bluuebunny/crossref_metadata_2025 huggingface dataset:
In Vivo Characterization of the Peptide Deformylase Inhibitor LBM415 in Murine Infection Models
Authors: Osborne Colin S. , Neckermann Georg , Fischer Evelin , Pecanka Robert , Yu Donghui , Manni Kari , Goldovitz Julie , Amaral Kerri , Dzink-Fox JoAnn , Ryder Neil S.
Published: July 2009

LBM415 is an antibacterial agent belonging to the peptide deformylase inhibitor class of compounds. It has previously been shown to demonstrate good activity in vitro against a range of pathogens. In this study, the in vivo efficacy of LBM415 was evaluated in various mouse infection models. We investigated activity against a systemic infection model caused by intraperitoneal inoculation ofStaphylococcus aureus(methicillin [meticillin] susceptible [MSSA] and methicillin resistant [MRSA]) andStreptococcus pneumoniae(penicillin susceptible [PSSP] and multidrug resistant [MDRSP]), a thigh infection model caused by intramuscular injection of MRSA, and a lung infection produced by intranasal inoculation of PSSP. In the systemic MSSA and MRSA infections, LBM415 was equivalent to linezolid and vancomycin. In the systemic PSSP infection, LBM415 was equivalent to linezolid, whereas against systemic MDRSP infection, the LBM415 50% effective dose (ED50) was 4.8 mg/kg (dosed subcutaneously) and 36.6 mg/kg (dosed orally), compared to 13.2 mg/kg for telithromycin and >60 mg/kg for penicillin V and clarithromycin. In the MRSA thigh infection, LBM415 significantly reduced thigh bacterial levels compared to those of untreated mice, with levels similar to those after treatment with linezolid at the same dose levels. In the pneumonia model, the ED50to reduce the bacterial lung burden by >4 log10in 50% of treated animals was 23.3 mg/kg for LBM415, whereas moxifloxacin showed an ED50of 14.3 mg/kg. In summary, LBM415 showed in vivo efficacy in sepsis and specific organ infection models irrespective of resistance to other antibiotics. Results suggest the potential of peptide deformylase inhibitors as a novel class of therapeutic agents against antibiotic-resistant pathogens.
The Arabinosyltransferase EmbC Is Inhibited by Ethambutol in
Mycobacterium tuberculosis
Authors: Goude R. , Amin A. G. , Chatterjee D. , Parish T.
Published: July 2009

Ethambutol (EMB) is an antimycobacterial drug used extensively for the treatment of tuberculosis caused by
Mycobacterium tuberculosis
. EMB targets the biosynthesis of the cell wall, inhibiting the synthesis of both arabinogalactan and lipoarabinomannan (LAM), and is assumed to act via inhibition of three arabinosyltransferases: EmbA, EmbB, and EmbC. EmbA and EmbB are required for the synthesis of arabinogalactan, and at least one enzyme (
M. tuberculosis
EmbA [EmbA
Mt
]) is essential in
M. tuberculosis
. EmbC
Mt
is also essential for the viability of
M. tuberculosis
but is involved in the synthesis of LAM. We show that mutations in EmbC
Mt
that reduce its arabinosyltransferase activity result in increased sensitivity to EMB and the production of smaller LAM species in
M. tuberculosis
. Overexpression of EmbC
Mt
was not tolerated in
M. tuberculosis
, but overexpression of
M
ycobacterium smegmatis
EmbC (EmbC
Ms
) led to EMB resistance and the production of larger LAM species in
M. tuberculosis
. Treatment of wild-type
M. tuberculosis
strains with EMB led to inhibition of LAM synthesis, resulting in the production of smaller species of LAM. In contrast, no change in LAM production was seen in EMB-resistant strains. Overexpression of EmbB
Ms
in
M. tuberculosis
also resulted in EMB resistance, but at a lower level than that caused by EmbC
Ms
. Overexpression of EmbA
Mt
in
M. tuberculosis
had no effect on EMB resistance. Thus, there is a direct correlation between EmbC activity and EMB resistance, as well as between EmbC activity and the size of the LAM species produced, confirming that EmbC is one of the cellular targets of EMB action.
Antimalarial Activity of Tigecycline, a Novel Glycylcycline Antibiotic
Authors: Starzengruber P. , Thriemer K. , Haque R. , Khan W. A. , Fuehrer H. P. , Siedl A. , Hofecker V. , Ley B. , Wernsdorfer W. H. , Noedl H.
Published: July 2009

Tigecycline is a novel glycylcycline antibiotic with a broad antibacterial spectrum. Tigecycline was tested with 66 clinical isolates of
Plasmodium falciparum
from Bangladesh using the histidine-rich protein 2 in vitro drug susceptibility assay. The 50% and 90% inhibitory concentrations of tigecycline were 699 (95% confidence interval, 496 to 986) and 5,905 nM (4,344 to 8,028). Tigecycline shows no activity correlation with traditional antimalarials and has substantial antimalarial activity on its own.
Anti-Human Immunodeficiency Virus Activity, Cross-Resistance, Cytotoxicity, and Intracellular Pharmacology of the 3′-Azido-2′,3′-Dideoxypurine Nucleosides
Authors: Sluis-Cremer Nicolas , Koontz Dianna , Bassit Leda , Hernandez-Santiago Brenda I. , Detorio Mervi , Rapp Kim L. , Amblard Franck , Bondada Lavanya , Grier Jason , Coats Steven J. , Schinazi Raymond F. , Mellors John W.
Published: July 2009

