bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Microbicidal Effects of Human Histone Proteins H2A and H2B on
Leishmania
Promastigotes and Amastigotes
Authors: Wang Yingwei , Chen Yang , Xin Lijun , Beverley Stephen M. , Carlsen Eric D. , Popov Vsevolod , Chang Kwang-Poo , Wang Ming , Soong Lynn 
Published: December 2010

ABSTRACT

Recent studies have shown that histone proteins can act as antimicrobial peptides in host defense against extracellular bacteria, fungi, and
Leishmania
promastigotes. In this study, we used human recombinant histone proteins to further study their leishmaniacidal effects and the underlying mechanisms. We found that the histones H2A and H2B (but not H1
0
) could directly and efficiently kill promastigotes of
Leishmania amazonensis
,
L. major
,
L. braziliensis
, and
L. mexicana
in a treatment dose-dependent manner. Scanning electron microscopy revealed surface disruption of histone-treated promastigotes. More importantly, the preexposure of promastigotes to histone proteins markedly decreased the infectivity of promastigotes to murine macrophages (Mφs)
in vitro
. However, axenic and lesion-derived amastigotes of
L. amazonensis
and
L. mexicana
were relatively resistant to histone treatment, which correlated with the low levels of intracellular H2A in treated amastigotes. To understand the mechanisms underlying these differential responses, we investigated the role of promastigote surface molecules in histone-mediated killing. Compared with the corresponding controls, transgenic
L. amazonensis
promastigotes expressing lower levels of surface gp63 proteins were more susceptible to histone H2A, while
L. major
and
L. mexicana
promastigotes with targeted deletion of the lipophosphoglycan 2 (
lpg2
) gene (but not the
lpg1
gene) were more resistant to histone H2A. We discuss the influence of promastigote major surface molecules in the leishmaniacidal effect of histone proteins. This study provides new information on host innate immunity to different developmental stages of
Leishmania
parasites.
Sialic Acid Transport Contributes to Pneumococcal Colonization
Authors: Marion Carolyn , Burnaugh Amanda M. , Woodiga Shireen A. , King Samantha J. 
Published: December 2010

ABSTRACT

Streptococcus pneumoniae
is a major cause of pneumonia and meningitis. Airway colonization is a necessary precursor to disease, but little is known about how the bacteria establish and maintain colonization. Carbohydrates are required as a carbon source for pneumococcal growth and, therefore, for colonization. Free carbohydrates are not readily available in the naso-oropharynx; however, N- and O-linked glycans are common in the airway. Sialic acid is the most common terminal modification on N- and O-linked glycans and is likely encountered frequently by
S. pneumoniae
in the airway. Here we demonstrate that sialic acid supports pneumococcal growth when provided as a sole carbon source. Growth on sialic acid requires import into the bacterium. Three genetic regions have been proposed to encode pneumococcal sialic acid transporters: one sodium solute symporter and two ATP binding cassette (ABC) transporters. Data demonstrate that one of these,
satABC
, is required for transport of sialic acid. A
satABC
mutant displayed significantly reduced growth on both sialic acid and the human glycoprotein alpha-1. The importance of
satABC
for growth on human glycoprotein suggests that sialic acid transport may be important
in vivo
. Indeed, the
satABC
mutant was significantly reduced in colonization of the murine upper respiratory tract. This work demonstrates that
S. pneumoniae
is able to use sialic acid as a sole carbon source and that utilization of sialic acid is likely important during pneumococcal colonization.
Full Virulence of
Pseudomonas aeruginosa
Requires OprF
Authors: Fito-Boncompte Laurène , Chapalain Annelise , Bouffartigues Emeline , Chaker Hichem , Lesouhaitier Olivier , Gicquel Gwendoline , Bazire Alexis , Madi Amar , Connil Nathalie , Véron Wilfried , Taupin Laure , Toussaint Bertrand , Cornelis Pierre , Wei Qing , Shioya Koki , Déziel Eric , Feuilloley Marc G. J. , Orange Nicole , Dufour Alain , Chevalier Sylvie 
Published: December 2010

