bluuebunny/crossref_metadata_2025 huggingface dataset:
Oil field and freshwater isolates of Shewanella putrefaciens have lipopolysaccharide polyacrylamide gel profiles characteristic of marine bacteria
Authors: Pickard Christopher , Foght Julia M. , Pickard Michael A. , Westlake Donald W. S.
Published: October 2009

The lipopolysaccharide structure of oil field and freshwater isolates of bacteria that reduce ferric iron, recently classified as strains of Shewanella putrefaciens, was analyzed using polyacrylamide gel electrophoresis and a lipopolysaccharide-specific silver-staining procedure. The results demonstrate that all the oil field and freshwater isolates examined exhibited the more hydrophobic R-type lipopolysaccharide, which has been found to be characteristic of Gram-negative marine bacteria. This hydrophobic lipopolysaccharide would confer an advantage on bacteria involved in hydrocarbon degradation by assisting their association with the surface of oil droplets.Key words: lipopolysaccharide, Shewanella, aquatic bacteria, classification.
Isolation of a hydrogen-producing bacterium, Clostridium beijerinckii strain AM21B, from termites
Authors: Taguchi Fumiaki , Chang Jun Dan , Mizukami Naoki , Saito-Taki Tatsuo , Hasegawa Katsushige , Morimoto Masayoshi
Published: October 2009

Clostridium beijerinckii strain AM21B was isolated from termites. At uncontrolled pH, it produced 108.9 mmol of hydrogen in 24 h from 10 g of glucose at a conversion rate of 105.7 mmol/g dry cells, and it produced 101.6 mmol of hydrogen in 24 h from 10 g of starch at pH 6.0, at a conversion rate of 77.6 mmol/g dry cells at pH 7.0. The hourly maximum hydrogen evolution rates were 22.3 mmol/h from glucose and 18.3 mmol/h from starch at pH 6.5 and 36 °C. Strain AM21B also produced hydrogen from arabinose, cellobiose, fructose, galactose, lactose, sucrose, and xylose at conversion efficiencies ranging from 15.7 to 19.0 mmol/g of substrate for 24 h.Key words: hydrogen production, carbohydrates, bacteria, termites, Clostridium beijerinckii.
The string edit distance matching problem with moves
Authors: Cormode Graham , Muthukrishnan S.
Published: October 2009

The edit distance between two strings
S
and
R
is defined to be the minimum number of character inserts, deletes, and changes needed to convert
R
to
S
. Given a text string
t
of length
n
, and a pattern string
p
of length
m
, informally, the string edit distance matching problem is to compute the smallest edit distance between
p
and substrings of
t
.

We relax the problem so that: (a) we allow an additional operation, namely,
substring moves
; and (b) we allow approximation of this string edit distance. Our result is a near-linear time deterministic algorithm to produce a factor of
O
(log
n
log*
n
) approximation to the string edit distance with moves. This is the first known significantly subquadratic algorithm for a string edit distance problem in which the distance involves nontrivial alignments. Our results are obtained by embedding strings into
L
1
vector space using a simplified parsing technique, which we call
edit-sensitive parsing
(ESP).
Tight bounds for worst-case equilibria
Authors: Czumaj Artur , Vöcking Berthold
Published: October 2009

We study the problem of traffic routing in noncooperative networks. In such networks, users may follow selfish strategies to optimize their own performance measure and therefore, their behavior does not have to lead to optimal performance of the entire network. In this article we investigate the worst-case coordination ratio, which is a game-theoretic measure aiming to reflect the price of selfish routing.

Following a line of previous work, we focus on the most basic networks consisting of parallel links with linear latency functions. Our main result is that the worst-case coordination ratio on
m
parallel links of possibly different speeds is

Θ(log
m
/log log log
m
).

In fact, we are able to give an exact description of the worst-case coordination ratio, depending on the number of links and ratio of speed of the fastest link over the speed of the slowest link. For example, for the special case in which all
m
parallel links have the same speed, we can prove that the worst-case coordination ratio is Γ
(−1)
(
m
) + Θ(1), with Γ denoting the Gamma (factorial) function. Our bounds entirely resolve an open problem posed recently by Koutsoupias and Papadimitriou [1999].
On the difficulty of some shortest path problems
Authors: Hershberger John , Suri Subhash , Bhosle Amit
Published: October 2009

We prove superlinear lower bounds for some shortest path problems in directed graphs, where no such bounds were previously known. The central problem in our study is the
replacement paths
problem: Given a directed graph
G
with non-negative edge weights, and a shortest path
P
= {
e
1
,
e
2
, …,
e

p

} between two nodes
s
and
t
, compute the shortest path distances from
s
to
t
in each of the
p
graphs obtained from
G
by deleting one of the edges
e
i
. We show that the replacement paths problem requires Ω(
m
√
n
) time in the worst case whenever
m
=
O
(
n
√
n
). Our construction also implies a similar lower bound on the
k
shortest simple paths problem for a broad class of algorithms that includes all known algorithms for the problem. To put our lower bound in perspective, we note that both these problems (replacement paths and
k
shortest simple paths) can be solved in near-linear time for
undirected
graphs.
The Pathogenesis of Acute Pulmonary Viral and Bacterial Infections: Investigations in Animal Models
Authors: Lipscomb Mary F. , Hutt Julie , Lovchik Julie , Wu Terry , Lyons C. Rick
Published: October 2009

