bluuebunny/crossref_metadata_2025 huggingface dataset:
Lysyl oxidase oxidizes basic fibroblast growth factor and inactivates its mitogenic potential
Authors: Li Wande , Nugent Matthew A. , Zhao Yinzhi , Chau Anne N. , Li Sandy J. , Chou Iih‐Nan , Liu Guanmei , Kagan Herbert M.
Published: December 2002

Lysyl oxidase (LO) plays a central role in the crosslinking of collagen and elastin in the extracellular matrix. Here we demonstrate that basic fibroblast growth factor (bFGF), a polypeptide which regulates proliferation, differentiation, and migration of a variety of cell types, is a substrate of LO. The oxidation of lysine residues in bFGF by LO resulted in the covalent crosslinking of bFGF monomers to form dimers and higher order oligomers and dramatically altered its biological properties. Both the mitogenic potential and the nuclear localization of bFGF were markedly inhibited in the Swiss 3T3 cells upon its oxidation by LO. NIH 3T3 IgBNM 6‐1 cells (6‐1 cells) overexpress bFGF which participates in an autocrine mechanism accounting for the transformation of these cells into a tumorigenic state. Exposure of the 6‐1 cells to nanomolar concentrations of LO in culture oxidized lysine and generated crosslinkages in bFGF within the cell and markedly reduced proliferative rates. The lack of LO expression has been correlated with hyperproliferative cell growth, while this enzyme has been identified as a suppressor of ras‐induced tumorigenesis. The present results illustrate a mechanism by which LO can depress normal and transformed cell growth. © 2002 Wiley‐Liss, Inc.
Protein kinase C ζ nuclear translocation mediates the occurrence of radioresistance in friend erythroleukemia cells
Authors: Cataldi A. , Centurione L. , Di Pietro R. , Rapino M. , Bosco D. , Grifone G. , Garaci F. , Rana R.
Published: December 2002

Friend erythroleukemia cells require high doses (15 Gy) of ionizing radiation to display a reduced rate of proliferation and an increased number of dead cells. Since ionizing radiation can activate several signaling pathways at the plasma membrane which can lead to the nuclear translocation of a number of proteins, we looked at the intranuclear signaling system activated by Protein Kinases C, being this family of enzymes involved in the regulation of cell growth and death. Our results show an early and dose‐dependent increased activity of ζ and ε isoforms, although PKC ζ is the only isoform significantly active and translocated into the nuclear compartment upon low (1.5 Gy) and high (15 Gy) radiation doses. These observations are concomitant and consistent with an increase in the anti‐apoptotic protein Bcl‐2 level upon both radiation doses. Our results point at the involvement of the PKC pathway in the survival response to ionizing radiation of this peculiar cell line, offering PKC ζ for consideration as a possible target of pharmacological treatments aimed at amplifying the effect of such a genotoxic agent. © 2002 Wiley‐Liss, Inc.
P53 licensed to kill? Operating the assassin
Authors: Haupt Susan , Louria‐Hayon Igal , Haupt Ygal
Published: December 2002

The p53 protein is a key player in the cellular response to stress. Proper regulation of p53 is imperative for the suppression of tumor development. This regulation is largely governed by its master inhibitor, Mdm2, which both blocks p53 activities and promotes its destabilization. This tight regulation of p53 by Mdm2 must be interrupted under stress conditions in order for p53 to be stabilized in an active form. A combined action of partner proteins and modifying enzymes is essential for the relief of p53 from Mdm2. The recent revelation of p53 association with the PML‐nuclear bodies provides one explanation of how this regulatory network is coordinated within the nucleus in response to certain stress conditions. Thus, it is not only the nature of the p53 regulatory complex but also the spatial and temporal context of this association that governs the output inhibitory signals mediated by p53. © 2002 Wiley‐Liss, Inc.
PTEN regulation of neural development and CNS stem cells
Authors: Li Li , Liu Fenghua , Ross Alonzo H.
Published: December 2002

Even though phosphorylation of phosphatidylinositols by phosphoinositide 3‐kinase (PI3K) has an important and pervasive role in the nervous system, there is little known about the phosphatases that reverse this reaction. Such a phosphatase, phosphatase and tensin homologue deleted on chromosome 10 (PTEN), was cloned as a tumor suppressor for gliomas. PTEN is expressed in most, if not all, neurons and is localized in the nucleus and cytoplasm. Recently, a series of papers using PTEN conditional knockouts has greatly extended our knowledge of PTEN's role during development. Loss of PTEN results in disorganization of the brain, probably due to a flaw in cell migration. In addition, there is a gradual increase in the size of neuronal soma, mimicking Lhermitte‐Duclos disease. Recent experiments in our laboratory with adult PTEN +/− mice demonstrate that PTEN regulates migration of precursor cells in the subventricular zone to the olfactory bulb. We also found that PTEN haploinsufficiency can protect precursor cells from apoptosis in response to oxidative stress. Collectively, these studies demonstrate that PTEN does much more than suppressing tumors. It is a master regulator in developing and adult brain. © 2002 Wiley‐Liss, Inc.
Oligonucleotide‐based microarray for DNA methylation analysis: Principles and applications
Authors: Shi Huidong , Maier Sabine , Nimmrich Inko , Yan Pearlly S. , Caldwell Charles W. , Olek Alexander , Huang Tim Hui‐Ming
Published: December 2002

