bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Bioluminescent Transposon Reporter-Trap Identifies Tumor-Specific Microenvironment-Induced Promoters in Salmonella for Conditional Bacterial-Based Tumor Therapy
Authors: Flentie Kelly , Kocher Brandon , Gammon Seth T. , Novack Deborah V. , McKinney Jeffrey S. , Piwnica-Worms David 
Published: May 2012

Abstract
Salmonella specifically localize to malignant tumors in vivo, a trait potentially exploitable as a delivery system for cancer therapeutics. To characterize mechanisms and genetic responses of Salmonella during interaction with living neoplastic cells, we custom-designed a promoterless transposon reporter containing bacterial luciferase. Analysis of a library containing 7,400 independent Salmonella transposon insertion mutants in coculture with melanoma or colon carcinoma cells identified five bacterial genes specifically activated by cancer cells: adiY, yohJ, STM1787, STM1791, and STM1793. Experiments linked acidic pH, a common characteristic of the tumor microenvironment, to a strong, specific, and reversible stimulus for activation of these Salmonella genes in vitro and in vivo. Indeed, a Salmonella reporter strain encoding a luciferase transgene regulated by the STM1787 promoter, which contains a tusp motif, showed tumor-induced bioluminescence in vivo. Furthermore, Salmonella expressing Shiga toxin from the STM1787 promoter provided potent and selective antitumor activity in vitro and in vivo, showing the potential for a conditional bacterial-based tumor-specific therapeutic.
Significance: Salmonella, which often encounter acidic environments during classical host infection, may co-opt evolutionarily conserved pathways for tumor colonization in response to the acidic tumor microenvironment. We identified specific promoter sequences that provide a platform for targeted Salmonella-based tumor therapy in vivo. Cancer Discov; 2(7); 624–37. ©2012 AACR.
Read the Commentary on this article by Hoffman, p. 588.
This article is highlighted in the In This Issue feature, p. 569.
Hematopoietic Interferon Regulatory Factor 8-Deficiency Accelerates Atherosclerosis in Mice
Authors: Döring Yvonne , Soehnlein Oliver , Drechsler Maik , Shagdarsuren Erdenechimeg , Chaudhari Sweena M. , Meiler Svenja , Hartwig Helene , Hristov Mihail , Koenen Rory R. , Hieronymus Thomas , Zenke Martin , Weber Christian , Zernecke Alma 
Published: May 2012

Objective—
Inflammatory leukocyte accumulation drives atherosclerosis. Although monocytes/macrophages and polymorphonuclear neutrophilic leukocytes (PMN) contribute to lesion formation, sequelae of myeloproliferative disease remain to be elucidated.

Methods and Results—

We used mice deficient in interferon regulatory factor 8 (IRF8
−/−
) in hematopoietic cells that develop a chronic myelogenous leukemia-like phenotype. Apolipoprotein E-deficient mice reconstituted with IRF8
−/−
or IRF8
−/−
apolipoprotein E-deficient bone marrow displayed an exacerbated atherosclerotic lesion formation compared with controls. The chronic myelogenous leukemia-like phenotype in mice with IRF8
−/−
bone marrow, reflected by an expansion of PMN in the circulation, was associated with an increased lesional accumulation and apoptosis of PMN, and enlarged necrotic cores. IRF8
−/−
compared with IRF8
+/+
PMN displayed unaffected reactive oxygen species formation and discharge of PMN granule components. In contrast, accumulating in equal numbers at sites of inflammation, IRF8
−/−
macrophages were defective in efferocytosis, lipid uptake, and interleukin-10 cytokine production. Importantly, depletion of PMN in low-density lipoprotein receptor or apolipoprotein E-deficient mice with IRF8
−/−
or IRF8
−/−
apolipoprotein E-deficient bone marrow abrogated increased lesion formation.

Conclusion—
These findings indicate that a chronic myelogenous leukemia-like phenotype contributes to accelerated atherosclerosis in mice. Among proatherosclerotic effects of other cell types, this, in part, is linked to an expansion of functionally intact PMN.
Macrophage-Derived Angiopoietin-Like Protein 2 Accelerates Development of Abdominal Aortic Aneurysm
Authors: Tazume Hirokazu , Miyata Keishi , Tian Zhe , Endo Motoyoshi , Horiguchi Haruki , Takahashi Otowa , Horio Eiji , Tsukano Hiroto , Kadomatsu Tsuyoshi , Nakashima Yukiko , Kunitomo Ryuji , Kaneko Yasushi , Moriyama Shuji , Sakaguchi Hisashi , Okamoto Ken , Hara Masahiko , Yoshinaga Takashi , Yoshimura Koichi , Aoki Hiroki , Araki Kimi , Hao Hiroyuki , Kawasuji Michio , Oike Yuichi 
Published: May 2012

Objective—
Recently, we reported that angiopoietin-like protein 2 (Angptl2) functions in various chronic inflammatory diseases. In the present study, we asked whether Angptl2 and its associated chronic inflammation contribute to abdominal aortic aneurysm (AAA).

