bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rho family GTPase inhibition reveals opposing effects of mitogen‐activated protein kinase kinase/extracellular signal‐regulated kinase and Janus kinase/signal transducer and activator of transcription signaling cascades on neuronal survival
Authors: Loucks F. Alexandra , Le Shoshona S. , Zimmermann Angela K. , Ryan Kristen R. , Barth Holger , Aktories Klaus , Linseman Daniel A. 
Published: April 2006

AbstractRho family GTPases promote the survival of certain neuronal populations. However, pro‐survival and pro‐death signaling pathways regulated downstream of Rho GTPases are largely unknown. Cerebellar granule neurons (CGNs) exposed to Clostridium difficile toxin B (ToxB), a monoglucosyltransferase that specifically inhibits Rho GTPases, die by a mitochondrial apoptotic cascade. Using a high‐throughput immunoblotting screen (BD Powerblot), we found that ToxB markedly reduced the expression of Rac1 and c‐Raf, upstream components of a Rac‐dependent mitogen‐activated protein (MAP) kinase pathway. Moreover, ToxB rapidly suppressed a p21‐activated kinase/MAP kinase kinase (MEK)/extracellular signal‐regulated kinase (ERK)1/2 signaling cascade that normally promotes degradation of the Bcl‐2 homology‐3 (BH3)‐only protein Bim, a key initiator of mitochondrial apoptosis. In contrast to c‐Raf down‐regulation, ToxB enhanced expression of the transcription factor, signal transducer and activator of transcription‐1 (STAT1). Both STAT1 up‐regulation and apoptosis induced by ToxB were prevented by a pan‐inhibitor of Janus kinases (JAKs), indicating that JAK/STAT signaling was pro‐apoptotic in CGNs. Most significantly, direct inhibition of MEK was sufficient to trigger JAK‐dependent STAT1 expression, suggesting that cross‐talk between MEK/ERK and JAK/STAT pathways plays a key role in regulating neuronal survival. Finally, ERK dephosphorylation and STAT1 up‐regulation induced by ToxB were mimicked by a dominant‐negative (N17) mutant of Rac1. These data suggest that the MEK/ERK cascade functions downstream of Rac GTPase to actively repress pro‐apoptotic JAK/STAT signaling in healthy CGNs.
A yeast 2‐hybrid analysis of human GTP cyclohydrolase I protein interactions
Authors: Swick Lance , Kapatos Gregory 
Published: April 2006

AbstractThe yeast 2‐hybrid system was used to identify protein domains involved in the oligomerization of human guanosine 5′‐triphosphate (GTP) Cyclohydrolase I (GCH1) and the interaction of GCH1 with its regulatory partner, GCH1 feedback regulatory protein (GFRP). When interpreted within the structural framework derived from crystallography, our results indicate that the GCH1 N‐terminal α‐helices are not the only domains involved in the formation of dimers from monomers and also suggest an important role for the C‐terminal α‐helix in the assembly of dimers to form decamers. Moreover, a previously unknown role of the extended N‐terminal α–helix in the interaction of GCH1 and GFRP was revealed. To discover novel GCH1 protein binding partners, we used the yeast 2‐hybrid system to screen a human brain library with GCH1 N‐terminal amino acids 1–96 as prey. This protruding extension of GCH1 contains two canonical Type‐I Src homology‐3 (SH3) ligand domains located within amino acids 1–42. Our screen yielded seven unique clones that were subsequently shown to require amino acids 1–42 for binding to GCH1. The interaction of one of these clones, Activator of Heat Shock 90 kDa Protein (Aha1), with GCH1 was validated by glutathione‐s‐transferase (GST) pull‐down assay. Although the physiological relevance of the Aha1–GCH1 interaction requires further study, Aha1 may recruit GCH1 into the endothelial nitric oxide synthase/heat shock protein (eNOS/Hsp90) complex to support changes in endothelial nitric oxide production through the local synthesis of BH4.
Cannabinoid modulation of electrically evoked pH and oxygen transients in the nucleus accumbens of awake rats
Authors: Cheer Joseph F. , Wassum Kate M. , Wightman R. Mark 
Published: April 2006

