bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population Pharmacokinetics of Extended-Infusion Piperacillin-Tazobactam in Hospitalized Patients with Nosocomial Infections
Authors: Felton T. W. , Hope W. W. , Lomaestro B. M. , Butterfield J. M. , Kwa A. L. , Drusano G. L. , Lodise T. P. 
Published: May 2012

ABSTRACT

While extended infusions of piperacillin-tazobactam (TZP) are increasingly used in practice, the effect of infusion on the pharmacokinetic (PK) profile of TZP has not been widely assessed. To assess its effect on the pharmacokinetic profile of TZP, seven serum samples were collected from 11 hospitalized patients who received 3.375 g TZP intravenously for 4 h every 8 h. Population pharmacokinetic models were fit to the PK data utilizing first-order, Michaelis-Menten (MM), and parallel first-order/MM clearance. A population PK model with first-order clearance was fit to the tazobactam PK data. Monte Carlo simulations (MCSs) were used to determine the most effective administration schedule to ensure that free piperacillin concentrations were above the MIC for at least 50% of the dosing interval (50%
f
T>MIC) and to quantify the extent of the nonlinear clearance. The model incorporating parallel linear/MM clearance best fit the piperacillin PK data. The MCSs demonstrated that approximately 50% of the administered piperacillin is cleared by the nonlinear clearance mechanism. The results of the MCSs also revealed that more intensive TZP extended infusion dosing schemes (3.375 to 4.5 g intravenously [3-h infusion] every 6 h) than those commonly used in clinical practice were needed to maximize the 50%
f
T>MIC for MICs of ≥8 mg/liter. This study suggests that extended infusion of TZP is the most effective method of administration for patients with nosocomial infections. Due to the hyperclearance nature of the hospitalized patient populations studied, more intensive TZP dosing regimens may be needed to maximize
f
T>MIC in certain hospitalized populations.
In Vitro
Activity of TP-271 against Mycobacterium abscessus, Mycobacterium fortuitum, and Nocardia Species
Authors: Cynamon Michael , Jureller Jeff , Desai Balaji , Ramachandran Krithika , Sklaney Mary , Grossman Trudy H. 
Published: May 2012

ABSTRACT

The
in vitro
activities of TP-271, a novel fluorocycline antimicrobial, against 22 isolates of
Mycobacterium abscessus
, 22 isolates of
Mycobacterium fortuitum
, and 19 isolates of
Nocardia
spp. were studied by a microtiter broth dilution method. The MIC
90
s for
M. abscessus
,
M. fortuitum
, and
Nocardia
spp. were 0.5 μg/ml, 0.03 μg/ml, and 8 μg/ml, respectively. TP-271 was significantly more active than the respective control drug in virtually all tests.
Evaluation of the Immunogenicity and Vaccine Potential of Recombinant Plasmodium falciparum Merozoite Surface Protein 8
Authors: Alaro James R. , Angov Evelina , Lopez Ana M. , Zhou Hong , Long Carole A. , Burns James M. 
Published: May 2012

ABSTRACTThe C-terminal 19-kDa domain of merozoite surface protein 1 (MSP119) is the target of protective antibodies but alone is poorly immunogenic. Previously, using thePlasmodium yoeliimurine model, we fusedP. yoeliiMSP119(PyMSP119) with full-lengthP. yoeliimerozoite surface protein 8 (MSP8). Upon immunization, the MSP8-restricted T cell response provided help for the production of high and sustained levels of protectivePyMSP119- andPyMSP8-specific antibodies. Here, we assessed the vaccine potential of MSP8 of the human malaria parasite,Plasmodium falciparum. Distinct fromPyMSP8,P. falciparumMSP8 (PfMSP8) contains an N-terminal asparagine and aspartic acid (Asn/Asp)-rich domain whose function is unknown. Comparative analysis of recombinant full-lengthPfMSP8 and a truncated version devoid of the Asn/Asp-rich domain,PfMSP8(ΔAsn/Asp), showed that both proteins were immunogenic for T cells and B cells. All T cell epitopes utilized mapped within rPfMSP8(ΔAsn/Asp). The dominant B cell epitopes were conformational and common to both rPfMSP8 and rPfMSP8(ΔAsn/Asp). Analysis of nativePfMSP8 expression revealed thatPfMSP8 is present intracellularly in late schizonts and merozoites. Following invasion,PfMSP8 is found distributed on the surface of ring- and trophozoite-stage parasites. Consistent with a low and/or transient expression ofPfMSP8 on the surface of merozoites,PfMSP8-specific rabbit IgG did not inhibit thein vitrogrowth ofP. falciparumblood-stage parasites. These studies suggest that the further development ofPfMSP8 as a malaria vaccine component should focus on the use ofPfMSP8(ΔAsn/Asp) and its conserved, immunogenic T cell epitopes as a fusion partner for protective domains of poor immunogens, includingPfMSP119.
Differential Contribution of Bacillus anthracis Toxins to Pathogenicity in Two Animal Models
Authors: Levy Haim , Weiss Shay , Altboum Zeev , Schlomovitz Josef , Glinert Itai , Sittner Assa , Shafferman Avigdor , Kobiler David 
Published: May 2012