Acute viral and bacterial infections in the lower respiratory tract are major causes of morbidity and mortality worldwide. The proper study of pulmonary infections requires interdisciplinary collaboration among physicians and biomedical scientists to develop rational hypotheses based on clinical studies and to test these hypotheses in relevant animal models. Animal models for common lung infections are essential to understand pathogenic mechanisms and to clarify general mechanisms for host protection in pulmonary infections, as well as to develop vaccines and therapeutics. Animal models for uncommon pulmonary infections, such as those that can be caused by category A biothreat agents, are also very important because the infrequency of these infections in humans limits in-depth clinical studies. This review summarizes our understanding of innate and adaptive immune mechanisms in the lower respiratory tract and discusses how animal models for selected pulmonary pathogens can contribute to our understanding of the pathogenesis of lung infections and to the search for new vaccines and therapies.
Toward an Antibody-Based HIV-1 Vaccine
Authors: Hoxie James A.
Published: October 2009

Developing an HIV-1 vaccine that can elicit antibodies to prevent infection has been a formidable challenge. Although no single immunogen has generated antibodies that can neutralize diverse isolates, progress has been made in understanding (a) the structure of the HIV-1 envelope glycoprotein, which is targeted by neutralizing antibodies, (b) how HIV-1 evades antibodies made by an infected host, and (c) how rare monoclonal antibodies can exhibit broadly neutralizing activity. Advances in structural and molecular biology coupled with new approaches to isolate neutralizing antibodies from HIV-1-infected individuals are enhancing our understanding of what humoral immune responses will be required for a vaccine. This review summarizes progress in understanding the host antibody response to HIV-1 and current strategies for applying this information to develop an effective vaccine.
Preinvasive Breast Cancer
Authors: Sgroi Dennis C.
Published: October 2009

Preinvasive breast cancer accounts for approximately one-third of all newly diagnosed breast cancer cases in the United States and constitutes a spectrum of neoplastic lesions with varying degrees of differentiation and clinical behavior. High-throughput genetic, epigenetic, and gene-expression analyses have enhanced our understanding of the relationship of these early neoplastic lesions to normal breast tissue, and they strongly suggest that preinvasive breast cancer develops and evolves along two distinct molecular genetic and biological pathways that correlate with tumor grade. Although unique epigenetic and gene-expression changes are not observed in the tumor epithelial compartment during the transition from preinvasive to invasive disease, distinct molecular alterations are observed in the tumor-stromal and myoepithelial cells. This suggests that the stromal and myoepithelial microenvironment of preinvasive breast cancer actively participates in the transition from preinvasive to invasive disease. An improved understanding of the transition from preinvasive to invasive breast cancer will pave the way for novel preventative and therapeutic strategies.
New Methods for Evaluation of Spent Fuel Condition during Long‐Term Storage in Slovakia
Authors: Mikloš M. , Kršjak V.
Published: October 2009

Experiences with an advanced spent nuclear fuel management in Slovakia are presented in this paper. The evaluation and monitoring procedures are based on practices at the Slovak wet interim spent fuel storage facility in NPP Jaslovské Bohunice. Since 1999, leak testing of WWER‐440 fuel assemblies are provided by special leak tightness detection system “Sipping in pool” delivered by Framatomeanp with external heating for the precise defects determination. In 2006, a new inspection stand “SVYP‐440” for monitoring of spent nuclear fuel condition was inserted. This stand has the possibility to open WWER‐440 fuel assemblies and examine fuel elements. Optimal ways of spent fuel disposal and monitoring of nuclear fuel condition were designed. With appropriate approach of conservativeness, new factor for specifying spent fuel leak tightness is introduced in the paper. By using computer simulations (based on SCALE 4.4a code) for fission products creation and measurements by system “Sipping in pool,” the limit values of leak tightness were established.
Serotonin Reuptake Inhibitor and Fluvoxamine-Induced Severe Hyponatremia in a 49-Year-Old Man
Authors: Gabriel Adel
Published: October 2009

Objectives. To describe a case of fluvoxamine-induced severe hyponatremia, most likely due to abnormal antidiuretic hormone excretion (SIADH), and to discuss the implication for maintenance treatments for these patients.Clinical Observations. Although this syndrome had its incidence most commonly among the elderly, we report a case of severe hyponatremia (serum sodium <114 mmol/L), in a relatively young male.Treatment. Symptoms responded well to IV hyperosmolar sodium and to the discontinuation of fluvoxamine. This patient was maintained for treatment on an alternative Selective Serotonin Reuptake Inhibitor (SSRI), Citalopram, without developing recurrence of symptoms.Outcome and Conclusion. Protocols to monitor the maintenance treatments in high-risk patients may be needed to prevent recurrence of serious complications.
Composition Operators from the Weighted Bergman Space to thenth Weighted Spaces on the Unit Disc
Authors: Stević Stevo
Published: October 2009

The boundedness of the composition operator from the weighted Bergman space to the recently introduced by the author, thenth weighted space on the unit disc, is characterized. Moreover, the norm of the operator in terms of the inducing function and weights is estimated.
Linking Innate and Adaptive Immunity: Human Vγ9Vδ2 T Cells Enhance CD40 Expression and HMGB-1 Secretion
Authors: Kalyan Shirin , Chow Anthony W.
Published: October 2009

γδT cells play an important role in regulating the immune response to stress stimuli; however, the mean by which these innate lymphocytes fulfill this function remains poorly defined. The main subset of human peripheral bloodγδT cells responds to nonpeptidic antigens, such as isopentylpyrophosphate (IPP), a metabolite in the mevalonate pathway for both eukaryote and prokaryote cells. IPP-primedγδT cells significantly augment the inflammatory response mediated by monocytes andαβT cells to TSST-1, the staphylococcal superantigen that is the major causative agent of toxic shock syndrome. Here we show that the small pool of activated peripheralγδT cells induces an early upregulation of CD40 on monocytes and the local release of High Mobility Group Box-1 (HMGB-1), the molecule designated as the late mediator of systemic inflammation. This finding provides a new basis for howγδT cells may serve as influential modulators of both endogenous and exogenous stress stimuli.
A NovelSCN5AMutation in a Patient with Coexistence of Brugada Syndrome Traits and Ischaemic Heart Disease
Authors: Holst Anders G. , Calloe Kirstine , Jespersen Thomas , Cedergreen Pernille , Winkel Bo G. , Jensen Henrik Kjaerulf , Leren Trond P. , Haunso Stig , Svendsen Jesper Hastrup , Tfelt-Hansen Jacob
Published: October 2009

