bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antithrombin III (AT) and recombinant tissue plasminogen activator (R-TPA) used singly and in combination versus supportive care for treatment of endotoxin-induced disseminated intravascular coagulation (DIC) in the neonatal pig
Authors: Davis-Jackson Rachel , Correa Hernan , Horswell Ronald , Sadowska-Krowicka Halina , McDonough Kathleen , Debata Chittaranjan , Gardner Renee' , Penn Duna 
Published: May 2006

AbstractBackgroundDisseminated intravascular coagulation (DIC) is a pathological disturbance of the complex balance between coagulation and anticoagulation that is precipitated by vascular injury, acidosis, endotoxin release and/or sepsis and characterized by severe bleeding and excessive clotting. The innately low levels of coagulation factors found in newborn infants place them at extremely high risk for DIC. Anecdotal reports suggest that either anticoagulant or fibrinolytic therapy may alleviate some of the manifestations of DIC. To test the hypothesis that replacement of both anticoagulants and fibrinolytics may improve survival and outcome better than either single agent or supportive care alone, we utilized a neonatal piglet model of endotoxin-induced DIC.MethodsDIC was induced in twenty-seven neonatal pigs (7 to 14 days of age) by intravenous administration of E. coli endotoxin (800 μg/kg over 30 min). The piglets were divided into 4 groups on the basis of treatment protocol [A: supportive care alone; B: Antithrombin III (AT, 50 μg/kg bolus, 25 μg/kg per hr continuous infusion) and supportive care; C: Recombinant Tissue Plasminogen Activator (R-TPA, 25 μg/kg per hr continuous infusion) and supportive care; D: AT, R-TPA and supportive care] and monitored for 3 primary outcome parameters (survival time, macroscopic and microscopic organ involvement) and 4 secondary outcome parameters (hematocrit; platelet count; fibrinogen level; and antithrombin III level).ResultsCompared with supportive care alone, combination therapy with AT and R-TPA resulted in a significant improvement of survival time, hematocrit, AT level, macroscopic and microscopic organ involvement, p < 0.05. Compared with supportive care alone, R-TPA alone significantly reduced macroscopic organ involvement and AT alone increased AT levels.ConclusionThe findings suggest that combining AT, R-TPA and supportive care may prove more advantageous in treating the clinical manifestations of DIC in this neonatal pig model than either single modality or supportive care alone.
An active form of Vav1 induces migration of mammary epithelial cells by stimulating secretion of an epidermal growth factor receptor ligand
Authors: Wilsbacher Julie L , Moores Sheri L , Brugge Joan S 
Published: May 2006

AbstractBackgroundVav proteins are guanine nucleotide exchange factors (GEF) for Rho family GTPases and are activated following engagement of membrane receptors. Overexpression of Vav proteins enhances lamellipodium and ruffle formation, migration, and cell spreading, and augments activation of many downstream signaling proteins like Rac, ERK and Akt. Vav proteins are composed of multiple structural domains that mediate their GEF function and binding interactions with many cellular proteins. In this report we examine the mechanisms responsible for stimulation of cell migration by an activated variant of Vav1 and identify the domains of Vav1 required for this activity.ResultsWe found that expression of an active form of Vav1, Vav1Y3F, in MCF-10A mammary epithelial cells increases cell migration in the absence or presence of EGF. Vav1Y3F was also able to drive Rac1 activation and PAK and ERK phosphorylation in MCF-10A cells in the absence of EGF stimulation. Mutations in the Dbl homology, pleckstrin homology, or cysteine-rich domains of Vav1Y3F abolished Rac1 or ERK activation in the absence of EGF and blocked the migration-promoting activity of Vav1Y3F. In contrast, mutations in the SH2 and C-SH3 domains did not affect Rac activation by Vav1Y3F, but reduced the ability of Vav1Y3F to induce EGF-independent migration and constitutive ERK phosphorylation. EGF-independent migration of MCF-10A cells expressing Vav1Y3F was abolished by treatment of cells with an antibody that prevents ligand binding to the EGF receptor. In addition, conditioned media collected from Vav1Y3F expressing cells stimulated migration of parental MCF-10A cells. Lastly, treatment of cells with the EGF receptor inhibitory antibody blocked the Vav1Y3F-induced, EGF-independent stimulation of ERK phosphorylation, but had no effect on Rac1 activation or PAK phosphorylation.ConclusionOur results indicate that increased migration of active Vav1 expressing cells is dependent on Vav1 GEF activity and secretion of an EGF receptor ligand. In addition, activation of ERK downstream of Vav1 is dependent on autocrine EGF receptor stimulation while active Vav1 can stimulate Rac1 and PAK activation independent of ligand binding to the EGF receptor. Thus, stimulation of migration by activated Vav1 involves both EGF receptor-dependent and independent activities induced through the Rho GEF domain of Vav1.
Analysing the causes of chronic cough: relation to diesel exhaust, ozone, nitrogen oxides, sulphur oxides and other environmental factors
Authors: Groneberg-Kloft Beatrix , Kraus Thomas , Mark Anke van , Wagner Ulrich , Fischer Axel 
Published: May 2006