Gene silencing via promoter CpG island hypermethylation offers tumor cells growth advantages. This epigenetic event is pharmacologically reversible, and uncovering a unique set of methylation‐silenced genes in tumor cells can bring a new avenue to cancer treatment. However, high‐throughput tools capable of surveying the methylation status of multiple gene promoters are needed for this discovery process. Herein we describe an oligonucleotide‐based microarray technique that is both versatile and sensitive in revealing hypermethylation in defined regions of the genome. DNA samples are bisulfite‐treated and PCR‐amplified to distinguish CpG dinucleotides that are methylated from those that are not. Fluorescently labeled PCR products are hybridized to arrayed oligonucleotides that can discriminate between methylated and unmethylated alleles in regions of interest. Using this technique, two clinical subtypes of non‐Hodgkin's lymphomas, mantle cell lymphoma, and grades I/II follicular lymphoma, were further separated based on the differential methylation profiles of several gene promoters. Work is underway in our laboratory to extend the interrogation power of this microarray system in multiple candidate genes. This novel tool, therefore, holds promise to monitor the outcome of various epigenetic therapies on cancer patients. © 2002 Wiley‐Liss, Inc.
Establishment of dependence relationships between genome replication and mitosis
Authors: Clarke Duncan J.
Published: December 2002

Although budding yeast cell biology and genetics provided a powerful system to isolate S‐phase checkpoint mutants, initial studies relied on a defect not likely to be relevant in higher eukaryotes. The first mutants were isolated for their inability to restrain mitotic spindle elongation in S‐phase. Since most eukaryotes do not assemble spindles until prometaphase the validity of this approach might have been questioned. However, these early studies were designed with a highly valid assumption in mind; that checkpoints have a variety of targets, but comprise conserved kinase cascades that make up these signaling pathways. The task that lies ahead is to determine targets of the S‐phase checkpoint relevant to mammals. One step forward might be the realization that the budding yeast S‐phase checkpoint prevents loss of sister chromatid cohesion while DNA replication is ongoing. If this mechanism is conserved in mammals, it could prove vital for chromosome segregation fidelity. © 2002 Wiley‐Liss, Inc.
The 5′‐untranslated RNA of the human dhfr minor transcript alters transcription pre‐initiation complex assembly at the major (core) promoter
Authors: Blume Scott W. , Meng Zheng , Shrestha Kedar , Snyder Richard C. , Emanuel Peter D.
Published: December 2002

The human dhfr minor transcript is distinguished from the predominant dhfr mRNA by an ∼400 nucleotide extension of the 5′‐untranslated region, which corresponds to the major (core) promoter DNA (its template). Based on its unusual sequence composition, we hypothesized that the minor transcript 5′‐UTR might be capable of altering transcription pre‐initiation complex assembly at the core promoter, through direct interactions of the RNA with specific regulatory polypeptides or the promoter DNA itself. We found that the minor transcript 5′‐UTR selectively sequesters transcription factor Sp3, and to a lesser extent Sp1, preventing their binding to the dhfr core promoter. This allows a third putative transcriptional regulatory protein, which is relatively resistant to sequestration by the minor transcript RNA, the opportunity to bind the dhfr core promoter. The selective sequestration of Sp3 > Sp1 by the minor transcript 5′‐UTR involves an altered conformation of the RNA, and a structural domain of the protein distinct from that required for binding to DNA. As a consequence, the minor transcript 5′‐UTR inhibits transcription from the core promoter in vitro (in trans) in a concentration‐dependent manner. These results suggest that the dhfr minor transcript may function in vivo (in cis) to regulate the transcriptional activity of the major (core) promoter. © 2002 Wiley‐Liss, Inc.
Increased proteasome‐dependent degradation of estrogen receptor‐alpha by TGF‐β1 in breast cancer cell lines
Authors: Petrel Trevor A. , Brueggemeier Robert W.
Published: December 2002

Normal mammary epithelial cells are rapidly induced to G1 arrest by the widely expressed cytokine, transforming growth factor beta (TGF‐β1). Studies in established breast cancer cell lines that express the estrogen receptor alpha (ERα) have demonstrated loss of this responsiveness. This inverse correlation suggests interpathway signaling important to cell growth and regulation. The adenocarcinoma breast cell line BT474, which was not growth arrested by TGF‐β1, was used as a model of estrogen‐inducible growth to explore interpathway crosstalk. Although BT474 cells were not growth‐arrested by TGF‐β1 as determined by flow cytometry analysis and 5′‐bromo‐3′‐deoxyuridine incorporation into DNA, estrogen receptor protein levels were attenuated by 100 pM TGF‐β1 after 6 h. This decrease in ERα reached 50% of untreated control levels by 24 h of treatment and was further supported by a 50% decrease in estrogen‐inducible DNA synthesis. Inspection of ERα transcripts suggested that this decrease was primarily the result of altered ERα protein stability or availability. Use of the proteasome inhibitor, MG132, abolished all effects on ERα by TGF‐β1. Collectively, this data supports a role for TGF‐β1 in regulating the growth of otherwise insensitive breast cancer cells through modulation of ERα stability. © 2002 Wiley‐Liss, Inc.
Proteomic analyses of arsenic‐induced cell transformation with SELDI‐TOF ProteinChip® technology
Authors: He Qing‐Yu , Yip Ta‐Tung , Li Muyao , Chiu Jen‐Fu
Published: December 2002

