bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I Clinical and Pharmacokinetic Study of Kahalalide F Administered Weekly as a 1-Hour Infusion to Patients with Advanced Solid Tumors
Authors: Pardo Beatriz , Paz-Ares Luis , Tabernero Josep , Ciruelos Eva , García Margarita , Salazar Ramón , López Ana , Blanco María , Nieto Antonio , Jimeno José , Izquierdo Miguel Ángel , Trigo José Manuel
Published: February 2008

Purpose: A dose-escalation, phase I study evaluated the safety, pharmacokinetics, and efficacy of a weekly 1-h regimen of kahalalide F, a cyclic depsipeptide isolated from the marine mollusk Elysia rufescens, in adult patients with advanced solid tumors and no standard treatment available.

Experimental Design: Patients received an i.v. 1-h infusion of kahalalide F once weekly until disease progression or unacceptable toxicity. The starting kahalalide F dose was 266 μg/m2, and dose escalation proceeded based on the worst toxicity found in the previous cohort.

Results: Thirty-eight patients were enrolled at three Spanish institutions and received once-weekly kahalalide F 1-h infusions at doses between 266 and 1,200 μg/m2. Dose-limiting toxicities consisted of transient grade 3/4 increases in transaminase blood levels. The maximum tolerated dose for this kahalalide F schedule was 800 μg/m2, and the recommended dose for phase II studies was 650 μg/m2. No accumulated toxicity was found. One patient with malignant melanoma had unconfirmed partial response, one patient with metastatic lung adenocarcinoma had minor response, and six patients with different types of metastatic solid tumors had stable disease for 2.8 to 12.7 months. The noncompartmental pharmacokinetics of this kahalalide F schedule was linear and showed a narrow distribution and short body residence. The transaminitis associated with kahalalide F was dose dependent.

Conclusions: The maximum tolerated dose was 800 μg/m2. Dose-limiting toxicities with weekly kahalalide F 1-h i.v. infusions were transient grade 3/4 increases in blood transaminase levels, and 650 μg/m2 was declared the recommended dose for phase II studies. This schedule showed a favorable safety profile and hints of antitumor activity.
Enhancement of Antitumor Radiation Efficacy and Consistent Induction of the Abscopal Effect in Mice by ECI301, an Active Variant of Macrophage Inflammatory Protein-1α
Authors: Shiraishi Kenshiro , Ishiwata Yoshiro , Nakagawa Keiichi , Yokochi Shoji , Taruki Chiho , Akuta Teruo , Ohtomo Kuni , Matsushima Kouji , Tamatani Takuya , Kanegasaki Shiro
Published: February 2008

Purpose: We studied whether i.v. administration of a chemokine after local tumor site irradiation could prevent remaining, as well as distant, nonirradiated tumor cell growth by leukocyte recruitment.

Experimental Design: Tumors were implanted s.c. in the right or both flanks. After local irradiation at the right flank, ECI301, a human macrophage inflammatory protein-1α variant was injected i.v. Tumor volumes were measured every 3 days after treatment.

Results: In Colon26 adenocarcinoma-bearing BALB/c mice, repeated daily administration (over 3-5 consecutive days) of 2 μg per mouse ECI301 after local irradiation of 6 Gy prolonged survival without significant toxicity, and in about half of the treated mice, the tumor was completely eradicated. Three weekly administrations of ECI301 after local irradiation also led to significant, although less effective, antitumor radiation efficacy. ECI301 also inhibited growth of other syngenic tumor grafts, including MethA fibrosarcoma (BALB/c) and Lewis lung carcinoma (C57BL/6). Importantly, tumor growth at the nonirradiated site was inhibited, indicating that ECI301 potentiated the abscopal effect of radiation. This abscopal effect observed in BALB/c and C57BL/6 mice was tumor-type independent. Leukocyte depletion studies suggest that CD8+ and CD4+ lymphocytes and NK1.1 cells were involved.

Conclusions: Marked inhibition of tumor growth at the irradiated site, with complete tumor eradication and consistent induction of the abscopal effect, was potentiated by i.v. administration of ECI301. The results of this study may offer a new concept for cancer therapy, namely chemokine administration after local irradiation, leading to development of novel therapeutics for the treatment of advanced metastatic cancer.
Adrenocortical carcinoma survival rates correlated to genomic copy number variants
Authors: Stephan Elizabeth A. , Chung Tae-Hoon , Grant Clive S. , Kim Seungchan , Von Hoff Daniel D. , Trent Jeffrey M. , Demeure Michael J.
Published: February 2008

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy accounting for between 0.02% and 0.2% of all cancer deaths. Surgical removal offers the only current potential for cure. Unfortunately, ACC has undergone metastatic spread in 40% to 70% of patients at the time of diagnosis. Standard chemotherapy with mitotane is often ineffective with intolerable side effects. The modern molecular technology of comparative genomic hybridization allows the examination of DNA for chromosomal alterations, which can lend biological insight into cancer processes. Genomes of 25 ACC clinical samples were queried on the Agilent 44K Human Genome comparative genomic hybridization array detecting regions of chromosomal gain and loss within the tumor population. Commonly shared amplifications appearing in ≥50% of tumors at P ≤ 10−4 include regions within chromosomes 5, 7, 12, 16q, and 20. Deleted genomic regions within ACC include portions of chromosomes 1, 3p, 10q, 11, 14q, 15q, 17, and 22q. Genomic aberrations in regions associated with differential survival (P ≤ 0.05) and presence in ≥20% of tumors include amplifications of 6q, 7q, 12q, and 19p. Deletions within stratified survival groups include localized regions within 3, 8, 10p, 16q, 17q, and 19q. Statistical analysis of this genetic landscape reveals a set of chromosomal aberrations strongly associated with survival in an accumulation-dependent fashion. These regions may hold prognostic indicators and offer therapeutic targets that can be used to develop novel treatments for aggressive tumors. [Mol Cancer Ther 2008;7(2):425–31]
A new mechanism of drug resistance in breast cancer cells: fatty acid synthase overexpression-mediated palmitate overproduction
Authors: Liu Hailan , Liu Yang , Zhang Jian-Ting
Published: February 2008

