bluuebunny/crossref_metadata_2025_split huggingface dataset:
pH Manipulation as a Novel Strategy for Treating Mucormycosis
Authors: Trzaska Wioleta J. , Correia Joao N. , Villegas Maria T. , May Robin C. , Voelz Kerstin 
Published: September 2015

ABSTRACT
Mucormycosis is a fatal fungal disease caused by several organisms within the order Mucorales. In recent years, traumatic injury has emerged as a novel risk factor for mucormycosis. Current antifungal therapy is ineffective, expensive, and typically requires extensive surgical debridement. There is thus a pressing need for safe prophylactic treatment that can be rapidly and easily applied to high-risk patients, such as those with major trauma injuries. Acetic acid has been used as a topical treatment for burn wounds for centuries and has proven activity against Gram-negative bacteria. Here, we demonstrate that acetic acid is also highly effective against major pathogenic groups of Mucorales, even at very low concentrations (0.3%). This antifungal effect is not seen with other acids, such as hydrochloric and lactic acid, suggesting that acetic acid activity against Mucorales spores is not solely evoked by low environmental pH. In agreement with this, we demonstrate that the antifungal activity of acetic acid arises from a combination of its ability to potently lower intracellular pH and from pH-independent toxicity. Thus, dilute acetic acid may offer a low-cost, safe, prophylactic treatment for patients at risk of invasive mucormycosis following traumatic injury.
Novel Plasmid-Borne Multidrug Resistance Gene Cluster Including
lsa
(E) from a Linezolid-Resistant Enterococcus faecium Isolate of Swine Origin
Authors: Si Hongbin , Zhang Wan-Jiang , Chu Shengbo , Wang Xiu-Mei , Dai Lei , Hua Xin , Dong Zhimin , Schwarz Stefan , Liu Siguo 
Published: September 2015

ABSTRACT

A novel nonconjugative plasmid of 28,489 bp from a porcine linezolid-resistant
Enterococcus faecium
isolate was completely sequenced. This plasmid harbored a novel type of multiresistance gene cluster that comprised the resistance genes
lnu
(B),
lsa
(E),
spw
,
aadE
,
aphA3
, and two copies of
erm
(B), which account for resistance to macrolides, lincosamides, streptogramins, pleuromutilins, streptomycin, spectinomycin, and kanamycin/neomycin. Structural comparisons suggested that this plasmid might have developed from other enterococcal plasmids by insertion element (IS)-mediated interplasmid recombination processes.
Whole-Genome Sequencing Identifies Emergence of a Quinolone Resistance Mutation in a Case of Stenotrophomonas maltophilia Bacteremia
Authors: Pak Theodore R. , Altman Deena R. , Attie Oliver , Sebra Robert , Hamula Camille L. , Lewis Martha , Deikus Gintaras , Newman Leah C. , Fang Gang , Hand Jonathan , Patel Gopi , Wallach Fran , Schadt Eric E. , Huprikar Shirish , van Bakel Harm , Kasarskis Andrew , Bashir Ali 
Published: September 2015

ABSTRACT

Whole-genome sequences for
Stenotrophomonas maltophilia
serial isolates from a bacteremic patient before and after development of levofloxacin resistance were assembled
de novo
and differed by one single-nucleotide variant in
smeT
, a repressor for multidrug efflux operon
smeDEF
. Along with sequenced isolates from five contemporaneous cases, they displayed considerable diversity compared against all published complete genomes. Whole-genome sequencing and complete assembly can conclusively identify resistance mechanisms emerging in
S. maltophilia
strains during clinical therapy.
Bacillus anthracis
tagO
Is Required for Vegetative Growth and Secondary Cell Wall Polysaccharide Synthesis
Authors: Lunderberg J. Mark , Liszewski Zilla Megan , Missiakas Dominique , Schneewind Olaf 
Published: September 2015