In this study, we demonstrated that low levels (1.5 μM) of arsenite induces B[a]P‐treated lung cell transformation. We then used a proteomic approach to identify protein expression by ProteinChips, which could potentially be important for transformation induced by this toxic metal. Most of the protein peaks in cell extracts of all samples, including the control, B[a]P‐treated, and B[a]P + As‐treated cells are identical. However, surface‐enhanced laser desorption/ionization time of flight (SELDI‐TOF) analysis with Cu‐ProteinChips and WCX‐ProteinChips revealed several dramatically different protein peaks that appeared in lung cells after being transformed by a treatment of 1.5 μM arsenite for 12 weeks. SAX2 ProteinChip also identified a prominent protein peak that was preferentially expressed in control cells. Interestingly, by using a SAX2 chip, we were able to detect several protein peaks that increased their expression in lung epithelial cells (LEC) treated with only B[a]P. Identification and characterization of these proteins may reveal the molecular basis of As‐induced cell transformation and provide insight into the mechanisms by which arsenic induces carcinogenesis. © 2002 Wiley‐Liss, Inc.
Copernican stem cells: Regulatory constellations in adult hippocampal neurogenesis
Authors: Fabel Klaus , Toda Hiroki , Fabel Konstanze , Palmer Theo
Published: December 2002

In the adult, neurogenesis occurs where constellations of signaling molecules are correctly orchestrated and where competent cells are present to interpret these signals. As the instruments used to observe adult neurogenesis become more sophisticated, the concept of a discrete competent “stem cell” has become less concrete. Neural progenitor cells once thought committed to a single lineage can be influenced to become multipotent and somatic tissues appear to yield cells capable of tremendous peripheral and central lineage potential. The variety of cell types that appear competent to generate neurons suggests that the “Hilios” of adult neurogenesis may not necessarily be a single cellular entity but rather the sum of signals that dictate, “Make a new neuron here.” These signals may not be limited to the recruitment of preexisting neural stem cells but may also, in some subtle way, reprogram local precursors to create “stem‐like cells,” where needed. © 2002 Wiley‐Liss, Inc.
An intranuclear frame for chromatin compartmentalization and higher‐order folding
Authors: Barboro Paola , D'Arrigo Cristina , Mormino Michele , Coradeghini Rosella , Parodi Silvio , Patrone Eligio , Balbi Cecilia
Published: December 2002

Recent ultrastructural, immunoelectron, and confocal microscopy observations done in our laboratory [Barboro et al. [2002] Exp. Cell. Res. 279:202–218] have confirmed that lamins and the nuclear mitotic apparatus protein (NuMA) are localized inside the interphase nucleus in a polymerized form. This provided evidence of the existence of a RNA stabilized lamin/NuMA frame, consisting of a web of thin (∼3 and ∼5 nm) lamin filaments to which NuMA is anchored mainly in the form of discrete islands, which might correspond to the minilattices described by Harborth et al. [1999] (EMBO. J. 18:1689–1700). In this article we propose that this scaffold is involved in the compartmentalization of both chromatin and functional domains and further determines the higher‐order nuclear organization. This hypothesis is strongly supported by the scrutiny of different structural transitions which occur inside the nucleus, such as chromatin displacement and rearrangements, the collapse of the internal nuclear matrix after RNA digestion and the disruption of chromosome territories induced by RNase A and high salt treatment. All of these destructive events directly depend on the loss of the stabilizing effect exerted on the different levels of structural organization by the interaction of RNA with lamins and/or NuMA. Therefore, the integrity of nuclear RNA must be safeguarded as far as possible to isolate the matrix in the native form. This material will allow for the first time the unambiguous ultrastructural localization inside the INM of the components of the functional domains, so opening new avenues of investigation on the mechanisms of gene expression in eukaryotes. © 2003 Wiley‐Liss, Inc.
What are the characteristics of cycling cells in the adult central nervous system?
Authors: Goldman James E.
Published: December 2002

Many regions of the adult central nervous system contain cycling cells. Such cells comprise a relatively small fraction of the total population of the CNS. Work over decades has attempted to determine the normal fates of these cells and their fates under pathological conditions. The recent interest in “stem” cells and “progenitors” in the adult CNS has sparked a much revived exploration into the nature of these cells and in the signals by which they may be induced to differentiate into mature neurons or glia. This population has not yet been fully characterized, although it has become clear that this is a heterogeneous group of cells, differing in morphology, antigen expression, migratory capacity, and potential fates. © 2002 Wiley‐Liss, Inc.
Paradoxical role of apoptosis in tumor progression
Authors: Gurova Katerina V. , Gudkov Andrei V.
Published: December 2002

Tumors frequently acquire resistance to apoptosis that is expected to contribute to malignant phenotype and reduce sensitivity to treatment. In fact, inactivation of p53 tumor suppressor gene resulting in suppression of apoptosis serves as a negative prognostic marker. Surprisingly, expression of a strong anti‐apoptotic protein Bcl‐2, another mechanism to avoid apoptosis, was found to be associated with a favorable prognosis. This paradoxical anti‐progressor function of Bcl‐2 has been explained in literature based on the negative effect of Bcl‐2 on cell proliferation. Here, by analyzing accumulated experimental and clinical data, we provide evidence supporting another hypothesis that defines apoptosis as an accelerator of tumor progression. The mechanism of anti‐progressor function of Bcl‐2 is based on creation of tumors that maintain control of genomic stability by eliminating selective advantages for the cells that acquire resistance to apoptosis through loss of p53. Thus, inhibition of apoptosis does not lead to loss of genomic stability and creates tumor environment that no longer supports further tumor progression and inhibitors of apoptosis can be considered as factors suppressing tumor progression. © 2002 Wiley‐Liss, Inc.
Microsatellite DNA library for Caiman latirostris
Authors: Zucoloto Rodrigo Barban , Verdade Luciano Martins , Coutinho Luiz Lehmann
Published: December 2002