Brugada syndrome (BrS) is a primary electrical heart disease, which can lead to sudden cardiac death. In older patients with BrS, the disease may coexist with ischaemic heart disease (IHD) and recent studies support a synergistic proarrhythmic effect of the two disease entities. We report a case that illustrates this. The index patient was a middle-aged patient with BrS traits, IHD, and aborted sudden cardiac death. Mutation analysis discovered a novel mutation P468L in theNaV1.5 sodium channel. Surprisingly, voltage-clamp experiments on the wild-type and mutantNaV1.5 channels expressed in HEK cells revealed no functional effect of the mutation. In a patient like ours, the distinction between IHD and BrS as the cause of an aborted sudden cardiac death is hard to establish and mounting evidence shows that coexistence of the two may have a synergistic proarrhythmic effect.
An epidermal growth factor receptor variant III–targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme
Authors: Sampson John H. , Archer Gary E. , Mitchell Duane A. , Heimberger Amy B. , Herndon James E. , Lally-Goss Denise , McGehee-Norman Sharon , Paolino Alison , Reardon David A. , Friedman Allan H. , Friedman Henry S. , Bigner Darell D.
Published: October 2009

Conventional therapies for glioblastoma multiforme (GBM) fail to target tumor cells exclusively, such that their efficacy is ultimately limited by nonspecific toxicity. Immunologic targeting of tumor-specific gene mutations, however, may allow more precise eradication of neoplastic cells. The epidermal growth factor receptor variant III (EGFRvIII) is a consistent and tumor-specific mutation widely expressed in GBMs and other neoplasms. The safety and immunogenicity of a dendritic cell (DC)–based vaccine targeting the EGFRvIII antigen was evaluated in this study. Adults with newly diagnosed GBM, who had undergone gross-total resection and standard conformal external beam radiotherapy, received three consecutive intradermal vaccinations with autologous mature DCs pulsed with an EGFRvIII-specific peptide conjugated to keyhole limpet hemocyanin. The dose of DCs was escalated in cohorts of three patients. Patients were monitored for toxicity, immune response, radiographic and clinical progression, and death. No allergic reactions or serious adverse events were seen. Adverse events were limited to grade 2 toxicities. The maximum feasible dose of antigen-pulsed mature DCs was reached at 5.7 × 107 ± 2.9 × 107 SD without dose-limiting toxicity. EGFRvIII-specific immune responses were evident in most patients. The mean time from histologic diagnosis to vaccination was 3.6 ± 0.6 SD months. Median time to progression from vaccination was 6.8 months [95% confidence interval (C.I.95), 2.5–8.8], and median survival time from vaccination was 18.7 months (C.I.95, 14.5–25.6). Overall median survival from time of histologic diagnosis was 22.8 months (C.I.95, 17.5–29). This study establishes the EGFRvIII mutation as a safe and immunogenic tumor-specific target for immunotherapy. [Mol Cancer Ther 2009;8(10):2773–9]
Therapeutic potential of hepatocyte growth factor/scatter factor neutralizing antibodies: Inhibition of tumor growth in both autocrine and paracrine hepatocyte growth factor/scatter factor:c-Met-driven models of leiomyosarcoma
Authors: Gao Chong-Feng , Xie Qian , Zhang Yu-Wen , Su Yanli , Zhao Ping , Cao Brian , Furge Kyle , Sun Jan , Rex Karen , Osgood Tao , Coxon Angela , Burgess Teresa L. , Vande Woude George F.
Published: October 2009

Hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, c-Met, have been implicated in the growth and progression of a variety of solid human tumors. Thus, inhibiting HGF/SF:c-Met signaling may provide a novel therapeutic approach for treating human tumors. We have generated and characterized fully human monoclonal antibodies that bind to and neutralize human HGF/SF. In this study, we tested the effects of the investigational, human anti-human HGF/SF monoclonal antibody, AMG 102, and a mixture of mouse anti-human HGF/SF monoclonal antibodies (Amix) on HGF/SF-mediated cell migration, proliferation, and invasion in vitro. Both agents had high HGF/SF-neutralizing activity in these cell-based assays. The HGF/SF:c-Met pathway has been implicated in the growth of sarcomas; thus, we also investigated the effect of AMG 102 on the growth of human leiomyosarcoma (SK-LMS-1) in HGF/SF transgenic C3H severe combined immunodeficient mice engineered to express high levels of human HGF/SF, as well as tumor growth of an autocrine variant of the SK-LMS-1 cell line (SK-LMS-1TO) in nude mice. The results indicate that interrupting autocrine and/or paracrine HGF/SF:c-Met signaling with AMG 102 has profound antitumor effects. These findings suggest that blocking HGF/SF:c-Met signaling may provide a potent intervention strategy to treat patients with HGF/SF:c-Met–dependent tumors. [Mol Cancer Ther 2009;8(10):2803–10]
A modeling analysis of the effects of molecular size and binding affinity on tumor targeting
Authors: Schmidt Michael M. , Wittrup K. Dane
Published: October 2009