ABSTRACT

Bacillus anthracis
elaborates a linear secondary cell wall polysaccharide (SCWP) that retains surface (S)-layer and associated proteins via their S-layer homology (SLH) domains. The SCWP is comprised of trisaccharide repeats [→4)-β-ManNAc-(1→4)-β-GlcNAc-(1→6)-α-GlcNAc-(1→] and tethered via acid-labile phosphodiester bonds to peptidoglycan. Earlier work identified UDP-GlcNAc 2-epimerases GneY (BAS5048) and GneZ (BAS5117), which act as catalysts of ManNAc synthesis, as well as a polysaccharide deacetylase (BAS5051), as factors contributing to SCWP synthesis. Here, we show that
tagO
(BAS5050), which encodes a UDP-
N
-acetylglucosamine:undecaprenyl-P
N
-acetylglucosaminyl 1-P transferase, the enzyme that initiates the synthesis of murein linkage units, is required for
B. anthracis
SCWP synthesis and S-layer assembly. Similar to
gneY-gneZ
mutants,
B. anthracis
strains lacking
tagO
cannot maintain cell shape or support vegetative growth. In contrast, mutations in BAS5051 do not affect
B. anthracis
cell shape, vegetative growth, SCWP synthesis, or S-layer assembly. These data suggest that TagO-mediated murein linkage unit assembly supports SCWP synthesis and attachment to the peptidoglycan via acid-labile phosphodiester bonds. Further,
B. anthracis
variants unable to synthesize SCWP trisaccharide repeats cannot sustain cell shape and vegetative growth.

IMPORTANCE
Bacillus anthracis
elaborates an SCWP to support vegetative growth and envelope assembly. Here, we show that some, but not all, SCWP synthesis is dependent on
tagO
-derived murein linkage units and subsequent attachment of SCWP to peptidoglycan. The data implicate secondary polymer modifications of peptidoglycan and subcellular distributions as a key feature of the cell cycle in Gram-positive bacteria and establish foundations for work on the molecular functions of the SCWP and on inhibitors with antibiotic attributes.
NagR Differentially Regulates the Expression of the
glmS
and
nagAB
Genes Required for Amino Sugar Metabolism by Streptococcus mutans
Authors: Zeng Lin , Burne Robert A. 
Published: September 2015

ABSTRACT

The ability of bacteria to metabolize glucosamine (GlcN) and
N
-acetyl-
d
-glucosamine (GlcNAc) is considered important for persistent colonization of the oral cavity. In the dental caries pathogen
Streptococcus mutans
, the NagR protein regulates the expression of
glmS
, which encodes a GlcN-6-P synthetase, and
nagA
(GlcNAc-6-P deacetylase) and
nagB
(GlcN-6-P deaminase), which are required for the catabolism of GlcNAc and GlcN. Two NagR-binding sites (
dre
) were identified in each of the promoter regions for
nagB
and
glmS
. Using promoter-reporter gene fusions, the role of each
dre
site was examined in the regulation of
glmS
and
nagB
promoter activities in cells grown with glucose, GlcNAc, or GlcN. A synergistic relationship between the two
dre
sites in the
glmS
promoter that required proper spacing was observed, but that was not the case for
nagB
. Binding of purified NagR to DNA fragments from both promoter regions, as well as to
dre
sites alone, was strongly influenced by particular sugar phosphates. Using a random mutagenesis approach that targeted the effector-binding domain of NagR, mutants that displayed aberrant regulation of both the
glmS
and
nagAB
genes were identified. Collectively, these findings provide evidence that NagR is essential for regulation of genes for both the synthesis and catabolism of GlcN and GlcNAc in
S. mutans
, and that NagR engages differently with the target promoter regions in response to specific metabolites interacting with the effector-binding domain of NagR.

IMPORTANCE
Glucosamine and
N
-acetylglucosamine are among the most abundant naturally occurring sugars on the planet, and they are catabolized by many bacterial species as sources of carbon and nitrogen. Representing a group called lactic acid bacteria (LAB), the human dental caries pathogen
Streptococcus mutans
is shown to differ from known paradigm organisms in that it possesses a GntR/HutC-type regulator, NagR, that is required for the regulation of both catabolism of GlcN and biosynthesis. Results reported here reveal a simple and elegant mechanism whereby NagR differentially regulates two opposing biological processes by surveying metabolic intermediates. This study provides insights that may contribute to the development of novel therapeutic tools to combat dental caries and other infectious diseases.
The crossover from metal to semi-conductor in Cu-doped LiFeAs system
Authors: Xing L. Y. , Wang X. C. , Deng Z. , Zhang S. J. , Feng S. M. , Li W. M. , Liu Q. Q. , Jin C. Q. 
Published: September 2015

A series of [Formula: see text] single crystal with the doping level [Formula: see text] were grown. The resistivity measurement was conducted. The results show that the 10% Cu doping completely suppresses superconducting transition temperature and when the doping level increases to 16%, it presents a semiconducting behavior in the region of 2 K to 300 K.
DPCS
Authors: Gottscho Mark , BanaiyanMofrad Abbas , Dutt Nikil , Nicolau Alex , Gupta Puneet 
Published: September 2015