New genetic markers were characterized for the broad‐snouted caiman (Caiman latirostris) by constructing libraries enriched for microsatellite DNA. Construction and characterization of these libraries are described in the present study. One microsatellite marker was developed from a (ACC‐TGG)nenriched microsatellite DNA library, and 12 microsatellite markers were developed from a (AC‐TG)nenriched microsatellite DNA library. These markers were tested in wild‐caught animals, and these tests resulted in ten new polymorphic microsatellites for C. latirostris. J. Exp. Zool. (Mol. Dev. Evol.) 294:346–351, 2002. © 2002 Wiley‐Liss, Inc.
The crocodilian mitochondrial control region: general structure, conserved sequences, and evolutionary implications
Authors: Ray David Alfred , Densmore Llewellyn
Published: December 2002

We present the first comprehensive analysis of the crocodilian control region. We have analyzed sequences from all three families of Crocodylia (Crocodylidae, Gavialidae, Alligatoridae), incorporating all genera exceptPaleosuchusandMelanosuchus. Within the control region of other vertebrates, several sequence motifs and their order appear to be conserved. Herein, we compare aligned crocodilian D‐loop sequences to homologous sequences from other vertebrates ranging from fish to birds. Among other findings, we have discovered that while domain I tends to be shorter than the same region in mammals and birds, it contains sequences similar in structure to both the goose‐hairpin and termination associated sequences (TAS). Domain II is highly conservative with regard to size among the taxa examined and contains several of the conserved sequence boxes characterized in other vertebrates. Domain III contains several interesting sequence motifs including tandemly repeated sequences, a long poly‐A region in the Crocodylidae, and possible bidirection promoter sequences.J. Exp. Zool. (Mol. Dev. Evol.) 294:334–345, 2002. © 2002 Wiley‐Liss, Inc.
Generation of a sequence characterized amplified region probe for authentication of crocodilian species
Authors: Chung‐Fai Yau Forrest , Wong Ka‐Lok , Wang Jun , Pui‐Hay But Paul , Shaw Pang‐Chui
Published: December 2002

A 209‐base pair (bp) crocodilian‐specific sequence characterized amplified region (SCAR) was identified from a 425‐bp randomly amplified polymorphic DNA (RAPD) fragment. The 209‐bp SCAR was produced from amplifications of DNA extracted from fresh and/or dry meat samples from at least three species of Crocodylus, Caiman crocodylus, and Alligator mississippiensis. No amplification was observed from DNA of other common animal species. The use of SCAR opens the way for quick authentication of crocodilian samples for conservation biology and trade regulation. J. Exp. Zool. (Mol. Dev. Evol.) 294:382–386, 2002. © 2002 Wiley‐Liss, Inc.
Microgeographic variation in Caiman latirostris
Authors: Verdade Luciano Martins , Zucoloto Rodrigo Barban , Coutinho Luiz Lehmann
Published: December 2002

In theory, geographic scale is related to genetic variation at the population level, whereas microgeographic scale may reveal intra‐population structure such as social groups and families. In the present work, both levels of genetic variation in the broad‐snouted caiman (Caiman latirostris) were evaluated in small wetlands associated with the Piracicaba River and some of its tributaries in the state of São Paulo, Brazil. Genetic variation was determined using microsatellite DNA markers originally developed for the American alligator (Alligator mississipiensis) and previously tested in pedigreed captive broad‐snouted caimans. Using these markers, we were able to detect variability among individuals from different sites, even those within a small geographic distance. Genetic results suggest that the groups sampled at each site are composed predominantly of related individuals. A possible combination of high mortality and low natality rates results in a low number of successfully dispersed individuals per generation. Future studies using a recently constructed Caiman latirostris microsatellite library (Zucoloto et al., 2002) might help us to understand metapopulation processes that may be occurring within this species. J. Exp. Zool. (Mol. Dev. Evol.) 294:387–396, 2002. © 2002 Wiley‐Liss, Inc.
Identification of purebredCrocodylus siamensisfor reintroduction in Vietnam
Authors: Fitzsimmons Nancy Nelson , Buchan Jason Craig , Lam Phan Viet , Polet Gert , Hung Ton That , Thang Nguyen Quoc , Gratten Jacob
Published: December 2002

Crocodylus siamensis, the Siamese crocodile, is a critically endangered species of freshwater crocodile previously distributed throughout much of SE Asia. Recovery plans call for reintroductions to the wild using founder individuals currently in captivity, mostly in commercial crocodile farms. On many farmsC. siamensishas been intentionally hybridised with either Cuban crocodiles,C. rhombifer, or the estuarine crocodile,C. porosus, and hybrids may be difficult to distinguish morphologically. We report on the combined use of microsatellite and mtDNA genetic markers to determine the species status of potential founder individuals for reintroduction ofC. siamensis. Genetic markers were used to characterise 103 captive and wild‐caught individuals ofC. siamensis,C. rhombiferandC. porosusin Vietnam and to distinguish purebred versus hybrid individuals. Although the microsatellite loci used had some overlap of allele sizes among species, assignment tests allowed differentiation. Four hybrids were identified, two of which had not been recognised morphologically as hybrids, and one of these was thought to be aC. siamensissuitable for reintroduction. Ten of the identified purebredC. siamensiswere subsequently released into Cat Tien National Park in southern Vietnam.J. Exp. Zool. (Mol. Dev. Evol.) 294:373–381, 2002. © 2002 Wiley‐Liss, Inc.
Low mitochondrial DNA variation among American alligators and a novel non‐coding region in crocodilians
Authors: Glenn Travis C. , Staton Joseph L. , Vu Alex T. , Davis Lisa M. , Bremer Jaime R. Alvarado , Rhodes Walter E. , Brisbin I. Lehr , Sawyer Roger H.
Published: December 2002