A diverse array of tumor targeting agents ranging in size from peptides to nanoparticles is currently under development for applications in cancer imaging and therapy. However, it remains largely unclear how size differences among these molecules influence their targeting properties. Here, we develop a simple, mechanistic model that can be used to understand and predict the complex interplay between molecular size, affinity, and tumor uptake. Empirical relationships between molecular radius and capillary permeability, interstitial diffusivity, available volume fraction, and plasma clearance were obtained using data in the literature. These relationships were incorporated into a compartmental model of tumor targeting using MATLAB to predict the magnitude, specificity, time dependence, and affinity dependence of tumor uptake for molecules across a broad size spectrum. In the typical size range for proteins, the model uncovers a complex trend in which intermediate-sized targeting agents (MW, ∼25 kDa) have the lowest tumor uptake, whereas higher tumor uptake levels are achieved by smaller and larger agents. Small peptides accumulate rapidly in the tumor but require high affinity to be retained, whereas larger proteins can achieve similar retention with >100-fold weaker binding. For molecules in the size range of liposomes, the model predicts that antigen targeting will not significantly increase tumor uptake relative to untargeted molecules. All model predictions are shown to be consistent with experimental observations from published targeting studies. The results and techniques have implications for drug development, imaging, and therapeutic dosing. [Mol Cancer Ther 2009;8(10):2861–71]
Pentagalloylglucose induces autophagy and caspase-independent programmed deaths in human PC-3 and mouse TRAMP-C2 prostate cancer cells
Authors: Hu Hongbo , Chai Yubo , Wang Lei , Zhang Jinhui , Lee Hyo Jeong , Kim Sung-Hoon , Lü Junxuan
Published: October 2009

Penta-1,2,3,4,6-O-galloyl-β-d-glucose (PGG) suppresses the in vivo growth of human DU145 and PC-3 prostate cancer xenografts in nude mice, suggesting potential utility as a prostate cancer chemotherapeutic or chemopreventive agent. Our earlier work implicates caspase-mediated apoptosis in DU145 and LNCaP prostate cancer cells as one mechanism for the anticancer activity. We show here that, in the more aggressive PC-3 prostate cancer cell line, PGG induced programmed cell deaths lacking the typical caspase-mediated apoptotic morphology and biochemical changes. In contrast, PGG induced patent features of autophagy, including formation of autophagosomes and lipid modification of light chain 3 after 48 hours of PGG exposure. The “autophagic” responses were also observed in the murine TRAMP-C2 cells. Caspase inhibition exacerbated PGG-induced overall death. As for molecular changes, we observed a rapid inhibition of the phosphorylation of mammalian target of rapamycin–downstream targets S6K and 4EBP1 by PGG in PC-3 and TRAMP-C2 cells but not that of mammalian target of rapamycin itself, along with increased AKT phosphorylation. Whereas the inhibition of phosphatidylinositol 3-kinase increased PGG-induced apoptosis and autophagy, experiments with pharmacologic inducer or inhibitor of autophagy or by knocking down autophagy mediator Beclin-1 showed that autophagy provided survival signaling that suppressed caspase-mediated apoptosis. Knocking down of death receptor-interacting protein 1 kinase increased overall death without changing light chain 3-II or caspase activation, thus not supporting death receptor-interacting protein 1–necroptosis for PGG-induction of autophagy or other programmed cell death. Furthermore, PGG-treated PC-3 cells lost clonogenic ability. The induction by PGG of caspase-independent programmed cell death in aggressive prostate cancer cell lines supports testing its merit as a potential drug candidate for therapy of caspase-resistant recurrent prostate cancer. [Mol Cancer Ther 2009;8(10):2833–43]
Escape from hsa-miR-519c enables drug-resistant cells to maintain high expression of ABCG2
Authors: To Kenneth K.W. , Robey Robert W. , Knutsen Turid , Zhan Zhirong , Ried Thomas , Bates Susan E.
Published: October 2009

Overexpression of ABCG2 has been reported in cell lines selected for drug resistance and it is widely believed to be important in the clinical pharmacology of anticancer drugs. We and others have previously identified and validated two microRNAs (miRNA; hsa-miR-519c and hsa-miR-520h) targeting ABCG2. In this study, the shortening of the ABCG2 3′ untranslated region (3′UTR) was found to be a common phenomenon in several ABCG2-overexpressing resistant cell lines, which as a result removes the hsa-miR-519c binding site and its repressive effects on mRNA stability and translation blockade, thereby contributing to drug resistance. On the other hand, reduced expression of hsa-miR-520h, previously thought to have allowed ABCG2 overexpression, was found to be caused by the sequestering of the miRNA by the highly expressed ABCG2. In drug-sensitive cells, inhibitors against hsa-miR-519c and hsa-miR-520h could augment the cytotoxic effect of mitoxantrone, suggesting a substantial role for both miRNAs in controlling ABCG2 level and thereby anticancer drug response. However, in drug-resistant cells, altering the levels of the two miRNAs did not have any effect on sensitivity to mitoxantrone. Taken together, these studies suggest that in ABCG2-overexpressing drug-resistant cells, hsa-miR-519c is unable to affect ABCG2 expression because the mRNA lacks its binding site, whereas hsa-miR-520h is sequestered and unable to limit ABCG2 expression. Given the recent observation that a truncated 3′UTR is also observed in ABCG2-overexpressing human embryonic stem cells, our results in drug-resistant cell lines suggest that 3′UTR truncation is a relatively common mechanism of ABCG2 regulation. [Mol Cancer Ther 2009;8(10):2959–68]
Tubulin-based antimitotic mechanism of E7974, a novel analogue of the marine sponge natural product hemiasterlin
Authors: Kuznetsov Galina , TenDyke Karen , Towle Murray J. , Cheng Hongsheng , Liu Junke , Marsh Joanne P. , Schiller Shawn E.R. , Spyvee Mark R. , Yang Hu , Seletsky Boris M. , Shaffer Christina J. , Marceau Veronique , Yao Ye , Suh Edward M. , Campagna Silvio , Fang Francis G. , Kowalczyk James J. , Littlefield Bruce A.
Published: October 2009

