bluuebunny/crossref_metadata_2025_split huggingface dataset:
LEADER Program Results for 2009: an Activity and Spectrum Analysis of Linezolid Using 6,414 Clinical Isolates from 56 Medical Centers in the United States
Authors: Farrell David J. , Mendes Rodrigo E. , Ross James E. , Sader Helio S. , Jones Ronald N. 
Published: June 2011

ABSTRACTThe LEADER Program monitors thein vitroactivity of linezolid in sampled U.S. medical centers using reference broth microdilution methods with supporting molecular investigations in a central laboratory design. This report summarizes data obtained in 2009, the 6th consecutive year of this longitudinal study. A total of 6,414 isolates from 56 medical centers in all nine Census regions across the United States participated in 2009. For the six leading species/groups, the following linezolid MIC90values were observed:Staphylococcus aureus, 2 μg/ml; coagulase-negative staphylococci (CoNS), 1 μg/ml;Enterococcusspp., 2 μg/ml;Streptococcus pneumoniae, 1 μg/ml; viridans group streptococci, 1 μg/ml; and beta-hemolytic streptococci, 1 μg/ml. Linezolid resistance was only 0.34% overall, with no evidence of significant increase in the LEADER Program since 2006. The predominant linezolid resistant mechanism found was a G2576T mutation in the 23S rRNA. L3/L4 riboprotein mutations were also found. The mobile multidrug-resistantcfrgene was found in four strains (twoS. aureusstrains and one strain each ofS. epidermidisandS. capitis) from four different states, suggesting persistence but a lack of dissemination. Linezolid continues to exhibit excellent activity and spectrum, and this study documents the need for continued monitoring of emerging mechanisms of resistance over a wide geographic area.
A Francisella tularensis Locus Required for Spermine Responsiveness Is Necessary for Virulence
Authors: Russo Brian C. , Horzempa Joseph , O'Dee Dawn M. , Schmitt Deanna M. , Brown Matthew J. , Carlson Paul E. , Xavier Ramnik J. , Nau Gerard J. 
Published: June 2011

ABSTRACT

Tularemia is a debilitating febrile illness caused by the category A biodefense agent
Francisella tularensis
. This pathogen infects over 250 different hosts, has a low infectious dose, and causes high morbidity and mortality. Our understanding of the mechanisms by which
F. tularensis
senses and adapts to host environments is incomplete. Polyamines, including spermine, regulate the interactions of
F. tularensis
with host cells. However, it is not known whether responsiveness to polyamines is necessary for the virulence of the organism. Through transposon mutagenesis of
F. tularensis
subsp.
holarctica
live vaccine strain (LVS), we identified FTL_0883 as a gene important for spermine responsiveness. In-frame deletion mutants of FTL_0883 and FTT_0615c, the homologue of FTL_0883 in
F. tularensis
subsp.
tularensis
Schu S4 (Schu S4), elicited higher levels of cytokines from human and murine macrophages compared to wild-type strains. Although deletion of FTL_0883 attenuated LVS replication within macrophages
in vitro
, the Schu S4 mutant with a deletion in FTT_0615c replicated similarly to wild-type Schu S4. Nevertheless, both the LVS and the Schu S4 mutants were significantly attenuated
in vivo
. Growth and dissemination of the Schu S4 mutant was severely reduced in the murine model of pneumonic tularemia. This attenuation depended on host responses to elevated levels of proinflammatory cytokines. These data associate responsiveness to polyamines with tularemia pathogenesis and define FTL_0883/FTT_0615c as an
F. tularensis
gene important for virulence and evasion of the host immune response.
Chitin-Induced Carbotype Conversion in Vibrio vulnificus
Authors: Neiman Jana , Guo Yunzhi , Rowe-Magnus Dean A. 
Published: June 2011