We analyzed 1317–1823 base pairs (bp) of mitochondrial DNA sequence beginning in the 5' end of cytochrome b (cyt b) and ending in the central domain of the control region for 25 American alligators (Alligator mississippiensis) and compared these to a homologous sequence from a Chinese alligator (A. sinensis). Both species share a non‐coding spacer between cyt b and tRNAThr. Chinese alligator cyt b differs from that of the American alligator by 17.5% at the nucleotide level and 13.8% for inferred amino acids, which is consistent with their presumed ancient divergence. Only two cyt b haplotypes were detected among the 25 American alligators (693–1199 bp surveyed), with one haplotype shared among 24 individuals. One alligator from Mississippi differed from all other alligators by a single silent substitution. The control region contained only slightly more variation among the 25 American alligators, with two variable positions (624 bp surveyed), yielding three haplotypes with 22, two, and one individuals in each of these groups. Previous genetic studies examining allozymes and the proportion of variable microsatellite DNA loci also found low levels of genetic diversity in American alligators. However, in contrast with allozymes, microsatellites, and morphology, the mtDNA data shows no evidence of differentiation among populations from the extremes of the species range. These results suggest that American alligators underwent a severe population bottleneck in the late Pleistocene, resulting in nearly homogenous mtDNA among all American alligators today. J. Exp. Zool. (Mol. Dev. Evol.) 294:312–324, 2002. © 2002 Wiley‐Liss, Inc.
Genetic relationships of American alligator populations distributed across different ecological and geographic scales
Authors: Ryberg Wade A. , Fitzgerald Lee A. , Honeycutt Rodney L. , Cathey James C.
Published: December 2002

Although much work has been conducted on coastal populations of the American alligator (Alligator mississippiensis), less is known about the population dynamics and genetic structure of populations of alligators confined to inland habitats. DNA microsatellite loci, derived from the American alligator, were used to investigate patterns of genetic variation within and between populations of alligators distributed at coastal and inland localities in Texas. These data were used to evaluate the genetic discreteness of different alligator stocks relative to their basic ecology at these sites. Observed mean heterozygosities across seven loci for both coastal and inland populations ranged from 0.50–0.61, with both inland and coastal populations revealing similar patterns of variation. Measures of Fst revealed significant population differentiation among all populations; however, analyses of molecular variance (AMOVAs) failed to demonstrate any apparent geographic pattern relative to the population differentiation indicated by Fst values. Each population contained unique alleles for at least one locus. Additionally, assignment tests based on the distribution of genotypes placed 76% of individuals to their source population. These genetic data suggest considerable subdivision among alligator populations, possibly influenced by demographic and life history differences as well as barriers to dispersal. These results have clear implications for management. Rather than managing alligators in Texas as a single panmictic population, translocation programs and harvest quotas should consider the ecological and genetic distinctiveness of local alligator populations. J. Exp. Zool. (Mol. Dev. Evol.) 294:325–333, 2002. © 2002 Wiley‐Liss, Inc.
Studies on the molecular evolution of the crocodylia: footprints in the sands of time
Authors: Dessauer Herbert C. , Glenn Travis C. , Densmore Llewellyn D.
Published: December 2002

A reasonably large number of studies focusing on the molecular evolution of crocodilians have been completed during the past 100 years. Proteins were initially studied before DNA was known to carry the genetic information of cells and organisms, and were subsequently studied to infer changes at the DNA level. More recently, studies on the DNA itself have been completed. We have had the pleasure of taking part in or facilitating many studies conducted over the past 50 years, especially several of the earliest studies done using newly developed molecular techniques. We provide a review of the molecular genetic studies on crocodilians, summarizing the findings of these studies as well as the context in which they were undertaken. This review is a personal look at the history of molecular studies on the evolutionary biology of crocodilians. Our excuse for this focus is that our professors, our students and we have had the opportunity to be among the first to apply many new techniques to studies of crocodilians since 1950, when one of us (HCD) was a graduate student of Roland Coulson and Tom Hernandez. Although we will review much of the material in this subject area, we do not claim that it is complete. Instead, we focus our presentation on work in which we have participated or with which we are particularly familiar. We especially focus on materials relevant to the research presented at the 2nd International Crocodilian DNA Workshop, 7–9 November, 2001, at the San Diego Zoo. Thus, the following review also stands as a tribute to our mentors, students, and colleagues. J. Exp. Zool. (Mol. Dev. Evol.) 294:302–311, 2002. © 2002 Wiley‐Liss, Inc.
Increased risk of chronic hepatitis in children with cancer
Authors: Sevinir Betül , Meral Adalet , Günay Ünsal , Özkan Tanju , Özuysal Sema , Sinirtas Melda
Published: December 2002

Background

There is a risk of viral hepatitis for children with cancer. Both hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in countries with high prevalence cause major problems in the management of cancer patients. In this study, we evaluated the incidence and chronicity of HBV and HCV infections in children with malignant diseases receiving chemotherapy.

Procedure

One hundred ninety‐eight children with cancer (mean age = 7.5 ± 2.5 years) and 100 healthy children as a control group were screened for HBV and HCV. Liver function tests, the number of transfusions, HBV and HCV serology were regularly monitored. In seropositive children, HBV‐DNA and HCV‐RNA were measured. Chronic hepatitis was defined as having an alanine aminotransferase (ALT) level three times of upper normal limit, positive HBV and HCV antigenemia for longer than 6 months. Liver biopsies were performed in all children with chronic hepatitis. The relationship between the chronic hepatitis and study parameters was statistically analyzed.