Although the approved nucleoside reverse transcriptase (RT) inhibitors (NRTI) are integral components of therapy for human immunodeficiency virus type 1 (HIV-1) infection, they can have significant limitations, including the selection of NRTI-resistant HIV-1 and cellular toxicity. Accordingly, there is a critical need to develop new NRTI that have excellent activity and safety profiles and exhibit little or no cross-resistance with existing drugs. In this study, we report that the 3′-azido-2′,3′-dideoxypurine nucleosides (ADPNs) 3′-azido-2′,3′-dideoxyadenosine (3′-azido-ddA) and 3′-azido-2′,3′-dideoxyguanosine (3′-azido-ddG) exert potent antiviral activity in primary human lymphocytes and HeLa and T-cell lines (50% inhibitory concentrations [IC
50
s] range from 0.19 to 2.1 μM for 3′-azido-ddG and from 0.36 to 10 μM for 3′-azido-ddA) and that their triphosphate forms are incorporated as efficiently as the natural dGTP or dATP substrates by HIV-1 RT. Importantly, both 3′-azido-ddA and 3′-azido-ddG retain activity against viruses containing K65R, L74V, or M184V (IC
50
change of <2.0-fold) and against those containing three or more thymidine analog mutations (IC
50
change of <3.5-fold). In addition, 3′-azido-ddG does not exhibit cytotoxicity in primary lymphocytes or epithelial or T-cell lines and does not decrease the mitochondrial DNA content of HepG2 cells. Furthermore, 3′-azido-ddG is efficiently phosphorylated to 3′-azido-ddGTP in human lymphocytes, with an intracellular half-life of the nucleoside triphosphate of 9 h. The present data suggest that additional preclinical studies are warranted to assess the potential of ADPNs for treatment of HIV-1 infection.
Differential Expression of
ccrA
in Methicillin-Resistant
Staphylococcus aureus
Strains Carrying Staphylococcal Cassette Chromosome
mec
Type II and IVa Elements
Authors: Higgins Paul G. , Rosato Adriana E. , Seifert Harald , Archer Gordon L. , Wisplinghoff Hilmar
Published: July 2009

Excision of staphylococcal cassette chromosome
mec
(SCC
mec
) is mediated through the
ccrA
- and -
B
-encoded recombinases. We investigated the effects of different antimicrobial agents on
ccrA
expression by using a
ccrA
::
lacZ
fusion and reverse transcription-PCR with methicillin (meticillin)-resistant
Staphylococcus aureus
strains MW2 (SCC
mec
IVa) and N315 (SCC
mec
II). Upregulation of
ccrA
was observed upon exposure to β-lactam antibiotics. Vancomycin increased
ccrA
expression in MW2 but had no effect on N315. Vancomycin may contribute to the transfer of SCC
mec
IVa but have no effect in SCC
mec
II.
Staphylococcus aureus
Mutant Screen Reveals Interaction of the Human Antimicrobial Peptide Dermcidin with Membrane Phospholipids
Authors: Li Min , Rigby Kevin , Lai Yuping , Nair Vinod , Peschel Andreas , Schittek Birgit , Otto Michael
Published: July 2009

Antimicrobial peptides (AMPs) form an important part of the innate host defense. In contrast to most AMPs, human dermcidin has an anionic net charge. To investigate whether bacteria have developed specific mechanisms of resistance to dermcidin, we screened for mutants of the leading human pathogen,
Staphylococcus aureus
, with altered resistance to dermcidin. To that end, we constructed a plasmid for use in mariner-based transposon mutagenesis and developed a high-throughput cell viability screening method based on luminescence. In a large screen, we did not find mutants with strongly increased susceptibility to dermcidin, indicating that
S. aureus
has no specific mechanism of resistance to this AMP. Furthermore, we detected a mutation in a gene of unknown function that resulted in significantly increased resistance to dermcidin. The mutant strain had an altered membrane phospholipid pattern and showed decreased binding of dermcidin to the bacterial surface, indicating that dermcidin interacts with membrane phospholipids. The mode of this interaction was direct, as shown by assays of dermcidin binding to phospholipid preparations, and specific, as the resistance to other AMPs was not affected. Our findings indicate that dermcidin has an exceptional value for the human innate host defense and lend support to the idea that it evolved to evade bacterial resistance mechanisms targeted at the cationic character of most AMPs. Moreover, they suggest that the antimicrobial activity of dermcidin is dependent on the interaction with the bacterial membrane and might thus assist with the determination of the yet unknown mode of action of this important human AMP.
Effect of β-1,6-Glucan Inhibitors on the Invasion Process of
Candida albicans
: Potential Mechanism of Their In Vivo Efficacy
Authors: Kitamura Akihiro , Higuchi Saito , Hata Masato , Kawakami Katsuhiro , Yoshida Kumi , Namba Kenji , Nakajima Ryohei
Published: July 2009

β-1,6-Glucan is a fungus-specific cell wall component that is essential for the retention of many cell wall proteins. We recently reported the discovery of a small molecule inhibitor of β-1,6-glucan biosynthesis in yeasts. In the course of our study of its derivatives, we found a unique feature in their antifungal profile. D21-6076, one of these compounds, exhibited potent in vitro and in vivo antifungal activities against
Candida glabrata
. Interestingly, although it only weakly reduced the growth of
Candida albicans
in conventional media, it significantly prolonged the survival of mice infected by the pathogen. Biochemical evaluation of D21-6076 indicated that it inhibited β-1,6-glucan synthesis of
C. albicans
, leading the cell wall proteins, which play a critical role in its virulence, to be released from the cell. Correspondingly, adhesion of
C. albicans
cells to mammalian cells and their hyphal elongation were strongly reduced by the drug treatment. The results of the experiment using an in vitro model of vaginal candidiasis showed that D21-6076 strongly inhibited the invasion process of
C. albicans
without a significant reduction in its growth in the medium. These evidences suggested that D21-6076 probably exhibited in vivo efficacy against
C. albicans
by inhibiting its invasion process.
Improved Murine Model of Malaria UsingPlasmodium falciparumCompetent Strains and Non-Myelodepleted NOD-scid IL2RγnullMice Engrafted with Human Erythrocytes
Authors: Jiménez-Díaz María Belén , Mulet Teresa , Viera Sara , Gómez Vanessa , Garuti Helen , Ibáñez Javier , Alvarez-Doval Angela , Shultz Leonard D. , Martínez Antonio , Gargallo-Viola Domingo , Angulo-Barturen Iñigo
Published: July 2009

