytes. Myeloprotection was observed only when SCF was administered concomitantly with cisplatin and kept constantly present during the days following chemotherapy treatment.
Conclusions: SCF treatment can prevent the occurrence of chemotherapy-induced anemia and thrombocytopenia in mice, indicating a potential use of this cytokine in the supportive therapy of cancer patients. Clin Cancer Res; 17(19); 6185–91. ©2011 AACR.
Variants in Inflammation Genes Are Implicated in Risk of Lung Cancer in Never Smokers Exposed to Second-hand Smoke
Authors: Spitz Margaret R. , Gorlov Ivan P. , Amos Christopher I. , Dong Qiong , Chen Wei , Etzel Carol J. , Gorlova Olga Y. , Chang David W. , Pu Xia , Zhang Di , Wang Liang , Cunningham Julie M. , Yang Ping , Wu Xifeng 
Published: August 2011

Abstract
Lung cancer in lifetime never smokers is distinct from that in smokers, but the role of separate or overlapping carcinogenic pathways has not been explored. We therefore evaluated a comprehensive panel of 11,737 single-nucleotide polymorphisms (SNP) in inflammatory-pathway genes in a discovery phase (451 lung cancer cases, 508 controls from Texas). SNPs that were significant were evaluated in a second external population (303 cases, 311 controls from the Mayo Clinic). An intronic SNP in the ACVR1B gene, rs12809597, was replicated with significance and restricted to those reporting adult exposure to environmental tobacco smoke. Another promising candidate was an SNP in NR4A1, although the replication OR did not achieve statistical significance. ACVR1B belongs to the TGFR-β superfamily, contributing to resolution of inflammation and initiation of airway remodeling. An inflammatory microenvironment (second-hand smoking, asthma, or hay fever) is necessary for risk from these gene variants to be expressed. These findings require further replication, followed by targeted resequencing, and functional validation.
Significance: Beyond passive smoking and family history of lung cancer, little is known about the etiology of lung cancer in lifetime never smokers that accounts for about 15% of all lung cancers in the United States. Our two-stage candidate pathway approach examined a targeted panel of inflammation genes and has identified novel structural variants that appear to contribute to risk in patients who report prior exposure to sidestream smoking. Cancer Discovery; 1(5): 420–9. ©2011 AACR.
This article is highlighted in the In This Issue feature, p. 367
Heme Induces Heme Oxygenase 1 via Nrf2
Authors: Boyle Joseph J. , Johns Michael , Lo Jonathan , Chiodini Alessandra , Ambrose Nicola , Evans Paul C. , Mason Justin C. , Haskard Dorian O. 
Published: August 2011

Objective—
Intraplaque hemorrhage (IPH) is an important progression event in advanced atherosclerosis, in large part because of the delivery of prooxidant hemoglobin in erythrocytes. We have previously defined a novel macrophage phenotype (hemorrhage-associated-mac) in human advanced plaques with IPH. These may be atheroprotective in view of raised heme oxygenase 1 (HO-1), CD163, and interleukin-10 expression and suppressed oxidative stress.

Methods and Results—

We have used a combination of small interfering RNA and pharmacological reagents, protein analysis, and oxidative stress measurements to dissect the pathway leading to the development of this phenotype. We found that erythrocytes, hemoglobin, or purified heme similarly induced CD163 and suppressed human leukocyte antigen and reactive oxygen species. HO-1 was required for the development of each of these features. Challenge of macrophages with purified heme provoked nuclear translocation of Nrf2, and Nrf2 small interfering RNA resulted in significant inhibition of the ability of heme to induce HO-1 protein. Furthermore,
tert
-butyl-hydroquinone, which activates Nrf2, upregulated CD163, suppressed human leukocyte antigen, and induced interleukin-10, further supporting a role for Nrf2-mediated signaling. However, an inducible protein transactivator is also probably necessary, as heme-induced HO-1 mRNA expression was fully inhibited by the protein synthesis inhibitor cycloheximide.