ABSTRACT

The virulence of
Bacillus anthraci
s, the causative agent of anthrax, stems from its antiphagocytic capsule, encoded by pXO2, and the tripartite toxins encoded by pXO1. The accepted paradigm states that anthrax is both an invasive and toxinogenic disease and that the toxins play major roles in pathogenicity. We tested this assumption by a systematic study of mutants with combined deletions of the
pag
,
lef
, and
cya
genes, encoding protective antigen (PA), lethal factor (LF), and edema factor (EF), respectively. The resulting seven mutants (single, double, and triple) were evaluated following subcutaneous (s.c.) and intranasal (i.n.) inoculation in rabbits and guinea pigs. In the rabbit model, virulence is completely dependent on the presence of PA. Any mutant bearing a
pag
deletion behaved like a pXO1-cured mutant, exhibiting complete loss of virulence with attenuation indices of over 2,500,000 or 1,250 in the s.c. or i.n. route of infection, respectively. In marked contrast, in guinea pigs, deletion of
pag
or even of all three toxin components resulted in relatively moderate attenuation, whereas the pXO1-cured bacteria showed complete attenuation. The results indicate that a pXO1-encoded factor(s), other than the toxins, has a major contribution to the virulence mechanism of
B. anthracis
in the guinea pig model. These unexpected toxin-dependent and toxin-independent manifestations of pathogenicity in different animal models emphasize the importance and need for a comprehensive evaluation of
B. anthracis
virulence in general and in particular for the design of relevant next-generation anthrax vaccines.
The Hydrophilic Translocator for Vibrio parahaemolyticus, T3SS2, Is Also Translocated
Authors: Zhou Xiaohui , Ritchie Jennifer M. , Hiyoshi Hirotaka , Iida Tetsuya , Davis Brigid M. , Waldor Matthew K. , Kodama Toshio 
Published: May 2012

ABSTRACT

The pathogenesis of the diarrheal disease caused by
Vibrio parahaemolyticus
, a leading cause of seafood-associated enteritis worldwide, is dependent upon a type III secretion system, T3SS2. This apparatus enables the pathogen to inject bacterial proteins (effectors) into the cytosol of host cells and thereby modulate host processes. T3SS effector proteins transit into the host cell via a membrane pore (translocon) typically formed by 3 bacterial proteins. We have identified the third translocon protein for T3SS2: VopW, which was previously classified as an effector protein for a homologous T3SS in
V. cholerae
. VopW is a hydrophilic translocon protein; like other such proteins, it is not inserted into the host cell membrane but is required for insertion of the two hydrophobic translocators, VopB2 and VopD2, that constitute the membrane channel. VopW is not required for secretion of T3SS2 effectors into the bacterial culture medium; however, it is essential for transfer of these proteins into the host cell cytoplasm. Consequently, deletion of
vopW
abrogates the virulence of
V. parahaemolyticus
in several animal models of diarrheal disease. Unlike previously described hydrophilic translocators, VopW is itself translocated into the host cell cytoplasm, raising the possibility that it functions as both a translocator and an effector.
Observational study on factors related to health-promoting community activity development in primary care (frAC Project): a study protocol
Authors: March Sebastià , Ripoll Joana , Ruiz-Giménez Juan Luís , Montaner Gomis Isabel , Benedé Azagra Carmen Belén , Elizalde Soto Lázaro , Vidal Mª Clara , Bauzà Amengual M de Lluc , Planas Juan Trinidad , Maria Pérez Mariano Damiana , Llull Sarralde Micaela , Bajo Viñas Rosa , Jordan Martin Matilde , Solano Villarubia Carmen , Rodriguez Bajo Maria , Cordoba Victoria Manuela , Badia Capdevila Marta , Serrano Ferrandez Elena , Bosom Diumenjo Maria , Zabaleta del Olmo Nieves , Bolívar-Ribas Bonaventura , Antoñanzas Lombarte Angel , Bregel Cotaina Samantha , Calvo Tocado Ana , Olivan Blázquez Barbara , Magallón Botaya Rosa , Marín Palacios Pilar , Echauri Ozcoidi Margarita , Perez-Jarauta Mª Jose , Ramos Maria 
Published: May 2012