AbstractCannabinoid receptors have been implicated in the regulation of blood flow in the cerebral vasculature. Because the nucleus accumbens (NAc) shows high levels of central cannabinoid receptor 1 (CB1) expression we examined the effects of cannabinoids on the local transient alkaline shifts and increases in extracellular oxygen induced by electrical stimulation of the medial forebrain bundle (MFB) in conscious animals. These changes result from increases in cerebral blood flow (CBF) and metabolism in the NAc that are evoked by the stimulation. Oxygen and pH changes were monitored using fast‐scan cyclic voltammetry at carbon‐fiber microelectrodes in the NAc of freely moving rats. Administration of the cannabinoid receptor agonist WIN55,212‐2 potently inhibited extracellular oxygen and pH changes, an effect that was reversed and prevented by pre‐treatment with the CB1receptor antagonists SR141716A and AM251. The effects on pH following WIN55,212‐2 were similar to those following nimodipine, a recognized vasodilator. When AM251 was injected alone, the amplitude of electrically evoked pH shifts was unaffected. Administration of AM404 and VDM11, endocannabinoid transport inhibitors, partially inhibited pH transients in a CB1receptor‐dependent manner. The present findings suggest that CB1receptor activation modulates changes in two well‐established indices of local blood flow and metabolism resulting from electrically evoked activation of ascending fibers. Although endogenous cannabinoid tone alone is not sufficient to modify these responses, uptake blockade demonstrates that the system has the potential to exert CB1‐specific effects similar to those of full agonists.
Non‐steroidal anti‐inflammatory drug‐related hepatic damage in France and Spain: analysis from national spontaneous reporting systems
Authors: Lapeyre‐Mestre Maryse , De Castro Ana Maria Rueda , Bareille Marie‐Pierre , Pozo Javier Garcia del , Requejo Ana Alvarez , Arias Louis Martin , Montastruc Jean‐Louis , Carvajal Alfonso 
Published: April 2006

AbstractSeveral non‐steroidal anti‐inflammatory drugs (NSAIDs) have been associated with liver damage. The aim of this study was to compare proportions of hepatic adverse drug reaction reports associated with NSAIDs in France and Spain. Information from the Spanish and French pharmacovigilance databases were used from 1982 to 2001. To assess the risk of liver injury, the case/non‐case methodology was applied, ‘cases’ being reports of liver damage and ‘non‐cases’ or controls, all other reports. Exposure was considered as the presence of at least one NSAID. Liver injury risk was estimated for each drug in the two databases by calculation of reporting odds ratio in cases and non‐cases, with its 95% confidence interval. Out of 62 456 reports from the Spanish database, 2114 (3.38%) were identified as liver injuries, whereas there were 27 372 liver injuries out of 200 046 (13.68%) in the French database. In Spain, there was a significant association between liver injuries and droxicam, sulindac, and nimesulide. The risk was also slightly above 1 for aceclofenac. In France, the risk was very high with clometacin, followed by sulindac, and was slightly above 1 for naproxen, diclofenac, piroxicam, and tenoxicam. This study shows that some NSAIDs are associated with reports of hepatic injuries when compared with other drugs, and most of those have been withdrawn from the market for this reason. However, the frequency of drug‐related hepatic injuries reported differed in the French and Spanish databases, and some drugs did not show the same risk level in the two countries. These discrepancies could be explained in part not only by reporting rates, but also by difference in drug use patterns and/or by genetic or environmental factors.
Haloperidol in the Acute Treatment of Migraine: A Randomized, Double‐Blind, Placebo‐Controlled Study
Authors: Honkaniemi Jari , Liimatainen Suvi , Rainesalo Sirpa , Sulavuori Sari 
Published: April 2006

