bluuebunny/crossref_metadata_2025 huggingface dataset:
Tigecycline Exhibits Inhibitory Activity against
Clostridium difficile
in the Colon of Mice and Does Not Promote Growth or Toxin Production
Authors: Jump Robin L. P. , Li Yuejin , Pultz Michael J. , Kypriotakis Georgios , Donskey Curtis J.
Published: December 2010

Tigecycline is a broad-spectrum glycylcycline antibiotic with potent
in vitro
activity against
Clostridium difficile
. We used a mouse model to test the hypothesis that tigecycline has a low propensity to promote colonization and toxin production by
C. difficile
due to inhibitory activity in the colon. Mice (5 to 8 per group) received subcutaneous injections of tigecycline (low and high doses) alone or in combination with clindamycin for 6 days. Growth of and toxin production by 3 strains of
C. difficile
(tigecycline MICs ≤ 0.012 μg/ml) were measured in cecal contents collected 6 h or 3 days after the final antibiotic dose. Antibiotic concentrations were measured using a bioassay, and concentrations of total anaerobes and
Bacteroides
spp. were measured. The effects of tigecycline on rendering mice susceptible to colonization with and reducing the burden of
C. difficile
were also examined. In comparison to saline controls, clindamycin promoted the growth of
C. difficile
(
P
< 0.001) in cecal contents, whereas tigecycline did not. Tigecycline did not suppress total anaerobes or
Bacteroides
spp. in comparison to saline controls. Concurrent administration of tigecycline prevented clindamycin-induced promotion of
C. difficile
in cecal contents collected 6 h or 3 days (high dose only) after the final antibiotic dose. Tigecycline did not promote the establishment of colonization in mice, yet it did not reduce concentrations of
C. difficile
in animals with established colonization. In summary, tigecycline did not promote the growth of or toxin production by
C. difficile
, probably due to inhibitory activity against
C. difficile
and relative sparing of indigenous anaerobic microflora.
Assessment of Clarithromycin Susceptibility in Strains Belonging to the
Mycobacterium abscessus
Group by
erm
(41) and
rrl
Sequencing
Authors: Bastian Sylvaine , Veziris Nicolas , Roux Anne-Laure , Brossier Florence , Gaillard Jean-Louis , Jarlier Vincent , Cambau Emmanuelle
Published: December 2010

Clarithromycin was the drug of choice for
Mycobacterium abscessus
infections until inducible resistance due to
erm
(41) was described. Because
M. abscessus
was split into
M. abscessus
sensu stricto,
Mycobacterium massiliense
, and
Mycobacterium bolletii
, we looked for
erm
(41) in the three species and determined their clarithromycin susceptibility levels. Ninety strains were included: 87 clinical strains from cystic fibrosis patients (61%) and others (39%), representing 43
M. abscessus
, 30
M. massiliense
, and 14
M. bolletii
strains identified on a molecular basis, and 3 reference strains. Clarithromycin and azithromycin MICs were determined by broth microdilution and Etest with a 14-day incubation period. Mutations in
rrl
(23S rRNA gene) known to confer acquired clarithromycin resistance were also sought.
erm
(41) was detected in all strains but with two deletions in all
M. massiliense
strains. These strains were indeed susceptible to clarithromycin (MIC
90
of 1 μg/ml) except for four strains with
rrl
mutations.
M. abscessus
strains harbored an intact
erm
(41) but had a T/C polymorphism at the 28th nucleotide: T28 strains (Trp10 codon) demonstrated inducible clarithromycin resistance (MIC
90
of >16 μg/ml), while C28 strains (Arg10) were susceptible (MIC
90
of 2 μg/ml) except for two strains with
rrl
mutations.
M. bolletii
strains had
erm
(41) sequences similar to the sequence of the T28
M. abscessus
group, associated with inducible clarithromycin resistance (MIC
90
of >16 μg/ml).
erm
(41) sequences appeared species specific within the
M. abscessus
group and were fully concordant with clarithromycin susceptibility when
erm
(41) sequencing was associated with detection of
rrl
mutations. Clarithromycin-resistant strains, including the six
rrl
mutants, were more often isolated in cystic fibrosis patients, but this was not significantly associated with a previous treatment.
Fluoroquinolone Resistance among
Mycobacterium tuberculosis
Strains from Karachi, Pakistan: Data from Community-Based Field Clinics
Authors: Rafiq Yasraba , Jabeen Kauser , Hasan Rumina , Jafri Sana , Laiq Rabia , Malik Faisal , Mangi Rafique , Channa Abid , Hasan Zahra
Published: December 2010

A fluoroquinolone (FQ) resistance rate of 5.9% is reported in 205
Mycobacterium tuberculosis
isolates from patients presenting to field clinics in Karachi, Pakistan (2006 to 2009). FQ resistance among multidrug-resistant (MDR) strains was 11.1% (5/45), and it was 4.9% (5/103) in
M. tuberculosis
strains susceptible to all first-line agents. Spoligotyping of resistant strains did not show dominance of one strain type. Our data reflect considerable FQ-resistant
M. tuberculosis
isolates and the need to consider inclusion of FQ within first-line sensitivity testing in such settings.
Pharmacokinetic Interaction Study of Ritonavir-Boosted Saquinavir in Combination with Rifabutin in Healthy Subjects
Authors: Zhang Xiaoping , Fettner Scott , Zwanziger Elke , Rowell Lucy , Salgo Miklos
Published: December 2010