IntroductionAccording to Spanish health regulations, primary care professionals have the responsibility to carry out health-promoting community activities (CAs). However, in practice, their implementation is not as widespread as it should be. The aims of this study were to identify factors within the team, the community and the professionals that influence the development of these activities and to describe the community interventions in progress.Methods and analysisThis study is an observational analytical retrospective study. The information will be collected from five Spanish regions: Catalonia, Madrid, the Balearic Islands, Navarra and Aragón. The authors will contact primary care teams (PCTs) and identify the CAs from the previous year. The research team will conduct a peer review whether the inclusion criteria are met. In the health centres where CAs are implemented, the authors will select professionals carrying them out and randomly select an identical number of professionals not doing these activities. In the centres where no CA is implemented, three professionals will be randomly selected. The selected professionals will complete the questionnaires for individual-level variables. Information about the registered population and the PCTs will be collected through questionnaires and secondary sources.OutcomesVariables will be collected from the community, the PCTs, the individual professionals and CAs.AnalysisA descriptive analysis of all the variables will be carried out, along with a bivariate and a logistic regression analysis, with CAs being the primary outcome.Ethics and disseminationThis study has been approved by the Research Ethics Committee of the Jordi Gol y Gurina Foundation in Barcelona and area 11 in Madrid. The questionnaire distributed to the professionals will be anonymous.
Fra-1 Promotes Breast Cancer Chemosensitivity by Driving Cancer Stem Cells from Dormancy
Authors: Lu Dan , Chen Si , Tan Xiaoyue , Li Na , Liu Chenghu , Li Zongjin , Liu Ze , Stupack Dwayne G. , Reisfeld Ralph A. , Xiang Rong 
Published: May 2012

Abstract
Fra-1 is a member of the Fos transcription factor family that is highly expressed in multiple cancers, playing important roles in transformation, proliferation, and metastasis. In this study, we observed an inverse correlation between the expression of Fra-1 in human stage II breast cancer tissues and the corresponding level of clinical chemoresistance. Extending these findings in vitro, we found that knockdown of Fra-1 in breast tumor cells was sufficient to confer resistance to doxorubicin and cyclophosphamide, whereas enhanced Fra-1 expression could render these cells chemosensitive. The tumor cell side population, which is enriched for cancer stem cells, was found to be associated with chemoresistance. Increased side population fractions were detected among tumor cell lines subjected to Fra-1 knockdown. In contrast, enhanced expression of Fra-1 was correlated with a decreased side population fraction, and significantly, this finding was recapitulated in vivo, where tumors with enhanced expression of Fra-1 were found to have blunted growth. Tumor cells subjected to Fra-1 knockdown grew faster and were larger in size. Taken together, our findings suggest that Fra-1 may be an important prognostic marker for breast cancer therapy. Cancer Res; 72(14); 3451–6. ©2012 AACR.
Identification of Serum Biomarker Signatures Associated with Pancreatic Cancer
Authors: Wingren Christer , Sandström Anna , Segersvärd Ralf , Carlsson Anders , Andersson Roland , Löhr Matthias , Borrebaeck Carl A. K. 
Published: May 2012