Murine models ofPlasmodium falciparummalaria may become crucial tools in drug discovery. Here we show that non-myelodepleted NOD-scid IL2Rγnullmice engrafted with human erythrocytes support an infectious burden up to tenfold higher than that supported by engrafted NOD-scid β2microglobulinnullmice. The new model was validated for drug discovery and was used to assess the therapeutic efficacy of 4-pyridones, selective inhibitors ofP. falciparumcytochromebc1.
In Vitro Activities of Trioxaquines against
Schistosoma mansoni
Authors: Boissier Jérôme , Coslédan Frédéric , Robert Anne , Meunier Bernard
Published: July 2009

We report the in vitro activities of trioxaquines against larval and adult-stage schistosomes at 5 and 50 μg/ml, respectively. Such activities are equivalent to that of praziquantel, the major and rather unique drug currently used for the treatment of schistosomiasis. In this range of concentrations, artemisinin derivatives (artesunate and artemether) have no activity.
Anidulafungin in Combination with Amphotericin B against
Aspergillus fumigatus
Authors: Spreghini Elisabetta , Orlando Fiorenza , Santinelli Alfredo , Pisa Eleonora , Loretelli Cristian , Manso Esther , Milici Maria Eleonara , Scalise Giorgio , Barchiesi Francesco
Published: July 2009

We investigated the effects of anidulafungin alone and in combination with amphotericin B against
Aspergillus fumigatus
. Indifference was the only type of interaction observed in vitro. Anidulafungin at 1 and 5 mg/kg of body weight/day, amphotericin B at 1 mg/kg/day, and combination therapy prolonged the survival of mice with invasive aspergillosis. Anidulafungin at 5 mg/kg/day, alone and in combination with amphotericin B, reduced the kidney fungal burden. Overall, the combination was not superior to the most active single drug.
Pharmacodynamics of Vancomycin at Simulated Epithelial Lining Fluid Concentrations against Methicillin-Resistant
Staphylococcus aureus
(MRSA): Implications for Dosing in MRSA Pneumonia
Authors: Harigaya Yoriko , Bulitta Jürgen B. , Forrest Alan , Sakoulas George , Lesse Alan J. , Mylotte Joseph M. , Tsuji Brian T.
Published: July 2009

Little is known regarding killing activity of vancomycin against methicillin (meticillin)-resistant
Staphylococcus aureus
(MRSA) in pneumonia since the extent of vancomycin penetration into epithelial lining fluid (ELF) has not been definitively established. We evaluated the impact of the extent of ELF penetration on bacterial killing and resistance by simulating a range of vancomycin exposures (24-h free drug area under the concentration-time curve [ƒAUC
24
]/MIC) using an in vitro pharmacodynamic model and population-based mathematical modeling. A high-dose, 1.5-g-every-12-h vancomycin regimen according to American Thoracic Society/Infectious Diseases Society of America guidelines (trough concentration, 15 mg/liter) with simulated ELF/plasma penetration of 0, 20, 40, 60, 80, or 100% (ƒAUC
24
/MIC of 0, 70, 140, 210, 280, or 350) was evaluated against two
agr
-functional, group II MRSA clinical isolates obtained from patients with a bloodstream infection (MIC = 1.0 mg/liter) at a high inoculum of 10
8
CFU/ml. Despite high vancomycin exposures and 100% penetration, all regimens up to a ƒAUC
24
/MIC of 350 did not achieve bactericidal activity. At regimens of ≤60% penetration (ƒAUC
24
/MIC ≤ 210), stasis and regrowth occurred, amplifying the development of intermediately resistant subpopulations. Regimens simulating ≥80% penetration (ƒAUC
24
/MIC ≥ 280) suppressed development of resistance. Resistant mutants amplified by suboptimal vancomycin exposure displayed reduced rates of autolysis (Triton X-100) at 72 h. Bacterial growth and death were well characterized by a Hill-type model (
r
2
≥ 0.984) and a population pharmacodynamic model with a resistant and susceptible subpopulation (
r
2
≥ 0.965). Due to the emergence of vancomycin-intermediate resistance at a ƒAUC
24
/MIC of ≤210, exceeding this exposure breakpoint in ELF may help to guide optimal dosage regimens in the treatment of MRSA pneumonia.
The RD1 Locus in the
Mycobacterium tuberculosis
Genome Contributes to Activation of Caspase-1 via Induction of Potassium Ion Efflux in Infected Macrophages
Authors: Kurenuma Takeshi , Kawamura Ikuo , Hara Hideki , Uchiyama Ryosuke , Daim Sylvia , Dewamitta Sita Ramyamali , Sakai Shunsuke , Tsuchiya Kohsuke , Nomura Takamasa , Mitsuyama Masao
Published: July 2009

A genomic locus called “region of difference 1” (RD1) in
Mycobacterium tuberculosis
has been shown to contribute to the generation of host protective immunity as well as to the virulence of the bacterium. To gain insight into the molecular mechanism, we investigated the difference in the cytokine-inducing ability between H37Rv and a mutant strain deficient for RD1 (ΔRD1). We found that RD1 is implicated in the production of caspase-1-dependent cytokines, interleukin-18 (IL-18) and IL-1β, from infected macrophages. The expression of these cytokines was similarly induced after infection with H37Rv and ΔRD1. However, the activation of caspase-1 was observed only in H37Rv-infected macrophages. The cytokine production and caspase-1 activation were induced independently of type I interferon receptor signaling events. We also found that the activation of caspase-1 was markedly inhibited with increasing concentrations of extracellular KCl. Furthermore, the production of IL-18 and IL-1β and caspase-1 activation were induced independently of a P2X7 purinergic receptor, and the inability of ΔRD1 in caspase-1 activation was compensated for by nigericin, an agent inducing the potassium ion efflux. Based on these results, we concluded that RD1 participates in caspase-1-dependent cytokine production via induction of the potassium ion efflux in infected macrophages.
Anaplasma phagocytophilum
Dense-Cored Organisms Mediate Cellular Adherence through Recognition of Human P-Selectin Glycoprotein Ligand 1
Authors: Troese Matthew J. , Carlyon Jason A.
Published: July 2009