Methods and Results—

Immunohistochemistry revealed that Angptl2 is abundantly expressed in infiltrating macrophages within the vessel wall of patients with AAA and in a CaCl
2
-induced AAA mouse model. When Angptl2-deficient mice were used in the mouse model, they showed decreased AAA development compared with wild-type mice, as evidenced by reduction in aneurysmal size, less severe destruction of vessel structure, and lower expression of proinflammatory cytokines and matrix metalloproteinase-9. However, no difference in the number of infiltrating macrophages within the aortic aneurysmal vessel wall was observed between genotypes. AAA development was also significantly suppressed in wild-type mice that underwent Angptl2-deficient bone marrow transplantation. Expression levels of proinflammatory cytokines and metalloproteinase-9 in Angptl2-deficient macrophages were significantly decreased, and those decreases were rescued by treatment of Angptl2 deficient macrophages with exogenous Angptl2.

Conclusion—
Macrophage-derived Angptl2 contributes to AAA development by inducing inflammation and degradation of extracellular matrix in the vessel wall, suggesting that targeting the Angptl2-induced inflammatory axis in macrophages could represent a new strategy for AAA therapy.
Serum-Glucocorticoid Regulated Kinase 1 Regulates Alternatively Activated Macrophage Polarization Contributing to Angiotensin II–Induced Inflammation and Cardiac Fibrosis
Authors: Yang Min , Zheng Jiao , Miao Yanjv , Wang Ying , Cui Wei , Guo Jun , Qiu Shulan , Han Yalei , Jia Lixin , Li Huihua , Cheng Jizhong , Du Jie 
Published: May 2012

Objective—
Inflammatory responses play a pivotal role in the pathogenesis of hypertensive cardiac remodeling. Macrophage recruitment and polarization contribute to the development of cardiac fibrosis. Although serum-glucocorticoid regulated kinase 1 (SGK1) is a key mediator of fibrosis, its role in regulating macrophage function leading to cardiac fibrosis has not been investigated. We aimed to determine the mechanism by which SGK1 regulates the cardiac inflammatory process, thus contributing to hypertensive cardiac fibrosis.

Methods and Results—
After angiotensin II infusion in mice, cardiac hypertrophy and fibrosis developed in wild-type but not SGK1 knockout mice, with equal levels of hypertension in both groups. Compared with wild-type hearts, SGK1 knockout hearts showed less infiltration of leukocytes and macrophages. Importantly, SGK1 deficiency led to decreased proportion of alternatively activated (M2) macrophages and increased levels of profibrotic cytokines. Angiotensin II infusion induced phosphorylation and nuclear localization of signal transducer and activator of transcription 3 (STAT3) whereas SGK1 knockout hearts showed this effect attenuated. In a 3-dimensional peptide gel culture, inhibition of STAT3 suppressed differentiation into M2 macrophages. Coculture of macrophages with cardiac fibroblasts in 3-dimensional peptide gel stimulated the expression of α-smooth muscle actin and collagen in cardiac fibroblasts. However, SGK1 knockout mice with macrophage deficiency showed reduced fibroblast-to-myofibroblast transition.

Conclusion—
SGK1 may play an important role in macrophage recruitment and M2 macrophage activation by activating the STAT3 pathway, which leads to angiotensin II–induced cardiac fibrosis.
Interleukin-12p35 Deletion Promotes CD4 T-Cell–Dependent Macrophage Differentiation and Enhances Angiotensin II–Induced Cardiac Fibrosis
Authors: Li Yulin , Zhang Congcong , Wu Yina , Han Yalei , Cui Wei , Jia Lixin , Cai Lun , Cheng Jizhong , Li Huihua , Du Jie 
Published: May 2012

Objective—
Interleukin-12 is essential for the differentiation of naïve T cells into interferon-γ–producing T cells, which regulate inflammatory responses. We investigated this process of regulating hypertension-induced cardiac fibrosis.