Multidrug resistance is a major problem in successful cancer chemotherapy. Various mechanisms of resistance, such as ABC transporter-mediated drug efflux, have been discovered using established model cancer cell lines. While characterizing a drug-resistant breast cancer cell line, MCF7/AdVp3000, we found that fatty acid synthase (FASN) is overexpressed. In this study, we showed that ectopic overexpression of FASN indeed causes drug resistance and that reducing the FASN expression increased the drug sensitivity in breast cancer cell lines MCF7 and MDA-MB-468 but not in the normal mammary epithelial cell line MCF10A1. Use of FASN inhibitor, Orlistat, at low concentrations also sensitized cells with FASN overexpression to anticancer drugs. The FASN-mediated drug resistance appears to be due to a decrease in drug-induced apoptosis from an overproduction of palmitic acid by FASN. Together with previous findings of FASN as a poor prognosis marker for breast cancer patients, our results suggest that FASN overexpression is a new mechanism of drug resistance and may be an ideal target for chemosensitization in breast cancer chemotherapy. [Mol Cancer Ther 2008;7(2):263–70]
Mesothelin is a malignant factor and therapeutic vaccine target for pancreatic cancer
Authors: Li Min , Bharadwaj Uddalak , Zhang Rongxin , Zhang Sheng , Mu Hong , Fisher William E. , Brunicardi F. Charles , Chen Changyi , Yao Qizhi
Published: February 2008

Given the high fatality rate of pancreatic cancer, an effective treatment for this devastating disease is urgently needed. We have shown that mesothelin expression was higher in human pancreatic cancer cells than in human pancreatic duct epithelial cells, and mesothelin mRNA was substantially overexpressed in 18 of 21 (86%) clinical pancreatic adenocarcinoma specimens when compared with the surrounding normal tissues. However, the biological functions of mesothelin in tumor progression are not clearly understood. Here we studied the effects of mesothelin overexpression in pancreatic cancer cell proliferation and migration in vitro and pancreatic cancer progression in vivo. We found that forced expression of mesothelin significantly increased tumor cell proliferation and migration by 90% and 300%, respectively, and increased tumor volume by 4-fold in the nude mice xenograft model when compared with the vector control cell line. Silencing of mesothelin inhibited cell proliferation and migration in pancreatic cancer cells and ablated tumor progression in vivo. Vaccination with chimeric virus-like particles that contain human mesothelin substantially inhibited tumor progression in C57BL/6J mice. The increases in mesothelin-specific antibodies and CTL activity and the decrease in regulatory T cells correlated with reduced tumor progression and prolonged survival. This study revealed novel functions of mesothelin and suggested a new therapeutic vaccine strategy whereby mesothelin is targeted to control pancreatic cancer progression. [Mol Cancer Ther 2008;7(2):286–96]
6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol, a specific glutathione S-transferase inhibitor, overcomes the multidrug resistance (MDR)-associated protein 1–mediated MDR in small cell lung cancer
Authors: Filomeni Giuseppe , Turella Paola , Dupuis Maria Luisa , Forini Olindo , Ciriolo Maria Rosa , Cianfriglia Maurizio , Pezzola Silvia , Federici Giorgio , Caccuri Anna Maria
Published: February 2008

In the present work, we have investigated the antitumor activity of 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) on aggressive small cell lung cancer. NBDHEX not only is cytotoxic toward the parental small cell lung cancer H69 cell line (LC50 of 2.3 ± 0.6 μmol/L) but also overcomes the multidrug resistance of its variant, H69AR, which overexpresses the ATP-binding cassette transporter multidrug resistance–associated protein 1 (MRP1; LC50 of 4.5 ± 0.9 μmol/L). Drug efflux experiments, done in the presence of a specific inhibitor of MRP1, confirmed that NBDHEX is not a substrate for this export pump. Interestingly, NBDHEX triggers two different types of cell death: a caspase-dependent apoptosis in the H69AR cells and a necrotic phenotype in the parental H69 cells. The apoptotic pathway triggered by NBDHEX in H69AR cells is associated with c-Jun NH2-terminal kinase and c-Jun activation, whereas glutathione oxidation and activation of p38MAPK is observed in the NBDHEX-treated H69 cells. In contrast to the parental cells, the higher propensity to die through apoptosis of the H69AR cell line may be related to the lower expression of the antiapoptotic protein Bcl-2. Therefore, down-regulation of a factor crucial for cell survival makes H69AR cells more sensitive to the cytotoxic action of NBDHEX, which is not a MRP1 substrate. We have previously shown that NBDHEX is cytotoxic toward P-glycoprotein–overexpressing tumor cell lines. Therefore, NBDHEX seems a very promising compound in the search for new molecules able to overcome the ATP-binding cassette family of proteins, one of the major mechanisms of multidrug resistance in cancer cells. [Mol Cancer Ther 2008;7(2):371–9]
CHM-1, a novel synthetic quinolone with potent and selective antimitotic antitumor activity against human hepatocellular carcinoma in vitro and in vivo
Authors: Wang Shih-Wei , Pan Shiow-Lin , Huang Yu-Chun , Guh Jih-Hwa , Chiang Po-Cheng , Huang Der-Yi , Kuo Sheng-Chu , Lee Kuo-Hsiung , Teng Che-Ming
Published: February 2008