Anaplasma phagocytophilum
is an obligate intracellular bacterium that infects granulocytes to cause human granulocytic anaplasmosis. The susceptibilities of human neutrophils and promyelocytic HL-60 cells to
A. phagocytophilum
are linked to bacterial usage of P-selectin glycoprotein ligand 1 (PSGL-1) as a receptor for adhesion and entry.
A. phagocytophilum
undergoes a biphasic developmental cycle, transitioning between a smaller electron dense-cored cell (DC), which has a dense nucleoid, and a larger, pleomorphic electron lucent reticulate cell (RC), which has a dispersed nucleoid. The pathobiological roles of each form have not been elucidated. To ascertain the role of each form, we used electron microscopy to monitor bacterial binding, entry, and intracellular development within HL-60 cells. Only DCs were observed binding to and inducing uptake by HL-60 cells. By 12 h, internalized DCs had transitioned to RCs, which had initiated replication. By 24 h, large RC numbers were observed within individual inclusions. Reinfection had occurred by 36 h, as individual, vacuole-enclosed DCs and RCs were again observed. The abilities of DC- and RC-enriched
A. phagocytophilum
populations to bind and/or infect HL-60 cells or Chinese hamster ovary cells transfected to express PSGL-1 (PSGL-1 CHO) were compared. Only DCs bound PSGL-1 CHO cells and did so in a PSGL-1-blocking antibody-inhibitable manner. These results demonstrate that the respective roles of
A. phagocytophilum
DCs and RCs are consistent with analogous forms of other obligate intracellular pathogens that undergo biphasic development and hint that the PSGL-1-targeting adhesin(s) may be upregulated or optimally posttranslationally modified on DCs.
Shiga Toxin 1-Induced Proinflammatory Cytokine Production Is Regulated by the Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin Signaling Pathway
Authors: Cherla Rama P. , Lee Sang-Yun , Mulder Renée A. , Lee Moo-Seung , Tesh Vernon L.
Published: July 2009

Shiga toxin 1 (Stx1) transiently increases the expression of proinflammatory cytokines by macrophage-like THP-1 cells in vitro. Increased cytokine production is partly due to activation of the translation initiation factor eIF4E through a mitogen-activated protein kinase (MAPK)- and Mnk1-dependent pathway. eIF4E availability for translation initiation is regulated by association with eIF4E binding proteins (4E-BP). In this study, we showed that Stx1 transiently induced 4E-BP hyperphosphorylation, which may release eIF4E for translation initiation. Phosphorylation of 4E-BP at priming sites T37 and T46 was not altered by Stx1 but was transiently increased at S65, concomitant with increased cytokine expression. Using kinase inhibitors, we showed that 4E-BP phosphorylation was dependent on phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR) activation but did not require MAPKs. Stx1 treatment resulted in increased levels of cytosolic Ca
2+
. PI3K and Akt activation led to the phosphorylation and inactivation of the positive cytokine regulator glycogen synthase kinase 3α/β (GSK-3α/β). PI3K, Akt, and mTOR inhibitors and small interfering RNA knockdown of Akt expression all increased, whereas a GSK-3α/β inhibitor decreased, Stx1-induced soluble tumor necrosis factor alpha and interleukin-1β production. Overall, these findings suggest that despite transient activation of 4E-BP, the PI3K/Akt/mTOR pathway negatively influences cytokine induction by inactivating the positive regulator GSK-3α/β.
Seven-Star Needle Stimulation Improves Language and Social Interaction of Children with Autistic Spectrum Disorders
Authors: Chan Agnes S. , Cheung Mei-Chun , Sze Sophia L. , Leung Winnie W.
Published: July 2009

This is a randomized controlled trial that aimed to evaluate the effect of the Seven-star Needle Stimulation treatment on children with Autistic Spectrum Disorders (ASD). Thirty-two children with ASD were assigned randomly into the treatment and control groups. Children in the treatment group underwent 30 sessions of stimulation over 6 weeks, while children in the control group were on a waiting list and did not receive treatment during this period of time. Intervention consisted of a treatment regime comprising of 30 sessions of Seven-star Needle Stimulation, delivered over 6 weeks. Each session lasted 5 to 10 min, children in the treatment group were stimulated at the front and back sides of their body and the head by using Seven-star Needles. The change in the children's behavior was evaluated using parents' report and neurophysiological changes were measured by quantitative EEG (qEEG). Results showed that the treatment group demonstrated significant improvement in language and social interaction, but not in stereotyped behavior or motor function, compared to the control group. qEEG spectral amplitudes in the treatment, but not in the control group, were also reduced significantly. The results suggested that Seven-star Needle Stimulation might be an effective intervention to improve language and social functioning of children with ASD.
DYNAMIC DRAG OF DISLOCATION BY POINT DEFECTS IN NEAR-SURFACE CRYSTAL LAYER
Authors: MALASHENKO V. V.
Published: July 2009

The effect of the surface on edge dislocation glide in the crystal with point defects both on the surface and in the bulk is studied theoretically. It is shown that the drag force of dislocation can be reduced by the image forces to several orders of magnitude in nanoscale region.
SELF-CONSISTENT T-MATRIX APPROXIMATION TO THE HUBBARD MODEL FOR A FINITE NUMBER OF SITES
Authors: JEMAÏ MOHSEN
Published: July 2009