ABSTRACT

As an etiological agent of bacterial sepsis and wound infections,
Vibrio vulnificus
is unique among the
Vibrionaceae
. The most intensely studied of its virulence factors is the capsular polysaccharide (CPS). Over 100 CPS types have been identified, yet little is known about the genetic mechanisms that drive such diversity. Chitin, the second-most-abundant polysaccharide in nature, is known to induce competence in
Vibrio
species. Here, we show that the frequency of chitin-induced transformation in
V. vulnificus
varies by strain and that (GlcNAc)
2
is the shortest chitin-derived polymer capable of inducing competence. Transformation frequencies (TFs) increased 8-fold when mixed-culture biofilms were exposed to a strain-specific lytic phage, suggesting that the lysis of dead cells during lytic infection increased the amount of extracellular DNA within the biofilm that was available for transfer. Furthermore, we show that
V. vulnificus
can undergo chitin-dependent carbotype conversion following the uptake and recombination of complete
cps
loci from exogenous genomic DNA (gDNA). The acquisition of a partial locus was also demonstrated when internal regions of homology between the endogenous and exogenous loci existed. This suggested that the same mechanism governing the transfer of complete
cps
loci also contributed to their evolution by generating novel combinations of CPS biosynthesis genes. Since no evidence that
cps
loci were preferentially acquired during natural transformation (random transposon-tagged DNA was readily taken up in chitin transformation assays) exists, the phenomenon of chitin-induced transformation likely plays an important but general role in the evolution of this genetically promiscuous genus.
Diagnostic accuracy of transient elastography (FibroScan) versus the aspartate transaminase to platelet ratio index in assessing liver fibrosis in chronic hepatitis B: The role in primary care setting
Authors: Lesmana C Rinaldi A , Salim Simon , Hasan Irsan , Sulaiman Andri S , Gani Rino A , Pakasi Levina S , Lesmana Laurentius A , Krisnuhoni Ening , Budihusodo Unggul 
Published: June 2011

BackgroundA non-invasive method to assess liver fibrosis by measuring liver stiffness with transient elastography (TE) has been recently introduced. The role of TE among chronic hepatitis B (CHB) patients in starting antiviral therapy in the primary care setting is still controversial because of its high cost. The AST to platelet ratio index (APRI) could be a much cheaper alternative.ObjectivesThis study compares the diagnostic accuracy of TE and APRI in assessing liver fibrosis in CHB patients.Patients and MethodsA cross-sectional study in CHB patients intending to start antiviral treatment. Liver fibrosis was staged according to the METAVIR scoring system. Liver stiffness was measured by TE performed on the same day with liver biopsy, while APRI was calculated as follows: APRI=(AST/upper limit of normal)×100/platelet count (109/l). Cutoff levels of liver stiffness and APRI were calculated by using the receiver operating characteristic curve to detect significant liver fibrosis, defined as fibrosis stage F2 or more.Results117 patients were enrolled in the study; their mean age was 40.6±10.97 years. The median liver stiffness was 5.9 kPa (2.5–48 kPa) and the median APRI was 0.239 (0.09–2.73). The cutoff level of liver stiffness was 5.85 kPa for ≥F2 with an AUC of 0.614, 60.3% sensitivity, 63.6% specificity, 73.3% PPV, 49.1% NPV and a LR+ of 1.66. The APRI cutoff level was 0.235 for F≥2 with an AUC of 0.693, 64.4% sensitivity, 70.5% specificity, 78.3% PPV, 54.4% NPV and a LR+ of 2.18. Both methods gave comparable diagnostic accuracy.ConclusionAPRI is a useful marker to screen liver fibrosis in the primary care setting when TE is not available.
Akt-Dependent Glucose Metabolism Promotes Mcl-1 Synthesis to Maintain Cell Survival and Resistance to Bcl-2 Inhibition
Authors: Coloff Jonathan L. , Macintyre Andrew N. , Nichols Amanda G. , Liu Tingyu , Gallo Catherine A. , Plas David R. , Rathmell Jeffrey C. 
Published: June 2011

Abstract
Most cancer cells utilize aerobic glycolysis, and activation of the phosphoinositide 3-kinase/Akt/mTOR pathway can promote this metabolic program to render cells glucose dependent. Although manipulation of glucose metabolism may provide a means to specifically eliminate cancer cells, mechanistic links between cell metabolism and apoptosis remain poorly understood. Here, we examined the role and metabolic regulation of the antiapoptotic Bcl-2 family protein Mcl-1 in cell death upon inhibition of Akt-induced aerobic glycolysis. In the presence of adequate glucose, activated Akt prevented the loss of Mcl-1 expression and protected cells from growth factor deprivation-induced apoptosis. Mcl-1 associated with and inhibited the proapoptotic Bcl-2 family protein Bim, contributing to cell survival. However, suppression of glucose metabolism led to induction of Bim, decreased expression of Mcl-1, and apoptosis. The proapoptotic Bcl-2/Bcl-xL/Bcl-w inhibitor, ABT-737, shows clinical promise, but Mcl-1 upregulation can promote resistance. Importantly, inhibition of glucose metabolism or mTORC1 overcame Mcl-1–mediated resistance in diffuse large B cell leukemic cells. Together these data show that Mcl-1 protein synthesis is tightly controlled by metabolism and that manipulation of glucose metabolism may provide a mechanism to suppress Mcl-1 expression and sensitize cancer cells to apoptosis. Cancer Res; 71(15); 5204–13. ©2011 AACR.
Inhibition of miR-193a Expression by Max and RXRα Activates K-Ras and PLAU to Mediate Distinct Aspects of Cellular Transformation
Authors: Iliopoulos Dimitrios , Rotem Asaf , Struhl Kevin 
Published: June 2011

