bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

ABSTRACT

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

ABSTRACT

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

ABSTRACT

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

ABSTRACTThe 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

ABSTRACTHistoplasma 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.
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

ObjectiveThe 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.MethodsCases 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.ResultsFor 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.ConclusionThe 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.
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

AbstractA 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

Abstract
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

Abstract
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

AbstractIntrauterine 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

Abstract
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

Abstract
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

Abstract
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.