Methods and Results—

Mice infused with angiotensin II showed a marked increase in interleukin-12p35 expression in cardiac macrophages. The degree of cardiac fibrosis was significantly enhanced in interleukin-12p35 knockout (p35-KO) mice compared with wild-type (WT) littermates in response to angiotensin II. Fibrotic hearts of p35-KO mice showed increased accumulation of alternatively activated (M2) macrophages and expression of M2 genes such as Arg-1 and Fizz1. Bone marrow–derived macrophages from WT or p35-KO mice did not differ in differentiation in response to angiotensin II treatment; however, in the presence of CD4
+
T cells, macrophages from p35-KO mice differentiated into M2 macrophages and showed elevated expression of transforming growth factor-β. Moreover, CD4
+
T-cell–treated p35-KO macrophages could stimulate cardiac fibroblasts to differentiate into α-smooth muscle actin–positive and collagen I–positive myofibroblasts in 3-dimensional nanofiber gels. Neutralizing antibodies against transforming growth factor-β inhibited myofibroblast formation induced by M2 macrophages.

Conclusion—

Deficiency in interleukin-12p35 regulates angiotensin II–induced cardiac fibrosis by promoting CD4
+
T-cell–dependent differentiation of M2 macrophages and production of transforming growth factor-β.
Stearic Acid Accumulation in Macrophages Induces Toll-Like Receptor 4/2-Independent Inflammation Leading to Endoplasmic Reticulum Stress–Mediated Apoptosis
Authors: Anderson Emily K. , Hill Andrea A. , Hasty Alyssa H. 
Published: May 2012

Objective—
Elevated serum free fatty acid levels are associated with an increased risk of cardiovascular disease and type 2 diabetes mellitus. Macrophages are recruited to atherosclerotic plaques and metabolic tissues during obesity and accumulate lipids, including free fatty acids. We investigated the molecular consequences of intracellular saturated free fatty acid accumulation in macrophages.

Methods and Results—
Previously, we demonstrated that cotreatment of mouse peritoneal macrophages (MPMs) with stearic acid and triacsin C (an inhibitor of long-chain acyl coenzyme A synthetases) results in intracellular free fatty acid accumulation and apoptosis. Here, we used Western blotting analysis, real-time reverse transcription polymerase chain reaction, and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining to assess endoplasmic reticulum (ER) stress, inflammation, and apoptosis in MPMs. Intracellular stearic acid accumulation induces Toll-like receptor 4/2-independent inflammation that results in ER stress–mediated apoptosis of MPMs. Polarization of MPMs to a proinflammatory M1 phenotype increases their susceptibility to inflammation and ER stress, but not apoptosis, in response to cotreatment with stearic acid and triacsin C.

Conclusion—
Intracellular accumulation of stearic acid in MPMs activates inflammatory signaling, leading to ER stress–mediated apoptosis. M1 macrophages are more prone to stearic acid–induced inflammation and ER stress. These same pathways may be activated in macrophages residing in atherosclerotic plaques and metabolic tissues during conditions of obesity and hyperlipidemia.
Poor Prognosis in Warfarin-Associated Intracranial Hemorrhage Despite Anticoagulation Reversal
Authors: Dowlatshahi Dar , Butcher Kenneth S. , Asdaghi Negar , Nahirniak Susan , Bernbaum Manya L. , Giulivi Antonio , Wasserman Jason K. , Poon Man-Chiu , Coutts Shelagh B. 
Published: May 2012

Background and Purpose
Anticoagulant-associated intracranial hemorrhage (aaICH) presents with larger hematoma volumes, higher risk of hematoma expansion, and worse outcome than spontaneous intracranial hemorrhage. Prothrombin complex concentrates (PCCs) are indicated for urgent reversal of anticoagulation after aaICH. Given the lack of randomized controlled trial evidence of efficacy, and the potential for thrombotic complications, we aimed to determine outcomes in patients with aaICH treated with PCC.

Methods
We conducted a prospective multicenter registry of patients treated with PCC for aaICH in Canada. Patients were identified by local blood banks after the release of PCC. A chart review abstracted clinical, imaging, and laboratory data, including thrombotic events after therapy. Hematoma volumes were measured on brain CT scans and primary outcomes were modified Rankin Scale at discharge and in-hospital mortality.

Results
Between 2008 and 2010, 141 patients received PCC for aaICH (71 intraparenchymal hemorrhages). The median age was 78 years (interquartile range, 14), 59.6% were male, and median Glasgow Coma Scale was 14. Median international normalized ratio was 2.6 (interquartile range, 2.0) and median parenchymal hematoma volume was 15.8 mL (interquartile range, 31.8). Median post-PCC therapy international normalized ratio was 1.4: 79.5% of patients had international normalized ratio correction (<1.5) within 1 hour of PCC therapy. Patients with intraparenchymal hemorrhage had an in-hospital mortality rate of 42.3% with median modified Rankin Scale of 5. Significant hematoma expansion occurred in 45.5%. There were 3 confirmed thrombotic complications within 7 days of PCC therapy.