Abstract
MicroRNA profiling in isogenic models of cellular transformation involving either breast epithelial cells or fibroblasts reveals that expression of miR-193a is lower in transformed cells than in nontransformed cells. The transcription factors Max and RXRα bind directly to the miR-193a promoter and inhibit miR-193a expression during transformation. miR-193a inhibits cellular transformation by directly targeting the 3′ untranslated regions of PLAU and K-Ras. Interestingly, miR-193a controls anchorage-independent growth in soft agar through K-Ras, whereas it affects invasive growth through PLAU. miR-193a overexpression inhibits the tumorigenicity of developmentally diverse but not all cancer cell types, and it inhibits tumor growth in colon- and breast-derived xenografts. Finally, expression of miR-193a is inversely correlated with PLAU and K-Ras in human colon adenocarcinomas. Thus, a pathway in which Max and RXRα inhibit miR-193a expression, thereby activating the PLAU and K-Ras oncogenes is important for distinct aspects of cellular transformation, as well as tumor growth and colon (and perhaps other types of) cancer. Cancer Res; 71(15); 5144–53. ©2011 AACR.
New Strategies in Metastatic Melanoma: Oncogene-Defined Taxonomy Leads to Therapeutic Advances
Authors: Flaherty Keith T. , Fisher David E. 
Published: June 2011

Abstract
The discovery of BRAF and KIT mutations provided the first basis for a molecular classification of cutaneous melanoma on therapeutic grounds. As BRAF-targeted therapy quickly moves toward regulatory approval and incorporation as standard therapy for patients with metastatic disease, proof of concept has also been established for targeting mutated KIT in melanoma. NRAS mutations have long been known to be present in a subset of melanomas and represent an elusive subgroup for targeted therapies. Matching patient subgroups defined by genetic aberrations in the phosphoinositide 3-kinase and p16/cyclin dependent kinase 4 (CDK4) pathways with appropriate targeted therapies has not yet been realized. And, an increasing understanding of lineage-specific transcriptional regulators, most notably MITF, and how they may play a role in melanoma pathophysiology, has provided another axis to approach with therapies. The foundation has been established for individual oncogene targeting, and current investigations seek to understand the intersection of these susceptibilities and other described potential targets and pathways. The melanoma field stands poised to take the lead among cancer subtypes in advancing combination therapy strategies that simultaneously target multiple biologic underpinnings of the disease. Clin Cancer Res; 17(15); 4922–8. ©2011 AACR.
Inhibition of Src Family Kinases and Receptor Tyrosine Kinases by Dasatinib: Possible Combinations in Solid Tumors
Authors: Montero Juan Carlos , Seoane Samuel , Ocaña Alberto , Pandiella Atanasio 
Published: June 2011

AbstractDasatinib is a small molecule tyrosine kinase inhibitor that targets a wide variety of tyrosine kinases implicated in the pathophysiology of several neoplasias. Among the most sensitive dasatinib targets are ABL, the SRC family kinases (SRC, LCK, HCK, FYN, YES, FGR, BLK, LYN, and FRK), and the receptor tyrosine kinases c-KIT, platelet-derived growth factor receptor (PDGFR) α and β, discoidin domain receptor 1 (DDR1), c-FMS, and ephrin receptors. Dasatinib inhibits cell duplication, migration, and invasion, and it triggers apoptosis of tumoral cells. As a consequence, dasatinib reduces tumoral mass and decreases the metastatic dissemination of tumoral cells. Dasatinib also acts on the tumoral microenvironment, which is particularly important in the bone, where dasatinib inhibits osteoclastic activity and favors osteogenesis, exerting a bone-protecting effect. Several preclinical studies have shown that dasatinib potentiates the antitumoral action of various drugs used in the oncology clinic, paving the way for the initiation of clinical trials of dasatinib in combination with standard-of-care treatments for the therapy of various neoplasias. Trials using combinations of dasatinib with ErbB/HER receptor antagonists are being explored in breast, head and neck, and colorectal cancers. In hormone receptor–positive breast cancer, trials using combinations of dasatinib with antihormonal therapies are ongoing. Dasatinib combinations with chemotherapeutic agents are also under development in prostate cancer (dasatinib plus docetaxel), melanoma (dasatinib plus dacarbazine), and colorectal cancer (dasatinib plus oxaliplatin plus capecitabine). Here, we review the preclinical evidence that supports the use of dasatinib in combination for the treatment of solid tumors and describe various clinical trials developed following a preclinical rationale. Clin Cancer Res; 17(17); 5546–52. ©2011 AACR.
The a3 Isoform Vacuolar Type H+-ATPase Promotes Distant Metastasis in the Mouse B16 Melanoma Cells
Authors: Nishisho Toshihiko , Hata Kenji , Nakanishi Masako , Morita Yoshihiro , Sun-Wada Ge-Hong , Wada Yoh , Yasui Natsuo , Yoneda Toshiyuki 
Published: June 2011