Within the 1D Hubbard model, linear closed chains with various numbers of sites are considered in particle–particle self-consistent random phase approximation (SCRPA) for the T-matrix. Encouraging results with a minimal numerical effort are obtained, confirming earlier results with this theory for other models. SCRPA solves the two-site problem exactly. It therefore contains the two electrons and high density Fermi gas limits correctly.
BOOSTING ROBUSTNESS OF A NAMED ENTITY RECOGNIZER
Authors: POIBEAU THIERRY
Published: July 2009

Since the Message Understanding Conferences on Information Extraction in the 80's and 90's, Named Entity ReCognition (NERC) is a well-established task in the Natural Language Processing (NLP) community. However, very different systems seem to perform very similarly when applied to the same corpus. In this paper, we present a state-of-the-art NERC system. This tool is a hybrid system, based on different resources and techniques. We then propose a protocol to "deconstruct" and evaluate the different components of a complex named entity recognition system. We examine the performance of such a system with learning capacities and reduced initial knowledge on medium-size unlabelled corpora.
Transcriptional changes in right ventricular tissues are enriched in the outflow tract compared with the apex during chronic pulmonary embolism in rats
Authors: Zagorski John , Obraztsova Maria , Gellar Michael A. , Kline Jeffrey A. , Watts John A.
Published: July 2009

Moderate to severe pulmonary embolism (PE) can cause pulmonary arterial hypertension and right ventricular (RV) heart damage. Previous studies from our laboratory indicate that the basal outflow tract of the RV is injured and has acute inflammation followed by tissue remodeling while the apex appears normal. The present studies examine transcription responses to chronic PE in RV apex and outflow tracts using DNA microarrays to identify transcription responses by region. Changes predominated in the RV outflow tract (8,575 genes showed ≥1.5-fold expression change). Gene ontology and KEGG analyses indicated a significant decrease in genes involved in cellular respiration and energy metabolism and increases in inflammatory cell adhesion molecules and extracellular matrix proteins. Signal pathways for wound healing such as fibroblast growth factor, collagen synthesis, and CCN proteins (named for the first three members of the family: cysteine-rich protein 61, connective tissue growth factor, and nephroblastoma overexpressed gene) were strongly upregulated. In comparison, few genes (422) showed significant change in the RV apex tissue. Apex-selective genes included two genes affecting metabolism and a stretch-sensitive transcription factor (ankyrin repeat domain 1). We conclude that the RV outflow tract is subject to strong proinflammatory and profibrotic remodeling transcriptional responses in chronic PE. Severe loss of genes involved in cellular respiration is consistent with previous histology indicating a shift in cell types present within the outflow tract tissue away from highly energy-dependant cardiomyocytes to less metabolically active cells during remodeling. The apex region of the RV had few compensating adaptations.
Cannabinoid receptor 1 is a potential drug target for treatment of translocation-positive rhabdomyosarcoma
Authors: Oesch Susanne , Walter Dagmar , Wachtel Marco , Pretre Kathya , Salazar Maria , Guzmán Manuel , Velasco Guillermo , Schäfer Beat W.
Published: July 2009

Gene expression profiling has revealed that the gene coding for cannabinoid receptor 1 (CB1) is highly up-regulated in rhabdomyosarcoma biopsies bearing the typical chromosomal translocations PAX3/FKHR or PAX7/FKHR. Because cannabinoid receptor agonists are capable of reducing proliferation and inducing apoptosis in diverse cancer cells such as glioma, breast cancer, and melanoma, we evaluated whether CB1 is a potential drug target in rhabdomyosarcoma. Our study shows that treatment with the cannabinoid receptor agonists HU210 and Δ9-tetrahydrocannabinol lowers the viability of translocation-positive rhabdomyosarcoma cells through the induction of apoptosis. This effect relies on inhibition of AKT signaling and induction of the stress-associated transcription factor p8 because small interfering RNA–mediated down-regulation of p8 rescued cell viability upon cannabinoid treatment. Finally, treatment of xenografts with HU210 led to a significant suppression of tumor growth in vivo. These results support the notion that cannabinoid receptor agonists could represent a novel targeted approach for treatment of translocation-positive rhabdomyosarcoma. [Mol Cancer Ther 2009;8(7):1838–45]
Identification and preclinical characterization of AZ-23, a novel, selective, and orally bioavailable inhibitor of the Trk kinase pathway
Authors: Thress Kenneth , MacIntyre Terry , Wang Haiyun , Whitston Dave , Liu Zhong-Ying , Hoffmann Ethan , Wang Tao , Brown Jeffrey L. , Webster Kevin , Omer Charles , Zage Peter E. , Zeng Lizhi , Zweidler-McKay Patrick A.
Published: July 2009

Tropomyosin-related kinases (TrkA, TrkB, and TrkC) are receptor tyrosine kinases that, along with their ligands, the neurotrophins, are involved in neuronal cell growth, development, and survival. The Trk-neurotrophin pathway may also play a role in tumorigenesis through oncogenic fusions, mutations, and autocrine signaling, prompting the development of novel Trk inhibitors as agents for cancer therapy. This report describes the identification of AZ-23, a novel, potent, and selective Trk kinase inhibitor. In vitro studies with AZ-23 showed improved selectivity over previous compounds and inhibition of Trk kinase activity in cells at low nanomolar concentrations. AZ-23 showed in vivo TrkA kinase inhibition and efficacy in mice following oral administration in a TrkA-driven allograft model and significant tumor growth inhibition in a Trk-expressing xenograft model of neuroblastoma. AZ-23 represents a potent and selective Trk kinase inhibitor from a novel series with the potential for use as a treatment for cancer. [Mol Cancer Ther 2009;8(7):1818–27]
Long-Term Favorable Results by Arteriovenous Graft with Omniflow II Prosthesis for Hemodialysis
Authors: Palumbo Roberto , Niscola Pasquale , Calabria Santo , Fierimonte Sabrina , Bevilacqua Monica , Scaramucci Laura , Tolu Barbara , de Fabritiis Paolo , Bondanini Francesco
Published: July 2009