ABSTRACT

OprF is a general outer membrane porin of
Pseudomonas aeruginosa
, a well-known human opportunistic pathogen associated with severe hospital-acquired sepsis and chronic lung infections of cystic fibrosis patients. A multiphenotypic approach, based on the comparative study of a wild-type strain of
P. aeruginosa
, its isogenic
oprF
mutant, and an
oprF
-complemented strain, showed that OprF is required for
P. aeruginosa
virulence. The absence of OprF results in impaired adhesion to animal cells, secretion of ExoT and ExoS toxins through the type III secretion system (T3SS), and production of the quorum-sensing-dependent virulence factors pyocyanin, elastase, lectin PA-1L, and exotoxin A. Accordingly, in the
oprF
mutant, production of the signal molecules
N
-(3-oxododecanoyl)-
l
-homoserine lactone and
N
-butanoyl-
l
-homoserine lactone was found to be reduced and delayed, respectively.
Pseudomonas
quinolone signal (PQS) production was decreased, while its precursor, 4-hydroxy-2-heptylquinoline (HHQ), accumulated in the cells. Taken together, these results show the involvement of OprF in
P. aeruginosa
virulence, at least partly through modulation of the quorum-sensing network. This is the first study showing a link between OprF, PQS synthesis, T3SS, and virulence factor production, providing novel insights into virulence expression.
Robust Decentralized Virtual Coordinate Systems in Adversarial Environments
Authors: Zage David , Nita-Rotaru Cristina 
Published: December 2010

Virtual coordinate systems provide an accurate and efficient service that allows hosts on the Internet to determine the latency to arbitrary hosts without actively monitoring all of the nodes in the network. Many of the proposed systems were designed with the assumption that all of the nodes are altruistic. However, this assumption may be violated by compromised nodes acting maliciously to degrade the accuracy of the coordinate system. As numerous peer-to-peer applications come to rely on virtual coordinate systems to achieve good performance, it is critical to address the security of such systems.
In this work, we demonstrate the vulnerability of decentralized virtual coordinate systems to insider (or Byzantine) attacks. We propose techniques to make the coordinate assignment robust to malicious attackers without increasing the communication cost. We use both spatial and temporal correlations to perform context-sensitive outlier analysis to reject malicious updates and prevent unnecessary and erroneous adaptations. We demonstrate the attacks and mitigation techniques in the context of a well-known virtual coordinate system using simulations based on three representative, real-life Internet topologies of hosts and corresponding Round Trip Times (RTT). We show the effects of the attacks and the utility of the mitigation techniques on the virtual coordinate system as seen by higher-level applications, elucidating the utility of deploying robust virtual coordinate systems as network services.
A Hybrid-Extragradient Scheme for System of Equilibrium Problems, Nonexpansive Mappings, and Monotone Mappings
Authors: Peng Jian-Wen , Wu Soon-Yi , Fan Gang-Lun 
Published: December 2010

AbstractWe introduce a new iterative scheme based on both hybrid method and extragradient method for finding a common element of the solutions set of a system of equilibrium problems, the fixed points set of a nonexpansive mapping, and the solutions set of a variational inequality problems for a monotone and "Equation missing"-Lipschitz continuous mapping in a Hilbert space. Some convergence results for the iterative sequences generated by these processes are obtained. The results in this paper extend and improve some known results in the literature.
General Viscosity Approximation Methods for Common Fixed Points of Nonexpansive Semigroups in Hilbert Spaces
Authors: Li Xue-song , Huang Nan-jing , Kim JongKyu 
Published: December 2010