Conclusions
PCC therapy rapidly corrected international normalized ratio in the majority of patients, yet mortality and morbidity rates remained high. Rapid international normalized ratio correction alone may not be sufficient to alter prognosis after aaICH.
Clopidogrel Load for Emboli Reduction in Patients With Symptomatic Carotid Stenosis Undergoing Urgent Carotid Endarterectomy
Authors: Tsivgoulis Georgios , Kerasnoudis Antonios , Krogias Christos , Vadikolias Konstantinos , Meves Saskia H. , Heliopoulos Ioannis , Georgakarakos Efstratios , Piperidou Charitomeni , Alexandrov Andrei V. 
Published: May 2012

Background and Purpose—
Microembolic signals (MES) on transcranial Doppler are an independent risk factor for recurrent stroke in patients with extracranial symptomatic/asymptomatic carotid artery stenosis (CARAS). Clopidogrel load (300 mg) combined with dual antiplatelet therapy has been shown to reduce MES in patients with symptomatic CARAS. We sought to determine feasibility of clopidogrel load in decreasing asymptomatic embolization in patients with symptomatic CARAS undergoing urgent carotid endarterectomy within the first 2 weeks from the index event.

Subjects and Methods—
Consecutive patients with symptomatic CARAS (70%–99%) and presence of MES on 1-hour baseline (<24 hours from the index event) transcranial Doppler monitoring of ipsilateral middle cerebral artery were treated with clopidogrel load followed by clopidogrel (75 mg)±aspirin (100 mg) during the elapsed time period between hospital admission and urgent carotid endarterectomy at 3 tertiary-care stroke centers. Repeat 1-hour transcranial Doppler monitoring was performed the day before surgery. Bleeding complications during surgery and recurrent strokes or transient ischemic attacks during the first month of ictus were prospectively recorded.

Results—

A total of 11 symptomatic CARAS patients (mean age, 66±7 years; 73% men; 64% acute ischemic strokes) were treated with clopidogrel load followed by dual (67%) or single (33%) antiplatelet therapy. MES count was significantly reduced between baseline (median count, 8 MES/h; interquartile range, 6–19) and repeat transcranial Doppler monitoring (0 MES/h; interquartile range, 0–3;
P
=0.003). No bleeding complications, recurrent strokes, or transient ischemic attacks were documented.

Conclusions—
Our pilot observational study provides preliminary nonrandomized data regarding the potential efficacy of clopidogrel load to reduce asymptomatic embolization in patients with symptomatic CARAS before urgent carotid endarterectomy.
Extremes in Otolaryngology Resident Surgical Case Numbers
Authors: Rosenberg Tara L. , Franzese Christine B. 
Published: May 2012

ObjectiveUnderstand (1) significance between minimum, mean, and maximum case numbers for otolaryngology resident surgical procedures; (2) weaknesses of Accreditation Council for Graduate Medical Education (ACGME) resident case log system contributing to inaccurate data/case inflation; and (3) when excessive case load may transform education into service.Study DesignCross‐sectional survey using a national database.SettingAcademic otolaryngology residency programs.Subjects/MethodsReview of otolaryngology resident national data reports from ACGME resident case log system performed from 2004 to 2010. Minimum, mean, standard deviation, and maximum values for total number of resident surgeon cases and for specific surgical procedures were compared. Case unbundling, resident data entry habits, and tracked vs untracked Current Procedural Terminology (CPT) codes were reviewed.ResultsMean total number of resident surgeon cases remained constant (1699.5 ± 424.2 to 1772.2 ± 517). Minimum total number of cases ranged from 730 to 811 (approaching 2 standard deviations below the mean). Zero was reported as the minimum case number for some procedures. Maximum for total number of cases increased (3559 to 4857) and surpassed the mean by 4 to 5 standard deviations. Some procedures have maximums greater than 11 standard deviations above the mean. The authors identified untracked CPT codes and variations in resident case log documentation habits.ConclusionsLarge differences between the minimum, mean, and maximum resident surgeon case numbers exist. Establishing minimum case number requirements for otolaryngology residents should be considered. Educational benefit derived from excessive case load is unclear. Critical examination of the ACGME resident case log system and resident documentation habits is needed to improve accuracy of reporting.
The Effects of Systemic, Topical, and Intralesional Steroid Treatments on Apoptosis Level of Nasal Polyps
Authors: Kapucu Burak , Cekin Engin , Erkul Bulent Evren , Cincik Hakan , Gungor Atila , Berber Ufuk 
Published: May 2012

