bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting Cancer with Bugs and Liposomes: Ready, Aim, Fire
Authors: Cheong Ian , Huang Xin , Thornton Katherine , Diaz Luis A. , Zhou Shibin 
Published: October 2007

AbstractOne of the major challenges facing cancer therapy today is achieving specificity. Current efforts to meet this challenge are focused on developing targeted therapeutics specific to the cancer cell. An alternative approach is to selectively deliver cytotoxic agents to the tumor site. With this end in mind, liposomes optimized for physical robustness have been developed and used clinically as drug delivery vehicles. Paradoxically, the effectiveness of these liposomes is hampered by the suboptimal release of bioavailable drug. This article will highlight the recent advance in using a novel lipase secreted by the tumor-colonizing anaerobic bacterium Clostridium novyi-NT to induce the targeted release of liposomal payloads within tumors. [Cancer Res 2007;67(20):9605–8]
Helper Function of Memory CD8+ T Cells: Heterologous CD8+ T Cells Support the Induction of Therapeutic Cancer Immunity
Authors: Nakamura Yutaro , Watchmaker Payal , Urban Julie , Sheridan Brian , Giermasz Adam , Nishimura Fumihiko , Sasaki Kotaro , Cumberland Rachel , Muthuswamy Ravikumar , Mailliard Robbie B. , Larregina Adriana T. , Falo Louis D. , Gooding William , Storkus Walter J. , Okada Hideho , Hendricks Robert L. , Kalinski Pawel 
Published: October 2007

AbstractIn contrast to the well-established efficacy of preventive vaccines, the effectiveness of therapeutic vaccines remains limited. To develop effective vaccination regimens against cancer, we have analyzed the effect of effector and memory CD8+ T cells on the ability of dendritic cells to mediate the immunologic and antitumor effects of vaccination. We show that in contrast to effector CD8+ T cells that kill antigen-carrying dendritic cells, IFNγ-producing memory CD8+ T cells act as “helper” cells, supporting the ability of dendritic cells to produce interleukin-12 (IL-12) p70. Promoting the interaction of tumor antigen-carrying dendritic cells with memory-type “heterologous” (tumor-irrelevant) CD8+ T cells strongly enhances the IL-12p70-dependent immunogenic and therapeutic effects of vaccination in the animals bearing established tumors. Our data show that the suppressive and helper functions of CD8+ T cells are differentially expressed at different phases of CD8+ T-cell responses. Selective performance of helper functions by memory (in contrast to effector) CD8+ T cells helps to explain the phenomenon of immune memory and facilitates the design of effective therapeutic vaccines against cancer and chronic infections. [Cancer Res 2007;67(20):10012–8
Loss of Hepatocyte Growth Factor/c-Met Signaling Pathway Accelerates Early Stages of N-nitrosodiethylamine–Induced Hepatocarcinogenesis
Authors: Takami Taro , Kaposi-Novak Pal , Uchida Koichi , Gomez-Quiroz Luis E. , Conner Elizabeth A. , Factor Valentina M. , Thorgeirsson Snorri S. 
Published: October 2007

Abstract
Hepatocyte growth factor (HGF) has been reported to have both positive and negative effects on carcinogenesis. Here, we show that the loss of c-Met signaling in hepatocytes enhanced rather than suppressed the early stages of chemical hepatocarcinogenesis. c-Met conditional knockout mice (c-metfl/fl, AlbCre+/−; MetLivKO) treated with N-nitrosodiethylamine developed significantly more and bigger tumors and with a shorter latency compared with control (w/w, AlbCre+/−; Cre-Ctrl) mice. Accelerated tumor development was associated with increased rate of cell proliferation and prolonged activation of epidermal growth factor receptor (EGFR) signaling. MetLivKO livers treated with N-nitrosodiethylamine also displayed elevated lipid peroxidation, decreased ratio of reduced glutathione to oxidized glutathione, and up-regulation of superoxide dismutase 1 and heat shock protein 70, all consistent with increased oxidative stress. Likewise, gene expression profiling done at 3 and 5 months after N-nitrosodiethylamine treatment revealed up-regulation of genes associated with cell proliferation and stress responses in c-Met mutant livers. The negative effects of c-Met deficiency were reversed by chronic p.o. administration of antioxidant N–acetyl–l-cysteine. N–acetyl–l-cysteine blocked the EGFR activation and reduced the N-nitrosodiethylamine–initiated hepatocarcinogenesis to the levels of Cre-Ctrl mice. These results argue that intact HGF/c-Met signaling is essential for maintaining normal redox homeostasis in the liver and has tumor suppressor effect(s) during the early stages of N-nitrosodiethylamine–induced hepatocarcinogenesis. [Cancer Res 2007;67(20):9844–51]
Inhibition of MEK Sensitizes Human Melanoma Cells to Endoplasmic Reticulum Stress-Induced Apoptosis
Authors: Jiang Chen Chen , Chen Li Hua , Gillespie Susan , Wang Yu Fang , Kiejda Kelly A. , Zhang Xu Dong , Hersey Peter 
Published: October 2007