Objective.—To assess the efficacy and safety of IV haloperidol in treatment of acute migraine headache in a double‐blind, randomized, placebo‐controlled study design.Background.—Neuroleptics are mainly used as antiemetics in acute migraine. In a previous open trial haloperidol was effective in relieving migraine pain.Design.—Patients were randomized into 2 groups receiving intravenously either 5 mg haloperidol in 500 mL of normal saline or 500 mL of normal saline alone. Pain was assessed by visual analogue scale (VAS) before and 1 to 3 hours after the infusion. If the patient felt no relief in pain intensity 1 to 3 hours after the infusion and had received placebo, he/she then received haloperidol infusion as an open trial. The open trial also included 7 patients who refused from the placebo‐controlled trial. About 1 month after the infusion the patients were contacted by telephone and interviewed about the side effects of the treatment.Results.—Forty patients were enrolled into the double‐blind, placebo‐controlled study. Before the infusion the VAS values were 7.7 in the haloperidol and 7.2 in the placebo group. After the infusion the VAS values were 2.2 in the haloperidol and 6.3 in the placebo group (P < .0001). Significant pain relief was achieved in 80% of the patients treated with haloperidol, whereas only 3 patients (15%) responded to placebo (P < .0001). Seventeen patients treated with placebo without response together with 7 patients who refused from the placebo‐controlled study participated in the open trial. In this group VAS declined from 6.7 to 2.4 and 79% of these patients felt significant pain relief. The most common side effects caused by haloperidol were sedation and akathisia, the latter being more troublesome. These effects were very common in patients participating in the double‐blind (80%) and open (88%) trials. Sixteen percent of the patients considered the side effects intolerable and would not like the migraine attacks to be treated with haloperidol in the future. Three patients (7%) returned to the emergency ward because of a relapse.Conclusions.—This study shows that IV haloperidol is very effective in relieving migraine‐associated pain. Because the majority of the patients had taken other medication without response, haloperidol appears to be an effective rescue medication even when other types of treatment have failed. Relapses are rare, but side effects are common, limiting the use of haloperidol in some patients.
Migraine Care Among Different Ethnicities: Do Disparities Exist?
Authors: Nicholson Robert A. , Rooney Megan , Vo Kelly , O'Laughlin Erinn , Gordon Melanie 
Published: April 2006

Objective.—Evaluate whether, in a primary care setting, Caucasians (C) and African Americans (AA) with moderately to severely disabling migraines differed in regards to: utilizing the health‐care system for migraine care, migraine diagnosis and treatment, level of mistrust in the health‐care system, perceived communication with their physician, and perceived migraine triggers.Background.—Research has documented ethnic disparities in pain management. However, almost no research has been published concerning potential disparities in utilization, diagnosis, and/or treatment of migraine. It is also important to consider whether ethnic differences exist for trust and communication between patients and physicians, as these are essential when diagnosing and treating migraine.Methods.—Adult patients with headache (n = 313) were recruited from primary care waiting rooms. Of these, 131 (AA = 77; C = 54) had migraine, moderate to severe headache‐related disability, and provided socioeconomic status (SES) data. Participants completed measures of migraine disability (MIDAS), migraine health‐care utilization, diagnosis and treatment history, mistrust of the medical community, patient–physician communication (PPC), and migraine triggers. Analysis of covariance (controlling for SES and recruitment site), chi‐square, and Pearson product moment correlations were conducted.Results.—African Americans were less likely to utilize the health‐care setting for migraine treatment (AA = 46% vs. C = 72%, P < .001), to have been given a headache diagnosis (AA = 47% vs. C = 70%, P < .001), and to have been prescribed acute migraine medication (AA = 14% vs. C = 37%, P < .001). Migraine diagnosis was low for both groups, and <15% of all participants had been prescribed a migraine‐specific medication or a migraine preventive medication despite suffering moderate to severe levels of migraine disability. African Americans had less trust in the medical community (P < .001, η2= 0.26) and less positive PPC (P < .001, η2= 0.11). Also, the lower the trust and communication, the less likely they were to have ever seen (or currently be seeing) a doctor for migraine care or to have been prescribed medication.Conclusions.—Migraine utilization, diagnosis, and treatment were low for both groups. However, this was especially true for African Americans, who also reported lower levels of trust and communication with doctors relative to Caucasians. The findings highlight the need for improved physician and patient education about migraine diagnosis and treatment, the importance of cultural variation in pain presentation, and the importance of communication when diagnosing and treating migraine.
No effect of eccentric training on jumper's knee in volleyball players during the competitive season: a randomized clinical trial
Authors: Visnes H. , Hoksrud A. , Cook J. , Bahr R. 
Published: April 2006