The effect of multiple doses of rifabutin (150 mg) on the pharmacokinetics of saquinavir-ritonavir (1,000 mg of saquinavir and 100 mg of ritonavir [1,000/100 mg]) twice daily (BID) was assessed in 25 healthy subjects. Rifabutin reduced the area under the plasma drug concentration-time curve from 0 to 12 h postdose (AUC
0-12
), maximum observed concentration of drug in plasma (
C
max
), and minimum observed concentration of drug in plasma at the end of the dosing interval (
C
min
) for saquinavir by 13%, 15%, and 9%, respectively, for subjects receiving rifabutin (150 mg) every 3 days with saquinavir-ritonavir BID. No effects of rifabutin on ritonavir AUC
0-12
,
C
max
, and
C
min
were observed. No adjustment of the saquinavir-ritonavir dose (1,000/100 mg) BID is required when the drugs are administered in combination with rifabutin. The effect of multiple doses of saquinavir-ritonavir on rifabutin pharmacokinetics was evaluated in two groups of healthy subjects. In group 1 (
n
= 14), rifabutin (150 mg) was coadministered every 3 days with saquinavir-ritonavir BID. The AUC
0-72
and
C
max
of the active moiety (rifabutin plus 25-
O
-desacetyl-rifabutin) increased by 134% and 130%, respectively, compared with administration of rifabutin (150 mg) once daily alone. Rifabutin exposure increased by 53% for AUC
0-72
and by 86% for
C
max
. In group 3 (
n =
13), rifabutin was coadministered every 4 days with saquinavir-ritonavir BID. The AUC
0-96
and
C
max
of the active moiety increased by 60% and 111%, respectively, compared to administration of 150 mg of rifabutin once daily alone. The AUC
0-96
of rifabutin was not affected, and
C
max
increased by 68%. Monitoring of neutropenia and liver enzyme levels is recommended for patients receiving rifabutin with saquinavir-ritonavir BID.
Newly Discovered and Characterized Antivirulence Compounds Inhibit Bacterial Mono-ADP-Ribosyltransferase Toxins
Authors: Turgeon Zachari , Jørgensen René , Visschedyk Danielle , Edwards Patrick R. , Legree Sarah , McGregor Caroline , Fieldhouse Robert J. , Mangroo Dev , Schapira Matthieu , Merrill A. Rod
Published: December 2010

The mono-ADP-ribosyltransferase toxins are bacterial virulence factors that contribute to many disease states in plants, animals, and humans. These toxins function as enzymes that target various host proteins and covalently attach an ADP-ribose moiety that alters target protein function. We tested compounds from a virtual screen of commercially available compounds combined with a directed poly(ADP-ribose) polymerase (PARP) inhibitor library and found several compounds that bind tightly and inhibit toxins fromPseudomonas aeruginosaandVibrio cholerae. The most efficacious compounds completely protected human lung epithelial cells against the cytotoxicity of these bacterial virulence factors. Moreover, we determined high-resolution crystal structures of the best inhibitors in complex with cholix toxin to reveal important criteria for inhibitor binding and mechanism of action. These results provide new insight into development of antivirulence compounds for treating many bacterial diseases.
Agglutination ofHistoplasma capsulatumby IgG Monoclonal Antibodies against Hsp60 Impacts Macrophage Effector Functions
Authors: Guimarães Allan Jefferson , Frases Susana , Pontes Bruno , de Cerqueira Mariana Duarte , Rodrigues Marcio L. , Viana Nathan Bessa , Nimrichter Leonardo , Nosanchuk Joshua Daniel
Published: December 2010

Histoplasma capsulatumcan efficiently survive within macrophages, facilitatingH. capsulatumtranslocation from the lung into the lymphatics and bloodstream. We have recently generated monoclonal antibodies (MAbs) to anH. capsulatumsurface-expressed heat shock protein of 60 kDa (Hsp60) that modify disease in a murine histoplasmosis model. Interestingly, the MAbs induced different degrees of yeast cell agglutinationin vitro. In the present study, we characterized the agglutination effects of the antibodies to Hsp60 onH. capsulatumyeast cells by light microscopy, flow cytometry, dynamic light scattering, measuring zeta potential, and using optical tweezers. We found that immunoglobulin Gs (IgGs) to Hsp60 causeH. capsulatumaggregation dependent on the (i) concentration of MAbs, (ii) MAb binding constant, and (iii) IgG subclass. Furthermore, infection of macrophages using agglutinates of various sizes after incubation with different Hsp60-binding MAbs induced association to macrophages through distinct cellular receptors and differentially affected macrophage antifungal functions. Hence, the capacity of IgG MAbs to agglutinateH. capsulatumsignificantly impacted pathogenic mechanisms ofH. capsulatumduring macrophage infection, and the effect was dependent on the antibody subclass and antigen epitope.
Corporate social responsibility: not just for big business
Authors: Glennon Alison
Published: December 2010

In recent years, corporate social responsibility has become a much‐used phrase, but some may think it is only applicable to large companies with a reputation to maintain. Yet, veterinary practices, from the smallest sole principal practice through to the large chains, do not exist in a vacuum – they all have an impact on the local community, wider society and the environment in which they operate. Alison Glennon explains how adopting corporate social responsibility can help a practice's bottom line, as well as provide a ‘feel good factor’.
Tethered dog dies
Authors: Swan Pippa
Published: December 2010

When transporting a client's dog between clinics in their estate car, a vet secures the animal with a lead in the boot, as it is boisterous. On arrival the dog is found dead and looks to have become trapped with the lead round its neck. The noises the dog had been making had seemed to be agitation and when they stopped the vet assumed it had gone to sleep. Should a criminal prosecution be brought against the vet and the Royal College of Veterinary Surgeons be informed?
Medical management of acute and chronic vomiting in dogs and cats
Authors: McGrotty Yvonne
Published: December 2010

Vomiting is a common presentation in small animal practice and can be associated with a wide variety of both gastrointestinal and systemic diseases. A logical diagnostic approach is required to identify the underlying cause to ensure that appropriate therapy can be instituted. Medical management of vomiting can involve drug therapy, fluid therapy and dietary manipulation. This article describes the physiology and pharmacological control of acute and chronic vomiting in dogs and cats.
The Latino adolescent male mortality peak revisited: attribution of homicide and motor vehicle crash death
Authors: Vaca Federico E , Anderson Craig L , Hayes-Bautista David E
Published: December 2010

Objective

The Latino Epidemiologic Paradox describes favourable health profiles for Latinos compared to non-Latino whites despite poverty, low education, and low access to healthcare. The objective of this study was to determine if the anomaly to the Latino Epidemiological Paradox and the Latino Adolescent Male Mortality Peak in California mortality data persists.