AbstractThis paper is devoted to the strong convergence of two kinds of general viscosity iteration processes for approximating common fixed points of a nonexpansive semigroup in Hilbert spaces. The results presented in this paper improve and generalize some corresponding results in (X. Li et al., 2009, S. Li et al., 2009, and Marino and Xu, 2006).
Critical Point Theorems and Ekeland Type Variational Principle with Applications
Authors: Lin Lai-Jiu , Wang Sung-Yu , Ansari QamrulHasan 
Published: December 2010

AbstractWe introduce the notion of "Equation missing"-spaces which is much weaker than cone metric spaces defined by Huang and X. Zhang (2007). We establish some critical point theorems in the setting of "Equation missing"-spaces and, in particular, in the setting of complete cone metric spaces. Our results generalize the critical point theorem proposed by Dancs et al. (1983) and the results given by Khanh and Quy (2010) to "Equation missing"-spaces and cone metric spaces. As applications of our results, we characterize the completeness of "Equation missing"-space (cone metric spaces and quasimetric spaces are special cases of "Equation missing"-space) and studying the Ekeland type variational principle for single variable vector-valued functions as well as for multivalued bifunctions in the setting of cone metric spaces.
MicroRNAs miR-199a-5p and -3p Target the Brm Subunit of SWI/SNF to Generate a Double-Negative Feedback Loop in a Variety of Human Cancers
Authors: Sakurai Kouhei , Furukawa Chihiro , Haraguchi Takeshi , Inada Ken-ichi , Shiogama Kazuya , Tagawa Takanobu , Fujita Shuji , Ueno Yoshihito , Ogata Aya , Ito Mai , Tsutsumi Yutaka , Iba Hideo 
Published: December 2010

Abstract
The chromatin remodeling complex SWI/SNF is an important epigenetic regulator that includes one Brm or BRG1 molecule as catalytic subunit. Brm and BRG1 do not function identically, so this complex can regulate gene expression either positively or negatively, depending on the promoter to which it is recruited. Notably, Brm attenuation due to posttranscription suppression occurs often in human tumor cells, in which this event contributes to their oncogenic potential. Here, we report that the 3′-untranslated region of Brm mRNA has two sites that are efficiently targeted by the microRNAs miR-199a-5p and -3p, revealing a novel mechanism for modulation of Brm-type SWI/SNF activity. Computational mapping of the putative promoter region of miR-199a-2 (miPPR-199a-2) has defined it as the major contributing genetic locus for miR-199a-5p and-3p production in these tumor cell lines. We validated this predicted region by direct promoter analysis to confirm that Egr1 is a strong positive regulator of the miR-199a-2 gene. Importantly, we also showed that Egr1, miR-199a-5p, and miR-199a-3p are expressed at high levels in Brm-deficient tumor cell lines but only marginally in Brm-expressing tumor cells. Finally, we also obtained evidence that Brm negatively regulates Egr1. Together, our results reveal that miR-199a and Brm form a double-negative feedback loop through Egr1, leading to the generation of these two distinct cell types during carcinogenesis. This mechanism may offer a partial explanation for why miR-199a-5p and -3p have been reported to be either upregulated or downregulated in a variety of tumors. Cancer Res; 71(5); 1680–9. ©2010 AACR.
TGF-β Promotion of Gli2-Induced Expression of Parathyroid Hormone-Related Protein, an Important Osteolytic Factor in Bone Metastasis, Is Independent of Canonical Hedgehog Signaling
Authors: Johnson Rachelle W. , Nguyen Mai P. , Padalecki Susan S. , Grubbs Barry G. , Merkel Alyssa R. , Oyajobi Babatunde O. , Matrisian Lynn M. , Mundy Gregory R. , Sterling Julie A. 
Published: December 2010