Aims and Methods: In order to decrease arteriovenous graft (AVG) failure and improve long-term patency, we used Omniflow II to perform AVG for hemodialysis access in 38 patients with very compromised vessels who were not suitable for other forms of AVG. Results: At a median follow-up of 38 (range 6–55) months, 31/38 (81%) patients were still alive. At 6, 12 ,18 and 24 months, primary patency was 92, 80, 68 and 60%, whereas secondary patency was 83, 80, 78 and 75%, respectively. The cumulative 38-month prosthetic AVG patency was 70%. No infective event related to the vascular prosthesis occurred. Neither AVG thrombosis nor modifications in thrombophilic pattern were observed; these findings confirm the high hemocompatibility of this prosthetic vascular device. Conclusion: Our experience is extremely encouraging for the use of new biosynthetic devices such as Omniflow II.
Fibrogenic Growth Factors in Encapsulating Peritoneal Sclerosis
Authors: Braun N. , Reimold F. , Biegger D. , Fritz P. , Kimmel M. , Ulmer C. , Alscher M.D.
Published: July 2009

Background: Increased local levels of fibrogenic growth hormones contribute substantially to the process of encapsulating peritoneal sclerosis (EPS) in animal models. Methods: We analyzed probes from patients with normal kidney function (n = 10), with normal kidney function and inflammation (n = 10), on PD without (n = 10) and with EPS (n = 9). We investigated the degree of fibrosis and the number of vessels and vasculopathy. Additionally, we investigated the expression of NFκB, TGFβ1, TGFβ1 receptor, TGFβ2, TGFβ2 receptor, FGF-BP, CTGF and VEGF by immunohistochemistry. Results: In EPS, we found an exclusive upregulation of VEGF (normal 0, appendicitis 1.0 ± 1.2, PD 1.7 ± 1.8 and EPS 5.7 ± 4.4; p < 0.0001), whereas in PD, CTGF was significantly increased (normal 6.0 ± 2.8, appendicitis 7.3 ± 2.5, PD 10.0 ± 1.8 and EPS 7.3 ± 2.1; p = 0.0059). The results for the TGFβ system and NFκB were not uniform, in EPS no increases were demonstrable. Vasculopathy was significantly more pronounced in EPS (normal 0.4 ± 0.5, appendicitis 0.2 ± 0.3, PD 1.0 ± 0.7 and EPS 1.6 ± 1.2; p < 0.0001) than in PD or inflammation (normal 30 ± 16, appendicitis 82 ± 48, PD 1,936 ± 952 and EPS 2,613 ± 1,209; p < 0.0001), whereas the density of vessels were decreased (normal 125 ± 114, appendicitis 817 ± 347, PD 81 ± 57 and EPS 36 ± 33; p < 0.0001). Conclusions: The process of EPS was associated with increased VEGF in the peritoneum. The reduced density of vessels compared with marked fibrosis could point to hypoxia as an inducer.
Genetic Polymorphisms of Hypoxia-Inducible Factor-1 Alpha and Cardiovascular Disease in Hemodialysis Patients
Authors: Zheng Zhen Lon , Hwang Young-Hwan , Kim Seong Kyun , Kim Sejoong , Son Min Jung , Ro Han , Sung Su-Ah , Lee Hyun Hee , Chung Woo Kyung , Joo Kwon Wook , Yang Jaeseok
Published: July 2009

Background: Hemodialysis patients are prone to ischemic events potentially aggravated by hypoxia. The key player in adaptation to hypoxia is hypoxia-inducible factor-1 alpha (HIF-1α). Therefore, we investigated the association of HIF-1α polymorphisms with ischemia/hypoxia-related events in hemodialysis patients. Methods: Patients on maintenance hemodialysis were enrolled from 4 training hospitals in Korea. Seven single nucleotide polymorphisms (SNP) of HIF-1α were genotyped. The association of these SNP with hypoxia-related clinical outcomes (ischemic diseases and anemia) and cancer was analyzed. Results: A total of 376 patients participated in the study. No significant difference in genotype distribution was found between subjects with and without the hypoxia-related events. Three sets of linkage disequilibrium blocks were made for haplotype analyses (rs2783778 and rs7148720 in 5′ upstream region; rs7143164 and rs10873142; rs2301113, rs11549465 and rs2057482). Of these, the CT haplotype in the first set was associated with both acute myocardial infarction and frequent intradialytic hypotension (acute myocardial infarction: adjusted odds ratio = 0.15, 95% CI: 0.03–0.69; frequent intradialytic hypotension: adjusted odds ratio = 0.29, 95% CI: 0.12–0.72). Conclusion: Genetic polymorphisms of HIF-1α were associated with acute myocardial infarction and intradialytic hypotension in hemodialysis patients.
Evaluation of Cerebellar Asymmetry in Alzheimer’s Disease: A Stereological Study
Authors: Kusbeci Ozge Yilmaz , Bas Orhan , Gocmen-Mas Nuket , Karabekir Hamit Selim , Yucel Aylin , Ertekin Tolga , Yazici Ayse Canan
Published: July 2009