Methods

Cases were California residents (1999–2006) of any race and ethnicity that died (N=1 866 743) in California from any cause of death. Mortality rates and rate ratios were calculated according to causes of death for 5 year age groups.

Results

For males and females combined, age adjusted mortality rates were 509 for Latinos and 681 for non-Latino whites per 100 000/year. Latino male mortality rate ratios exceeded 1.0 compared to non-Latino white males only for age groups 15–19 years (1.41, 95% CI 1.35 to 1.49) and 20–24 years (1.24, 95% CI 1.19 to 1.29). Latinas had lower mortality rates than non-Latino white females for all ages over 15 years. Male homicide rates for Latinos increased over the study period, but did not reach the rates reported for the years 1989–1997. Both male homicide and motor vehicle crash mortality rates were higher for Latinos than non-Latino whites and peaked at 20–24 years. The Latino crash mortality rate exceeded the rate for non-Latino whites overall and for each year 2003–2006. Crash mortality for males aged 15–24 years increased from 2000 to 2006.

Conclusion

The anomaly and the mortality peak persist, with notable attribution to homicide and crashes. Without homicide, the mortality peak would not exist. Mortality disparities for Latino adolescent males from these two causes of death in California appear to be growing.
Ubiquity symposium 'What is computation?'
Authors: Rosenbloom Paul S.
Published: December 2010

In this fifth article in the ACM Ubiquity symposium on What is computation? Paul S. Rosenbloom explains why he believes computing is the fourth great scientific domain, on par with the physical, life, and social sciences. Editor
Collaboration in System Administration
Authors: Haber Eben M. , Kandogan Eser , Maglio Paul
Published: December 2010

George was in trouble. A seemingly simple deployment was taking all morning, and there seemed no end in sight. His manager kept coming in to check on his progress, as the customer was anxious to have the deployment done. He was supposed to be leaving for a goodbye lunch for a departing co-worker, adding to the stress. He had called in all kinds of help, including colleagues, an application architect, technical support, and even one of the system developers. He used e-mail, instant messaging, face-to-face contacts, his phone, and even his office mate’s phone to communicate with everyone. And George was no novice. He had been working as a Web-hosting administrator for three years, and he had a bachelor’s degree in computer science. But it seemed that all the expertise being brought to bear was simply not enough. Why was George in trouble? We’ll find out.
High PTP4A3 Phosphatase Expression Correlates with Metastatic Risk in Uveal Melanoma Patients
Authors: Laurent Cécile , Valet Fabien , Planque Nathalie , Silveri Licia , Maacha Selma , Anezo Océane , Hupe Philippe , Plancher Corine , Reyes Cécile , Albaud Benoit , Rapinat Audrey , Gentien David , Couturier Jérôme , Sastre-Garau Xavier , Desjardins Laurence , Thiery Jean-Paul , Roman-Roman Sergio , Asselain Bernard , Barillot Emmanuel , Piperno-Neumann Sophie , Saule Simon
Published: December 2010

A high percentage of uveal melanoma patients develop metastatic tumors predominantly in the liver. We studied the molecular profiles derived from gene expression microarrays and comparative genomic hybridization microarrays, to identify genes associated with metastasis in this aggressive cancer. We compared 28 uveal melanomas from patients who developed liver metastases within three years of enucleation with 35 tumors from patients without metastases or who developed metastases more than 3 years after enucleation. Protein tyrosine phosphatase type IV A member 3 (PTP4A3/PRL3), was identified as a strong predictor of metastasis occurrence. We demonstrated that the differential expression of this gene, which maps to 8q24.3, was not merely a consequence of 8q chromosome overrepresentation. PTP4A3 overexpression in uveal melanoma cell lines significantly increased cell migration and invasiveness in vivo, suggesting a direct role for this protein in metastasis. Our findings suggest that PTP4A3 or its cellular substrates could constitute attractive therapeutic targets to treat metastatic uveal melanomas. Cancer Res; 71(3); 666–74. ©2010 AACR.
Invasive Prostate Carcinoma Driven by c-Src and Androgen Receptor Synergy
Authors: Cai Houjian , Babic Ivan , Wei Xiao , Huang Jiaoti , Witte Owen N.
Published: December 2010

Cellular Src (c-Src) integrates a large number of signal transduction pathways regulating cell division, migration, and other aspects of cell physiology. Mutations of Src kinase have not been described in human prostate cancer, but evidence for increased levels of expression accompanying cancer progression has been reported. We analyzed overexpression of c-Src in naïve mouse prostate epithelium and observed no change in tubule formation frequency or histologic structure. However, when enhanced c-Src expression is coupled with enhanced expression of androgen receptor (AR), it results in a strong activation of Src kinase activity accompanied by activation of the MAPK pathway, and enhanced AR activity. Similar to the pathology induced by constitutively active c-Src(Y529F), the tubules progress to frank carcinoma with invasion and display markers of epithelial-to-mesenchymal transition. These combined results suggest that nonmutated Src kinase may play a more important role in the genesis and progression of prostate cancer than previously appreciated and that epigenetic changes that enhance the level of AR may select for enhanced expression of c-Src with accompanying activation and a strong drive to malignant progression. Cancer Res; 71(3); 862–72. ©2010 AACR.
Hedgehog Signaling Drives Cellular Survival in Human Colon Carcinoma Cells
Authors: Mazumdar Tapati , DeVecchio Jennifer , Shi Ting , Jones Janay , Agyeman Akwasi , Houghton Janet A.
Published: December 2010