Abstract
Past studies have shown that activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK is a common cause for resistance of melanoma cells to death receptor–mediated or mitochondria-mediated apoptosis. We report in this study that inhibition of the MEK/ERK pathway also sensitizes melanoma cells to endoplasmic reticulum (ER) stress-induced apoptosis, and this is mediated, at least in part, by caspase-4 activation and is associated with inhibition of the ER chaperon glucose-regulated protein 78 (GRP78) expression. Treatment with the ER stress inducer tunicamycin or thapsigargin did not induce significant apoptosis in the majority of melanoma cell lines, but resistance to these agents was reversed by the MEK inhibitor U0126 or MEK1 small interfering RNA (siRNA). Induction of apoptosis by ER stress when MEK was inhibited was caspase dependent with caspase-4, caspase-9, and caspase-3 being involved. Caspase-4 seemed to be the apical caspase in that caspase-4 activation occurred before activation of caspase-9 and caspase-3 and that inhibition of caspase-4 by a specific inhibitor or siRNA blocked activation of caspase-9 and caspase-3, whereas inhibition of caspase-9 or caspase-3 did not inhibit caspase-4 activation. Moreover, overexpression of Bcl-2 inhibited activation of caspase-9 and caspase-3 but had minimal effect on caspase-4 activation. Inhibition of MEK/ERK also resulted in down-regulation of GRP78, which was physically associated with caspase-4, before and after treatment with tunicamycin or thapsigargin. In addition, siRNA knockdown of GRP78 increased ER stress-induced caspase-4 activation and apoptosis. Taken together, these results seem to have important implications for new treatment strategies in melanoma by combinations of agents that induce ER stress and inhibitors of the MEK/ERK pathway. [Cancer Res 2007;67(20):9750–61]
Cdk2 Deficiency Decreases ras/CDK4-Dependent Malignant Progression, but Not myc-Induced Tumorigenesis
Authors: Macias Everardo , Kim Yongbaek , Miliani de Marval Paula L. , Klein-Szanto Andres , Rodriguez-Puebla Marcelo L. 
Published: October 2007

Abstract
We have previously shown that forced expression of CDK4 in mouse skin (K5CDK4 mice) results in increased susceptibility to squamous cell carcinoma (SCC) development in a chemical carcinogenesis protocol. This protocol induces skin papilloma development, causing a selection of cells bearing activating Ha-ras mutations. We have also shown that myc-induced epidermal proliferation and oral tumorigenesis (K5Myc mice) depends on CDK4 expression. Biochemical analysis of K5CDK4 and K5Myc epidermis as well as skin tumors showed that keratinocyte proliferation is mediated by CDK4 sequestration of p27Kip1 and p21Cip1, and activation of CDK2. Here, we studied the role of CDK2 in epithelial tumorigenesis. In normal skin, loss of CDK2 rescues CDK4-induced, but not myc-induced epidermal hyperproliferation. Ablation of CDK2 in K5CDK4 mice results in decreased incidences and multiplicity of skin tumors as well as malignant progression to SCC. Histopathologic analysis showed that K5CDK4 tumors are drastically more aggressive than K5CDK4/CDK2−/− tumors. On the other hand, we show that CDK2 is dispensable for myc-induced tumorigenesis. In contrast to our previous report of K5Myc/CDK4−/−, K5Myc/CDK2−/− mice developed oral tumors with the same frequency as K5Myc mice. Overall, we have established that ras-induced tumors are more susceptible to CDK2 ablation than myc-induced tumors, suggesting that the efficacy of targeting CDK2 in tumor development and malignant progression is dependent on the oncogenic pathway involved. [Cancer Res 2007;67(20):9713–20]
The Original Pathologische Anatomie Leiden-Endothelium Monoclonal Antibody Recognizes a Vascular Endothelial Growth Factor–Binding Site within Neuropilin-1
Authors: Jaalouk Diana E. , Ozawa Michael G. , Sun Jessica , Lahdenranta Johanna , Schlingemann Reinier O. , Pasqualini Renata , Arap Wadih 
Published: October 2007