Objectives: Alzheimer’s disease (AD) is the most common cause of dementia and, as previous studies have indicated, degenerative changes in the cerebellum occur in AD. It is well known that the cerebellum does not have a symmetric morphology and some pathological disorders, such as schizophrenia, epilepsy, autism and alcoholism, can cause asymmetrical changes in the cerebellum. In this study, we aimed to evaluate whether or not patients with AD show cerebellar asymmetry. We also intended to depict the probable volumetric asymmetry by using a stereological technique. Materials and Methods: The study evaluated the volu- metric measurements of each cerebellar hemisphere by applying a stereological method to MR images. This age- and gender-matched study was composed of 15 patients with probable AD and 14 healthy subjects (controls). MR images were analyzed by using the point-counting approach, holding to Cavalieri’s principle. Results: Although there was significant cerebellar atrophy in AD patients, the study showed no statistically significant cerebellar asymmetry according to age and gender, both in the study and control groups (p > 0.05). Conclusions: There was no difference in cerebellar asymmetry associated with age and gender between the AD patients and control subjects. The stereological evaluation of cerebellar asymmetry correlating with gender is of importance to both clinicians and anatomists. The technique is simple, inexpensive, reliable and unbiased.
Out Cold: Biochemical Regulation of Mammalian Hibernation – A Mini-Review
Authors: Storey Kenneth B.
Published: July 2009

Hibernating mammals offer an intriguing example of natural torpor and illustrate the regulatory mechanisms that control metabolic rate depression and the cell preservation strategies that support long-term viability in a hypometabolic state. These suggest applied strategies for improving the hypothermic preservation of human organs for transplant, and guidelines that could aid the development of torpor as an intervention strategy in human medicine. Recent advances in hibernation research have illustrated mechanisms that contribute to metabolic depression by orchestrating the global suppression of ATP-expensive transcription and translation including multiple forms of post-translational modification of proteins/enzymes (phosphorylation, acetylation, SUMOylation), mRNA storage mechanisms, and differential expression of microRNA species. DNA-screening technologies have also contributed new advances in understanding the range of cell functions that are impacted during torpor and point out some critical preservation strategies that aid long-term viability in a torpid state. These include antioxidant defenses, chaperones and the implementation of the unfolded protein response, and the enhancement of serpins (serine protease inhibitors) to control the actions of extracellular proteases in clotting and inflammation responses.
Solitary Subungual Keratoacanthoma Arising in an MSH2 Germline Mutation Carrier: Confirmation of a Relationship by Immunohistochemical Analysis
Authors: Stoebner P.E. , Fabre C. , Delfour C. , Joujoux J.M. , Roger P. , Dandurand M. , Meunier L.
Published: July 2009

Background: Muir-Torre syndrome (MTS) is an autosomal dominant disorder characterized by the concurrent or sequential development of at least 1 sebaceous gland tumor or keratoacanthoma and 1 or more internal malignancies. It is actually considered as a variant of hereditary nonpolyposis colorectal cancer (HNPCC) as both MTS and HNPCC are more often associated with germline mutations in the DNA mismatch repair (MMR) gene. Objective andMethods: We report the case of MTS diagnosed after the occurrence of a solitary subungual keratoacanthoma (SKA) in a man with a well-known family history of HNPCC and who is carrying a constitutional 1–7 deletion in the MSH2 MMR gene. Results: The link between the germline mutation and the skin tumor was reinforced by immunohistochemical staining. MSH2 immunoreactivity was decreased in SKA tumoral cells when compared to normal adjacent epidermis and to 5 cases of sporadic KA used as controls. Conclusion: This observation indicates that a solitary SKA may be the first clinical manifestation of MTS and brings up the relevance for regular dermatological screening for MTS-associated skin lesions among gene carriers (and symptomatic individuals) for HNPCC syndrome.
Catamenial Hemoptysis: A Nationwide Analysis in Korea
Authors: Kim Chong-Ju , Nam Hae-Seong , Lee Chang-Youl , Yum Ho-Kee , Yang Sei-Hoon , Seo Ki-Hyun , Son Choon-Hee , Kim Do-Jin , Jang Seung-Hun , Chung Man-Pyo , Park Yong-Bum , Lee Jae-Cheol , Ryu Jeong-Seon
Published: July 2009

Background: Hemoptysis is a potentially serious clinical problem. However, there is no consensus on the clinical characteristics, treatment and patient outcome of catamenial hemoptysis. Objective: Clinical characteristics, treatments and outcome in patients of catamenial hemoptysis were evaluated. Methods: We conducted a retrospective nationwide observational analysis of Korean patients with catamenial hemoptysis. Results: Nineteen patients with catamenial hemoptysis were evaluated from 13 tertiary-care hospitals in Korea. The median age of the patients was 25 years; 8 (42%) were ever-smokers. Eight patients were pathologically diagnosed; 11 were diagnosed by clinical criteria. Sixteen (84%) patients had a history of obstetric or gynecological procedures before developing hemoptysis. The mean amount of hemoptysis (mean ± SD) was 58.3 ± 71.3 for surgery, 46.4 ± 33.2 for hormonal and 29.1 ± 26.3 for conservative treatment groups. Hemoptysis did not recur in 8 (89%) of 9 patients after surgery. None of the patients in the hormonal or conservative treatment groups had persistent hemoptysis. There was an excellent outcome (complete remission and partial responses) in all patients with conservative treatment, suggesting that endometrial cells implanted into the lung may have a benign course. Conclusion: Patients without massive hemoptysis can be treated conservatively or with hormonal agents.
Degarelix: A New Approach for the Treatment of Prostate Cancer
Authors: Persson Bo-Eric , Kold Olesen Tine , Jensen Jens-Kristian
Published: July 2009