Conclusion—
Our experiments define an Nrf2-mediated pathway by which heme induces a homeostatic macrophage response following IPH.
Cathepsin L Activity Is Essential to Elastase Perfusion–Induced Abdominal Aortic Aneurysms in Mice
Authors: Sun Jiusong , Sukhova Galina K. , Zhang Jie , Chen Han , Sjöberg Sara , Libby Peter , Xiang Meixiang , Wang Jianan , Peters Christoph , Reinheckel Thomas , Shi Guo-Ping 
Published: August 2011

Objective—
The development of abdominal aortic aneurysms (AAA) requires extensive aortic wall matrix degradation. Human AAA lesions express high levels of cathepsin L (CatL), one of the most potent mammalian elastases. Whether this protease participates directly in AAA pathogenesis, however, is unknown.

Methods and Results—

We generated experimental AAA with aortic elastase perfusion in mice and established an essential role of CatL in AAA formation. After 14 days postperfusion, most wild-type (Ctsl
+/+
) mice developed AAA, but none of the CatL-deficient (Ctsl
−/−
) mice did. AAA lesion macrophage contents, CD4
+
T cell numbers, CD31
+
and laminin-5 angiogenic fragment γ2
+
microvessel numbers, and elastin fragmentation were all significantly lower in Ctsl
−/−
mice than in Ctsl
+/+
mice. While lesions from Ctsl
−/−
mice contained fewer Ki67
+
proliferating cells than did Ctsl
+/+
mice, the absence of CatL did not affect lesion apoptotic cell contents or medial smooth-muscle cell loss significantly. Mechanistic studies indicated that the absence of CatL reduced lesion chemokine monocyte chemotactic protein-1 content, macrophage and T-cell in vitro transmigration, and angiogenesis, and altered the expression and activities of matrix metalloproteinases and other cysteinyl cathepsins in inflammatory cells, vascular cells, and AAA lesions.

Conclusion—
CatL contributes to AAA formation by promoting lesion inflammatory cell accumulation, angiogenesis, and protease expression.
Association of Health Professional Shortage Areas and Cardiovascular Risk Factor Prevalence, Awareness, and Control in the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Allen Norrina B. , Diez-Roux Ana , Liu Kiang , Bertoni Alain G. , Szklo Moyses , Daviglus Martha 
Published: August 2011

Background—
Individuals living in primary care health professional shortage areas (PC-HPSA), often have difficulty obtaining medical care; however, no previous studies have examined association of PC-HPSA residence with prevalence of cardiovascular disease risk factors.

Methods and Results—
To examine this question, the authors used data from the Multi-Ethnic Study of Atherosclerosis baseline examination (2000–2002). Outcomes included the prevalence of diabetes, hypertension, hyperlipidemia, smoking, and obesity as well as the awareness and control of diabetes, hypertension, and hyperlipidemia. Multivariable Poisson models were used to examine the independent association of PC-HPSA residence with each outcome. Models were sequentially adjusted for demographics, acculturation, socioeconomic status, access to health care, and neighborhood socioeconomic status. Similar to the national average, 16.7% of Multi-Ethnic Study of Atherosclerosis participants lived in a PC-HPSA. In unadjusted analyses, prevalence rates of diabetes (14.8% versus 11.0%), hypertension (48.2% versus 43.1%), obesity (35.7% versus 31.1%), and smoking (15.5% versus 12.1%) were significantly higher among residents of PC-HPSAs. There were no significant differences in the awareness or control of diabetes, hypertension, or hyperlipidemia. After adjustment, residence in a PC-HPSA was not independently associated with cardiovascular disease risk factor prevalence, awareness, or control.

Conclusions—
This study suggests that increased prevalence of cardiovascular disease risk factors in PC-HPSAs are explained by the demographic and socioeconomic characteristics of their residents. Future interventions aimed at increasing the number of primary care physicians may not improve cardiovascular risk without first addressing other factors underlying health care disparities.
Two-Hour Improvement of Patients in the National Institute of Neurological Disorders and Stroke Trials and Prediction of Final Outcome
Authors: Hemmen Thomas M. , Ernstrom Karin , Raman Rema 
Published: August 2011

Background and Purpose—
Ongoing clinical trials are using early response to intravenous tissue-type plasminogen activator (tPA) to stratify patients into endovascular therapies. Little is known about the likelihood of early recovery and its correlation with final stroke outcome.