Fault-Tolerant Voltage-Scalable (FTVS) SRAM cache architectures are a promising approach to improve energy efficiency of memories in the presence of nanoscale process variation. Complex FTVS schemes are commonly proposed to achieve very low minimum supply voltages, but these can suffer from high overheads and thus do not always offer the best power/capacity trade-offs. We observe on our 45nm test chips that the “fault inclusion property” can enable lightweight fault maps that support multiple runtime supply voltages.
Based on this observation, we propose a simple and low-overhead FTVS cache architecture for power/capacity scaling. Our mechanism combines multilevel voltage scaling with optional architectural support for power gating of blocks as they become faulty at low voltages. A static (SPCS) policy sets the runtime cache VDD once such that a only a few cache blocks may be faulty in order to minimize the impact on performance. We describe a Static Power/Capacity Scaling (SPCS) policy and two alternate Dynamic Power/Capacity Scaling (DPCS) policies that opportunistically reduce the cache voltage even further for more energy savings.
This architecture achieves lower static power for all effective cache capacities than a recent more complex FTVS scheme. This is due to significantly lower overheads, despite the inability of our approach to match the min-VDD of the competing work at a fixed target yield. Over a set of SPEC CPU2006 benchmarks on two system configurations, the average total cache (system) energy saved by SPCS is 62% (22%), while the two DPCS policies achieve roughly similar energy reduction, around 79% (26%). On average, the DPCS approaches incur 2.24% performance and 6% area penalties.
Shielding Applications from an Untrusted Cloud with Haven
Authors: Baumann Andrew , Peinado Marcus , Hunt Galen 
Published: September 2015

Today’s cloud computing infrastructure requires substantial trust. Cloud users rely on both the provider’s staff and its globally distributed software/hardware platform not to expose any of their private data.
We introduce the notion of shielded execution, which protects the confidentiality and integrity of a program and its data from the platform on which it runs (i.e., the cloud operator’s OS, VM, and firmware). Our prototype, Haven, is the first system to achieve shielded execution of unmodified legacy applications, including SQL Server and Apache, on a commodity OS (Windows) and commodity hardware. Haven leverages the hardware protection of Intel SGX to defend against privileged code and physical attacks such as memory probes, and also addresses the dual challenges of executing unmodified legacy binaries and protecting them from a malicious host. This work motivated recent changes in the SGX specification.
CCR 20th Anniversary Commentary: Triple-Negative Breast Cancer in 2015—Still in the Ballpark
Authors: Narod Steven A. , Dent Rebecca A. , Foulkes William D. 
Published: September 2015

Abstract
The research article by Dent and colleagues, which was published in the August 1, 2007, issue of Clinical Cancer Research, provided a clinical description of metastatic progression of triple-negative breast cancers. Finding successful treatment strategies for women with triple-negative breast cancer remains a challenge. Clin Cancer Res; 21(17); 3813–4. ©2015 AACR.
See related article by Dent et al., Clin Cancer Res 2007;13(15) August 1, 2007;4429–34
Clinical and Translational Results of a Phase II, Randomized Trial of an Anti–IGF-1R (Cixutumumab) in Women with Breast Cancer That Progressed on Endocrine Therapy
Authors: Gradishar William J. , Yardley Denise A. , Layman Rachel , Sparano Joseph A. , Chuang Ellen , Northfelt Donald W. , Schwartz Gary N. , Youssoufian Hagop , Tang Shande , Novosiadly Ruslan , Forest Amelie , Nguyen Tuan S. , Cosaert Jan , Grebennik Dmitri , Haluska Paul 
Published: September 2015