Results

HBsAg positivity, anti‐HCV, and mixed (HBV and HCV) infection were found in 11.6, 5.5, 2% of children, respectively. Most HBV infected children developed chronic hepatitis (48%) while 26 and 21.7% became carriers and immune, respectively. One died of acute fulminant HBV hepatitis. Of HCV infected children, 63.6% also had positive HCV‐RNA. Four children with mixed infection (100%) all progressed to chronic hepatitis. In this setting, chronic hepatitis was observed in 22 of 38 infected children (57.8%). The majority had leukemia and lymphoma. Children with HBsAg antigenemia developed chronic hepatitis in shorter time than HCV positive children (median 13 months vs. 51 months, P < 0.001).

Conclusion

We observed an increased incidence of chronic hepatitis and even mortality due to HBV infection. This suggests that HBV and HCV infections are serious causes of morbidity and mortality in children with cancer. Med Pediatr Oncol 2003;40:104–110. © 2003 Wiley‐Liss, Inc.
Ciprofloxacin and amoxicillin as continuation treatment of febrile neutropenia in pediatric cancer patients
Authors: Park Julie R. , Coughlin James , Hawkins Douglas , Friedman Debra L. , Burns Jane L. , Pendergrass Thomas
Published: December 2002

Background

The empiric administration of anti‐microbial therapy significantly reduces the morbidity and mortality associated with febrile neutropenic episodes in oncology patients. Outpatient empiric antibiotic therapy can be safely administered to a subset of febrile neutropenic patients at low risk for clinical complications.

Procedure

Pediatric cancer patients presenting with febrile neutropenia after non‐myeloablative chemotherapy and who met institutional criteria for early hospital discharge following a minimum of 48‐hr inpatient empiric intravenous ceftazidime were eligible for the study. The feasibility and efficacy of an outpatient continuation therapy of oral ciprofloxacin (CPR) 25–30 mg/kg/day divided BID and amoxicillin (AMX) 30–50 mg/kg/day divided TID was assessed.

Results

Thirty febrile neutropenic episodes in 26 patients were treated with outpatient oral CPR/AMX therapy. Oral CPR/AMX therapy was feasible in 28 (93%) and efficacious in 26 (87%) of treatment episodes. CPR/AMX was discontinued due to abdominal pain and diarrhea (n = 2), recurrent fever (n = 3), or gastrointestinal bleeding (n = 1). No patient developed new bacteremia or cardiopulmonary decompensation. Bone/joint pain or gastrointestinal symptoms occurred in 27% of treatment episodes. Duration of neutropenia, lower absolute neutrophil count (ANC) (< 100/mm3) at start of oral antibiotic therapy and active malignant disease were associated with failure of oral antibiotic therapy.

Conclusions

It is feasible to administer oral CPR/AMX as continuation antibiotic therapy for a selected subgroup of febrile neutropenic episodes defined after initial hospitalization and empiric antibiotic therapy. Prospectively randomized trials will be required to analyze adequately the efficacy of an oral CPR/AMX outpatient antibiotic regimen for treatment of febrile neutropenia in pediatric oncology patients. Med Pediatr Oncol 2003;40:93–98. © 2003 Wiley‐Liss, Inc.
Perfusion MRI and SPECT of brain after treatment for childhood acute lymphoblastic leukemia
Authors: Pääkkö Eija , Lehtinen Satu , Harila‐Saari Arja , Ahonen Aapo , Jauhiainen Jukka , Torniainen Pentti , Pyhtinen Juhani , Lanning Marjatta
Published: December 2002

Background

Treatment of childhood leukemia may cause perfusion defects in the brain observed by SPECT. Perfusion MRI is a novel method to study brain perfusion which has not been used previously in this setting. This study was performed to compare SPECT with perfusion MRI in patients with acute lymphoblastic leukemia (ALL) after treatment.

Procedure

Nineteen children or young adults underwent perfusion MRI at the cessation of treatment (n = 9) or 4–8 years after the treatment (n = 10). Seventeen of them also underwent SPECT at the time of MRI (within 0–3 days, n = 14) or a couple of months later (1.5–6 months, n = 3). SPECT images and relative cerebral blood volume (CBV) and cerebral blood flow (CBF) maps from perfusion MRI were analyzed visually. Relative CBV ratios of gray matter to white matter and thalamus to white matter were also calculated from the perfusion MRI.

Results

Perfusion MRI did not show any focal perfusion defects, while small defects were observed by SPECT in five of 17 children (29%) in the basal, frontal or temporal areas on the left. No significant differences were observed by perfusion MRI in the relative CBV ratios in the different treatment groups. Time since treatment, age at diagnosis, brain irradiation, or findings in conventional MRI or SPECT did not have any effect on the relative perfusion values either.

Conclusions

SPECT may show small perfusion defects after treatment for childhood leukemia which are not visible by perfusion MRI. The clinical significance or prognosis of these defects is not known. Med Pediatr Oncol 2003;40:88–92. © 2003 Wiley‐Liss, Inc.
Post‐induction residual disease in translocation t(12;21)‐positive childhood ALL
Authors: Seyfarth Jeanette , Madsen Hans O. , Nyvold Charlotte , Ryder Lars P. , Clausen Niels , Jonmundsson Gudmundur K. , Wesenberg Finn , Schmiegelow Kjeld
Published: December 2002

Background

t(12;21)(p1 3;q22), the most frequent chromosomal translocation found in childhood acute lymphoblastic leukemia (ALL), occurs in ∼ 25% of B‐lineage ALL cases and has been claimed to carry a good prognosis.