Hepatocellular carcinoma is highly chemoresistant to currently available chemotherapeutic agents. In this study, 2′-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone (CHM-1), a synthetic 6,7-substituted 2-phenyl-4-quinolone, was identified as a potent and selective antitumor agent in human hepatocellular carcinoma. CHM-1 induced growth inhibition of HA22T, Hep3B, and HepG2 cells in a concentration-dependent manner but did not obviously impair the viability of normal cells at the IC50 for liver cancer cells. CHM-1-induced apoptosis was also characterized by immunofluorescence microscopy. CHM-1 interacted with tubulin at the colchicine-binding site, markedly inhibited tubulin polymerization both in vitro and in vivo, and disrupted microtubule organization. CHM-1 caused cell cycle arrest at G2-M phase by activating Cdc2/cyclin B1 complex activity. CHM-1-induced cell death, activation of Cdc2 kinase activity, and elevation of MPM2 phosphoepitopes were profoundly attenuated by roscovitine, a specific cyclin-dependent kinase inhibitor. CHM-1 did not modulate the caspase cascade, and the pan-caspase-inhibitor z-VAD-fmk did not abolish CHM-1-induced cell death. However, CHM-1 induced the translocation of apoptosis-inducing factor (AIF) from mitochondria to the nucleus. Small interfering RNA targeting of AIF substantially attenuated CHM-1-induced AIF translocation. Importantly, CHM-1 inhibited tumor growth and prolonged the lifespan in mice inoculated with HA22T cells. In conclusion, we show that CHM-1 exhibits a novel antimitotic antitumor activity against human hepatocellular carcinoma both in vitro and in vivo via a caspase-independent pathway. CHM-1 is a promising chemotherapeutic agent worthy of further development into a clinical trial candidate for treating cancer, especially hepatocellular carcinoma. [Mol Cancer Ther 2008;7(2):350–60]
Growth inhibition by STI571 in combination with radiation in human chronic myelogenous leukemia K562 cells
Authors: Huguet Florence , Giocanti Nicole , Hennequin Christophe , Croisy Martine , Touboul Emmanuel , Favaudon Vincent
Published: February 2008

Altered radiation responses by STI571 (Imatinib, Glivec), a specific inhibitor of the tyrosine kinase activity of Bcr-Abl, was assessed in K562 chronic myelogenous leukemia cells using growth inhibition and colony formation assays. Flow cytometry, Western blotting, and microscope observation were used to determine cell cycle redistribution, erythroid differentiation, apoptosis, necrosis, senescence, and expression and phosphorylation of effectors downstream from Bcr-Abl as endpoints. STI571 (≥24-h contact) retarded the growth of K562 cells and elicited reduction in the G2-phase content due to an efficient arrest in early S phase rather than to the disruption of the G2 checkpoint as confirmed by analysis of Lyn and CDK1 phosphorylation. STI571 brought about the inhibitory dephosphorylation of Bcr-Abl and STAT5, but the expression of DNA-PKcs and Rad51 was unaffected and the interaction between radiation and STI571 was strictly additive with regard to induction of apoptosis. Overall STI571 interacted cooperatively with radiation to retard the growth of K562 cells but did not affect intrinsic radiosensitivity. However, STI571 and radiation acted antagonistically with each other with regard to induction of senescence and erythroid differentiation. [Mol Cancer Ther 2008;7(2):398–406]
Preclinical pharmacokinetic/pharmacodynamic models of gefitinib and the design of equivalent dosing regimens in EGFR wild-type and mutant tumor models
Authors: Wang Shining , Guo Ping , Wang Xiaomin , Zhou Qingyu , Gallo James M.
Published: February 2008

Epidermal growth factor receptor (EGFR) inhibitors, such as gefitinib, are examples of targeted anticancer drugs whose drug sensitivity is related to gene mutations that adds a pharmacogenetic (PG) dimension to any pharmacokinetic (PK) and pharmacodynamic (PD) analysis. The goal of this investigation was to cast the combined PG/PK/PD variables into models that could be used to design equivalent PK/PD dosing regimens for gefitinib in genetically distinct tumor models. To this end, groups of mice bearing either s.c. LN229-wild-type EGFR or LN229-EGFRvIII mutant tumors, an EGFR inhibitor-sensitizing mutation, were given gefitinib at doses of 10 mg/kg i.v., 50 mg/kg intraarterially, and 150 mg/kg p.o. In each group, gefitinib plasma and tumor concentrations were quantitated, as were tumoral amounts of phosphorylated extracellular signal-regulated kinase (ERK) 1/2 (pERK), a PD end point that was shown to respond in a dose-dependent manner in each tumor type. Hybrid physiologically based PK/PD models were developed for each tumor type, which consisted of a forcing function describing the plasma drug concentration profile, a tumor compartment depicting drug disposition in tumor, and a mechanistic target-response PD model characterizing pERK in the tumor. Gefitinib showed analogous PK properties in each tumor type yet different PD characteristics consistent with the EGFR status of the tumors. Using the PK/PD model for each tumor type, simulations were done to define multiple-dose regimens for gefitinib that yielded equivalent PD profiles of pERK in each tumor type. The novel concept of PK/PD equivalent dosing regimens could be applied in drug development and to delineate PG differences in drug activity. [Mol Cancer Ther 2008;7(2):407–17]
Regulation of GST-MDA-7 toxicity in human glioblastoma cells by ERBB1, ERK1/2, PI3K, and JNK1-3 pathway signaling
Authors: Yacoub Adly , Gupta Pankaj , Park Margaret A. , Rhamani Mohammed , Hamed Hossein , Hanna David , Zhang Guo , Sarkar Devanand , Lebedeva Irina V. , Emdad Luni , Koumenis Costas , Curiel David T. , Grant Steven , Fisher Paul B. , Dent Paul
Published: February 2008