Abstract
Air pollution remains a leading cause of many respiratory diseases including chronic cough. Although episodes of incidental, dramatic air pollution are relatively rare, current levels of exposure of pollutants in industrialized and developing countries such as total articles, diesel exhaust particles and common cigarette smoke may be responsible for the development of chronic cough both in children and adults. The present study analyses the effects of common environmental factors as potential causes of chronic cough. Different PubMed-based researches were performed that related the term cough to various environmental factors. There is some evidence that chronic inhalation of diesel can lead to the development of cough. For long-term exposure to nitrogen dioxide (NO2), children were found to exhibit increased incidences of chronic cough and decreased lung function parameters. Although a number of studies did not show that outdoor pollution directly causes the development of asthma, they have demonstrated that high levels pollutants and their interaction with sunlight produce ozone (O3) and that repeated exposure to it can lead to chronic cough. In summary, next to the well-known air pollutants which also include particulate matter and sulphur dioxide, a number of other indoor and outdoor pollutants have been demonstrated to cause chronic cough and therefore, environmental factors have to be taken into account as potential initiators of both adult and pediatric chronic cough.
Large-scale and high-confidence proteomic analysis of human seminal plasma
Authors: Pilch Bartosz , Mann Matthias 
Published: May 2006

Abstract
Background
The development of mass spectrometric (MS) techniques now allows the investigation of very complex protein mixtures ranging from subcellular structures to tissues. Body fluids are also popular targets of proteomic analysis because of their potential for biomarker discovery. Seminal plasma has not yet received much attention from the proteomics community but its characterization could provide a future reference for virtually all studies involving human sperm. The fluid is essential for the survival of spermatozoa and their successful journey through the female reproductive tract.

Results
Here we report the high-confidence identification of 923 proteins in seminal fluid from a single individual. Fourier transform MS enabled parts per million mass accuracy, and two consecutive stages of MS fragmentation allowed confident identification of proteins even by single peptides. Analysis with GoMiner annotated two-thirds of the seminal fluid proteome and revealed a large number of extracellular proteins including many proteases. Other proteins originated from male accessory glands and have important roles in spermatozoan survival.

Conclusion
This high-confidence characterization of seminal plasma content provides an inventory of proteins with potential roles in fertilization. When combined with quantitative proteomics methodologies, it should be useful for studies of fertilization, male infertility, and prostatic and testicular cancers.
Immune phenomena involved in the in vivo regression of fibrosarcoma cells expressing cell-associated IL-1α
Authors: Dvorkin Tatyana , Song Xiaoping , Argov Shmuel , White Rosalyn M , Zoller Margot , Segal Shraga , Dinarello Charles A , Voronov Elena , Apte Ron N 
Published: May 2006