Aberrant activation of Hedgehog (HH) signaling is implicated in many human cancers. Classical HH signaling is characterized by Smoothened (Smo)-dependent activation of Gli1 and Gli2, which transcriptionally regulate target genes. A small molecule inhibitor of Gli1 and Gli2, GANT61, was used to block HH signaling in human colon carcinoma cell lines that express HH signaling components. GANT61 administration induced robust cytotoxicity in 5 of 6 cell lines and moderate cytotoxicity in the remaining 1 cell line. In comparison, the classical Smo inhibitor, cyclopamine, induced modest cytotoxicity. Further, GANT61 treatment abolished the clonogenicity of all six human colon carcinoma cell lines. Analysis of the molecular mechanisms of GANT61-induced cytotoxicity in HT29 cells showed increased Fas expression and decreased expression of PDGFRα, which also regulates Fas. Furthermore, DR5 expression was increased whereas Bcl-2 (direct target of Gli2) was downregulated following GANT61 treatment. Suppression of Gli1 by shRNA mimicked the changes in gene expression observed in GANT61-treated cells. Overexpression of dominant-negative FADD (to abrogate Fas/DR5-mediated death receptor signaling) and/or Bcl-2 (to block mitochondria-mediated apoptosis) partially rescued GANT61-induced cytotoxicity in HT29 cells. Thus, activated GLI genes repress DR5 and Fas expressions while upregulating Bcl-2 and PDGFRα expressions to inhibit Fas and facilitate cell survival. Collectively, these results highlight the importance of Gli activation downstream of Smo as a therapeutic target in models of human colon carcinoma. Cancer Res; 71(3); 1092–102. ©2010 AACR.
Effect of Maternal and Postweaning Folic Acid Supplementation on Mammary Tumor Risk in the Offspring
Authors: Ly Anna , Lee Hanna , Chen Jianmin , Sie Karen K. Y. , Renlund Richard , Medline Alan , Sohn Kyoung-Jin , Croxford Ruth , Thompson Lilian U. , Kim Young-In
Published: December 2010

Intrauterine and early life exposure to folic acid has significantly increased in North America owing to folic acid fortification, widespread supplemental use, and periconceptional supplementation. We investigated the effects of maternal and postweaning folic acid supplementation on mammary tumor risk in the offspring. Female rats were placed on a control or folic acid–supplemented diet prior to mating and during pregnancy and lactation. At weaning, female pups from each maternal diet group were randomized to the control or supplemented diet and mammary tumors were induced with 7,12 dimethylbenz[a]anthracene at puberty. At necropsy, mammary tumor parameters, genomic DNA methylation, and DNA methyltransferase activity were determined in the offspring. Both maternal and postweaning folic acid supplementation significantly increased the risk of mammary adenocarcinomas in the offspring (OR = 2.1, 95% CI 1.2–3.8, P = 0.008 and OR = 1.9, 95% CI 1.1–3.3, P = 0.03, respectively). Maternal folic acid supplementation also significantly accelerated the rate of mammary adenocarcinoma appearance (P = 0.002) and increased the multiplicity of mammary adenocarcinomas (P = 0.008) in the offspring. Maternal, but not postweaning, folic acid supplementation significantly reduced global DNA methylation (P = 0.03), whereas postweaning, but not maternal, folic acid supplementation significantly decreased DNA methyltransferase activity (P = 0.05) in nonneoplastic mammary glands of the offspring. Our findings suggest that a high intrauterine and postweaning dietary exposure to folic acid may increase the risk of mammary tumors in the offspring. Further, they suggest that this tumor-promoting effect may be mediated in part by altered DNA methylation and DNMT activity. Cancer Res; 71(3); 988–97. ©2010 AACR.
Breast Cancer Racial Disparities: Unanswered Questions
Authors: Ademuyiwa Foluso O. , Edge Stephen B. , Erwin Deborah O. , Orom Heather , Ambrosone Christine B. , Underwood Willie
Published: December 2010

Breast cancer is the most common noncutaneous cancer diagnosed in women in the United States and is second only to lung cancer as the leading cause of cancer-related mortality. Although mortality rates have been dropping steadily due to a variety of factors including improved treatment modalities and screening, substantial racial differences in outcome between blacks and whites persist. Although differences in health care utilization and access, tumor biology, and cancer management have been elucidated as possible reasons for disparities seen, it is likely that other interactions exist. The purpose of this review is, therefore, to present a comprehensive overview of the literature on racial disparities in breast cancer outcome and highlight potential causative factors that may contribute to disparities seen among blacks and whites with breast cancer. In addition, we make research recommendations by discussing some of the remaining gaps in knowledge that may lead to further understanding of disparities and consequently improved outcomes for all women with breast cancer. Cancer Res; 71(3); 640–4. ©2010 AACR.
Benign Mesenchymal Stromal Cells in Human Sarcomas
Authors: Morozov Alexei , Downey Robert J. , Healey John , Moreira Andre L. , Lou Emil , Franceschino Anna , Dogan Yildirim , Leung Roland , Edgar Mark , LaQuaglia Michael , Maki Robert G. , Moore Malcolm A.S.
Published: December 2010

Purpose: Recent evidence suggests that at least some sarcomas arise through aberrant differentiation of mesenchymal stromal cells (MSCs), but MSCs have never been isolated directly from human sarcoma specimens.