Abstract
Breast cancer frequently metastasizes to bone, in which tumor cells receive signals from the bone marrow microenvironment. One relevant factor is TGF-β, which upregulates expression of the Hedgehog (Hh) signaling molecule, Gli2, which in turn increases secretion of important osteolytic factors such as parathyroid hormone–related protein (PTHrP). PTHrP inhibition can prevent tumor-induced bone destruction, whereas Gli2 overexpression in tumor cells can promote osteolysis. In this study, we tested the hypothesis that Hh inhibition in bone metastatic breast cancer would decrease PTHrP expression and therefore osteolytic bone destruction. However, when mice engrafted with human MDA-MB-231 breast cancer cells were treated with the Hh receptor antagonist cyclopamine, we observed no effect on tumor burden or bone destruction. In vitro analyses revealed that osteolytic tumor cells lack expression of the Hh receptor, Smoothened, suggesting an Hh-independent mechanism of Gli2 regulation. Blocking Gli signaling in metastatic breast cancer cells with a Gli2-repressor gene (Gli2-rep) reduced endogenous and TGF-β–stimulated PTHrP mRNA expression, but did not alter tumor cell proliferation. Furthermore, mice inoculated with Gli2-Rep–expressing cells exhibited a decrease in osteolysis, suggesting that Gli2 inhibition may block TGF-β propagation of a vicious osteolytic cycle in this MDA-MB-231 model of bone metastasis. Accordingly, in the absence of TGF-β signaling, Gli2 expression was downregulated in cells, whereas enforced overexpression of Gli2 restored PTHrP activity. Taken together, our findings suggest that Gli2 is required for TGF-β to stimulate PTHrP expression and that blocking Hh-independent Gli2 activity will inhibit tumor-induced bone destruction. Cancer Res; 71(3); 822–31. ©2010 AACR.
Functional Recovery of the Donor Knee After Autologous Osteochondral Transplantation for Capitellar Osteochondritis Dissecans
Authors: Nishimura Akinobu , Morita Akimasa , Fukuda Aki , Kato Ko , Sudo Akihiro 
Published: December 2010

Background: Osteochondral autograft transplantation has been advocated to treat severe osteochondritis dissecans of the humeral capitellum in throwing athletes to reproduce the normal hyaline cartilage and achieve long-term elbow function. Although some authors have reported good outcomes, the current authors are concerned about functional recovery of the donor knee after osteochondral grafts have been harvested. Purpose: The present prospective study analyzed functional recovery of the donor knee after osteochondral graft harvest. Study Design: Case series; Level of evidence, 4. Methods: Twelve male patients (average age at surgery, 14.4 years) had severe osteochondritis dissecans of the humeral capitellum treated with osteochondral autograft transplantation from the contralateral knee joint. The donor knee of each patient was assessed for pain (visual analog scale), joint effusion, Lysholm score, radiographic findings, and muscle strength (60 and 180 deg/sec). Results: At 3 months after surgery, 10 patients were pain-free (visual analog scale score, 0); none had knee joint effusion; and 10 gained 100 points in the Lysholm score. However, muscle power (60 deg/sec) of the knee extensor revealed 8 patients with reduced muscle strength at 3 months compared with the preoperative level, although 11 patients reached preoperative knee extensor muscle strength at 12 months. Radiographic findings at 24 months showed that none of the patients had knee osteoarthritis. Conclusion: A time lag was evident in recovery between postoperative symptoms and muscle power at 3 months. However, harvesting osteochondral grafts did not exert adverse effects on donor knee function in young athletes at 2 years after undergoing osteochondral autograft transplantation for capitellar osteochondritis dissecans.
Single-Agent Lenalidomide in the Treatment of Previously Untreated Chronic Lymphocytic Leukemia
Authors: Chen Christine I. , Bergsagel P. Leif , Paul Harminder , Xu Wei , Lau Anthea , Dave Nimisha , Kukreti Vishal , Wei Ellen , Leung-Hagesteijn Chungyee , Li Zhi Hua , Brandwein Joseph , Pantoja Mariela , Johnston James , Gibson Spencer , Hernandez Tiffany , Spaner David , Trudel Suzanne 
Published: December 2010