Methods—
We analyzed the National Institute of Neurological Disorders and Stroke tPA dataset for patients with early improvement (EI), a change of ≥4, or score 0 on the 2-hour National Institutes of Health Stroke Scale (NIHSS) to predict good 90-day outcome. We adjusted for multiple confounders and divided the patients by baseline NIHSS score 0 to 10, 11 to 20, >20, and stroke type to analyze if EI predicted good outcome across stroke severities and types. We analyzed different EI thresholds to identify the best level of NIHSS change to predict good 90-day outcome using a receiver-operator characteristic curve.

Results—

In total, 183 of 624 (29.3%) patients had EI, 112 of 312 (35.9%) in the tPA group had EI, and 71 of 312 (22.7%) in the placebo group had EI (
P
<0.0001). Smokers (
P
=0.012) and patients treated in <90 minutes (
P
=0.008) were more likely to have EI; diabetic patients (
P
=0.023) were less likely to show EI. The baseline NIHSS (mean±SD) of patients with EI was 16.1±6.5 versus 14.3±7.4 (
P
=0.001). A 90-day modified Rankin Scale score of 0 to 1 was achieved in 68 of 112 (60.7%) tPA-treated patient with EI and 65 of 200 (32.5%) without (placebo groups 30 of 71 [42.3%] versus 53/241 [22.0%]). The adjusted odds ratio for good outcome was 1.71 (95% confidence interval [CI], 1.1–2.6;
P
=0.011) for tPA treatment and 7.69 (95% CI, 4.63–12.76;
P
<0.0001) for early improvement. EI predicted good outcome in patients with cardioembolic (13.6; 95% CI, 3.6–51.5) and small vessel (6.98; 95% CI, 2.86–17.03), but not large vessel stroke (1.82; 95% CI, 0.38–8.59). The receiver-operator characteristic curve showed that a threshold of 4 on the NIHSS for prediction of good outcome had a sensitivity of 84% and 36% specificity.

Conclusions—
Early improvement was more common in tPA-treated patients and was associated with good 90-day outcome. Whereas 32.5% of nonresponders after tPA had a good 90-day outcome, the use of EI to predict stroke outcome shows value.
Safety and Tolerability of Deferoxamine Mesylate in Patients With Acute Intracerebral Hemorrhage
Authors: Selim Magdy , Yeatts Sharon , Goldstein Joshua N. , Gomes Joao , Greenberg Steven , Morgenstern Lewis B. , Schlaug Gottfried , Torbey Michel , Waldman Bonnie , Xi Guohua , Palesch Yuko ,   The Deferoxamine Mesylate in Intracerebral Hemorrhage Investigators
Published: August 2011

Background and Purpose—
Treatment with the iron chelator, deferoxamine mesylate (DFO), improves neurological recovery in animal models of intracerebral hemorrhage (ICH). We aimed to evaluate the feasibility, safety, and tolerability of varying dose-tiers of DFO in patients with spontaneous ICH, and to determine the maximum tolerated dose to be adopted in future efficacy studies.

Methods—
This was a multicenter, phase-I, dose-finding study using the Continual Reassessment Method. DFO was administered by intravenous infusion for 3 consecutive days, starting within 18 hours of ICH onset. Subjects underwent repeated clinical assessments through 90 days, and computed tomography neuroimaging pre- and post-drug-administration.

Results—
Twenty subjects were enrolled onto 5 dose tiers, starting with 7 mg/kg per day and ending with 62 mg/kg per day as the maximum tolerated dose. Median age was 68 years (range, 50–90); 60% were men; and median Glasgow Coma Scale and National Institutes of Health Stroke Scale scores on admission were 15 (5–15) and 9 (0–39), respectively. ICH location was lobar in 40%, deep in 50%, and brain stem in 10%; intraventricular hemorrhage was present in 15%. DFO was discontinued because of adverse events in 2 subjects (10%). Six subjects (30%) experienced 12 serious adverse events, none of which were drug-related. DFO infusions were associated with mild blood-pressure-lowering effects. Fifty percent of patients had modified Rankin scale scores ≤2, and 39% had modified Rankin scale scores of 4 to 6 on day 90; 15% died.