Experimental Design: We examined human sarcoma cell lines and primary adherent cultures derived from human sarcoma surgical samples for features of MSCs. We further characterized primary cultures as either benign or malignant by the presence of tumor-defining genetic lesions and tumor formation in immunocompromised mice.

Results: We show that a dedifferentiated liposarcoma cell line DDLS8817 posesses fat, bone, and cartilage trilineage differentiation potential characteristic of MSCs. Primary sarcoma cultures have the morphology, surface immunophenotype, and differentiation potential characteristic of MSCs. Surprisingly, many of these cultures are benign, as they do not form tumors in mice and lack sarcoma-defining genetic lesions. Consistent with the recently proposed pericyte origin of MSCs in normal human tissues, sarcoma-derived benign MSCs (SDBMSCs) express markers of pericytes and cooperate with endothelial cells in tube formation assays. In human sarcoma specimens, a subset of CD146-positive microvascular pericytes expresses CD105, an MSC marker, whereas malignant cells largely do not. In an in vitro coculture model, SDBMSCs as well as normal human pericytes markedly stimulate the growth of sarcoma cell lines.

Conclusions: SDBMSCs/pericytes represent a previously undescribed stromal cell type in sarcoma that may contribute to tumor formation. Clin Cancer Res; 16(23); 5630–40. ©2010 AACR.
Foxo3a Suppression of Urothelial Cancer Invasiveness through Twist1, Y-Box–Binding Protein 1, and E-Cadherin Regulation
Authors: Shiota Masaki , Song YooHyun , Yokomizo Akira , Kiyoshima Keijiro , Tada Yasuhiro , Uchino Hiroshi , Uchiumi Takeshi , Inokuchi Junichi , Oda Yoshinao , Kuroiwa Kentaro , Tatsugami Katsunori , Naito Seiji
Published: December 2010

Purpose: Invasion and metastasis are key steps in the progression of urothelial cancer (UC) into a critical disease. Foxo3a is a member of the Foxo transcription factor family that modulates the expression of various genes. We aimed to elucidate the role of Foxo3a in UC invasion.

Experimental Design: Foxo3a mRNA and protein expressions in UC samples were investigated by gene expression assays and immunohistochemistry, respectively. Foxo3a expression was compared with clinicopathologic characteristics and patient prognoses based on UC samples. Quantitative real-time polymerase chain reaction, Western blotting, and migration assays were also conducted in UC cells.

Results: Foxo3a expression decreased in invasive UC; patients with low Foxo3a expression had poor disease-free survival, cancer-specific survival, and overall survival; Foxo3a knockdown in UC cells increased cellular motility. Foxo3a negatively regulated Twist1 and Y-box–binding protein 1 (YB-1), and positively regulated E-cadherin in KK47 and TCCsup cells that expressed Twist1, but not in T24 cells that did not express Twist1. Foxo3a-associated acetyltransferase p300 and Foxo3a acetylation status also affected UC motility.

Conclusion: The results of this study indicate that Foxo3a regulates motility of UC through negative regulation of Twist1 and YB-1, and through positive regulation of E-cadherin. This suggests that Foxo3a could act as an independent prognostic factor in UC and could represent a promising molecular target for cancer therapeutics. Clin Cancer Res; 16(23); 5654–63. ©2010 AACR.
Decreased Expression of Cyr61 Is Associated with Prostate Cancer Recurrence after Surgical Treatment
Authors: D'Antonio Katherine B. , Schultz Lucianna , Albadine Roula , Mondul Alison M. , Platz Elizabeth A. , Netto George J. , Getzenberg Robert H.
Published: December 2010

Purpose: Cysteine-rich angiogenic inducer 61 (Cyr61) is an extracellular matrix protein involved in the transduction of growth factor and hormone signaling. Previous studies have suggested that Cyr61 may be a marker for a more aggressive phenotype. In this study, we evaluated the association between Cyr61 staining intensity and subsequent recurrence after surgical treatment of clinically localized prostate cancer.

Experimental Design: A study of 229 men with recurrence and 229 controls matched on age, race, pathologic stage, and Gleason sum nested in a cohort of men who underwent radical prostatectomy for clinically localized prostate cancer, utilizing immunohistochemistry analysis of tissue microarray (TMA) sections, was conducted. Odds ratios (OR) of recurrence and 95% confidence intervals (CIs) were estimated using conditional logistic regression.

Results: Recurrence was identified in 12.2% of cases, and in 24.0% of controls that had at least 1 TMA spot containing cancer with a staining intensity of 3 (P = 0.001). Taking into account age, pathologic stage and grade, presurgery prostate-specific antigen concentration, and calendar of surgery as a measure of tissue block storage time, men with a Cyr61 staining intensity of 3 were 56% less likely to recur than men with a lower staining intensity (OR = 0.44, 95% CI = 0.22–0.90).