AbstractPurpose: This phase II trial evaluated the efficacy and safety of cixutumumab, a human anti–insulin-like growth factor receptor 1 (IGF-1R) monoclonal IgG1 antibody, and explored potential biomarkers in postmenopausal women with hormone receptor–positive breast cancer.Experimental Design: Patients with hormone receptor–positive breast cancer that progressed on antiestrogen therapy received (2:1 randomization) cixutumumab 10 mg/kg and the same antiestrogen (arm A) or cixutumumab alone (arm B) every 2 weeks (q2w). Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS) and safety. Correlative analyses of IGF-1R, total insulin receptor (IR), and IR isoforms A (IR-A) and B (IR-B) expression in tumor tissue were explored.Results: Ninety-three patients were randomized (arm A, n = 62; arm B, n = 31). Median PFS was 2.0 and 3.1 months for arm A and arm B, respectively. Secondary efficacy measures were similar between the arms. Overall, cixutumumab was well tolerated. IGF-1R expression was not associated with clinical outcomes. Regardless of the treatment, lower IR-A, IR-B, and total IR mRNA expression in tumor tissue was significantly associated with longer PFS [IR-A: HR, 2.62 (P = 0.0062); IR-B: HR, 2.21 (P = 0.0202); and total IR: HR, 2.18 (P = 0.0230)] and OS [IR-A: HR, 2.94 (P = 0.0156); IR-B: HR, 2.69 (P = 0.0245); and total IR: HR, 2.72 (P = 0.0231)].Conclusions: Cixutumumab (10 mg/kg) with or without antiestrogen q2w had an acceptable safety profile, but no significant clinical efficacy. Patients with low total IR, IR-A, and IR-B mRNA expression levels had significantly longer PFS and OS, independent of the treatment. The prognostic or predictive value of IR as a biomarker for IGF-1R–targeted therapies requires further validation. Clin Cancer Res; 22(2); 301–9. ©2015 AACR.
FDA Approval: Palbociclib for the Treatment of Postmenopausal Patients with Estrogen Receptor–Positive, HER2-Negative Metastatic Breast Cancer
Authors: Beaver Julia A. , Amiri-Kordestani Laleh , Charlab Rosane , Chen Wei , Palmby Todd , Tilley Amy , Zirkelbach Jeanne Fourie , Yu Jingyu , Liu Qi , Zhao Liang , Crich Joyce , Chen Xiao Hong , Hughes Minerva , Bloomquist Erik , Tang Shenghui , Sridhara Rajeshwari , Kluetz Paul G. , Kim Geoffrey , Ibrahim Amna , Pazdur Richard , Cortazar Patricia 
Published: September 2015

Abstract
On February 3, 2015, the FDA granted accelerated approval to palbociclib (IBRANCE, Pfizer Inc.), an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. The approval is based on a randomized, multicenter, open-label phase I/II trial (PALOMA-1) in 165 patients randomized to palbociclib (125 mg orally daily for 21 consecutive days, followed by 7 days off treatment) plus letrozole (2.5 mg orally daily) or letrozole alone. The phase II portion of the trial was divided into two cohorts: cohort 1 enrolled 66 biomarker-unselected patients and cohort 2 enrolled 99 biomarker-positive patients. The major efficacy outcome measure was investigator-assessed progression-free survival (PFS). A large magnitude of improvement in PFS was observed in patients receiving palbociclib plus letrozole compared with patients receiving letrozole alone (HR, 0.488; 95% confidence interval, 0.319–0.748). Multiple sensitivity analyses were supportive of clinical benefit. The most common adverse reaction in patients receiving palbociclib plus letrozole was neutropenia. This article summarizes the FDA thought process and data supporting accelerated approval based on PALOMA-1 that may be contingent upon verification and description of clinical benefit in the ongoing and fully accrued confirmatory trial PALOMA-2. Clin Cancer Res; 21(21); 4760–6. ©2015 AACR.
FDA Approval Summary: Lenvatinib for Progressive, Radio-iodine–Refractory Differentiated Thyroid Cancer
Authors: Nair Abhilasha , Lemery Steven J. , Yang Jun , Marathe Anshu , Zhao Liang , Zhao Hong , Jiang Xiaoping , He Kun , Ladouceur Gaetan , Mitra Amit K. , Zhou Liang , Fox Emily , Aungst Stephanie , Helms Whitney , Keegan Patricia , Pazdur Richard 
Published: September 2015