E7974 is a synthetic analogue of the marine sponge natural product hemiasterlin. Here, we show that E7974, such as parental hemiasterlin, acts via a tubulin-based antimitotic mechanism. E7974 inhibits polymerization of purified tubulin in vitro with IC50 values similar to those of vinblastine. In cultured human cancer cells, E7974 induces G2-M arrest and marked disruption of mitotic spindle formation characteristic of tubulin-targeted anticancer drugs. Extensive hypodiploid cell populations are seen in E7974-treated cells, indicating initiation of apoptosis after prolonged G2-M blockage. Consistent with this observation, E7974 induces caspase-3 activation and poly ADP ribose polymerase cleavage, typical biochemical markers of apoptosis. Only a short cellular exposure to E7974 is sufficient to induce maximum mitotic arrest, suggesting that E7974's antitumor effects in vivo may persist even after blood levels of the drug decrease after drug administration. Interactions of E7974 with purified tubulin were investigated using two synthetic tritiated photoaffinity analogues incorporating a benzophenone photoaffinity moiety at two different positions of the E7974 scaffold. Both analogues preferentially photolabeled α-tubulin, although minor binding to β-tubulin was also detected. E7974 thus seems to share a unique, predominantly α-tubulin–targeted mechanism with other hemiasterlin-based compounds, suggesting that, unlike many tubulin-targeted natural products and related drugs, the hemiasterlins evolved to mainly target α-tubulin, not β-tubulin subunits. [Mol Cancer Ther 2009;8(10):2852–60]
Low-dose metronomic cyclophosphamide combined with vascular disrupting therapy induces potent antitumor activity in preclinical human tumor xenograft models
Authors: Daenen Laura G. , Shaked Yuval , Man Shan , Xu Ping , Voest Emile E. , Hoffman Robert M. , Chaplin David J. , Kerbel Robert S.
Published: October 2009

Vascular disrupting agents preferentially target the established but abnormal tumor vasculature, resulting in extensive intratumoral hypoxia and cell death. However, a rim of viable tumor tissue remains from which angiogenesis-dependent regrowth can occur, in part through the mobilization and tumor colonization of circulating endothelial progenitor cells (CEP). Cotreatment with an agent that blocks CEPs, such as a vascular endothelial growth factor pathway–targeting biological antiangiogenic drug, results in enhanced antitumor efficacy. We asked whether an alternative therapeutic modality, low-dose metronomic chemotherapy, could achieve the same result given its CEP-targeting effects. We studied the combination of the vascular disrupting agent OXi4503 with daily administration of CEP-inhibiting, low-dose metronomic cyclophosphamide to treat primary orthotopic tumors with the use of the 231/LM2-4 breast cancer cell line and MeWo melanoma cell line. In addition, CEP mobilization and various tumor characteristics were assessed. We found that daily p.o. low-dose metronomic cyclophosphamide was capable of preventing the CEP spike and tumor colonization induced by OXi4503. This was associated with a decrease in the tumor rim and marked suppression of primary 231/LM2-4 growth in nude as well as severe combined immunodeficient mice. Similar results were found in MeWo-bearing nude mice. The delay in tumor growth was accompanied by significant decreases in microvessel density, perfusion, and proliferation, and a significant increase in tumor cell apoptosis. No overt toxicity was observed. The combination of OXi4503 and metronomic chemotherapy results in prolonged tumor control, thereby expanding the list of therapeutic agents that can be successfully integrated with metronomic low-dose chemotherapy. [Mol Cancer Ther 2009;8(10):2872–81]
Pentasomy 49,XXXXY Diagnosed in utero: Case Report and Systematic Review of Antenatal Findings
Authors: Peitsidis P. , Manolakos E. , Peitsidou A. , Petersen M.B. , Tsoplou P. , Kadir R. , Agapitos E.
Published: October 2009

Objectives: Pentasomy 49,XXXXY is a rare sex chromosome polysomy usually diagnosed postnatally by the combina- tion of mental retardation, facial dysmorphism, and genital, cardiac and skeletal malformations. Prenatal detection of 49,XXXXY is unusual and may be incidental due to non-specific ultrasound (US) findings. We report a case of 49,XXXXY diagnosed prenatally and present a literature review of the few prenatally diagnosed cases. Methods: We searched the PubMed electronic database without year and language restriction, using the keywords ‘Prenatal’, ‘Diagnosis’, and ‘49,XXXY’, performing a systematic review. Results: We report a 35-year-old patient with normal first-trimester US but increased combined risk for trisomies 18 and 13. Amniocentesis at 16 weeks of gestation revealed a 49,XXXXY karyotype. Pregnancy was terminated at 19 weeks’ gestation, and a male fetus with facial dysmorphism and hypospadia was delivered. A total of 12 articles were identified in the systematic review. All were case reports and dated from 1980 until 2008. The mean maternal age was 34.8 years (range 30–41). The most common prenatal US feature was cystic hygroma, present in 5 cases. Hypogenitalism was the most common macroscopic clinical feature identified after pathology examination in 7 cases. In 2 cases, there was an increase in first-trimester combined risk for trisomy 21. Conclusions: Pentasomy 49,XXXXY is associated with a variety of non-specific US findings, of which cystic hygroma was the commonest. No specific sequence of findings could be identified in this review.
Amniotic Fluid Index Accuracy in Mid-Trimester
Authors: Hernández-Herrera Ricardo J. , Ochoa-Torres Mauro , Salazar-García Dinorah , Solis-Estrada Bricia
Published: October 2009