Conclusions—
Consecutive daily infusions of DFO after ICH are feasible, well-tolerated, and not associated with excessive serious adverse events or mortality. Our findings lay the groundwork for future studies to evaluate the efficacy of DFO in ICH.
Higher Incidence of In-Hospital Complications in Patients With Clipped Versus Coiled Ruptured Intracranial Aneurysms
Authors: Vergouwen Mervyn D.I. , Fang Jiming , Casaubon Leanne K. , Stamplecoski Melissa , Robertson Annette , Kapral Moira K. , Silver Frank L. 
Published: August 2011

Background and Purpose—
After aneurysmal subarachnoid hemorrhage (SAH), patients with clipped aneurysms have a higher incidence of neurocognitive deficits and seizures compared with patients with coiled aneurysms. It remains unknown if patients with clipped aneurysms also have a higher incidence of other in-hospital complications.

Methods—
We used data from the Registry of the Canadian Stroke Network on consecutive patients admitted to hospital with aneurysmal SAH. Patients who died within 2 days after admission were excluded. Baseline characteristics, incidence of various in-hospital complications within 30 days after admission, length of stay, poor functional outcome (modified Rankin Scale score at discharge of ≥3), and mortality were compared between patients with clipped versus coiled aneurysms.

Results—

Of the 931 patients, 548 (59%) were clipped and 383 (41%) coiled. Baseline characteristics were similar. Compared with patients with coiled aneurysms, patients with clipped aneurysms had a higher incidence of in-hospital complications (37.2% versus 24.5% of patients;
P
<0.0001), poor functional outcome at discharge (69.4% versus 51.4%;
P
<0.0001), mortality (at discharge: 14.6% versus 9.1%;
P
=0.01), and a longer length of stay (17 [interquartile range, 11 to 29] versus 13 [interquartile range, 7 to 22] days;
P
<0.0001). Higher incidences were observed for urinary tract infection (
P
=0.02), pneumonia (
P
=0.01), cardiac/respiratory arrest (
P
=0.007), seizure (
P
=0.01), and decubitus ulcer (
P
=0.02). Urinary tract infection, pneumonia, cardiac/respiratory arrest, and seizure were independent predictors of poor functional outcome.

Conclusions—
Patients with clipped aneurysms have a higher incidence of in-hospital complications than patients with coiled aneurysms, which attributes to a higher risk of poor functional outcome and death and an increased length of stay.
High Levels of Apolipoprotein B/AI Ratio Are Associated With Intracranial Atherosclerotic Stenosis
Authors: Park Jong-Ho , Hong Keun-Sik , Lee Eun-Ja , Lee Juneyoung , Kim Dong-Eog 
Published: August 2011

Background and Purpose—
The apolipoprotein B (apoB)/apoAI ratio is recognized as a better indicator of cardiovascular disease than other cholesterol measures. Whether intracranial or extracranial atherosclerosis is more closely associated with an increased apoB/apoAI ratio has not been investigated.

Methods—
A total of 464 statin or fibrate naïve Korean patients with acute ischemic stroke was categorized into 3 groups: intracranial (ICAS, n=236), extracranial (n=44), and no cerebral atherosclerotic stenosis (n=184). The apoB/apoAI ratio and demographics, including the presence of metabolic syndrome, were compared among the groups.

Results—

The ICAS group showed a higher apoB/apoAI ratio (0.81±0.02) than both the extracranial atherosclerotic stenosis (0.74±0.03) and no cerebral atherosclerotic stenosis (0.72±0.02) groups (
P
=0.002). The ratio was substantially increased (0.93±0.03) in patients with advanced ICAS (≥3 intracranial stenoses). With a multivariable analysis, the highest apoB/apoAI ratio quartile was an independent predictor of ICAS (OR, 2.13; 95% CI, 1.05 to 4.33). A dose–response relationship was observed between the presence of advanced ICAS and the apoB/apoAI ratio quartiles (OR, 4.03; 95% CI, 1.26 to 12.88 for the second quartile; OR, 4.88; 95% CI, 1.54 to 15.49 for the third quartile; and OR, 7.79; 95% CI, 2.41 to 25.16 for the fourth quartile when referenced to the first quartile). Patients having more metabolic syndrome components were more likely to have ICAS, advanced ICAS, and a higher apoB/apoAI ratio (
P
<0.001 for all).