Androgen deprivation therapy remains the mainstay of medical treatment for prostate cancer. Generally, this is achieved with medical androgen deprivation rather than orchidectomy, as most patients find the permanency and psychological effects of the latter unacceptable. Gonadotrophin-releasing hormone (GnRH) agonists are the most widely used androgen deprivation therapy, but do have some drawbacks. The most apparent is the induction of a transient surge in serum testosterone that may stimulate tumor growth, causing patients to experience new or worsening cancer symptoms. These may include increased bone pain and urinary retention, and consequently delay the therapeutic benefit of these agents. These shortcomings led to the development of the GnRH antagonists/receptor blockers. Degarelix is a novel GnRH receptor blocker that has an immediate onset of action, producing a rapid decrease in luteinizing hormone and follicle-stimulating hormone leading to fast testosterone suppression without the initial surge associated with the GnRH agonists. Administration of subcutaneous degarelix depot has been investigated in multicenter, open-label, randomized, phase II trials of up to 1 year’s duration in patients with prostate cancer. Degarelix induced rapid luteinizing hormone suppression and fast, profound and sustained suppression of serum testosterone (≤0.5 ng/ml), with additional rapid and sustained reductions in dihydrotestosterone and prostate-specific antigen. Dose-finding trials indicate that a 240 mg starting dose and an 80 or 160 mg maintenance dose is most effective for long-term testosterone suppression. In a phase III, 1-year comparator trial, degarelix produced fast testosterone suppression and prostate-specific antigen reduction ≥2 weeks before clinically relevant changes were induced by the GnRH agonist leuprolide. Degarelix was as effective as leuprolide at reducing testosterone ≤0.5 ng/ml from 1 month to study end. Degarelix was well tolerated, with uneventful toxicology and no evidence of systemic allergic reactions. This new agent represents an important pharmacological development in the hormonal treatment of prostate cancer.
Spinal Cord Stimulation Improves Ventricular Function and Reduces Ventricular Arrhythmias in a Canine Postinfarction Heart Failure Model
Authors: Lopshire John C. , Zhou Xiaohong , Dusa Cristian , Ueyama Takeshi , Rosenberger Joshua , Courtney Nicole , Ujhelyi Michael , Mullen Thomas , Das Mithilesh , Zipes Douglas P.
Published: July 2009

Background—

Spinal cord stimulation (SCS) reduces the incidence of ventricular tachyarrhythmias in experimental models. This study investigated the effects of long-term SCS on ventricular function in a postinfarction canine heart failure model.

Methods and Results—

In stage 1, dogs underwent implantable cardioverter-defibrillator implantation and embolization of the left anterior descending artery followed by right ventricular pacing (240 ppm) for 3 weeks to produce heart failure. In stage 2, 28 surviving animals were assigned to the SCS (delivered at the T4/T5 spinal region for 2 hours 3 times a day), medicine (MED; carvedilol therapy at 12.5 mg PO BID), or control (CTRL; no therapy) group for the initial phase 1 study. In a subsequent phase 2 study, 32 stage 1 survivors were equally randomized to the SCS, MEDS (carvedilol plus ramipril 2.5 mg PO QD), SCS plus MEDS (concurrent therapy), or CTRL group. Animals were monitored for 5 weeks (phase 1) or 10 weeks (phase 2). In stage 3, all phase 1 animals underwent circumflex artery balloon occlusion for 1 hour. In the SCS group, left ventricular ejection fraction was 65±5% at baseline, 17±3% at the end of stage 1, and 47±7% at the end of stage 2. In the MED group, left ventricular ejection fraction was 61±4% at baseline, 18±3% at the end of stage 1, and 34±4% at the end of stage 2. In the CTRL group, left ventricular ejection fraction was 64±5% at baseline, 19±5% at the end of stage 1, and 28±3% at the end of stage 2. Left ventricular ejection fraction was significantly improved in the SCS compared with the MED and CTRL groups (
P
<0.001 for both). The mean number of spontaneous nonsustained ventricular tachyarrhythmias during stage 2 and the occurrence of ischemic ventricular tachyarrhythmias during stage 3 also were significantly decreased in the SCS (27±17 and 27%, respectively;
P
<0.03) and MED (58±42 and 33%;
P
<0.05) versus CTRL (88±52 and 76%) group. After 10 weeks in the phase 2 studies, the greatest recovery in ejection fraction was noted in the SCS (52±5%) and SCS+MEDS (46±4%) groups compared with the MEDS (38±2%) and CTRL (31±4%) groups.

Conclusion—

SCS significantly improved cardiac contractile function and decreased ventricular arrhythmias in canine heart failure.
Alcohol Consumption and Risk of Cardiovascular Disease and Death in Women
Authors: Djoussé Luc , Lee I-Min , Buring Julie E. , Gaziano J. Michael
Published: July 2009

Background—

Although an association between moderate alcohol consumption and decreased cardiovascular disease (CVD) and death has been reported, limited data are available on potential mediating mechanisms. We examined the association between alcohol and CVD and death in 26 399 women and estimated the proportion of reduced risk of CVD/death explained by a series of intermediate factors.

Methods and Results—

Alcohol consumption was self-reported at baseline, and CVD events and deaths were ascertained via follow-up questionnaires and medical records. Baseline levels of hemoglobin A1c, inflammatory markers, hemostatic factors, and lipids were measured. Blood pressure and hypercholesterolemia and treatment for lipids were self-reported. During a mean follow up of 12.2 years, 1039 CVD events and 785 deaths (153 CVD deaths) occurred. There was a J-shaped relation between alcohol consumption and incident CVD and total and CVD deaths in a multivariable model. Compared with abstainers, alcohol intake of 5 to 14.9 g/d was associated with 26%, 35%, and 51% lower risk of CVD, total death, and CVD death, respectively, in a multivariable model. For CVD risk reduction, lipids made the largest contribution to the lower risk of CVD (28.7%), followed by hemoglobin A1c/diabetes (25.3%), inflammatory/hemostatic factors (5%), and blood pressure factors (4.6%). All these mediating factors together explained 86.3%, 18.7%, and 21.8% of the observed lower risk of CVD, total death, and CVD death, respectively.

Conclusions—

These data suggest that alcohol effects on lipids and insulin sensitivity may account for a large proportion of the lower risk of CVD/death observed with moderate drinking under the assumption that the alcohol-CVD association is causal.