The present studies defined the biological effects of a GST fusion protein of melanoma differentiation-associated gene-7 (mda-7), GST-MDA-7 (1 and 30 nmol/L), on cell survival and cell signaling in primary human glioma cells in vitro. GST-MDA-7, in a dose- and time-dependent fashion killed glioma cells with diverse genetic characteristics; 1 nmol/L caused arrest without death, whereas 30 nmol/L caused arrest and killing after exposure. Combined inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT function was required to enhance 1 nmol/L GST-MDA-7 lethality in all cell types, whereas combined activation of MEK1 and AKT was required to suppress 30 nmol/L GST-MDA-7 lethality; both effects are mediated in part by modulating c-Jun NH2-terminal kinase (JNK) 1-3 activity. The geldanamycin 17AAG inhibited AKT and ERK1/2 in GBM cells and enhanced GST-MDA-7 lethality. JNK1-3 signaling promoted BAX activation and mitochondrial dysfunction. In GBM6 cells, GST-MDA-7 (30 nmol/L) transiently activated p38 mitogen-activated protein kinase, which was modestly protective against JNK1-3-induced toxicity, whereas GST-MDA-7 (300 nmol/L) caused prolonged intense p38 mitogen-activated protein kinase activation, which promoted cell death. In GBM12 cells that express full-length mutant activated ERBB1, inhibition of ERBB1 did not modify GST-MDA-7 lethality; however, in U118 established glioma cells, stable overexpression of wild-type ERBB1 and/or truncated active ERBB1vIII suppressed GST-MDA-7 lethality. Our data argue that combined inhibition of ERK1/2 and AKT function, regardless of genetic background, promotes MDA-7 lethality in human primary human glioma cells via JNK1-3 signaling and is likely to represent a more ubiquitous approach to enhancing MDA-7 toxicity in this cell type than inhibition of ERBB1 function. [Mol Cancer Ther 2008;7(2):314–29]
Formal Operations from a Twenty-First Century Perspective
Authors: Kuhn Deanna
Published: February 2008

The author reflects on Piaget’s 1972 article, ‘Intellectual evolution from adolescence to adulthood,’ addressed to questions regarding what he alleged to be the final, most advanced level of cognition in his developmental stage theory – formal operations, as described in his 1958 volume coauthored with Inhelder, The growth of logical thinking from childhood to adolescence. It is asked here whether, from a contemporary perspective, Piaget’s ideas regarding formal operations appear to have been right, and whether they have any current relevance, in particular concerning how best to support the development of intellectual potential during the second decade of life.
What We Thought We Knew and How We Came to Know It: Four Decades of Cross-Cultural Research from a Piagetian Point of View
Authors: Maynard Ashley E.
Published: February 2008

The major tenets of Piagetian theory, such as adaptation and constructionism, are compatible with a cross-cultural approach to the study of cognitive development, but there have been significant methodological and theoretical advances over the past 40 years. Piagetian theory directly influenced three phases of cross-cultural research, ranging from absolutist to relativist. As researchers incorporated the study of contexts of development, particularly cross-cultural contexts, new methods expanded the available toolbox of approaches. Recent directions in historical research, narrative and discourse research, and cognitive developmental neuroscience have helped to shed light on processes and mechanisms of developmental change and their relationship to culture.
Talk and the Development of Reasoning and Understanding
Authors: Mercer Neil
Published: February 2008

Wertsch’s clarification of Vygotsky’s claims about the role of social interaction in the development of children’s thinking made an important contribution to educational research. Revisiting that clarification, I suggest that ‘talk’ instead of ‘speech’ best describes Vygotsky’s concern with the functional dynamics of dialogue rather than the language system. Reviewing research on teacher-pupil interaction and collaborative activity amongst peers, I then consider what evidence has now emerged to support Vygotsky’s claims. The article ends with a brief summary of the current state of our understanding about the role of spoken dialogue in learning and development.
Agoraphobia Is a Disease: A Tribute to Sir Martin Roth
Authors: Fava Giovanni A. , Rafanelli Chiara , Tossani Eliana , Grandi Silvana
Published: February 2008

The evidence which has accumulated on the course of agoraphobia challenges the DSM view that phobic avoidance is secondary to panic attacks. In particular, a longitudinal study by Wittchen et al. indicates that agoraphobia, as a diagnostic category, is frequently independent of panic disorder and panic attacks, is unlikely to remit spontaneously and entails compromised quality of life. A staging system of agoraphobia is presented. Panic may ensue in the longitudinal development of agoraphobia, as well as of other anxiety disorders, and be conceptualized as a potential outcome in the course of anxiety, phobias and hypochondriasis as more than a specific disease entity. These recent research findings confirm the clinical observations and phenomenological research of Sir Martin Roth (1917–2006) and call for a reassessment of the concept of neurosis.
Agoraphobia and Panic
Authors: Wittchen Hans-Ulrich , Nocon Agnes , Beesdo Katja , Pine Daniel S. , Höfler Michael , Lieb Roselind , Gloster Andrew T.
Published: February 2008

Background: The relationship of panic attacks (PA), panic disorder (PD) and agoraphobia (AG) is controversial. The aim of the current study is to prospectively examine the 10-year natural course of PA, PD and AG in the first three decades of life, their stability and their reciprocal transitions. Methods: DSM-IV syndromes were assessed via Composite International Diagnostic Interview – Munich version in a 10-year prospective-longitudinal community study of 3,021 subjects aged 14–24 years at baseline. Results: (1) Incidence patterns for PA (9.4%), PD (with and without AG: 3.4%) and AG (5.3%) revealed differences in age of onset, incidence risk and gender differentiation. (2) Temporally primary PA and PD revealed only a moderately increased risk for subsequent onset of AG, and primary AG had an even lower risk for subsequent PA and PD. (3) In strictly prospective analyses, all baseline groups (PA, PD, AG) had low remission rates (0–23%). Baseline PD with AG or AG with PA were more likely to have follow-up AG, PA and other anxiety disorders and more frequent complications (impairment, disability, help-seeking, comorbidity) as compared to PD without AG and AG without PA. Conclusions: Differences in incidence patterns, syndrome progression and outcome, and syndrome stability over time indicate that AG exists as a clinically significant phobic condition independent of PD. The majority of agoraphobic subjects in this community sample never experienced PA, calling into question the current pathogenic assumptions underlying the classification of AG as merely a consequence of panic. The findings point to the necessity of rethinking diagnostic concepts and DSM diagnostic hierarchies.
Urinary Malondialdehyde Levels in Newborns following Delivery Room Resuscitation
Authors: Kumar Ashok , Panigrahi Inusha , Basu Sriparna , Dash D.
Published: February 2008