ObjectiveThe purpose of this study was to compare the apoptotic responses to systemic, topical, and intrapolyp injection of glucocorticoid with no treatment in nasal polyps.Study DesignProspective, randomized controlled study.SettingTertiary training hospital.Subjects and MethodsThe study was performed on 48 patients with nasal polyposis in the Department of Otorhinolaryngology between 2008 and 2009. Patients were assigned to 1 of 4 groups of 12 patients. Group A was treated with oral methylprednisolone 1 mg/kg/d, and the dose was tapered gradually. Group B received 0.3 mL triamcinolone acetonide (40 mg/mL), which was injected into polyp tissue. Group C was treated with topical 55 µg triamcinolone acetonide 2 times daily for 1 month. Group D received no medication. Samples were collected endoscopically after the seventh day for groups A and B, the first month for group C, and the first visit for group D. Apoptotic indexes were determined using the terminal deoxynucleotidyl transferase‐mediated dUTP nick end labeling method.ResultsStatistically significant differences in apoptotic index were found between each steroid‐medicated group and the control group (PD‐A =. 0001; PD‐B =. 003; PD‐C =. 026) and between groups A and C (PA‐C =. 012). Group B did not differ significantly from either group A or C (PA‐B =. 11; PB‐C =. 75).ConclusionsThe apoptotic index in nasal polyps treated with systemic, topical, and intrapolyp injection forms of glucocorticoids was higher than that in the control group. Systemic steroid treatment induced the most apoptosis.
Modeling the tribological abrasive wear behavior of woven composite materials using the planning design experimentation approach
Authors: Zenasni R , Hebbar A , Olay Jaime Vina 
Published: May 2012

This article addresses the experimental characterization of the abrasive wear of two woven fabric carbon fiber and glass fiber composite materials, taking into account the effect of moisture absorption. The composite materials were tested to three level loadings and two sliding speeds. The abrasive used was dry sand of size 0.6 µm, and the time of wear testing was 10 min. In order to study the effects of moisture on wear behavior, another series of samples was introduced into the tank of water during a period of 40 days at ambient temperature. The planning design experimentation approach was applied to obtain a mathematical model taking into account the influencing parameters on the wear behavior of the composites. The wear results have shown that for a higher turn speed and a load, the loss of matter increases. In the case of samples exposed to water absorption, the wear rate increases more than the dry samples. The micrographs of the surface of the samples tested were taken in order to characterize the wear mechanism.
Disparities in Health Status and Health Care Access and Use Among Older American Indians and Alaska Natives and Non-Hispanic Whites in California
Authors: Kim Giyeon , Bryant Ami N. , Goins R. Turner , Worley Courtney B. , Chiriboga David A. 
Published: May 2012

Objectives: The present study compared the characteristics of health status and health care access and use among older American Indians and Alaska Natives (AIANs) to those of non-Hispanic Whites (NHWs). Methods: Data were drawn from the 2009 California Health Interview Survey, with a total of 17,156 adults aged 60 and older (198 AIANs and 16,958 NHWs) analyzed. Results: Older AIANs reported poorer physical and mental health than did NHWs. AIANs were less likely than NHWs to see a medical doctor and have a usual source of medical care and were more likely than NHWs to delay getting needed medical care and report difficulty understanding the doctor at their last visit. Discussion: These findings highlight the vulnerability and unmet health care needs of older AIANs. More research on the older AIAN population is clearly needed to document their health care needs in order to better inform efforts to reduce health disparities.
Impact of Patient and Caregiver Transfer Training Provided by a Physical Therapist in the Hospice Setting
Authors: Turner Fernette , Seiger Cindy , Devine Nancy 
Published: May 2012

Background: As patients in hospice become increasingly dependent upon caregivers, physical therapy interventions can minimize the risk of injury to the patient or caregiver that may occur during transfers between surfaces. Case Description: A 68-year-old male hospice patient was referred to physical therapy for strengthening and transfer training after a fall that resulted in the patient remaining in bed for 5 weeks due to an increased fear of falling. Treatments focused on caregiver training for correct transfer techniques. Outcome: During 10 treatment sessions, the patient and caregiver became independent and safe with all transfers. Although the patient’s health declined, his risk for and fear of falling decreased. Confidence with transfers improved for the patient and caregiver. Discussion: Physical therapy “benefits were immeasurable” for the patient and caregiver by teaching them how to safely perform patient transfers with reduced risk of injury.