Abstract
Constitutive expression of cell-associated, but not secreted, interleukin-1α (IL-1α) by oncogene-transformed fibrosarcoma cells induced regressing tumors in mice, a phenomenon that was abrogated by the IL-1 inhibitor, the IL-1 receptor antagonist (IL-1Ra). On the contrary, non-IL-1α-expressing tumor cells induce progressive tumors in mice. In vivo and ex vivo experiments have shown that regression of IL-1α-positive fibrosarcoma cells depends on CD8+ T cells, which can also be activated in CD4+ T cell-depleted mice, with some contribution of natural killer cells. In spleens of mice bearing the non-IL-1α-expressing fibrosarcoma cells, some early and transient manifestations of antitumor-specific immunity, such as activation of specific proliferating T cells, are evident; however, no development of cytolytic T lymphocytes or other antitumor protective cells could be detected. In spleens of mice bearing the non-IL-1α-expressing fibrosarcoma cells, the development of early tumor-mediated suppression was observed, and in spleens of mice injected with IL-1α-positive fibrosarcoma cells, protective immunity developed in parallel to tumor regression. Treatment of mice bearing violent fibrosarcoma tumors with syngeneic-inactivated, IL-1α-positive fibrosarcoma cells, at a critical interval after injection of the malignant cells (Days 5–12), induced tumor regression, possibly by potentiating and amplifying transient antitumor cell immune responses or by ablation of tumor-mediated suppression. Membrane-associated IL-1α may thus serve as an adhesion molecule, which allows efficient cell-to-cell interactions between the malignant and immune effector cells that bear IL-1Rs and function as a focused cytokine with adjuvant activities at nontoxic, low levels of expression. Our results also point to the potential of using antitumor immunotherapeutic approaches using cell-associated IL-1α.
Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer
Authors: Rose-John Stefan , Scheller Jürgen , Elson Greg , Jones Simon A 
Published: May 2006

Abstract
Cytokine receptors, which exist in membrane-bound and soluble forms, bind their ligands with comparable affinity. Although most soluble receptors are antagonists and compete with their membrane-associated counterparts for the ligands, certain soluble receptors are agonists. In these cases, complexes of ligand and soluble receptor bind on target cells to second receptor subunits and initiate intracellular signaling. The soluble receptors of the interleukin (IL)-6 family of cytokines (sIL-6R, sIL-11R, soluble ciliary neurotrophic factor receptor) are agonists capable of transmitting signals through interaction with the universal signal-transducing receptor for all IL-6 family cytokines, gp130. In vivo, the IL-6/sIL-6R complex stimulates several types of cells, which are unresponsive to IL-6 alone, as they do not express the membrane IL-6R. We have named this process trans-signaling. The generation of soluble cytokine receptors occurs via two distinct mechanisms—limited proteolysis and translation—from differentially spliced mRNA. We have demonstrated that a soluble form of the IL-6 family signaling receptor subunit gp130, which is generated by differential splicing, is the natural inhibitor of IL-6 trans-signaling responses. We have shown that in many chronic inflammatory diseases, including chronic inflammatory bowel disease, peritonitis, rheumatoid arthritis, asthma, as well as colon cancer, IL-6 trans-signaling is critically involved in the maintenance of a disease state, by promoting transition from acute to chronic inflammation. Moreover, in all these models, the course of the disease can be disrupted by specifically interfering with IL-6 trans-signaling using the soluble gp130 protein. The pathophysiological mechanisms by which the IL-6/sIL-6R complex regulates the inflammatory state are discussed.
A novel role for IL-18 in corticosterone-mediated intestinal damage in a two-hit rodent model of alcohol intoxication and injury
Authors: Li Xiaoling , Rana Shadab N , Schwacha Martin G , Chaudry Irshad H , Choudhry Mashkoor A 
Published: May 2006