Abstract
Pancreatic cancer is an aggressive disease with poor prognosis, due, in part, to the lack of disease-specific biomarkers that could afford early and accurate diagnosis. With a recombinant antibody microarray platform, targeting mainly immunoregulatory proteins, we screened sera from 148 patients with pancreatic cancer, chronic pancreatitis, autoimmune pancreatitis (AIP), and healthy controls (N). Serum biomarker signatures were derived from training cohorts and the predictive power was evaluated using independent test cohorts. The results identified serum portraits distinguishing pancreatic cancer from N [receiver operating characteristics area under the curve (AUC) of 0.95], chronic pancreatitis (0.86), and AIP (0.99). Importantly, a 25-serum biomarker signature discriminating pancreatic cancer from the combined group of N, chronic pancreatitis, and AIP was determined. This signature exhibited a high diagnostic potential (AUC of 0.88). In summary, we present the first prevalidated, multiplexed serum biomarker signature for diagnosis of pancreatic cancer that may improve diagnosis and prevention in premalignant diseases and in screening of high-risk individuals. Cancer Res; 72(10); 2481–90. ©2012 AACR.
KRas Induces a Src/PEAK1/ErbB2 Kinase Amplification Loop That Drives Metastatic Growth and Therapy Resistance in Pancreatic Cancer
Authors: Kelber Jonathan A. , Reno Theresa , Kaushal Sharmeela , Metildi Cristina , Wright Tracy , Stoletov Konstantin , Weems Jessica M. , Park Frederick D. , Mose Evangeline , Wang Yingchun , Hoffman Robert M. , Lowy Andrew M. , Bouvet Michael , Klemke Richard L. 
Published: May 2012

Abstract
Early biomarkers and effective therapeutic strategies are desperately needed to treat pancreatic ductal adenocarcinoma (PDAC), which has a dismal 5-year patient survival rate. Here, we report that the novel tyrosine kinase PEAK1 is upregulated in human malignancies, including human PDACs and pancreatic intraepithelial neoplasia (PanIN). Oncogenic KRas induced a PEAK1-dependent kinase amplification loop between Src, PEAK1, and ErbB2 to drive PDAC tumor growth and metastasis in vivo. Surprisingly, blockade of ErbB2 expression increased Src-dependent PEAK1 expression, PEAK1-dependent Src activation, and tumor growth in vivo, suggesting a mechanism for the observed resistance of patients with PDACs to therapeutic intervention. Importantly, PEAK1 inactivation sensitized PDAC cells to trastuzumab and gemcitabine therapy. Our findings, therefore, suggest that PEAK1 is a novel biomarker, critical signaling hub, and new therapeutic target in PDACs. Cancer Res; 72(10); 2554–64. ©2012 AACR.
The Future Is Now: Chimeric Antigen Receptors as New Targeted Therapies for Childhood Cancer
Authors: Lee Daniel W. , Barrett David M. , Mackall Crystal , Orentas Rimas , Grupp Stephan A. 
Published: May 2012

AbstractImproved outcomes for children with cancer hinge on the development of new targeted therapies with acceptable short-term and long-term toxicity. Progress in basic, preclinical, and clinical arenas spanning cellular immunology, gene therapy, and cell-processing technologies have paved the way for clinical applications of chimeric antigen receptor–based therapies. This is a new form of targeted immunotherapy that merges the exquisite targeting specificity of monoclonal antibodies with the potent cytotoxicity, potential for expansion, and long-term persistence provided by cytotoxic T cells. Although this field is still in its infancy, clinical trials have already shown clinically significant antitumor activity in neuroblastoma, chronic lymphocytic leukemia, and B-cell lymphoma, and trials targeting a variety of other adult and pediatric malignancies are under way. Ongoing work is focused on identifying optimal tumor targets and elucidating and manipulating both cell- and host-associated factors to support expansion and persistence of the genetically engineered cells in vivo. In pediatric oncology, CD19 and GD2 are compelling antigens that have already been identified for targeting pre-B acute lymphoblastic leukemia and neuroblastoma, respectively, with this approach, but it is likely that other antigens expressed in a variety of childhood cancers will also soon be targeted using this therapy. The potential to target essentially any tumor-associated cell-surface antigen for which a monoclonal antibody can be made opens up an entirely new arena for targeted therapy of childhood cancer. Clin Cancer Res; 18(10); 2780–90. ©2012 AACR.
Epigenetic Changes in Pediatric Solid Tumors: Promising New Targets
Authors: Lawlor Elizabeth R. , Thiele Carol J. 
Published: May 2012

Abstract
Cancer is being reinterpreted in the light of recent discoveries related to the histone code and the dynamic nature of epigenetic regulation and control of gene programs during development, as well as insights gained from whole cancer genome sequencing. Somatic mutations in or deregulated expression of genes that encode chromatin-modifying enzymes are being identified with high frequency. Nowhere is this more relevant than in pediatric embryonal solid tumors. A picture is emerging that shows that classic genetic alterations associated with these tumors ultimately converge on the epigenome to dysregulate developmental programs. In this review, we relate how alterations in components of the transcriptional machinery and chromatin modifier genes contribute to the initiation and progression of pediatric solid tumors. We also discuss how dramatic progress in our understanding of the fundamental mechanisms that contribute to epigenetic deregulation in cancer is providing novel avenues for targeted cancer therapy. Clin Cancer Res; 18(10); 2768–79. ©2012 AACR.
Promising Therapeutic Targets in Neuroblastoma
Authors: Matthay Katherine K. , George Rani E. , Yu Alice L. 
Published: May 2012