Background: Delivery room resuscitation (DRR) is a common emergency in newborns, particularly in resource-poor settings where intrapartum monitoring is not readily available. It may give rise to oxidative stress in neonates due to reoxygenation and reperfusion of previously hypoxic and ischemic tissues. Urinary malondialdehyde (MDA), being non-invasive, may serve as a marker of oxidative stress in these infants. Objective: We assessed oxidative stress in term newborns requiring DRR by measuring MDA levels in urine and serum samples collected at 12–24 h of age. Methods: The study population consisted of 41 cases and 63 healthy age-matched control infants. The inclusion criterion was a need for positive pressure ventilation at birth for >1 min. MDA levels were measured colorimetrically by thiobarbituric acid reaction. Results: Urinary and serum MDA levels were found to be significantly higher in cases than in controls. Of the neonates given DRR, urinary and serum MDA values were elevated in those infants who passed meconium in utero, developed hypoxic ischemic encephalopathy or expired than in those who did not have these complications, but the difference was not significant. We found a significant correlation between urinary and serum MDA levels in infants given DRR. Conclusion: Newborns requiring DRR are subjected to significant oxidative stress which can be easily assessed by measuring urinary MDA levels.
Mechanisms of Hypoxemia Episodes in Spontaneously Breathing Preterm Infants after Mechanical Ventilation
Authors: Esquer Cristian , Claure Nelson , D’Ugard Carmen , Wada Yoshiro , Bancalari Eduardo
Published: February 2008

Background: Preterm infants often present with recurrent episodes of hypoxemia after mechanical ventilation. Objective: To evaluate the role of abdominal muscle activity and central apnea on the frequency and severity of hypoxemia episodes (HEs) in preterm infants with a history of mechanical ventilation. Methods: Continuous recordings of arterial oxygen saturation (SpO2), gastric pressure, respiratory inductance plethysmography and abdominal surface electromyography were obtained during 4 h from spontaneously breathing preterm infants who had recently been extubated and presented with frequent HEs. Results: Ten infants (gestational age 26.4 ± 1.1 weeks, body weight 816 ± 128 g, age 44 ± 21 days, FiO2 0.31 ± 0.09, mechanically ventilated for 33 ± 37 days) were studied 12 ± 7 (mean ± SD) days after extubation. These infants presented with 10.2 ± 9.3 HEs/h (SpO2 <88%, ≧10 s). Of these, 8.2 ± 6.2 HEs/h were associated with abdominal muscle contraction while only 2.0 ± 4.5 HEs/h were associated with ≧10 s apnea (p < 0.05). Of the more severe HEs (SpO2 <75%, ≧10 s), 2.7 ± 3.1 HEs/h were associated with abdominal contraction and only 0.7 ± 2.1 HEs/h with apnea (p < 0.05). Resting lung volume decreased by 69 ± 16% of tidal volume in HEs associated with abdominal contraction. Conclusions: In this group of premature infants who presented with frequent HEs after mechanical ventilation, most HEs were associated with abdominal muscles contraction and a loss in lung volume. These findings provide an alternate mechanism to explain these episodes in spontaneously breathing preterm infants with a history of mechanical ventilation.
Elevation of High-Mobility Group Box 1 Concentration in Asphyxiated Neonates
Authors: Okazaki Kaoru , Kondo Masatoshi , Kato Masahiko , Kakinuma Ryota , Nishida Akira , Noda Masahiro , Kimura Hirokazu
Published: February 2008

Background: In asphyxiated neonates, abnormal proinflammatory cytokine/chemokine production may be induced. High-mobility group box 1 (HMGB-1) protein is a new type of proinflammatory cytokine that induces abnormal inflammatory responses involving proinflammatory cytokine production. However, the physiological significance of HMGB-1 in asphyxia is poorly understood. Objectives: We aimed to evaluate whether serum HMGB-1 levels were changed in asphyxia by measuring the serum concentration of HMGB-1 in both asphyxiated and normally delivered neonates at birth. Methods: Using enzyme-linked immunosorbent assay, we measured the concentration of HMGB-1 in sera obtained from 53 asphyxiated neonates and 32 normally delivered neonates immediately after birth. Results: The serum concentrations of HMGB-1 in asphyxiated neonates were significantly higher than those in normally delivered neonates without asphyxia (p = 0.033). Conclusion: We suggest that the elevation of HMGB-1 might be associated with abnormal inflammatory responses involving the excessive production of proinflammatory cytokines in neonates with asphyxia.
Chronic Fatigue Syndrome after Human Parvovirus B19 Infection without Persistent Viremia
Authors: Seishima Mariko , Mizutani Yoko , Shibuya Yoshinao , Arakawa Chikako
Published: February 2008