Objective: The aim of this trial was to evaluate the correlation between amniotic fluid index (AFI) and the real amniotic volume in mid-trimester pregnancies. Methods: Eight women with mid-trimester anhydramnios pregnancies were included. Patients gave their informed consent. Those with premature rupture of membranes were excluded. Amnioinfusion was performed by instilling up to 400 ml of saline solution in 100 ml aliquots. With the patient in supine position, the AFI was determined by the sum of measurements of the deepest vertical pools in each of the 4 quadrants of the maternal uterus, evaluating the AFI after every 100 ml of infused solution. Statistical analysis was performed by analysis of variance, determination coefficient, linear correlation and t test. Results: We realized 29 AFI measurements after amnioinfusions of 100, 200, 300 and 400 ml of saline solution. The AFI ranges that corresponded to the infused volume were: after 100 ml = 5–11 cm (median 6.5 cm); after 200 ml = 9–12.7 cm (median 10.3 cm); after 300 ml = 10–17 cm (median 13.5 cm), and after 400 ml = 12–16 cm (median 15 cm). The correlation between the AFI and the volume infused was r = 0.81 (p < 0.0001), the variance was r2 = 0.65, suggesting that 65% of the variation in AFI measurements is directly accounted for by the amniotic fluid volume and 35% of the AFI measurements is accounted for by factors other than amniotic volume. Conclusions: We obtained a strong correlation between AFI and amnioinfusion volume (median of 6.5, 10.3, 13.5 and 15 cm after amniotic infusion of 100, 200, 300 and 400 ml of saline solution, respectively). The variance (0.65) suggests that 35% of AFI measurements is accounted for by factors other than amniotic fluid volume.
Total Blood Volume Is Maintained in Nonhydropic Fetuses with Severe Hemolytic Anemia
Authors: Pasman S.A. , Bil-van den Brink C.P. , Kamping M.A. , Adama van Scheltema P.N. , Oepkes D. , Vandenbussche F.P.H.A.
Published: October 2009

Objective: Fetal alloimmune anemia is associated with increased blood flow velocities and cardiomegaly. In severe cases, hydrops can develop. We investigated whether the decrease of red blood cell volume is associated with a reduction or expansion of plasma volume. Methods: In 86 alloimmunized fetuses that received a first intrauterine transfusion, we calculated fetal total blood volumes (i.e. fetoplacental blood volumes) using a dilutional principle of fetal hemoglobin with adult hemoglobin. The relation between total blood volume and estimated fetal weight, severity of anemia and hydrops was analyzed. Results: Gestational age ranged from 17 to 35 weeks. Mean hemoglobin deficit was 6.8 standard deviations (range 2.1–11.7) below the normal mean. Fetal total blood volume was significantly related to estimated fetal weight (p < 0.001). Mean total blood volume in nonhydropic fetuses was 123 ml/kg (n = 74) and in hydropic fetuses 144 ml/kg (n = 12). There was a significant relation between total blood volume per kg body weight and hydrops (p = 0.035); however, there was no relation with severity of anemia (p = 0.94). Conclusion: In the human nonhydropic fetus with severe hemolytic anemia, total blood volume is maintained: the decrease in red blood cell volume is thus compensated by an increase in plasma volume. In hydropic fetuses, however, total blood volume seems to be increased. This is in accordance with the hypothesis that congestive heart failure plays a role in the pathophysiology of hydrops in anemic fetuses.
Development of the Fetal Duodenum: A Postmortem Study
Authors: Desdicioglu K. , Malas M.A. , Evcil E.H.
Published: October 2009

Objective: To gather detailed morphometric data to be able to assess fetal development of the duodenum and its morphology. Material and Method: The present study was carried out on 222 human fetuses (114 males, 108 females) aged 9–40 weeks of gestation with no external pathology or anomaly. Fetuses were grouped based on gestational weeks, months and trimesters. Once general external measurements of the fetuses were carried out, the abdominal wall was dissected. The relationships between the duodenum and surrounding structures and its localization were determined. Morphometric data on height, width, length and diameters were gathered. Findings: Means and standard deviations of all parameters were calculated for each gestational week, month and trimester. There were significant relations between measured parameters and gestational age (p < 0.001). There were no sex differences in parameters (p > 0.05). All data were compared with previous studies and discussed. Conclusion: Data obtained in this study will contribute to other studies carried out in obstetrics, perinatology, forensic medicine and fetal pathology departments, aimed at identifying anomalies, pathologies and variations of the duodenum and treatment of such cases.
Total and Fetal Cell-Free DNA Analysis in Maternal Blood as Markers of Placental Insufficiency in Intrauterine Growth Restriction
Authors: Al Nakib M. , Desbrière R. , Bonello N. , Bretelle F. , Boubli L. , Gabert J. , Levy-Mozziconacci A.
Published: October 2009