Procedure

As part of the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL‐MRD 95 study, which includes children from Iceland, Norway, and Denmark diagnose d with ALL, patients were screened for the presence of t(12; 21) by reverse transcriptase‐polymerase chain reaction (RT‐PCR) at diagnosis, and their residual disease was quantified after 4 weeks of induction therapy (prednisolone, vincristine, doxorubicin, i.t. methotrexate) by a competitive, clone‐specific, semi‐nested PCR analysis.

Results

Among 96 children diagnosed with ALL, and quantified for post induction residual disease, 32 were t(12;21)‐positive. The median residual disease was similar for B‐precursor ALL patients with and without t(12;21) (0.009 vs. 0.03%, P  = 0.12).

Conclusions

Al though patients with t(12;21)‐positive ALL have been claimed to have a good outcome, these data indicate that this does not reflect a high sensitivity to prednisolone, vincristine, and doxo rubicin given during induction therapy. Med Pediatr Oncol 2003;40:82–87. © 2003 Wiley‐Liss, Inc.
Gamma‐knife radiosurgery in pediatric cerebral and skull base tumors
Authors: Hirth Asle , Pedersen Paal‐Henning , Baardsen Roald , Larsen John Ludvig , Krossnes Bård K. , Helgestad Jon
Published: December 2002

Background

This retrospective study of 12 children with cerebral or skull base tumors was undertaken to evaluate morbidity and outcome after gamma‐knife surgery.

Procedure

Twelve consecutive children treated with stereotactic radiosurgery in a curative intent were reviewed. There were five girls and seven boys. The mean age at diagnosis was 5.8 years and at radiosurgical treatment 8.4 years. There were four pilocytic astrocytomas, two craniopharyngeomas, two pineoblastomas, two ependymomas, and two other tumors of high malignancy. We used a 201‐source Co60 Leksell gamma knife and all children were treated in general anesthesia.

Results

The mean tumor volume was 3.7 cm3 and the mean tumor margin dose was 13.8 Gy. Seven patients remained stable after gamma‐knife treatment with a mean follow‐ up of 78.6 months. One patient died during follow‐up. The remaining four patients had progressive disease, two within and two outside the irradiated field, and have received further treatment. They are still alive with and without disease with a mean follow‐up of 96.8 months.

Conclusion

Gamma‐knife surgery is an effective treatment in some non‐resectable cerebral and skull base pediatric tumors. In most cases, it is used in combination with other therapeutic modalities. It is safe and well tolerated. Med Pediatr Oncol 2003;40:99–103. © 2003 Wiley‐Liss, Inc.
A discourse: The 2002 Wataru W. Sutow lecture Hodgkin disease in children—perspectives and progress
Authors: Donaldson Sarah S.
Published: December 2002

The Pioneer

Wataru W. Sutow, 1912–1981, was a remarkable and pivotal leader in pediatric oncology. Early in his medical career, he conducted important clinical and anthropometric studies among Japanese and Marshall Island children exposed to atomic radiation. These studies established standards for childhood growth and development still in use today. Dr. Sutow pioneered the multidisciplinary approach to childhood cancer by combining multidrug chemotherapy protocols with surgery and radiotherapy in the common childhood solid tumors. The textbook “Clinical Pediatric Oncology,” of which he was the senior editor, served to define the discipline of pediatric oncology and educate a new era of oncologists in the curative treatment for childhood cancer.

The Past and Present

The first edition of “Clinical Pediatric Oncology,” published in 1973, demonstrated that only children with early‐stage localized Hodgkin disease had a realistic opportunity for cure. Soon the use of combined‐modality therapy consisting of low‐dose, involved‐field radiation plus multi‐agent chemotherapy emerged, and made the goal of cure realistic for all patients. This approach is now universal. Today, the 5‐year relative survival rate for American children with Hodgkin disease, who are under 14 years of age, is 94%, a dramatic and remarkable achievement.

Future

Management of children with Hodgkin disease now involves clinical staging and risk‐adapted, combined‐modality therapy. Clinical and translational research initiatives that hold promise for children with Hodgkin disease in the future include: use of the WHO Classification System combining morphologic and biologic criteria; noninvasive staging procedures with increased sensitivity and specificity; development of a useful prognostic index to define groups for risk‐adapted therapy; high‐dose therapy with stem cell transplantation; and novel therapies. Med Pediatr Oncol 2003;40:73–81. © 2003 Wiley‐Liss, Inc.
A new suboptimal control design for cascaded non‐linear systems
Authors: Qu Zhihua , Cloutier James R.
Published: December 2002

A new suboptimal control design technique is proposed for a class of cascaded non‐linear systems. The design is based on a forward recursive design rather than a backstepping design, and it utilizes a non‐linear tracker derived using the state‐dependent algebraic Riccati equation approach. The proposed design has two distinct features. First, it provides suboptimal performance with respect to a performance index that is defined in terms of the original state and control variables and thus can be prescribed. Second, the forward recursive procedure eliminates differentiation of fictitious controls (or their functions), which makes the design much simpler in applications. Due to the use of the non‐linear tracker, the proposed design has the potential of producing less conservative results than non‐linear servo results. Copyright © 2002 John Wiley & Sons, Ltd.
Decentralized control strategies for dynamic routing
Authors: İftar Altuğ , J. Davison Edward
Published: December 2002