Conclusions: High Cyr61 staining intensity in adenocarcinoma was associated with a lower risk of recurrence after surgical treatment of prostate cancer independent of pathologic tumor characteristics. If validated in other sample sets, Cyr61 may serve as a tissue biomarker for stratifying men for risk of recurrence and thus could inform treatment decision making. Clin Cancer Res; 16(23); 5908–13. ©2010 AACR.
Personalizing Cancer Treatment in the Age of Global Genomic Analyses: PALB2 Gene Mutations and the Response to DNA Damaging Agents in Pancreatic Cancer
Authors: Villarroel Maria C. , Rajeshkumar N.V. , Garrido-Laguna Ignacio , De Jesus-Acosta Ana , Jones Siân , Maitra Anirban , Hruban Ralph H. , Eshleman James R. , Klein Alison , Laheru Daniel , Donehower Ross , Hidalgo Manuel
Published: December 2010

Metastasis and drug resistance are the major causes of mortality in patients with pancreatic cancer. Once developed, the progression of pancreatic cancer metastasis is virtually unstoppable with current therapies. Here, we report the remarkable clinical outcome of a patient with advanced, gemcitabine-resistant, pancreatic cancer who was later treated with DNA damaging agents, on the basis of the observation of significant activity of this class of drugs against a personalized xenograft generated from the patient's surgically resected tumor. Mitomycin C treatment, selected on the basis of its robust preclinical activity in a personalized xenograft generated from the patient's tumor, resulted in long-lasting (36+ months) tumor response. Global genomic sequencing revealed biallelic inactivation of the gene encoding PalB2 protein in this patient's cancer; the mutation is predicted to disrupt BRCA1 and BRCA2 interactions critical to DNA double-strand break repair. This work suggests that inactivation of the PALB2 gene is a determinant of response to DNA damage in pancreatic cancer and a new target for personalizing cancer treatment. Integrating personalized xenografts with unbiased exomic sequencing led to customized therapy, tailored to the genetic environment of the patient's tumor, and identification of a new biomarker of drug response in a lethal cancer. Mol Cancer Ther; 10(1); 3–8. ©2010 AACR. Mol Cancer Ther; 10(1); 3–8. ©2010 AACR.
AP-1 Regulates Cyclin D1 and c-MYC Transcription in an AKT-Dependent Manner in Response to mTOR Inhibition: Role of AIP4/Itch-Mediated JUNB Degradation
Authors: Vartanian Raffi , Masri Janine , Martin Jheralyn , Cloninger Cheri , Holmes Brent , Artinian Nicholas , Funk Alex , Ruegg Teresa , Gera Joseph
Published: December 2010

One mechanism by which AKT kinase-dependent hypersensitivity to mammalian target of rapamycin (mTOR) inhibitors is controlled is by the differential expression of cyclin D1 and c-MYC. Regulation of posttranscriptional processes has been demonstrated to be crucial in governing expression of these determinants in response to rapamycin. Our previous data suggested that cyclin D1 and c-MYC expression might additionally be coordinately regulated in an AKT-dependent manner at the level of transcription. Under conditions of relatively quiescent AKT activity, treatment of cells with rapamycin resulted in upregulation of cyclin D1 and c-MYC nascent transcription, whereas in cells containing active AKT, exposure repressed transcription. Promoter analysis identified AKT-dependent rapamycin responsive elements containing AP-1 transactivation sites. Phosphorylated c-JUN binding to these promoters correlated with activation of transcription whereas JUNB occupancy was associated with promoter repression. Forced overexpression of JunB or a conditionally active JunB-ER allele repressed cyclin D1 and c-MYC promoter activity in quiescent AKT-containing cells following rapamycin exposure. AIP4/Itch-dependent JUNB protein degradation was found to be markedly reduced in active AKT-containing cells compared with cells harboring quiescent AKT. Moreover, silencing AIP4/Itch expression or inhibiting JNK mediated AIP4 activity abrogated the rapamycin-induced effects on cyclin D1 and c-MYC promoter activities. Our findings support a role for the AKT-dependent regulation of AIP4/Itch activity in mediating the differential cyclin D1 and c-MYC transcriptional responses to rapamycin. Mol Cancer Res; 9(1); 115–30 ©2010 AACR.
Monitoring Sleep-Wake Rhythm with Actigraphy in Patients on Continuous Positive Airway Pressure Therapy
Authors: Otake Masafumi , Miyata Seiko , Noda Akiko , Koike Yasuo , Hara Yuki , Sugiura Mari , Minoshima Makoto , Kojima Jun , Nakata Seiichi , Nakashima Tsutomu
Published: December 2010

Background:Continuous positive airway pressure (CPAP) therapy has been shown to be effective in alleviating the underlying obstruction as well as reducing patients’ excessive sleepiness and improving their functioning and health-related quality of life. However, residual excessive sleepiness is observed in some patients even though CPAP therapy eliminates sleep apnea and desaturation. Objectives:The aim of this study was to determine the prognostic effect of actigraphic sleep-wake rhythm evaluation in the management of patients with obstructive sleep apnea syndrome (OSAS) treated with CPAP. Methods: Eighteen patients with OSAS diagnosed by standard polysomnography (PSG; 48.1 ± 12.5 years) were enrolled in this study. The sleep-wake parameters were determined by actigraphy before and after 1 month of CPAP treatment, and results were compared with PSG data. In addition, data obtained before CPAP were compared with those measured after 1 month of CPAP treatment. Results:The total sleep time (TST) and sleep efficiency using PSG were significantly correlated with those using actigraphy. Bland-Altman plots of TST and sleep efficiency confirmed good agreement between PSG and actigraphy data. Sleep efficiency significantly improved following CPAP compared to baseline, and sleep fragmentation and sleep fragmentation >5 min determined by actigraphy were significantly lower during CPAP therapy than at baseline. Movement was significantly lower on CPAP therapy than at baseline. Conclusions:Actigraphy provides a valuable sleep-wake rhythm assessment in outpatients with OSAS where PSG is difficult to perform.
Brown versus White Adipose Tissue: A Mini-Review
Authors: Saely Christoph H. , Geiger Kathrin , Drexel Heinz
Published: December 2010