Objective: To compare total and fetal DNA levels in the maternal plasma in three groups: pregnancies with intrauterine growth restriction (IUGR) due to placental insufficiency (PI) and other causes, and in control pregnancies. Methods: Total as well as fetal DNA was quantified in 78 maternal plasma samples. In 19 pregnancies, the fetus presented IUGR due to PI (group A), and in 31 pregnancies due to other causes (group B). The control group comprised 28 patients (group C). DNA quantification was done using real-time quantitative PCR with a standardized pool of plasmid calibrators. DNA concentrations of the three groups were compared using non-parametric tests (Kruskal-Wallis or Mann-Whitney tests). Results: The three groups did not statistically differ regarding maternal age (mean ± SD: 30.5 ± 5.4 years), gestational age (30 ± 5.3 weeks) or the proportion of male fetuses (48.2%). Plasma total DNA was significantly higher in group A compared to groups B and C (p = 0.001 for both). An increase in fetal DNA was only observed in group A for patients beyond 28 weeks of gestation. Conclusions: The plasma total DNA level is higher in patients with IUGR due to PI. These results suggest the presence of maternal endothelial damage independently of preeclampsia.
Impact of First-Trimester Aneuploidy Screening in a High-Risk Population
Authors: Nadel Allan S. , Likhite Marisa L.
Published: October 2009

Objective: To determine the impact on maternal decision-making of offering first-trimester screening to women at increased risk for fetal aneuploidy. Methods: A retrospective chart review of all patients ≥35 years of age at delivery who registered to deliver at Massachusetts General Hospital before (2000–2002; n = 1,604) and after (2003–2005; n = 1,915) the introduction of first-trimester screening. Demographics, the choice of screening test and/or invasive procedure (chorionic villus sampling or amniocentesis), and the detection rate of fetal aneuploidy were compared between the two groups by χ2 test. Aneuploid newborns without an antenatal diagnosis were reviewed in detail. Results: The fraction of women who accepted prenatal screening and/or an invasive procedure increased from 1,122/1,604 (70%) to 1,751/1,915 (91%, p < 0.01) after the introduction of first-trimester screening. Fewer invasive procedures were done in the second time period, due to a decrease from 40 to 14% in the fraction of women going straight to an invasive procedure without screening (p < 0.01). Similar numbers of aneuploid fetuses were detected prenatally in the two time periods: 21/22 (95%) in the first time period and 22/25 (88%) in the second (p = 0.36). All 4 cases not prenatally diagnosed involved the patient’s decision to decline screening or ignore positive screening results. Conclusion: The introduction of first-trimester screening in a high-risk population was associated with an increase in the acceptance of prenatal screening and a reduction in the invasive procedure rate without a concomitant decrease in the detection of fetal aneuploidy.
Loeys-Dietz Syndrome in Pregnancy: A Case Description and Report of a Novel Mutation
Authors: Gutman Guy , Baris Hagit N. , Hirsch Raphael , Mandel Dror , Yaron Yuval , Lessing Joseph B. , Kuperminc Michael J.
Published: October 2009

Loeys-Dietz syndrome is a syndrome caused by heterozygous mutations in the genes encoding type 1 or 2 transforming growth factor-β receptor (TGF-β-R1/2). The obstetrical manifestations are risk of rupture of the gravid uterus and the arteries, either during pregnancy or in the immediate postpartum period, and damage to the vagina, perineum and the colon. We describe, for the first time, a new TGF-β-R2 gene mutation in a family with several individuals who either had aortic rupture and dissection, sudden death or aortic root dilatation. The pregnancy was followed up and the baby was successfully delivered by a cesarean section at 34 weeks of gestation. The mother’s recovery was uneventful and the baby was negative for the mutation on postnatal molecular testing. With appropriate supervision and early delivery by cesarean section, women with Loeys-Dietz syndrome can tolerate pregnancy and delivery without any adverse effect.
First Trimester Diagnosis of Sirenomelia by 2D and 3D Ultrasound
Authors: Contu Rossana , Zoppi Maria A. , Axiana Carolina , Ibba Rosa M. , Monni Giovanni
Published: October 2009

A case of sirenomelia in a 27-year-old woman detected at 11 weeks 5 days of gestation is presented. It was suspected by two-dimensional sonography and color Doppler imaging. Three-dimensional ultrasound confirmed the final diagnosis. With detailed evaluation of the acquired volumes, valuable information was obtained about the anatomical as well as pathological features of the fetus.
Dichorionic Triamniotic Triplet Pregnancy Complicated by Acardius Acormus
Authors: Abi-Nader Khalil , Whitten Sara M. , Filippi Elisa , Scott Rosemary , Jauniaux Eric
Published: October 2009

This report describes an acardiac fetus of the acormus phenotype in a triplet pregnancy. The diagnosis was confirmed at 15 weeks. In the absence of signs of heart failure in the co-fetus the pregnancy was managed conservatively. The pregnancy was complicated by preterm labour and the fetuses were delivered at 26+5 weeks. The prenatal diagnosis of the acormus phenotype with a well-developed cephalic pole is extremely rare and has never been described antenatally in a higher order multiple pregnancy. We suggest that this rare acardiac fetus phenotype may have a different pathophysiology than those of other phenotypes. The report also summarizes the perinatal outcomes of triplet pregnancies complicated by an acardiac fetus, where the median gestational age at delivery is 26–27 weeks, and discusses the possible therapeutic interventions.
Cornelia de Lange Syndrome: A Recognizable Fetal Phenotype
Authors: Wilmink F.A. , Papatsonis D.N.M. , Grijseels E.W.M. , Wessels M.W.
Published: October 2009

We describe a fetus with Cornelia de Lange syndrome diagnosed after termination of pregnancy at 21 weeks. Prenatally, growth retardation, diaphragmatic hernia, cystic hygroma and a right hand with only three rays were diagnosed by ultrasound in the second trimester of pregnancy. Postnatal magnetic resonance imaging confirmed the prenatal findings, and the presence of the typical dysmorphic features led to the diagnosis of Cornelia de Lange syndrome. The diagnosis was confirmed by the finding of a truncating mutation in the NIPBL gene. This case illustrates that the diagnosis Cornelia the Lange syndrome can be suspected prenatally in the second trimester, and can be diagnosed in fetuses after induction or newborns at birth as the typical phenotype is present early.
Reversed Twin-to-Twin Transfusion Syndrome following Successful Laser Therapy
Authors: Fox Caroline E. , Chan Ben C. , Cox Phillip , Gornall Adam , Kilby Mark D.
Published: October 2009