Conclusions—
A higher apoB/apoAI ratio is a predictor of ICAS rather than of extracranial atherosclerotic stenosis or no cerebral atherosclerotic stenosis. The apoB/apoAI ratio might be a biomarker for ICAS in Asian patients with stroke.
Nicotine Replacement Therapy After Subarachnoid Hemorrhage Is Not Associated With Increased Vasospasm
Authors: Carandang Raphael A. , Barton Bruce , Rordorf Guy A. , Ogilvy Christopher S. , Sims John R. 
Published: August 2011

Background and Purpose—
A significant number of patients with aneurysmal subarachnoid hemorrhage are active smokers and at risk for acute nicotine withdrawal. There is conflicting literature regarding the vascular effects of nicotine and theoretical concern that it may worsen vasospasm. The literature on the safety of nicotine replacement therapy and its effects on vasospasm is limited.

Methods—
A retrospective analysis was conducted of a prospectively collected database of aneurysmal subarachnoid hemorrhage patients admitted to the neurointensive care unit from 1994 to 2008. Paired control subjects matched for age, sex, Fisher score, aneurysm size and number, hypertension, and current medication were analyzed. The primary outcome was clinical and angiographic vasospasm and the secondary outcome was Glasgow Outcome Score on discharge. Conditional logistic models were used to investigate univariate and multivariate relationships between predictors and outcome.

Results—

Two hundred fifty-eight active smoking patients were included of which 87 were treated with transdermal nicotine replacement therapy. Patients were well matched for age, sex, gender, Fisher score, aneurysm size and number, hypertension, and current medications, but patients who received nicotine replacement therapy had less severe Hunt-Hess scores and Glasgow coma scores. There was no difference in angiographic vasospasm, but patients who received nicotine replacement therapy were less likely to have clinical vasospasm (19.5 versus 32.8%;
P
=0.026) and a Glasgow Outcome Score <4 on discharge (62.6% versus 81.6%;
P
=0.005) on multivariate analysis.

Conclusions—
Nicotine replacement therapy was not associated with increased angiographic vasospasm and was associated with less clinical vasospasm and better Glasgow Outcome Score scores on discharge.
Ancrod and Fibrin Formation
Authors: Liu Shuo , Marder Victor J. , Levy David E. , Wang Shur-Jen , Yang Fan , Paganini-Hill Annlia , Fisher Mark J. 
Published: August 2011

Background and Purpose—
Ancrod, derived from Malayan pit viper venom, has been tested as ischemic stroke treatment in clinical trials with inconsistent results. We studied the actions of ancrod on fibrinolysis pathways in patient plasma samples and endothelial cell culture systems.

Methods—
We analyzed fibrinogen levels during the first 6 hours of ancrod infusion in patients entered in the Stroke Treatment with Ancrod Trial. For the in vitro study, human brain microvascular endothelial cells incubated with plasminogen or with human brain microvascular endothelial cell-conditioned medium were co-incubated with ancrod and fibrinogen under normal or oxygen-glucose deprivation conditions over 6 hours.

Results—
Fibrinogen levels decreased both in vivo and in vitro. Ancrod generated fibrinopeptide A, caused visible clot formation, and reduced levels of tissue-type plasminogen activator antigen in the human brain microvascular endothelial cell system and in a cell-free system with conditioned media.

Conclusions—
The in vitro results indicate that ancrod causes local fibrin formation and secondary depletion of tissue-type plasminogen activator by binding to fibrin clot. Ancrod-induced fibrin formation could result in cerebral microvascular occlusion and may explain the suboptimal clinical effects of ancrod in human stroke trials.