Abstract
For two decades, the antigen recognized by the Pathologische Anatomie Leiden-Endothelium (PAL-E) monoclonal antibody, a standard vascular endothelial cell marker, has remained elusive. Here, we used a combinatorial phage display–based approach (“epitope mapping”) to select peptides binding to the original PAL-E antibody. We found that a subset of the selected panel of peptides had motifs with strong homology to an exposed site within the b1 domain of human neuropilin-1 (NRP-1). We confirmed peptide binding by ELISA and by surface plasmon resonance. We also showed that the PAL-E antigen colocalizes with NRP-1 staining in endothelial cells. Crystal structure of the b1 domain in NRP-1 suggests that the PAL-E binding site overlaps with a vascular endothelial growth factor (VEGF) binding site. Taken together, these results indicate that NRP-1 is an endothelial cell antigen recognized by the true PAL-E antibody. The consistent biochemical, morphologic, and functional features between the PAL-E antigen and NRP-1 support our interpretation. Given that NRP-1 is a VEGF receptor, these results explain the attributes of the PAL-E antibody as a marker of vascular permeability and angiogenesis. [Cancer Res 2007;67(20):9623–9]
Supporting the Systematic Assessment of Clinical Processes: the MedFlow Method
Authors: Chimiak-Opoka J. , Ammenwerth E. , Saboor S. 
Published: October 2007

Summary

Objectives:
Healthcare is characterized by complex cooperation between highly specialized healthcare departments. This often leads to inefficient clinical processes. In orderto improve these processes, a systematic assessment method is needed. Such methods are still missing. The objective of this paper is to propose and evaluate a method to support the systematic and semi-automatic assessment of clinical processes, with special focus on the quality of information logistics.

Methods:
Criteria for the quality of information logistics were collected based on literature research and system analysis. Appropriate quality checks for these criteria were developed. An extended process modelling notation was developed. The method was evaluated in a pilot study.

Results:
An own model integrates four sub-models with each concentrating on distinct process aspects (i.e., control flow, data flow, tool usage, organizational information). In orderto assess the quality of a process, selected process details are combined in “views”. Weak points are then detected by applying specific rule-sets on these views. Each rule-set represents a pattern of critical cross-points which are searched for in the appropriate view-matrix. The MedFlow method was evaluated in a first pilot study in radiological departments – applying quality checks for the detection of e.g. media cracks or testing the transcription of information objects.

Conclusion:
The MedFlow method is best used to assess clinical processes regarding their control flow and information handling. The latter directly influences the quality of communication and thusthe quality of whole processes. However, this must be evaluated in further studies.
Large Histological Serial Sections for Computational Tissue Volume Reconstruction
Authors: Scherf N. , Einenkel J. , Horn L.-C. , Wentzensen N. , Loeffler M. , Kuska J.-P. , Braumann U.-D. 
Published: October 2007

Summary

Objectives:
A proof of principle study was conducted for microscopic tissue volume reconstructions using a new image processing chain operating on alternately stained large histological serial sections.

Methods:
Digital histological images were obtained from conventional brightfield transmitted light microscopy. A powerful nonparametric nonlinear optical flow-based registration approach was used. In order to apply a simple but computationally feasible sum-of-squared-differences similarity measure even in case of differing histological stainings, a new consistent tissue segmentation procedure was placed upstream.

Results:
Two reconstructions from uterine cervix carcinoma specimen were accomplished, one alternately stained with p16INK4a (surrogate tumor marker) and H&amp;E (routine reference), and another with three different alternate stainings, H&amp;E, p16INK4a, and CD3 (a T-lymphocyte marker). For both cases, due to our segmentation-based reference-free nonlinear registration procedure, resulting tissue reconstructions exhibit utmost smooth image-to-image transitions without impairing warpings.