Background: Brown adipose tissue (BAT) is abundant in small mammals and in newborns and helps them to survive cold temperatures. In adults, it had long been considered to be absent or at least of no relevance. Recent investigations, however, have fuelled interest in adult BAT. Objective: We aimed at (1) summarizing structural and physiological characteristics of BAT versus white adipose tissue (WAT); (2) discussing the development of the two adipose tissue types; (3) reviewing the data available from human studies on BAT, and (4) discussing the impact of aging. Methods: We summarize recent descriptions of BAT and WAT based on the original literature and reviews in the field, with emphasis on human BAT. Results: WAT and BAT have essentially antagonistic functions: WAT stores excess energy as triglycerides and BAT is specialized in the dissipation of energy through the production of heat. Considerable amounts of BAT are present in a substantial proportion of adult humans and relatively high quantities of BAT are associated with lower body weight. With increasing age, BAT decreases and body weight increases. Conclusions: Although the available cross-sectional data do not allow definite conclusions to be drawn concerning a causal relationship between loss of BAT and increasing body weight with advancing age or obesity-related metabolic disorders of older age, stimulation of BAT appears to be an attractive novel candidate target for the treatment of age-related obesity.
Biochemical Markers for Blood-Brain Barrier Dysfunction in Acute Ischemic Stroke Correlate with Evolution and Outcome
Authors: Brouns Raf , Wauters Annick , De Surgeloose Didier , Mariën Peter , De Deyn Peter P.
Published: December 2010

Background/Aims: We evaluated the cerebrospinal fluid/serum albumin ratio (AR) and kinetics of matrix metalloproteinase-9 (MMP-9) in blood as markers for blood-brain barrier (BBB) disruption after acute ischemic stroke. Methods: The AR was determined in 88 patients with acute ischemic stroke or transient ischemic attack. MMP-9 was measured on admission, 24, 72 h and 7 days after stroke onset. Results: The AR was related to stroke severity, the occurrence of stroke progression and the modified Rankin Scale score at month 3. MMP-9 levels on admission were significantly elevated compared to controls and dropped in the first 72 h after stroke, except in patients with stroke progression and larger infarcts in the subacute phase. Conclusions:We demonstrate that the extent of BBB breakdown in hyperacute stroke relates to initial stroke severity, stroke evolution and long-term outcome. The kinetics of MMP-9 confirm its pivotal role in secondary brain damage after ischemic stroke.
Safety of edoxaban, an oral factor Xa inhibitor, in Asian patients with non-valvular atrial fibrillation
Authors: Jeon Hui-Kyung , Lien Li-Ming , Lai Wen-Ter , Tse Hung-Fat , Chung Wook-Sung , Lee Tsong-Hai , Chen Shih-Ann , Chung Namsik
Published: December 2010

Edoxaban is an oral, reversible, direct factor Xa inhibitor in phase III clinical development for the prevention of stroke in atrial fibrillation (AF). A phase II study was undertaken to evaluate the safety and efficacy of edoxaban in Asian patients with non-valvular AF with CHADS2 score ≥1. In a multicentre, active-controlled, double-blind edoxaban and open-label warfarin, parallel-group study, a total of 235 patients from four Asian countries were randomly assigned to edoxaban 30 mg qd, 60 mg qd or warfarin dose adjusted to international normalised ratio of 2–3 for three months. The primary endpoint was the incidence of centrally adjudicated all bleeding events (major, clinically relevant non-major and minor). Secondary endpoints included thromboembolic events, biomarkers of thrombus formation and all adverse events (AEs). The incidence of all bleeding events (95% CI) was 20.3% (12.9, 30.4) for edoxaban 30 mg, 23.8% (15.8, 34.1) for edoxaban 60 mg, and 29.3% (20.2, 40.4) for warfarin. A subgroup analysis suggested low body weight (≤60 kg) may affect the incidence of bleeding events with edoxaban. The incidence of study drug-related AEs was 22% for edoxaban 30 mg, 29% for edoxaban 60 mg and 33% for warfarin. No thromboembolic events occurred in any treatment group. In conclusion, this phase II study found a trend for a reduction in the incidence of all bleeding events in Asian AF patients with edoxaban 30 mg and 60 mg compared with warfarin. Adverse events were similar between the edoxaban 60-mg and warfarin groups and were lower with the edoxaban 30-mg group.

ClinicalTrials.gov number: NCT00806624
Cardiovascular risk assessment in haemophilia patients
Authors: Baarslag Manuel , Peters Marjolein , Kruip Marieke , Kraaijenhagen Roderik , Den Heijer Martin , Büller Harry , Kamphuisen Pieter , Biere-Rafi Sara
Published: December 2010

Haemophilia patients have a reduced cardiovascular mortality, which may be the result of a lifelong deficiency of factor VIII or IX. On the other hand, the prevalence of risk factors may differ in these chronically ill patients compared to the general population. The prevalence of risk factors and expected risk of cardiovascular disease was compared in haemophilia patients and healthy controls. In adult haemophilia A and B patients, body mass index, blood pressure, cholesterol levels and fasting glucose levels were measured and compared to healthy age-matched males. The expected risk of mortality due to cardiovascular disease was calculated using a European risk prediction algorithm (SCORE). A total of 100 haemophilia A and B patients and 200 healthy controls were analysed. The mean age of the patients was 47 years (range 18–83). The number of haemophiliacs with hyperglycaemia (24%) and hypertension (51%) was higher than in the controls (p-values 0.001 and 0.03, respectively). The mean low-density lipoprotein (LDL) cholesterol level in cases was lower than the controls (3.02 mM (0.69–6.57) and 3.60 mM (1.68–5.95), respectively, p < 0.001). Fewer cases had increased LDL levels (p=0.045). No difference was found in the 10-year cardiovascular mortality risk >10% between cases and controls (12% and 7%, respectively, p = 0.18). The prevalence of risk factors and expected risk of cardiovascular disease in haemophilia patients is comparable to the general population. This strengthens the hypothesis that hypocoagulability may reduce cardiovascular mortality in haemophilia patients.
Epinephrine-mediated protein kinase C and Rap1b activation requires the co-stimulation of Gz-, Gq-, and Gi-coupled receptors
Authors: Canobbio Ilaria , Catricalà Silvia , Balduini Cesare , Lova Paolo , Guidetti Gianni Francesco , Torti Mauro
Published: December 2010