Background: It is unclear how often chronic fatigue syndrome (CFS) appears after human parvovirus B19 (B19) infection and whether prolonged B19 viremia or some other factors cause CFS. Objectives: To determine how often CFS appears after B19 infection and whether prolonged B19 DNA presence, antibody production and persistently reduced complement levels occur in CFS patients after B19 infection. Methods: Clinical findings were examined in 210 patients after B19 infection, and CH50, C3 and C4 levels were determined. B19 DNA and antibodies to B19 were also tested in 38 patients’ sera including 3 with CFS. Results: Serum B19 DNA disappeared after 4–5 months in all 18 patients tested. There are no differences in B19 DNA-positive period between patients with and without persistent symptoms. IgM antibody titers to B19 became reduced after 2 months in all 38 patients. Complement levels persistently decreased in a greater proportion of patients with persistent symptoms. Conclusions: The present study suggests that we should consider the possibility of CFS after B19 infection and that CFS may be derived from several aspects other than prolonged B19 DNA presence in sera.
Social Gradient in Dental Caries among Adolescents in Sri Lanka
Authors: Perera I. , Ekanayake L.
Published: February 2008

The aim of the present study was to assess the social inequality in dental caries among adolescents in Sri Lanka. A total of 1,225 15-year-olds were selected using a stratified cluster sampling technique from schools in the Colombo district. The data were collected by means of an oral examination and questionnaires to both children and their parents. There were statistically significant inverse gradients between caries prevalence, caries experience (DMFS) and all five socio-economic indicators considered. Maternal education and family affluence emerged as significant predictors of dental caries. The magnitude of social inequality in dental caries was assessed using the slope index of inequality (SII) and the concentration index based on the concentration curve. SII for all socio-economic indicators were negative and, except in relation to father’s occupation, they were statistically significant. With the socio-economic groups ordered from the lowest to the highest, a negative SII indicates that caries experience decreased with improving socio-economic status. The concentration index for DMFS was negative (–0.111) and statistically significant, indicating disproportionate concentration of dental caries among the poor children. In conclusion, this study has shown the existence of a social gradient with respect to dental caries among adolescents in Sri Lanka and it also illustrates the use of SII and concentration index as tools to determine the magnitude of social inequality in dental caries.
Oxidative Stress and ‘Monocyte Reprogramming’ in Septic Patients with Acute Kidney Injury Requiring CRRT
Authors: Silva Sandra , de Cal Massimo , Cruz Dinna , Lentini Paolo , Corradi Valentina , Gallo Giampiero , Salvatori Gabriella , Verbine Anton , Pogoshyan Lusine , Nalesso Federico , Brendolan Alessandra , Piccinni Pasquale , Ronco Claudio
Published: February 2008

Oxidative stress (OS) and monocyte HLA-DR expression are known to be predictive of mortality in sepsis; nevertheless, limited information exists regarding sepsis with acute kidney injury (AKI). The aim of the study was to correlate these markers with outcome in septic patients with AKI requiring continuous renal replacement therapy (CRRT). Advanced oxidation protein products (AOPP) were measured in 32 patients on days 1, 3, 7, 14, 21, and 28. In 14 we assessed the percentage of monocytes expressing HLA-DR (%DR+) and the HLA-DR mean fluorescence intensity (MFI). 20 healthy volunteers, 17 septic patients without AKI and 20 septic AKI patients not treated by CRRT were used for comparison. The mortality rate was 59%. Septic CRRT patients had higher AOPP and lower %DR+ (p < 0.001, both) than healthy controls. They also had higher AOPP than septic patients who did not develop AKI (p < 0.001). No difference was found in AOPP, %DR+ and MFI between survivors and non-survivors (day 1 and subsequent measurements). No correlation was seen between severity scores and OS/HLA-DR. OS and HLA-DR expression are altered in septic patients with AKI undergoing CRRT. However, this study was not able to confirm the usefulness of these markers in predicting survival in this subset of patients.
Usefulness of the Short IQCODE for Predicting Postoperative Delirium in Elderly Patients Undergoing Hip and Knee Replacement Surgery
Authors: Priner Mathieu , Jourdain Maud , Bouche Gauthier , Merlet-Chicoine Isabelle , Chaumier Jean-Albert , Paccalin Marc
Published: February 2008

Background/Objective: The prevalence of postoperative delirium in elderly patients is >30%. The objective of this prospective study was to determine the usefulness of the short form of the Informant Questionnaire on COgnitive Decline in the Elderly (short IQCODE) to predict the occurrence of postoperative delirium after elective hip and knee arthroplasty in the elderly. Methods: Consecutive patients, 60 years and older, who were admitted for elective hip or knee arthroplasty were included. The preoperative cognitive status was determined using the Mini-Mental State Examination (MMSE) and the short IQCODE. Postoperative delirium was diagnosed using the Confusion Assessment Method. Logistic regression was used to analyze the links between the preoperative test scores and the outcome of postoperative delirium. Results: One hundred and one patients completed the study (mean age 73.6 ± 6.6 years). The mean ± SD MMSE score was 26 ± 3, and the mean short IQCODE score was 50.7 ± 6.2. Postoperative delirium developed in 15 patients (14.8%). A short IQCODE score >50 was significantly associated with postoperative delirium (OR 12.7, 95% CI 1.4–115.5; p = 0.02). Conclusions: The short IQCODE appears to be a useful tool to predict the risk of postoperative delirium in elderly patients undergoing elective surgery. Detecting this complication could be of great interest to improve the postoperative survey of elderly patients.
Treatment with Combined Streptozotocin and Liposomal Doxorubicin in Metastatic Endocrine Pancreatic Tumors
Authors: Fjällskog Marie-Louise H. , Janson Eva T. , Falkmer Ursula G. , Vatn Morten H. , Öberg Kjell E. , Eriksson Barbro K.
Published: February 2008