BACKGROUND: The effect of surgery on patellar tendinopathy (jumper's knee) is questionable, and conservative treatment protocols have not been properly documented.PURPOSE: The aim of this study was to investigate the effect of a newly developed eccentric training program for patellar tendinopathy in volleyball players during the competitive season.STUDY DESIGN: Randomized clinical trial.METHODS: Patients were recruited from male and female elite volleyball teams in Norway, and the diagnosis was based on clinical examination alone. Of 51 players diagnosed with patellar tendinopathy, 29 could be included in the study. The training group (n=13) performed squats on a 25° decline board as a home exercise program (3 × 15 repetitions twice daily) for a 12‐week intervention period during the final half of the competitive season. The eccentric (downward) component was done on the affected leg. The control group (n=16) trained as usual. The primary outcome was a symptom‐based questionnaire developed specifically for patellar tendinopathy (Victorian Institute of Sport Assessment score), and patients were followed up before and after the intervention period, as well as after 6 and 30 weeks. All subjects self‐recorded training to document their activity level (eccentric training, volleyball training, matches, other training).RESULTS: There was no change in Victorian Institute of Sport Assessment score during the intervention period in the training (pre, 71.1±11.3; post, 70.2±15.4) or control group (pre, 76.4±12.1; post, 75.4±16.7), nor was there any change during the follow‐up period at 6 weeks or 6 months. The training group completed 8.2±4.6 weekly sessions of eccentric training during the intervention period (59% of the recommended volume), and there was no difference between groups in training or competition load.CONCLUSION: There was no effect on knee function from a 12‐week program with eccentric training among a group of volleyball players with patellar tendinopathy who continued to train and compete during the treatment period. Whether the training would be effective if the patients did not participate in sports activity is not known.
Expression of KLF5 is a Prognostic Factor for Disease-Free Survival and Overall Survival in Patients with Breast Cancer
Authors: Tong Dan , Czerwenka Klaus , Heinze Georg , Ryffel Martin , Schuster Eva , Witt Armin , Leodolter Sepp , Zeillinger Robert 
Published: April 2006

Abstract
Purpose: Kruppel-like factor (KLF5) is a cell growth mediator in various epithelial cells. Higher KLF5 increases cell growth rate and leads to transformed phenotypes. Because tumor cell proliferation is tightly associated with tumor progression, and consequently, with survival of cancer patients, we wanted to examine the prognostic value of KLF5 gene expression for patients with breast cancer.
Experimental Design: The gene expression levels of KLF5, ER, PR, HER2, and MKI67 were quantified in the tumor tissues of 90 patients with breast cancer and correlated with disease-free survival and overall survival of the patients. The correlations of gene expression between KLF5 and ER, PR, HER2, and MKI67 were analyzed. In addition, KLF5 expression was also compared with clinical data and age of patients.
Results: Statistically significant correlations were found between gene expression of KLF5 and both disease-free survival (univariate analysis) and overall survival (univariate and multivariate analysis). Patients with higher KLF5 expression had shorter disease-free survival and overall survival time, whereas patients with lower KLF5 expression had better survival. Moreover, KLF5 was also found to be positively correlated with HER2 and MKI67, and negatively correlated with age of the patients at diagnosis.
Conclusion: The gene expression of KLF5 is directly correlated with cell proliferation in vivo and is a prognostic factor for patients with breast cancer. Patients with higher KLF5 expression have shorter disease-free survival and overall survival than patients with lower KLF5 expression. In addition, KLF5 has higher expression in patients ages ≤50 years old than in patients &gt;50 years old.
Systemic Antitumor Effect of Intratumoral Injection of Dendritic Cells in Combination with Local Photodynamic Therapy
Authors: Saji Hisashi , Song Wenru , Furumoto Katsuyoshi , Kato Harubumi , Engleman Edgar G. 
Published: April 2006

AbstractPurpose: Photodynamic therapy (PDT), which is used clinically for the palliative treatment of cancer, induces local tumor cell death but has no effect on tumors in untreated sites. The purpose of this study was to determine if local PDT followed by intratumoral injection of naïve dendritic cells (IT-DC) induces systemic antitumor immunity that can inhibit the growth of untreated as well as PDT + IT-DC–treated tumors.Experimental Design: BALB/c or C57Bl/6 mice were injected s.c. with CT26 colorectal carcinoma cells and B16 melanoma cells, respectively, and following 10 to 12 days of tumor growth, the tumors were treated with PDT alone or PDT followed by IT-DC or IT-PBS. In other studies, tumors were established simultaneously in both lower flanks or in one flank and in the lungs, but only one flank was treated.Results: Whereas neither PDT nor IT-DC alone was effective, PDT + IT-DC eradicated both CT26 and B16 tumors in a significant proportion of animals and prolonged the survival of mice of which the tumors were not cured. The spleens of mice treated with PDT + IT-DC contained tumor-specific cytotoxic and IFN-γ-secreting T cells whereas the spleens of control groups did not. Moreover, adoptive transfer of splenocytes from successfully treated CT26 tumor-free mice protected naïve animals from a subsequent challenge with CT26, and this was mediated mainly by CD8 T cells. Most importantly, PDT plus IT-DC administered to one tumor site led to tumor regression at distant sites, including multiple lung metastases.Conclusions: PDT + IT-DC induces potent systemic antitumor immunity in mice and should be evaluated in the treatment of human cancer.
A Combination of Molecular Markers Accurately Detects Lymph Node Metastasis in Non–Small Cell Lung Cancer Patients
Authors: Xi Liqiang , Coello Michael C. , Litle Virginia R. , Raja Siva , Gooding William E. , Yousem Samuel A. , El-Hefnawy Talal , Landreneau Rodney J. , Luketich James D. , Godfrey Tony E. 
Published: April 2006