Abstract
Accumulating evidence indicates that the acidic microenvironments critically influence malignant behaviors of cancer including invasiveness, metastasis, and chemoresistance. Because the vacuolar-type H+-ATPase (V-ATPase) has been shown to cause extracellular acidification by pumping protons, we studied the role of V-ATPase in distant metastasis. Real-time PCR analysis revealed that the high-metastatic B16-F10 melanoma cells strongly expressed the a3 isoform V-ATPase compared to the low-metastatic B16 parental cells. Consistent with this, B16-F10 cells created acidic environments in lung metastases by acridine orange staining and strong a3 V-ATPase expression in bone metastases by immunohistochemistry. Immunocytochemical analysis showed B16-F10 cells expressed a3 V-ATPase not only in cytoplasm but also plasma membrane, whereas B16 parental cells exhibited its expression only in cytoplasm. Of note, knockdown of a3 V-ATPase suppressed invasiveness and migration with reduced MMP-2 and MMP-9 expression in B16-F10 cells and significantly decreased lung and bone metastases, despite that tumor growth was not altered. Importantly, administration of a specific V-ATPase a3 inhibitor FR167356 reduced bone metastasis of B16-F10 cells. These results suggest that a3 V-ATPase promotes distant metastasis of B16-F10 cells by creating acidic environments via proton secretion. Our results also suggest that inhibition of the development of cancer-associated acidic environments by suppressing a3 V-ATPase could be a novel therapeutic approach for the treatment of cancer metastasis. Mol Cancer Res; 9(7); 845–55. ©2011 AACR.
Cardiac Dysfunction and Noncardiac Dysfunction as Precursors of Heart Failure With Reduced and Preserved Ejection Fraction in the Community
Authors: Lam Carolyn S.P. , Lyass Asya , Kraigher-Krainer Elisabeth , Massaro Joseph M. , Lee Douglas S. , Ho Jennifer E. , Levy Daniel , Redfield Margaret M. , Pieske Burkert M. , Benjamin Emelia J. , Vasan Ramachandran S. 
Published: June 2011

Background—
Heart failure (HF) is a clinical syndrome characterized by signs and symptoms involving multiple organ systems. Longitudinal data demonstrating that asymptomatic cardiac dysfunction precedes overt HF are scarce, and the contribution of noncardiac dysfunction to HF progression is unclear. We hypothesized that subclinical cardiac and noncardiac organ dysfunction would accelerate the manifestation of HF.

Methods and Results—

We studied 1038 participants of the Framingham Heart Study original cohort (mean age, 76±5 years; 39% men) with routine assessment of left ventricular systolic and diastolic function. Major noncardiac organ systems were assessed with the use of serum creatinine (renal), serum albumin (hepatic), ratio of forced expiratory volume in 1 second to forced vital capacity (FEV
1
:FVC ratio; pulmonary), hemoglobin concentration (hematologic/oxygen-carrying capacity), and white blood cell count (systemic inflammation). On follow-up (mean, 11 years), there were 248 incident HF events (146 in women). After adjustment for established HF risk factors, antecedent left ventricular systolic dysfunction (hazard ratio, 2.33; 95% confidence interval, 1.43 to 3.78) and diastolic dysfunction (hazard ratio, 1.32; 95% confidence interval, 1.01 to 1.71) were associated with increased HF risk. After adjustment for cardiac dysfunction, higher serum creatinine, lower FEV1:FVC ratios, and lower hemoglobin concentrations were associated with increased HF risk (all
P
<0.05); serum albumin and white blood cell count were not. Subclinical dysfunction in each noncardiac organ system was associated with a 30% increased risk of HF (
P
=0.013).