Abstract
The FDA approved lenvatinib (Lenvima, Eisai Inc.) for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory (RAI-refractory) differentiated thyroid cancer (DTC). In an international, multicenter, double-blinded, placebo-controlled trial (E7080-G000-303), 392 patients with locally recurrent or metastatic RAI-refractory DTC and radiographic evidence of disease progression within 12 months prior to randomization were randomly allocated (2:1) to receive either lenvatinib 24 mg orally per day (n = 261) or matching placebo (n = 131) with the option for patients on the placebo arm to receive lenvatinib following independent radiologic confirmation of disease progression. A statistically significant prolongation of progression-free survival (PFS) as determined by independent radiology review was demonstrated [HR, 0.21; 95% confidence interval (CI), 0.16–0.28; P &lt; 0.001, stratified log-rank test], with an estimated median PFS of 18.3 months (95% CI, 15.1, NR) in the lenvatinib arm and 3.6 months (95% CI, 2.2–3.7) in the placebo arm. The most common adverse reactions, in order of decreasing frequency, observed in the lenvatinib-treated patients were hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, decreased weight, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia syndrome, abdominal pain, and dysphonia. Adverse reactions led to dose reductions in 68% of patients receiving lenvatinib at the 24 mg dose and 18% of patients discontinued lenvatinib for adverse reactions leading to residual uncertainty regarding the optimal dose of lenvatinib. Clin Cancer Res; 21(23); 5205–8. ©2015 AACR.
In Vivo Regulation of Colonic Cell Proliferation, Differentiation, Apoptosis, and P27Kip1 by Dietary Fish Oil and Butyrate in Rats
Authors: Hong Mee Young , Turner Nancy D. , Murphy Mary E. , Carroll Raymond J. , Chapkin Robert S. , Lupton Joanne R. 
Published: September 2015

Abstract
We have shown that dietary fish oil is protective against experimentally induced colon cancer, and the protective effect is enhanced by coadministration of pectin. However, the underlying mechanisms have not been fully elucidated. We hypothesized that fish oil with butyrate, a pectin fermentation product, protects against colon cancer initiation by decreasing cell proliferation and increasing differentiation and apoptosis through a p27Kip1-mediated mechanism. Rats were provided diets of corn or fish oil, with/without butyrate, and terminated 12, 24, or 48 hours after azoxymethane (AOM) injection. Proliferation (Ki-67), differentiation (Dolichos Biflorus Agglutinin), apoptosis (TUNEL), and p27Kip1 (cell-cycle mediator) were measured in the same cell within crypts in order to examine the coordination of cell cycle as a function of diet. DNA damage (N7-methylguanine) was determined by quantitative IHC analysis. Dietary fish oil decreased DNA damage by 19% (P = 0.001) and proliferation by 50% (P = 0.003) and increased differentiation by 56% (P = 0.039) compared with corn oil. When combined with butyrate, fish oil enhanced apoptosis 24 hours after AOM injection compared with a corn oil/butyrate diet (P = 0.039). There was an inverse relationship between crypt height and apoptosis in the fish oil/butyrate group (r = −0.53, P = 0.040). The corn oil/butyrate group showed a positive correlation between p27Kip1 expression and proliferation (r = 0.61, P = 0.035). These results indicate the in vivo effect of butyrate on apoptosis and proliferation is dependent on dietary lipid source. These results demonstrate the presence of an early coordinated colonocyte response by which fish oil and butyrate protects against colon tumorigenesis. Cancer Prev Res; 8(11); 1076–83. ©2015 AACR.
Continuous Estimate of Atlantic Oceanic Freshwater Flux at 26.5°N
Authors: McDonagh Elaine L. , King Brian A. , Bryden Harry L. , Courtois Peggy , Szuts Zoltan , Baringer Molly , Cunningham Stuart A. , Atkinson Chris , McCarthy Gerard 
Published: September 2015

Abstract
The first continuous estimates of freshwater flux across 26.5°N are calculated using observations from the RAPID–MOCHA–Western Boundary Time Series (WBTS) and Argo floats every 10 days between April 2004 and October 2012. The mean plus or minus the standard deviation of the freshwater flux (FW) is −1.17 ± 0.20 Sv (1 Sv ≡ 106 m3 s−1; negative flux is southward), implying a freshwater divergence of −0.37 ± 0.20 Sv between the Bering Strait and 26.5°N. This is in the sense of an input of 0.37 Sv of freshwater into the ocean, consistent with a region where precipitation dominates over evaporation. The sign and the variability of the freshwater divergence are dominated by the overturning component (−0.78 ± 0.21 Sv). The horizontal component of the freshwater divergence is smaller, associated with little variability and positive (0.35 ± 0.04 Sv). A linear relationship, describing 91% of the variance, exists between the strength of the meridional overturning circulation (MOC) and the freshwater flux (−0.37 − 0.047 Sv of FW per Sverdrups of MOC). The time series of the residual to this relationship shows a small (0.02 Sv in 8.5 yr) but detectable decrease in the freshwater flux (i.e., an increase in the southward freshwater flux) for a given MOC strength. Historical analyses of observations at 24.5°N are consistent with a more negative freshwater divergence from −0.03 to −0.37 Sv since 1974. This change is associated with an increased southward freshwater flux at this latitude due to an increase in the Florida Straits salinity (and therefore the northward salinity flux).