AbstractOccult lymph node metastasis (micrometastasis) is a good prognostic indicator in non–small cell lung cancer (NSCLC) and could be used to direct adjuvant chemotherapy in stage I patients. This study was designed to evaluate molecular markers for detection of occult lymph node metastasis in NSCLC, define the best marker or marker combination to distinguish positive from benign lymph nodes, and evaluate these markers in lymph nodes from pathologically node-negative (pN0) NSCLC patients. Potential markers were identified through literature and database searches and all markers were analyzed by quantitative reverse transcription-PCR in a primary screen of six NSCLC specimens and 10 benign nodes. Selected markers were further evaluated on 21 primary NSCLC specimens, 21 positive nodes, and 21 benign nodes, and the best individual markers and combinations were identified. A combination of three markers was further validated on an independent set of 32 benign lymph nodes, 38 histologically positive lymph nodes, and 462 lymph nodes from 68 pN0 NSCLC patients. Forty-two markers were evaluated in the primary screen and eight promising markers were selected for further analysis. A combination of three markers (SFTPB, TACSTD1, and PVA) was identified that provided perfect classification of benign and positive nodes in all sample sets. PVA and SFTPB are particularly powerful in tumors of squamous and adenocarcinoma histologies, respectively, whereas TACSTD1 is a good general marker for NSCLC metastasis. The combination of these genes identified 32 of 462 (7%) lymph nodes from 20 of 68 (29%) patients as potentially positive for occult metastasis. Long-term follow-up will determine the clinical relevance of these findings.
Roles of Nitric Oxide Synthase Inhibition and Vascular Endothelial Growth Factor Receptor-2 Inhibition on Vascular Morphology and Function in anIn vivoModel of Pancreatic Cancer
Authors: Camp E. Ramsay , Yang Anthony , Liu Wenbiao , Fan Fan , Somcio Ray , Hicklin Daniel J. , Ellis Lee M. 
Published: April 2006

AbstractPurpose: Both nitric oxide (NO) and vascular endothelial growth factor (VEGF) mediate tumor vascular function. Because these molecules regulate one another's expression, we hypothesized that NO synthase (NOS) inhibition produces effects comparable to those of anti-VEGF therapy on human pancreatic cancer xenografts.Experimental Design: L3.6pl human pancreatic cancer cells were s.c. implanted in nude mice. On day 6, mice were randomized to receive (a) PBS (control), (b) DC101 [VEGF receptor 2 (VEGFR-2) antibody] by i.p. injection, (c) N-nitro-l-arginine (NNLA; NOS inhibitor) in the drinking water, or (d) both DC101 and NNLA. Mice were killed on day 20.Results: DC101 and NNLA as single agents inhibited tumor growth by ∼50% to 60% (P &lt; 0.008 for both). Furthermore, combined therapy inhibited mean tumor growth by 89% (P &lt; 0.008). Combined inhibition of VEGFR-2 and NOS also decreased mean vessel counts by 65% (P &lt; 0.03) and vessel area by 80% versus controls (P &lt; 0.001). In contrast to DC101 where vessel diameter was similar to control, NNLA decreased mean vessel diameter by 42% (P &lt; 0.001). NNLA also led to a 54% (P &lt; 0.03) decrease in tumor uptake of the perfusion marker Hoechst 33342 versus controls whereas DC101 decreased Hoechst 33342 staining by 43% (P &lt; 0.03). The combination of inhibitors decreased perfusion by 73% (P &lt; 0.03).Conclusions: Although VEGFR-2 can mediate NOS activity, the combination of VEGFR-2 and NOS inhibition significantly increased the antivascular effect over single agent therapy. The addition of NOS inhibition led to an even further alteration of tumor vessel morphology and vascular perfusion compared with VEGFR-2 blockade, suggesting that NO and VEGFR-2 have distinct but complementary effects on the tumor vasculature.