Conclusions—
Antecedent cardiac dysfunction and noncardiac organ dysfunction are associated with increased incidence of HF, supporting the notion that HF is a progressive syndrome and underscoring the importance of noncardiac factors in its occurrence.
Persistent Weakening Trend in the Spring Sensible Heat Source over the Tibetan Plateau and Its Impact on the Asian Summer Monsoon
Authors: Duan Anmin , Li Fei , Wang Meirong , Wu Guoxiong 
Published: June 2011

Abstract
Using a dataset extended by the addition of data for 2004–08, this study reexamined the trend in the sensible heating (SH) flux at 73 meteorological stations over the Tibetan Plateau (TP) during 1980–2008 and investigated its impact on monsoon precipitation in the surrounding region. In contrast to ongoing climate warming, a weakening trend in SH is persistent over most of the plateau, despite a sharp increase in the ground–air temperature difference in 2004–08. The weakening trend in SH over the TP is primarily a response to the spatial nonuniformity of large-scale warming over the East Asian continent, which is characterized by much greater warming amplitude at mid- and high latitudes than over the tropics and subtropics. Furthermore, the suppressed air pump effect, which is driven by SH over the TP and acts as a strong forcing source, gives rise to reduced precipitation along the southern and eastern slopes of the plateau, and increased rainfall over northeastern India and the Bay of Bengal. No significantly stable correlation exists between the SH source over the TP and the overall trend or interdecadal variability in the East Asian or South Asian summer monsoon.
Prospects for Improving Subseasonal Predictions
Authors: Pegion Kathy , Sardeshmukh Prashant D. 
Published: June 2011

Abstract
Extending atmospheric prediction skill beyond the predictability limit of about 10 days for daily weather rests on the hope that some time-averaged aspects of anomalous circulations remain predictable at longer forecast lead times, both because of the existence of natural low-frequency modes of atmospheric variability and coupling to the ocean with larger thermal inertia. In this paper the week-2 and week-3 forecast skill of two global coupled atmosphere–ocean models recently developed at NASA and NOAA is compared with that of much simpler linear inverse models (LIMs) based on the observed time-lag correlations of atmospheric circulation anomalies in the Northern Hemisphere and outgoing longwave radiation (OLR) anomalies in the tropics. The coupled models are found to beat the LIMs only slightly, and only if an ensemble prediction methodology is employed. To assess the potential for further skill improvement, a predictability analysis based on the relative magnitudes of forecast signal and forecast noise in the LIM framework is conducted. Estimating potential skill by such a method is argued to be superior to using the ensemble-mean and ensemble-spread information in the coupled model ensemble prediction system. The LIM-based predictability analysis yields relatively conservative estimates of the potential skill, and suggests that outside the tropics the average coupled model skill may already be close to the potential skill, although there may still be room for improvement in the tropical forecast skill.
Tumor Satellite in Predicting Occult Nodal Metastasis of Tongue Cancer
Authors: Yang Tsung‐Lin , Lou Pei‐Jen , Chang Yih‐Leong , Wu Chen‐Tu , Wang Cheng‐Ping , Ko Jenq‐Yuh 
Published: June 2011

ObjectiveTongue cancer is well known to have a high potential for locoregional metastasis. However, controversy about electively treating the neck in early‐stage tongue cancer remains. Although many risk factors related to cervical occult nodal metastasis (ONM) have been investigated, the ability of the tumor to spread, a phenomenon that results from the intrinsic property of the tumor and its interaction with the surrounding environment, has seldom been addressed.Study DesignRetrospective case series with chart review.SettingTertiary referral hospital of university.SubjectsPatients with early‐stage squamous cell carcinoma of the oral tongue.ResultsIn 71 eligible enrolled patients, ONM was detected in 19 (27%) patients, while the results were negative (ONM(−)) in 52 (73%) patients. The average tumor satellite distance (TSD) in the ONM(+) group was 4.1 ± 4.3 mm, in contrast to that in the ONM(−) group (1.0 ± 1.5 mm; P <. 001). When stratified by increased TSD values, the significance of the difference between the 2 groups increased. For clinical applications, the optimal TSD threshold for determining the ONM probability was 3.5 mm. Multivariate analyses demonstrated that TSD was an independent prognosticator.ConclusionsThe results indicate that TSD is a feasible pathological parameter that is useful for determining the status of cervical nodal metastasis. It can be used as an indicator of potential cervical subclinical disease and as a guideline for deciding the necessity and modality of neck treatment.