Treatment with combined streptozotocin and liposomal doxorubicin is safe and efficient in patients with endocrine pancreatic tumors (EPTs). No cardiac toxicity was reported. Background: The combination of streptozotocin and doxorubicin has been shown to be superior to streptozotocin and fluorouracil in the treatment of metastatic EPTs. However, the risk of cardiac toxicity from anthracyclins hampers the usefulness of the drug combination. Liposomal doxorubicin has a lower frequency of cardiac adverse events compared to doxorubicin. We wanted to assess the efficacy and safety of combined streptozotocin and liposomal doxorubicin in patients with metastatic EPTs. Methods: Thirty patients with metastatic EPTs were recruited from three medical centers in Norway and Sweden during a time period of 3 years. All patients had histopathologically confirmed diagnoses and bidimensionally measurable lesions. 30 mg/m2 of liposomal doxorubicin was administered on day 1 of each cycle. During the first course, 1 g of streptozotocin was given on 5 consecutive days. Thereafter, 2 g of streptozotocin was given on day 1 only. Treatment was repeated every 3 weeks. Results: Twelve of 30 patients (40%) achieved an objective radiological response with a median duration of 9 months. Stabilization of disease was achieved in 17 of 30 patients (57%) for a median duration of 11 months. Only one patient had progressive disease as best response. The 2-year progression-free survival was 18% and the 2-year overall survival was 72%. The treatment was well tolerated. None of the patients experienced cardiac toxicity. Conclusion: We conclude that combined streptozotocin and liposomal doxorubicin is a safe and efficient treatment for EPTs. The efficacy seems to be comparable to that of combined streptozotocin and doxorubicin, whereas the cardiac toxicity clearly favors using the liposomal drug combination.
Site-Specific Atherogenic Gene Expression Correlates With Subsequent Variable Lesion Development in Coronary and Peripheral Vasculature
Authors: Mohler Emile R. , Sarov-Blat Lea , Shi Yi , Hamamdzic Damir , Zalewski Andrew , MacPhee Colin , Llano Raul , Pelchovitz Dan , Mainigi Sumeet K. , Osman Hashim , Hallman Troy , Steplewski Klaudia , Gertz Zachary , Lu Min Min , Wilensky Robert L
Published: February 2008

Objectives—

The relationship between specific gene regulation and subsequent development and progression of atherosclerosis is incompletely understood. We hypothesized that genes in the vasculature related to cholesterol metabolism, inflammation, and insulin signaling pathways are differentially regulated in a site-specific and time-dependent manner.

Methods and Results—

Expression of 59 genes obtained from coronary, carotid, and thoracic aortic arteries were characterized from diabetic (DM)/hypercholesterolemic (HC) swine (n=52) 1, 3, and 6 months after induction. Lesion development in the 3 arterial beds was quantified and characterized at 1, 3, 6, and 9 months. Progressive lesion development was observed in the coronary>thoracic aorta≫carotid arteries. Genes involved in cholesterol metabolism and insulin pathways were upregulated in coronaries>thoracic aortae>carotids. Inflammatory genes were more markedly upregulated in coronary arteries than the other 2 arteries. Genes implicated in plaque instability (eg, matrix metalloproteinase-9, CCL2 and Lp-PLA
2
mRNAs) were only upregulated at 6 months in coronary arteries.

Conclusions—

Variable gene expression, both in regard to the arterial bed and duration of disease, was associated with variable plaque development and progression. These findings may provide further insight into the atherosclerotic process and development of potential therapeutic targets.
Association Analysis of Allelic Variants of USF1 in Coronary Atherosclerosis
Authors: Kristiansson Kati , Ilveskoski Erkki , Lehtimäki Terho , Peltonen Leena , Perola Markus , Karhunen Pekka J.
Published: February 2008

Objective—USF1 regulates the transcription of more than 40 cardiovascular related genes and is well established as a gene associated with familial combined hyperlipidemia, a condition increasing the risk for coronary heart disease. No detailed data, however, exists on the impact of this gene to the critical outcome at the tissue level: different types of atherosclerotic lesions.

Methods and Results—We analyzed the USF1 in 2 autopsy series of altogether 700 middle-aged men (the Helsinki Sudden Death Study) with quantitative morphometric measurements of coronary atherosclerosis. SNPrs2516839, tagging common USF1 haplotypes, associated with the presence of several types of atherosclerotic lesions, particularly with the proportion of advanced atherosclerotic plaques (P=0.02) and area of calcified lesions (P<0.001) of the coronary arteries. Importantly, carriers of risk alleles ofrs2516839also showed a 2-fold risk for sudden cardiac death (genotype TT versus CC; OR 2.10, 95% CI 1.17 to 3.75,P=0.04). The risk effect ofrs2516839was present also in aorta samples of the men.

Conclusions—Our findings in this unique study sample suggest that USF1 contributes to atherosclerosis, the pathological arterial wall phenotype resulting in coronary heart disease and in its most dramatic consequence—sudden cardiac death.
Promotor Polymorphisms in Leukotriene C
4
Synthase and Risk of Ischemic Cerebrovascular Disease
Authors: Freiberg Jacob J. , Tybjærg-Hansen Anne , Sillesen Henrik , Jensen Gorm B. , Nordestgaard Børge G.
Published: February 2008

Objective—

Cysteinyl leukotrienes are involved in inflammation and possibly in early carotid atherosclerosis. We tested the hypothesis that the −444 A/C and −1072 G/A polymorphisms of the leukotriene C
4
synthase associate with risk of ischemic cerebrovascular disease.

Methods and Results—

We genotyped 10 592 individuals from the Danish general population, the Copenhagen City Heart Study. During 24 years of follow-up, 557 individuals developed ischemic cerebrovascular disease. The allele frequency was 0.07 for −1072 A and 0.29 for −444 C. Cumulative incidence for ischemic cerebrovascular disease was higher for −1072 AA versus GG genotype (log-rank:
P
=0.002), and lower for −444 CC versus AA genotype (log-rank:
P
=0.008). Combined genotypes showed corresponding cumulative incidence differences (log-rank:
P
=0.003). Multifactorially adjusted hazard ratios for ischemic cerebrovascular disease were 2.8(1.4 to 5.7) for −1072 AA versus GG genotype, 0.6(0.4 to 0.9) for −444 CC versus AA genotype, 2.5(1.2 to 5.4) for combined AA-AA versus GG-AA genotype, and 0.6(0.4 to 0.9) for combined GG-CC versus GG-AA genotype. Genotype did not associate with risk of deep venous thrombosis or severe carotid atherosclerosis, or with levels of platelets and coagulation factors.