Abstract
Recent findings from our laboratory have shown that acute alcohol (EtOH) intoxication before burn injury impairs intestinal immunity and barrier functions. To further delineate the mechanism of impaired intestinal barrier function, the present study examined the role of corticosterone (CORT) and interleukin (IL)-18, as CORT and IL-18 are elevated following a combined insult of EtOH intoxication and burn injury. Male rats (∼250 g) were gavaged with EtOH to achieve a blood EtOH level of ∼100 mg/dL prior to burn or sham injury (25% total body surface area). Immediately after injury, a group of rats was treated with CORT synthesis inhibitor metyrapone (25 mg/kg), with or without recombinant (r)IL-18 (50 μg/kg). Another group of rats was treated with caspase-1 inhibitor Ac-YVAD-CHO to block IL-18 production. On Day 1 after injury, there was a significant increase in blood CORT levels, intestinal levels of IL-18, neutrophil chemokines [cytokine-induced neutrophil chemoattractant 1 (CINC-1) and CINC-3], intercellular adhesion molecule-1, myeloperoxidase activity, and intestinal permeability in rats receiving a combined insult of EtOH and burn injury. Treatment of rats with CORT inhibitor or with caspase-1 inhibitor prevented the increase in all of the above parameters following a combined insult of EtOH and burn injury. Moreover, coadministration of rIL-18 in metyrapone-treated rats restored the above parameters, similar to those observed in rats receiving EtOH and burn injury. These findings suggest that a combined insult of EtOH and burn injury results in increased CORT levels, which in turn up-regulates intestinal IL-18 levels and thereby causes altered intestinal barrier function following a combined insult of EtOH intoxication and burn injury.
Phase I Study of EKB-569, an Irreversible Inhibitor of the Epidermal Growth Factor Receptor, in Patients With Advanced Solid Tumors
Authors: Erlichman Charles , Hidalgo Manuel , Boni Joseph P. , Martins Patricia , Quinn Susan E. , Zacharchuk Charles , Amorusi Peter , Adjei Alex A. , Rowinsky Eric K. 
Published: May 2006

PurposeThe maximum tolerated dose (MTD) and the dose-limiting toxicities of EKB-569, a selective, irreversible inhibitor of the epidermal growth factor receptor (EGFR), when administered orally once daily on an intermittent-dose schedule (14 days of a 28-day cycle) or on a continuous-dose schedule (each day of a 28-day cycle), were determined in patients with advanced solid tumors.Patients and MethodsPlanned dose escalation was 25, 50, 75, 125, 175, and 225 mg. Pharmacokinetic sampling was performed on days 1 and 14 for the intermittent-dose cohort and on days 1 and 15 for the continuous-dose cohort.ResultsThirty patients received a median of two cycles (range, one to 10 cycles) in the intermittent-dose cohort; 29 patients received a median of three cycles (range, one to eight cycles) in the continuous-dose cohort. Dose-limiting toxicity was grade 3 diarrhea, and the MTD was 75 mg EKB-569 per day for both cohorts. Other common toxicities included rash, nausea, and asthenia. Exposure to EKB-569 was dose proportional. At the MTD, the mean ± standard deviation terminal half-life was 21.7 ± 4.2 hours and peak concentration increased 1.2-fold from day 1 to day 14/15. No major antitumor responses were observed. However, one patient with non–small-cell lung cancer and one with cutaneous squamous cell carcinoma had stable disease for 33 and 24 weeks, respectively.ConclusionThe MTD of once-daily oral EKB-569 is 75 mg. The tolerable toxicity profile and long half-life of this irreversible EGFR inhibitor warrant its further evaluation as a single agent and in combination with other drugs.
Geriatric Syndromes in Elderly Patients Admitted to an Oncology–Acute Care for Elders Unit
Authors: Flood Kellie L. , Carroll Maria B. , Le Cyndi V. , Ball Linda , Esker Debbie A. , Carr David B. 
Published: May 2006

Purpose The goal of this study was to characterize an elderly population admitted to a novel Oncology–Acute Care for Elders (OACE) unit, determine the prevalence of functional dependencies and geriatric syndromes, and examine their suitability for an interdisciplinary model of care. Patients and Methods We conducted a retrospective review of 119 patients age 65 years or older who had a primary oncologic or hematologic diagnosis and were admitted to the OACE Unit. Standard geriatric screens were administered to assess mood, functional, and cognitive status. Demographic and medical data were compiled by review of patients' medical records. Results The mean age of the patients was 74.1 years (standard deviation, 5.9 years). The sample was predominantly white, of equal sex, had limitations in instrumental and basic activities of daily living, and a mean length of stay of 6 days. Geriatric syndromes detected by the OACE interdisciplinary team included cognitive impairment (dementia and/or delirium), depression, weight loss, and use of high-risk medications. Adverse events such as falls, restraint use, and pressure sores were rare. Conclusion In this descriptive study, many older cancer patients were found to have geriatric syndromes by the OACE team and these patients were considered appropriate for an interdisciplinary model of care. Additional studies are needed to compare the outcomes of hospitalized older oncology patients receiving an OACE intervention with those patients receiving usual care.
Comorbidity, Disability, and Geriatric Syndromes in Elderly Cancer Patients Receiving Home Health Care
Authors: Koroukian Siran M. , Murray Patrick , Madigan Elizabeth 
Published: May 2006