We have recently shown that ADP-induced activation of protein kinase C (PKC) requires the co-stimulation of both P2Y1 and P2Y12 receptors. In this work, we show that inhibition of ADP-mediated phosphorylation of pleckstrin, the main PKC substrate, caused by antagonists of the P2Y12 receptor can be reversed by stimulation of the α2-adrenergic receptor by epinephrine. However, we also observed that addition of epinephrine alone caused a marked phosphorylation of pleckstrin. This effect occurred in the absence of Gq stimulation, as it was not associated to intracellular Ca2+ release. Epinephrine-induced pleckstrin phosphorylation was time- and dose-dependent, and was inhibited by the α2-adrenergic antagonist yohimbin. Phosphorylation of pleckstrin did not occur when platelet stimulation with epinephrine was performed in the presence of the ADP scavenger apyrase, and was suppressed by antagonists of both P2Y1 and P2Y12 ADP receptors. Importantly, no release of dense granules was measured in epinephrine-treated platelets. Addition of epinephrine to platelets was also able to stimulate Rap1b activation. Similarly to pleckstrin phosphorylation, however, this effect was prevented in the presence of apyrase or upon pharmacologic blockade of either P2Y1 or P2Y12 receptors. These results indicate that sub-threshold amounts of ADP in the medium are essential to allow epinephrine stimulation of α2-adrenergic receptor to elicit platelet responses, and reveal a novel synergism among strong stimulation of Gz and sub-threshold stimulation of both Gq and Gi, able to dissociate PKC activation from intracellular Ca2+ mobilisation.
The effect of p22-PHOX (CYBA) polymorphisms on premature coronary artery disease (≤ 40 years of age)
Authors: Goliasch Georg , Grafl Andreas , Ponweiser Elisabeth , Blessberger Hermann , Tentzeris Ioannis , Wojta Johann , Schillinger Martin , Huber Kurt , Maurer Gerald , Mannhalter Christine , Sunder-Plaßmann Raute , Wiesbauer Franz
Published: December 2010

Acute myocardial infarction at a young age is associated with high morbidity and long-term mortality. The NADPH oxidase system as a main source of reactive oxygen species in vascular cells has been implicated in development and progression of coronary artery disease (CAD). In our study, we investigated the effect of polymorphisms in the p22-PHOX (CYBA) gene on CAD in young patients (≤ 40 years). We prospectively recruited 302 subjects into our multi-centre case control study, including 102 young myocardial infarction patients (≤ 40 years) from two high-volume cardiac catheterisation hospitals and frequency-matched them on age, gender, and center to 200 hospital controls in an approximate 2:1 ratio per case patient. The homozygote c.-930A>G promoter polymorphism was significantly more prevalent in the controls than in the infarction patients. In the adjusted logistic regression analysis, we detected a protective effect of the c.-930A>G promoter polymorphism against premature myocardial infarction. Using a logadditive/per-allele model, we detected an unadjusted odds ratio (OR) of 0.63 (95% confidence interval [CI] 0.45–0.9, p-value 0.011). In the adjusted model the association was more pronounced with an OR of 0.5 (95% CI 0.3–0.81, p-value 0.005). The C242T polymorphism and the 640A>G polymorphism did not differ significantly between the study groups. Furthermore we could not detect a significant effect for these polymorphisms in the logistic regression analysis. The present study suggests a protective association between the c.-930A>G promoter polymorphism in the p22-PHOX (CYBA) gene and the development of myocardial infarction in young individuals (≤ 40 years).
γ’/total fibrinogen ratio is associated with short-term outcome in ischaemic stroke
Authors: Cheung Elim , de Lau Lonneke , den Hertog Heleen , Leebeek Frank , Dippel Diederik , Koudstaal Peter , de Maat Moniek , van den Herik Evita
Published: December 2010

Fibrinogen γ’ (γ’) is a natural isoform of fibrinogen, and alters the rate of formation and the properties of clots. It could therefore affect outcome after ischaemic stroke. The prognostic significance of γ’ fibrinogen levels is, however, still unclear. It was the objective of this study to assess levels of γ’ in ischaemic stroke, and its association with short-term outcome. We included 200 ischaemic stroke patients and 156 control persons. Total fibrinogen and γ’ levels were measured; outcome at discharge was assessed by means of the modified Rankin Scale score (defined as unfavourable when >2). We compared levels between patients and controls using multiple linear regression analysis, and logistic regression analysis was used to assess the relationship between levels and outcome. All analyses were adjusted for age and sex. Mean γ’ levels were significantly higher in patients with ischaemic stroke than in controls (0.37 vs. 0.32 g/l, p<0.001), and patients also had a higher γ’/total fibrinogen ratio (0.102 vs. 0.096, p=0.19). The γ’/total fibrinogen ratio is associated with unfavourable outcome in patients with ischaemic stroke (odds ratio per unit increase of γ’/total fibrinogen ratio 1.27, 95% confidence interval 1.09–1.47). Our study shows that patients with ischaemic stroke have increased levels of fibrinogen γ’ and suggests a trend towards an increased γ’/total fibrinogen ratio in ischaemic stroke. Increased fibrinogen γ’ relative to total fibrinogen levels are associated with unfavourable outcome in the early phase after stroke.