The routing problem in multi‐destination data communication networks is considered. A dynamic model, which can incorporate arbitrary, different, time‐varying processing delays at different nodes, is developed to describe the network dynamics. Based on this model, controllers for routing control are proposed. The structures of the proposed controllers are motivated by an optimal control problem. These proposed controllers are completely decentralized in the sense that all necessary on‐line computations are done locally at each node. Furthermore, the information needed for these computations is related only to the queue lengths at the present node and the adjacent downstream nodes. Both cases when the controls can be continuously changed and when the controls are updated at discrete time instants are considered. In the latter case the controls at different nodes may be updated at different time instants (i.e. the network is not necessarily synchronous). It is shown that the controllers enjoy many desirable properties; in particular, they clear all the queues of the network in the absence of external message arrivals, in finite time. Furthermore, the controllers do not direct messages around a loop. They also have certain robustness properties. Some simulation results relating to a number of realistic problems are presented to illustrate various features of the controllers. Copyright © 2002 John Wiley & Sons, Ltd.
Plasma and red blood cell zinc in cystic fibrosis
Authors: Akanli Leyla , Lowenthal Diana B. , Gjonaj Suzette , Dozor Allen J.
Published: December 2002

The objectives of this study were to measure plasma and red blood cell (RBC) zinc concentrations in patients with cystic fibrosis (CF), and examine their relationship to nutritional status and pulmonary function. Plasma and RBC zinc levels were compared in 53 CF patients ranging in age from 0.5–46 years. Their relationships to weight (% ideal weight) and forced expired volume in 1 sec (FEV1) (% predicted value) were examined. After excluding improperly handled specimens, RBC zinc levels in 51 patients and plasma zinc concentrations in 40 patients were included for analysis. Sixteen of 51 (31%) patients had low RBC zinc levels compared to 4 of 40 (10%) with low plasma zinc concentrations (P < 0.01). Thirteen of 38 patients (34%) in whom both values were obtained had low RBC zinc concentrations compared to 4 of 38 (11%) with low plasma zinc levels (P < 0.022). Neither low RBC nor plasma zinc levels correlated with nutritional status or lung function.

In conclusion, about one third of patients with CF had low RBC zinc levels. Plasma zinc concentrations may not adequately reflect overall zinc status. This deficiency did not appear to be related to either nutritional status or lung function. The significance of low RBC zinc in CF is unknown. Pediatr Pulmonol. 2003; 35:2–7. © 2003 Wiley‐Liss, Inc.
Anterior bridging bronchus
Authors: Rishavy Thomas J. , Goretsky Michael J. , Langenburg Scott E. , Klein Michael D.
Published: December 2002

Previously reported patients with a bridging bronchus (BB) presented with respiratory distress. In addition, each patient had one or more associated anomalies. All but two patients progressed to cardiopulmonary failure and death. We describe a case of an anterior BB without associated anomalies, who did well without operative intervention. This patient presented with a cough at 6 months of age. Chest X‐ray was normal, but due to suspicion of foreign body aspiration, bronchoscopy was performed, which revealed a third bronchus at the carina. Bronchography demonstrated the anatomy of the BB. The patient has continued to do well without further intervention. Pediatr Pulmonol. 2003; 35:70–72. © 2003 Wiley‐Liss, Inc.
Is patient dropout from a longitudinal study of lung function predictable and reversible?
Authors: Turner Stephen W. , le Souëf Peter N.
Published: December 2002

Predictive factors for individuals dropping out from a longitudinal study of lung function have not been described, nor have methods for re‐recruiting dropouts been developed. Our aims were to identify factors predictive of dropout and methods of re‐recruiting dropouts from a longitudinal study of lung function. Details at enrollment into a longitudinal birth cohort study were compared between those who dropped out and those who were assessed 6 and 11 years later. Strategies for identifying individuals successfully contacted at 11 but not 6 years were described.

Of 253 infants enrolled prenatally, 123 (49%) were followed up at age 6 and 194 (77%) at age 11 years. At 6 years, independent risk factors for a child dropping out were: no other sibling enrolled (OR, 4.0; 95% CI, 1.6, 10.1; P = 0.003); being first‐born (OR, 2.8; 95% CI, 1.5, 5.2; P = 0.001); mother completing education at age 15 years (OR, 2.5; 95% CI, 1.3, 4.9; P = 0.007); and mother born overseas (OR, 2.3; 95% CI; 2.8; P = 0.01). The following were predictive of a child dropping out at 11 years: mother born overseas (OR, 4.8; 95% CI, 2.2, 10.2; P < 0.001); paternal smoker (OR, 3.1; 95% CI, 1.5, 6.5; P = 0.003); no other sibling enrolled (OR, 4.1; 95% CI, 1.1, 15.7; P = 0.04); and being first‐born (OR, 2.1; 95% CI, 1.0, 4.3; P < 0.05). Of the 74 families successfully followed up at 11 but not 6 years, 35 (47%) were contacted by using data already held in study records, and 32 (43%) were contacted by databases available to the public.

In conclusion, factors present at enrollment and predictive of dropout from a longitudinal cohort study can be identified. Using a variety of methods, re‐recruitment is possible for many individuals who previously dropped out. Pediatr Pulmonol. 2003; 35:29–33. © 2003 Wiley‐Liss, Inc.
Pulmonary function tests leading to the diagnosis of vascular ring in an infant
Authors: Amirav Israel , Rotschild Moshe , Bar‐Yishay Ephraim
Published: December 2002

A 5‐month‐old baby was referred to our pulmonary clinic because of chronic cough and wheeze, unresponsive to antiasthmatic treatment. Examination in the Infant Pulmonary Function Laboratory suggested an upper airway obstruction. An aberrant right subclavian artery was subsequently confirmed by a barium swallow, flexible bronchoscopy, and an angiographic reconstructed chest CT study. Due to modest symptoms a conservative medical approach was taken. At follow‐up 1 year later, the patient had fewer respiratory and gastrointestinal symptoms. Pediatr Pulmonol. 2003; 35:62–66. © 2003 Wiley‐Liss, Inc.