Purpose To assess the prevalence of comorbidity, disability, and geriatric syndromes, or a combination thereof, in elders with cancer receiving home health care (HHC). Patients and Methods Using the Ohio Cancer Incidence Surveillance System, we identified Ohio residents 65 years of age or older who were diagnosed with incident breast (n = 952), prostate (n = 324), or colorectal cancer (n = 1,276) during the 28-month study period, August 1999 through November 2001. We used the Outcome and Assessment Information Set, a database compiling comprehensive assessment forms completed for all HHC patients, to group individuals in independent and overlapping categories of comorbidity, disability, and geriatric syndromes on the basis of the patients' clinical condition 14 days before the date of the assessment. Results The proportion with no comorbidity, disability, or geriatric syndromes was 26.4% in breast cancer patients, 12.0% in prostate cancer patients, and 14.0% in colorectal cancer patients. The proportion of patients presenting all three entities at once was 11.7%, 24.7%, and 15.7%, respectively, in three cancer sites. As expected, the proportion of patients with no comorbidity, disability, or geriatric syndromes declined gradually with increasing age, and that of patients with all three entities was highest among patients 85 years or older. Conclusion The proposed taxonomy will help us gain a more nuanced understanding of older cancer patients' clinical presentation and may lead to a more accurate identification of older patients who might benefit from standard cancer treatment, and those who might experience adverse outcomes.
Immunohistochemical Test for MLH1 and MSH2 Expression Predicts Clinical Outcome in Stage II and III Colorectal Cancer Patients
Authors: Lanza Giovanni , Gafà Roberta , Santini Alessandra , Maestri Iva , Guerzoni Laura , Cavazzini Luigi 
Published: May 2006

Purpose To evaluate the prognostic significance of DNA mismatch repair (MMR) status in a large series of stage II and III colorectal cancer patients. The relationship among MMR status, adjuvant chemotherapy, and clinical outcome was also investigated. Patients and Methods The study included 718 patients with colorectal adenocarcinoma (393 stage II and 325 stage III) who underwent curative surgical resection. MMR status was determined by immunohistochemical analysis of MLH1 and MSH2 expression. Microsatellite instability (MSI) was assessed in 363 patients using mononucleotide and dinucleotide markers. Results One hundred fourteen (15.9%) carcinomas showed abnormal MMR protein (MMRP) expression (96 MLH1 negative and 18 MSH2 negative) and were classified as MMRP negative, whereas 604 tumors demonstrated normal MLH1/MSH2 immunoreactivity (MMRP positive). MLH1/MSH2 expression was closely related to MSI status (P < .001) and several clinicopathologic features. Patients with MMRP-negative carcinomas demonstrated a marked reduction in the risk of cancer-related death with respect to patients with MMRP-positive tumors (hazard ratio, 0.2579; 95% CI, 0.1289 to 0.5159). A better clinical outcome for patients with MMRP-negative tumors was observed in both stage II (P = .0006) and stage III (P = .0052) disease. In stage III disease, the survival advantage conferred by MMRP-negative tumors was more evident among patients treated with surgery alone than among patients who received adjuvant chemotherapy. A nonsignificant trend for survival benefit from adjuvant chemotherapy was observed among patients with MMRP-positive carcinomas but not among those with MMRP-negative carcinomas. Conclusion Immunohistochemical testing for MLH1/MSH2 expression provides useful prognostic information for the management of stage II and III colorectal cancer patients.