Abstract
Neuroblastoma, the most common extracranial solid tumor in children, is derived from neural crest cells. Nearly half of patients present with metastatic disease and have a 5-year event-free survival of &lt;50%. New approaches with targeted therapy may improve efficacy without increased toxicity. In this review we evaluate 3 promising targeted therapies: (i) 131I-metaiodobenzylguanidine (MIBG), a radiopharmaceutical that is taken up by human norepinephrine transporter (hNET), which is expressed in 90% of neuroblastomas; (ii) immunotherapy with monoclonal antibodies targeting the GD2 ganglioside, which is expressed on 98% of neuroblastoma cells; and (iii) inhibitors of anaplastic lymphoma kinase (ALK), a tyrosine kinase that is mutated or amplified in ∼10% of neuroblastomas and expressed on the surface of most neuroblastoma cells. Early-phase trials have confirmed the activity of 131I-MIBG in relapsed neuroblastoma, with response rates of ∼30%, but the technical aspects of administering large amounts of radioactivity in young children and limited access to this agent have hindered its incorporation into treatment of newly diagnosed patients. Anti-GD2 antibodies have also shown activity in relapsed disease, and a recent phase III randomized trial showed a significant improvement in event-free survival for patients receiving chimeric anti-GD2 (ch14.18) combined with cytokines and isotretinoin after myeloablative consolidation therapy. A recently approved small-molecule inhibitor of ALK has shown promising preclinical activity for neuroblastoma and is currently in phase I and II trials. This is the first agent directed to a specific mutation in neuroblastoma, and marks a new step toward personalized therapy for neuroblastoma. Further clinical development of targeted treatments offers new hope for children with neuroblastoma. Clin Cancer Res; 18(10); 2740–53. ©2012 AACR.
GDC-0941, a Novel Class I Selective PI3K Inhibitor, Enhances the Efficacy of Docetaxel in Human Breast Cancer Models by Increasing Cell Death In Vitro and In Vivo
Authors: Wallin Jeffrey J. , Guan Jane , Prior Wei Wei , Lee Leslie B. , Berry Leanne , Belmont Lisa D. , Koeppen Hartmut , Belvin Marcia , Friedman Lori S. , Sampath Deepak 
Published: May 2012

Abstract
Purpose: Docetaxel is a front-line standard-of-care chemotherapeutic drug for the treatment of breast cancer. Phosphoinositide 3-kinases (PI3K) are lipid kinases that regulate breast tumor cell growth, migration, and survival. The current study was intended to determine whether GDC-0941, an orally bioavailable class I selective PI3K inhibitor, enhances the antitumor activity of docetaxel in human breast cancer models in vitro and in vivo.
Experimental Design: A panel of 25 breast tumor cell lines representing HER2+, luminal, and basal subtypes were treated with GDC-0941, docetaxel, or the combination of both drugs and assayed for cellular viability, modulation of PI3K pathway markers, and apoptosis induction. Drug combination effects on cellular viability were also assessed in nontransformed MCF10A human mammary epithelial cells. Human xenografts of breast cancer cell lines and patient-derived tumors were used to assess efficacy of GDC-0941 and docetaxel in vivo.
Results: Combination of GDC-0941 and docetaxel decreased the cellular viability of breast tumor cell lines in vitro but to variable degrees of drug synergy. Compared with nontransformed MCF10A cells, the addition of both drugs resulted in stronger synergistic effects in a subset of tumor cell lines that were not predicted by breast cancer subtype. In xenograft models, GDC-0941 enhanced the antitumor activity of docetaxel with maximum combination efficacy observed within 1 hour of administering both drugs. GDC-0941 increased the rate of apoptosis in cells arrested in mitosis upon cotreatment with docetaxel.
Conclusion: GDC-0941 augments the efficacy of docetaxel by increasing drug-induced apoptosis in breast cancer models. Clin Cancer Res; 18(14); 3901–11. ©2012 AACR.