Conclusions:
Our combination of modern nonparametric nonlinear registration and consistent tissue segmentation has turned out to provide a superior tissue reconstruction quality.
Inhibition of microparticle release triggers endothelial cell apoptosis and detachment
Authors: Sturk Augueste , Hau Chi , Nieuwland Rienk , Abid Hussein Mohammed , Böing Anita 
Published: October 2007

SummaryEndothelial cell cultures contain caspase 3-containing microparticles (EMP), which are reported to form during or after cell detachment. We hypothesize that also adherent endothelial cells release EMP, thus protecting these cells from caspase 3 accumulation, detachment and apoptosis. Human umbilical vein endothelial cells (HUVEC) were incubated with and without inhibitors of microparticle release (Y-27632,calpeptin), both in the absence or presence of additional “external stress”, i.e. the apoptotic agent staurosporin (200 nM) or the activating cytokine interleukin (IL)-1α (5 ng/ml). Control cultures contained mainly viable adherent cells and minor fractions of apoptotic detached cells and microparticles in the absence of inhibitors. In the presence of inhibitors, caspase 3 accumulated in adherent cells and detachment tended to increase. During incubation with either staurosporin or IL-1α in the absence of inhibitors of microparticle release, adherent cells remained viable, and detachment and EMP release increased slightly. In the presence of inhibitors, dramatic changes occurred in staurosporin-treated cultures. Caspase 3 accumulated in adherent cells and >90% of the cells detached within 48 hours. In IL-1α-treated cultures no accumulation of caspase 3 was observed in adherent cells, although detachment increased. Scanning electron microscopy studies confirmed the presence of EMP on both adherent and detached cells. Prolonged culture of detached cells indicated a rapid EMP formation as well as some EMP formation at longer culture periods. Inhibition of EMP release causes accumulation of caspase 3 and promotes cell detachment, although the extent depends on the kind of “external stress”. Thus, the release of caspase 3-containing microparticles may contribute to endothelial cell survival.
The influence on INRs and coagulation factors of the time span between blood sample collection and intake of phenprocoumon or acenocoumarol: Consequences for the assessment of the dose
Authors: Hutten Barbara , Péquériaux Nathalie , Haas Fred , Levi Marcel , Sturk Augueste , van Geest-Daalderop Johanna 
Published: October 2007

SummaryManaging treatment with vitamin K antagonists, the prothrombin time (PT),expressed as international normalized ratio (INR), may not represent the INR during the entire 24 hour (h) period, and this variation may be different between long-acting phenprocoumon and short-acting acenocoumarol. For both drugs we investigated the variation in 24 h of the PT/INR, the consequences for the assessment of the doses and which vitamin K-dependent factor causes the daily variation. Patients on self-management took their medication at 6 p.m. and determined their INRs for eight weeks, once a week and three times daily (8.30 a.m., 6 p.m. and 11 p.m., thus 14.5 h, 24 h and 29 h after taking the medication, respectively). Acenocoumarol showed a significant variation in INRs over the 24 h period, with 22 out of 80 INRs >20% lower at 11 p.m. versus 8.30 a.m. Phenprocoumon showed only few variations. Patients managed by the anticoagulation clinic took their medication at 6 p.m. for four weeks and then at 8 a.m. for four weeks, 15 h and 25 h, respectively, before the weekly blood collection. PT/INR and coagulation factorsVII, X and II were determined. With acenocoumarol, taken 25 h before blood collection, the INRs were significantly different compared to 15 h, especially attributed to plasma levels of factorVII. Those on phenprocoumon were equal. These variations of INRs during 24 h may have major effects on the prescribed dose of short-acting vitamin K antagonists, such as acenocoumarol, especially for INRs at the limits of the therapeutic ranges.
Haemophilus somnus activation of brain endothelial cells: Potential role for local cytokine production and thrombosis in central nervous system (CNS) infection
Authors: Behling-Kelly Erica , Kim Kwang , Czuprynski Charles 
Published: October 2007