PurposeLenalidomide is an oral immunomodulatory drug with multiple effects on the immune system and tumor cell microenvironment leading to inhibition of malignant cell growth. Based on encouraging reports of lenalidomide in relapsed and refractory chronic lymphocytic leukemia (CLL), we investigated the first-line use of single-agent lenalidomide in CLL.Patients and MethodsUsing a starting dose of lenalidomide 10 mg/d for 21 days of a 28-day cycle and weekly 5-mg dose escalations to a target of 25 mg, we encountered severe toxicities (tumor lysis, fatal sepsis) in the first two patients enrolled. The study was halted and the protocol amended to a more conservative regimen: starting dose of lenalidomide 2.5 mg with monthly escalations to a target dose of 10 mg, and extended tumor lysis prophylaxis and monitoring. Gene expression profiles from patient samples before and after 7 days of lenalidomide were performed.ResultsTwenty-five patients were enrolled on the amended protocol. No further tumor lysis events were reported. Tumor flare was common (88%) but mild. Grade 3 to 4 neutropenia occurred in 72% of patients, with only five episodes of febrile neutropenia. The overall response rate was 56% (no complete responses). Although rapid peripheral lymphocyte reductions were observed, rebound lymphocytoses during the week off-therapy were common. Lenalidomide-induced molecular changes enriched for cytoskeletal and immune-related genes were identified.ConclusionLenalidomide is clinically active as first-line CLL therapy and is well-tolerated if a conservative approach with slow dose escalation is used. A lenalidomide-induced molecular signature provides insights into its immunomodulatory mechanisms of action in CLL.
WT1 Mutation and 11P15 Loss of Heterozygosity Predict Relapse in Very Low-Risk Wilms Tumors Treated With Surgery Alone: A Children's Oncology Group Study
Authors: Perlman Elizabeth J. , Grundy Paul E. , Anderson James R. , Jennings Lawrence J. , Green Daniel M. , Dome Jeffrey S. , Shamberger Robert C. , Ruteshouser E. Cristy , Huff Vicki 
Published: December 2010

Purpose Children's Oncology Group defines very low-risk Wilms tumors (VLRWT) as stage I favorable histology Wilms tumors weighing less than 550 g in children younger than 24 months of age. VLRWTs may be treated with nephrectomy alone. However, 10% to 15% of VLRWTs relapse without chemotherapy. Previous studies suggest that VLRWTs with low WT1 expression and/or 11p15 loss of heterozygosity (LOH) may have increased risk of relapse. The current study validates these findings within prospectively identified children with VLRWT who did not receive adjuvant chemotherapy. Patients and Methods Fifty-six VLRWTs (10 relapses) were analyzed for mutation of WT1, CTNNB1, and WTX; for 11p15 LOH using microsatellite analysis; and for H19DMR and KvDMR1 methylation. Results 11p15 LOH was identified in 19 (41%) of 46 evaluable VLRWTs and was significantly associated with relapse (P < .001); 16 of 19 were isodisomic for 11p15. WT1 mutation was identified in nine (20%) of 45 evaluable VLRWTs and was significantly associated with relapse (P = .004); all nine cases also had 11p15 LOH. All evaluable tumors showing LOH by microsatellite analysis also showed LOH by methylation analysis. Retention of the normal imprinting pattern was identified in 24 of 42 evaluable tumors, and none relapsed. Loss of imprinting at 11p15 was identified in one of 42 tumors. Conclusion WT1 mutation and 11p15 LOH are associated with relapse in patients with VLRWTs who do not receive chemotherapy. These may provide meaningful biomarkers to stratify patients for reduced chemotherapy in the future. VLRWTs show a different incidence of WT1 mutation and 11p15 imprinting patterns than has been reported in Wilms tumors of all ages.
Intravenous Calcium and Magnesium for Oxaliplatin-Induced Sensory Neurotoxicity in Adjuvant Colon Cancer: NCCTG N04C7
Authors: Grothey Axel , Nikcevich Daniel A. , Sloan Jeff A. , Kugler John W. , Silberstein Peter T. , Dentchev Todor , Wender Donald B. , Novotny Paul J. , Chitaley Umesh , Alberts Steven R. , Loprinzi Charles L. 
Published: December 2010