We report a case of severe twin-to-twin transfusion syndrome (TTTS) in which fetoscopic laser ablation was successfully performed at 21 weeks’ gestation. Despite successful resolution of signs on ultrasound examination after a period of 7 weeks, the donor developed polyhydramnios whereas the ‘initial’ recipient maintained normal liquor volume, features suggestive of ‘reversed TTTS’. Two live babies were delivered at 31 weeks’ gestation with good neonatal outcome. The karyotype of both babies was normal. No significant inter-twin difference in umbilical vein haemoglobin levels was present at delivery and placental injection studies did not identify persistent anastomoses. This case report supports the importance of close monitoring of the pregnancy following apparently successful laser therapy. Further research is needed to understand the pathophysiology of this condition.
Intrauterine Treatment of Large Fetal Neck Lymphangioma with OK-432
Authors: Mikovic Zeljko , Simic Radoje , Egic Amira , Stosic Opincal Tatjana , Koprivsek Katarina , Stanojevic Dusan , Bogavac Mirjana , Popovac Mirjana , Mandic Vesna
Published: October 2009

Lymphangiomas are benign vascular malformations of the lymphatic system and most commonly present in the neck area. Large lymphangiomas may compress and/or displace the larynx, trachea and esophagus and cause serious respiratory and feeding problems in neonates. Prenatal therapy could eliminate the risks of the mentioned complications. Prenatal therapy may include the EXIT (ex utero intrapartum treatment) procedure. As this procedure has certain risks for both the neonate and mother, the introduction of a safer method is justified. The use of OK-432, as a sclerosing agent, has shown positive results in several published cases of cystic hygroma, but there is no study about the prenatal use of this agent in the treatment of lymphangioma. The aim of this study was to present our experience with intrauterine intralesional injection of OK-432 in the treatment of neck lymphangiomas. Two cases of large multicystic neck lymphangiomas that were closely situated to the fetal airway were treated by single intralesional injection of OK-432. We noticed a progressive decrease in tumor volume throughout gestation. We did not experience any complications and there were no respiratory or feeding problems in the neonates. The esthetical appearance was satisfactory and both children were normal at the age of 2 years and 6 months, respectively. This report suggests that prenatal intralesional injection of OK-432 might be a safe and effective treatment in selected cases with large fetal neck lymphangiomas.
Value of Amniocentesis versus Fetal Tissue for Cytogenetic Analysis in Cases of Fetal Demise
Authors: Bryant Borders Ann E. , Greenberg Jessica , Plaga Stacey , Shepard-Hinton Megan , Yates Carin , Elias Sherman , Shulman Lee P.
Published: October 2009

Objective: Use of fetal tissue for cytogenetic analysis in cases of second- and third-trimester fetal demise frequently results in unacceptably high failure rates. We reviewed our ongoing use of amniocentesis prior to uterine evacuation to determine if this provided a better source of cells for cytogenetic analysis. Methods: We compared cytogenetic results using fetal tissues obtained following uterine evacuation to our ongoing use of amniotic fluid cell obtained by transabdominal amniocentesis prior to uterine evacuation from 2003 to 2008. Results: In 49 of the 63 cases evaluated by fetal tissue biopsies performed after uterine evacuation, a karyotypic analysis was obtained (77.8%). Among the 38 cases evaluated by amniocentesis, an amniotic fluid sample and fetal cytogenetic results were obtained in all 38 (100%) cases. Conclusion: Our findings indicate that amniocentesis is a more reliable source of cytogenetic information than fetal tissue in cases of second- and third-trimester fetal demise.
Prognosis of Spina Bifida in the Era of Prenatal Diagnosis and Termination of Pregnancy
Authors: Aguilera Susana , Soothill Peter , Denbow Mark , Pople Ian
Published: October 2009

Objective: To evaluate the current outcome of a selected prenatally diagnosed spina bifida group. Materials andMethods: We analyzed and followed up 74 cases of prenatally diagnosed spina bifida. Results: Termination of pregnancy was chosen in 72% of the cases and 28% were live-born. Chromosomal defects were identified in 16%, although only 1.6% in isolated cases. Of the 21 live births, 3 died in the neonatal period. The other 18 (86%) were all alive after an average follow-up of 3 years and 6 months (range 5 months to 7 years and 4 months). From this group 11% are wheelchair-dependent, 87% of the patients older than 2 years of age are walking, 33% have had cerebral shunting and 72% have normal neurodevelopment. There was a better outcome in patients with closed defects; however, the rates of neuropathic bladder (50%) remain a concern. Conclusions: Even with prenatal diagnosis and a tendency towards apparently less severe defects in the cases in which the pregnancies continue, the prognosis in terms of morbidity needs to remain guarded.
Prenatal Diagnosis of Fetal Cataract: Case Report and Review of the Literature
Authors: Léonard Alexandre , Bernard Pierre , Hiel Anne-Lise , Hubinont Corinne
Published: October 2009

Objectives: To report a case of prenatally diagnosed fetal cataract and conduct a systematic review of previously reported cases. Methods: Review of the literature based mainly on Pubmed search using specific keywords in order to list cataract causes diagnosed prenatally and in early childhood, isolated or associated with microphthalmia. Results and Discussion: A differential diagnosis list and specific prenatal diagnosis testing are suggested in order to offer the best management of this rare fetal condition.