SummaryThrombotic meningoencephalitis (TME) is a neurological condition in cattle characterized by fibrinopurulent meningitis with hemorrhage, abscess formation and thrombotic vasculitis throughout the central nervous system. The etiologic agent of TME is Haemophilus somnus, a gram-negative pleomorphic coccobacillus. Although the pathogenesis of TME is not well understood, the propensity of H. somnus to cause vasculitis and intravascular thrombosis suggests a critical role for the interactions between the bacteria and endothelial cells in inciting the disease. The goal of this study was to determine if H. somnus elicits an inflammatory and procoagulative response in bovine brain micro- vascular endothelial cells (BBEC) in vitro. We demonstrate that BBEC exposed to H. somnus secrete significant levels of the proinflammatory and procoagulative cytokines TNF-α and IL-1β. BBEC treated with H. somnus also display increased levels of IL-6 mRNA,another cytokine associated with coagulopathy in vivo. H. somnus-treated BBEC exhibited increased procoagulant activity and tissue factor expression and activity,along with a decreased ability to activate protein C and decreased expression of thrombomodulin mRNA. These changes would be expected to promote thrombus formation in vessels of the CNS, and potentially contribute to the pathogenesis of TME.
Heme oxygenase-1 inducer hemin prevents vascular thrombosis
Authors: Desbuards Nicolas , Rochefort Gaël , Schlecht Deborah , Machet Marie-Christine , Halimi Jean-Michel , Eder Véronique , Hyvelin Jean-Marc , Antier Daniel 
Published: October 2007

SummaryHemin is a heme oxygenase-1 (HO-1) inducer which provides endogenous carbon monoxide known for playing roles in cell proliferation,inflammation or aggregation process. The objective of the current study was to examine the effect of prophylactic treatment with hemin in a thrombosis vascular model. Three groups of Wistar rats, control (n=6), hemin (n=6) and hemin+HO-1 inhibitor (n=6), were used for this study. Hemintreated animals received hemin (50 mg/kg/d; I.P.) for seven days and HO-1 inhibitor group received hemin at the same dose and SnPP IX (60 mg/kg/d; I.P.). All animals were exposed to electric stimulation of the left carotid according to Kawasaki’s procedure to induce reproducible thrombus formation. The hemin treatment did not induce blood pressure disturbance. Effects of hemin on vascular thrombosis were quantified by histopathology and its influence on haemostasis was assessed by measuring prothrombin time (PT), activated partial thromboplastin time (APTT) and blood parameters at the end of treatment. The HO-1 mRNA and protein level variation were also checked out. Results showed that chronic treatment with hemin significantly (p<0.01) reduced the vascular occlusion degree when compared to control and hemin SnPP groups with 7.2 ± 4.6 vs. 71.1 ± 14.7 and 74.0 ± 8.8%, respectively. Moreover, we observed significant (p<0.05) perturbations of blood parameters in hemintreated and hemin-SnPP treated rats. Interestingly, hemin treatment did not significantly increase both PT and APTT. Finally, the HO-1 mRNA and protein levels were increased in hemintreated carotid artery. In conclusion, hemin by inducing HO-1 expression may be a preventive agent against clinical disorders associated to an increased risk of thrombosis events and may limit haemorrhagic risks.
The role of heparin and allied compounds in the treatment of sepsis
Authors: Cornet Alexander , Smit Ellen , Beishuizen Albertus , Groeneveld A. B. Johan 
Published: October 2007

SummaryThe crosstalk between coagulation and inflammation and the propensity for microthromboembolic disease during sepsis calls for anticoagulant measures to prevent tissue hypoxygenation and to attenuate organ damage and dysfunction. Only one anticoagulant, recombinant human activated protein C (aPC, drotrecogin-α) has a proven survival benefit when used as an adjunctive therapy for human sepsis, partly because of its anti-inflammatory effect. However, heparin (-like compounds) may exert similar beneficial anti-inflammatory actions as aPC, in spite of the relatively narrow therapeutic window for anticoagulation. This narrative review is based on a Medline search of relevant basic and clinical studies published in English and discusses the potential role of heparin in modulating inflammatory responses in the treatment of animal models and human sepsis and its harmful sequelae. In any case, the results of a metaanalysis based on animal data suggest a potentially life-saving effect of heparin (-like compounds) in the treatment of sepsis.Therefore, a prospective randomized clinical trial is called upon to study effects in human sepsis.