Purpose Cumulative sensory neurotoxicity (sNT) is the dose-limiting toxicity of oxaliplatin, which commonly leads to early discontinuation of oxaliplatin-based therapy in the palliative and adjuvant settings. In a nonrandomized, retrospective study, intravenous (IV) calcium/magnesium (Ca/Mg) was associated with reduced oxaliplatin-induced sNT. Methods Patients with colon cancer undergoing adjuvant therapy with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) were randomly assigned to Ca/Mg (1g calcium gluconate plus 1g magnesium sulfate pre- and post-oxaliplatin) or placebo, in a double-blinded manner. The primary end point was the percentage of patients with grade 2 or greater sNT at any time during or after oxaliplatin-based therapy by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version 3) criteria. An oxaliplatin-specific sNT scale and patient questionnaires were also used to assess sNT. After 104 of 300 planned patients were enrolled, the study was closed. This was due to preliminary reports from another trial that suggested that Ca/Mg decreased treatment efficacy; these data were subsequently found to be incorrect. Results Overall, 102 patients were available for analysis. Ca/Mg decreased the incidence of chronic, cumulative, grade 2 or greater sNT, as measured by NCI CTCAE (P = .038) and also by the oxaliplatin-specific sNT scale (P = .018). In addition, acute muscle spasms associated with oxaliplatin were significantly reduced (P = .01) No effect on acute, cold-induced sNT was found. No substantial differences in adverse effects were noted between Ca/Mg and placebo. Conclusion Despite early termination and decreased statistical power, this study supports IV Ca/Mg as an effective neuroprotectant against oxaliplatin-induced cumulative sNT in adjuvant colon cancer.
Second Primary Cancers After an Index Head and Neck Cancer: Subsite-Specific Trends in the Era of Human Papillomavirus–Associated Oropharyngeal Cancer
Authors: Morris Luc G.T. , Sikora Andrew G. , Patel Snehal G. , Hayes Richard B. , Ganly Ian 
Published: December 2010

Purpose Patients with head and neck squamous cell carcinoma (HNSCC) are at elevated risk of second primary malignancies (SPM), most commonly of the head and neck (HN), lung, and esophagus. Our objectives were to identify HNSCC subsite-specific differences in SPM risk and distribution and to describe trends in risk over 3 decades, before and during the era of human papillomavirus (HPV) –associated oropharyngeal SCC. Methods Population-based cohort study of 75,087 patients with HNSCC in the Surveillance, Epidemiology, and End Results (SEER) program. SPM risk was quantified by using standardized incidence ratios (SIRs), excess absolute risk (EAR) per 10,000 person-years at risk (PYR), and number needed to observe. Trends in SPM risk were analyzed by using joinpoint log-linear regression. Results In patients with HNSCC, the SIR of second primary solid tumor was 2.2 (95% CI, 2.1 to 2.2), and the EAR was 167.7 cancers per 10,000 PYR. The risk of SPM was highest for hypopharyngeal SCC (SIR, 3.5; EAR, 307.1 per 10,000 PYR) and lowest for laryngeal SCC (SIR, 1.9; EAR, 147.8 per 10,000 PYR). The most common SPM site for patients with oral cavity and oropharynx SCC was HN; for patients with laryngeal and hypopharyngeal cancer, it was the lung. Since 1991, SPM risk has decreased significantly among patients with oropharyngeal SCC (annual percentage change in EAR, −4.6%; P = .03). Conclusion In patients with HNSCC, the risk and distribution of SPM differ significantly according to subsite of the index cancer. Before the 1990s, hypopharynx and oropharynx cancers carried the highest excess risk of SPM. Since then, during the HPV era, SPM risk associated with oropharyngeal SCC has declined to the lowest risk level of any subsite.