Conclusions—

Leukotriene C
4

synthase
−1072 AA genotype predict increased risk, whereas −444 CC genotype predict decreased risk of ischemic cerebrovascular disease.
Gender Differences in Endothelial Progenitor Cells and Cardiovascular Risk Profile
Authors: Fadini Gian Paolo , de Kreutzenberg Saula , Albiero Mattia , Coracina Anna , Pagnin Elisa , Baesso Ilenia , Cignarella Andrea , Bolego Chiara , Plebani Mario , Nardelli Giovanni B. , Sartore Saverio , Agostini Carlo , Avogaro Angelo
Published: February 2008

Objective—

Endothelial progenitor cells (EPCs) participate in vascular homeostasis and angiogenesis. The aim of the present study was to explore EPC number and function in relation to cardiovascular risk, gender, and reproductive state.

Methods and Results—

As measured by flow-cytometry in 210 healthy subjects, CD34
+
KDR
+
EPCs were higher in fertile women than in men, but were not different between postmenopausal women and age-matched men. These gender gradients mirrored differences in cardiovascular profile, carotid intima-media thickness, and brachial artery flow-mediated dilation. Moreover, EPCs and soluble c-kit ligand varied in phase with menstrual cycle in ovulatory women, suggesting cyclic bone marrow mobilization. Experimentally, hysterectomy in rats was followed by an increase in circulating EPCs. EPCs cultured from female healthy donors were more clonogenic and adherent than male EPCs. Treatment with 17β-estradiol stimulated EPC proliferation and adhesion, via estrogen receptors. Finally, we show that the proangiogenic potential of female EPCs was higher than that of male EPCs in vivo.

Conclusions—

EPCs are mobilized cyclically in fertile women, likely to provide a pool of cells for endometrial homeostasis. The resulting higher EPC levels in women than in men reflect the cardiovascular profile and could represent one mechanism of protection in the fertile female population.
Telomere Gap Between Granulocytes and Lymphocytes Is a Determinant for Hematopoetic Progenitor Cell Impairment in Patients With Previous Myocardial Infarction
Authors: Spyridopoulos Ioakim , Erben Young , Brummendorf Tim H. , Haendeler Judith , Dietz Klaus , Seeger Florian , Kissel Christine K. , Martin Hans , Hoffmann Jedrzej , Assmus Birgit , Zeiher Andreas M. , Dimmeler Stefanie
Published: February 2008

Objective—

We have previously demonstrated that ischemic cardiomyopathy is associated with selective impairment of progenitor cell function in the bone marrow and in the peripheral blood, which may contribute to an unfavorable left ventricular remodeling process.

Methods and Results—

With this study, we intended to identify the influence of telomere length on bone marrow functionality in 50 patients with coronary artery disease (CAD) and previous myocardial infarction. Mean telomere length (mTL) was measured simultaneously in peripheral blood leukocytes and mononuclear bone marrow cells (BMC), using the flow-FISH method. Telomere erosion already occurred at the bone marrow level, whereby age (39 bp/yr,
P
=0.025) and the number of affected vessels (434 bp/vessel,
P
=0.029) were the only independent predictors. Lymphocytes demonstrated significant TL shortening between BMCs and peripheral blood in CAD patients (−1011±897 bp) as opposed to an increase in a young control group (+235±459 bp,
P
<0.001). SDF- and VEGF-specific migration of BMCs correlated with mTL of lymphocytes (
r
=0.42,
P
<0.001) and was significantly reduced in CAD patients. Finally, the telomere length difference between granulocytes and lymphocytes was the most determinant for telomere-associated bone marrow impairment (
P
<0.001).

Conclusion—

In patients with CAD, telomere shortening of BMCs is dependent on both age and the extent of CAD and correlates with bone marrow cell functionality.
C-Reactive Protein Enhances Tissue Factor Expression by Vascular Smooth Muscle Cells
Authors: Wu Jianbo , Stevenson Meredith J. , Brown Jordan M. , Grunz Elizabeth A. , Strawn Tammy L. , Fay William P.
Published: February 2008

Objective—

We examined the impact of C-reactive protein (CRP) on vascular smooth muscle cell (VSMC) expression of tissue factor (TF) and TF pathway inhibitor (TFPI).

Methods and Results—

TF mRNA, protein, and activity levels were significantly higher in VSMCs isolated from CRP-transgenic (Tg) mice than from wild-type (WT) mice. TFPI expression was significantly downregulated in CRP-Tg versus WT VSMCs. Transfection of human VSMCs with CRP expression plasmid significantly increased TF expression and decreased TFPI expression. Gene silencing of Fcγ receptor IIIa (FcγRIIIa) blocked the effect of CRP on VSMC TF expression. CRP activated p44/42, but not p38 or JNK MAP kinase (MAPK), and the effect of CRP on TF expression was blocked by pharmacological inhibitor of p44/42, but not p38 or JNK MAPK. Reactive oxygen species (ROS) scavengers blocked CRP-induced upregulation of VSMC TF expression. In vivo analyses revealed significant increases in TF expression and decreases in TFPI expression in carotid arteries of CRP-Tg mice versus WT mice.

Conclusion—

CRP increases TF and decreases TFPI expression by VSMCs in vitro and in vivo. Induction of TF expression by CRP is mediated by FcγRIIIa, p44/42 MAPK, and ROS generation. These data offer important insights into the role of CRP in the pathogenesis of arterial thrombosis.