bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Approximation Approach to General Robustness Assessment for Multidisciplinary Systems
Authors: Du Xiaoping , Zhang Yi 
Published: March 2010

Abstract
In many engineering applications, both random and interval variables exist. The mixture of both types of variables has been dealt with in robust design for single-disciplinary systems. This work focuses on robustness assessment for multidisciplinary systems with both random and interval variables. To alleviate the intensive computational demand, a semi-second-order Taylor expansion method is proposed to evaluate robustness. A performance function is approximated with linear terms of random and interval variables, as well as the interaction terms between the two types of variables. Then the maximum and minimum standard deviations of the performance function are computed. With the proposed method, the impact of both random and interval variables on the system robustness can be evaluated efficiently.
Toward Extracting All Phylogenetic Information from Matrices of Evolutionary Distances
Authors: Roch Sebastien 
Published: March 2010

Theoretically Speedy TreesPhylogenetic tree construction often uses distance matrix methods, which offer promising scalable methods for rapid building of very large phylogenies. It has generally been assumed that trees constructed from distance matrices are intrinsically less accurate than those inferred from maximum likelihood methods, but the latter are slower to make.Roch(p.1376; see the Perspective byAllman and Rhodes) theoretically examined this problem and showed that distance methods can achieve the same level of accuracy as likelihood methods. Thus, the generally assumed tradeoff between accuracy and speed in phylogenetic reconstruction can be overcome.
Revisiting Pneumococcal Carriage by Use of Broth Enrichment and PCR Techniques for Enhanced Detection of Carriage and Serotypes
Authors: Carvalho Maria da Gloria , Pimenta Fabiana C. , Jackson Delois , Roundtree Alexis , Ahmad Yusra , Millar Eugene V. , O'Brien Katherine L. , Whitney Cynthia G. , Cohen Adam L. , Beall Bernard W. 
Published: March 2010

ABSTRACT

The measurement of pneumococcal carriage in the nasopharyngeal reservoir is subject to potential confounders that include low-density and multiple-strain colonization. To compare different methodologies, we picked a random sampling of 100 nasopharyngeal specimens recovered from infants less than 2 years of age who were previously assessed for pneumococcal carriage and serotypes by a conventional method that used direct plating from the transport/storage medium (50 specimens were culture negative and 50 specimens were culture positive for pneumococci). We used a broth enrichment approach and a conventional PCR approach (with and without broth enrichment) to determine pneumococcal carriage and serotypes, and the results were compared to the initial conventional culture-based results. Additionally, we used a
lytA
-targeted real-time PCR for pneumococcal detection. Broth enrichment for both the culture-based and the PCR-based methods enhanced the isolation of pneumococci and detection of serotype diversity, with the most effective serotype deduction method being one that used broth enrichment prior to sequential multiplex PCR. Similarly, we also found that broth enrichment followed by the
lytA
-specific real-time PCR was the most sensitive for the detection of apparent pneumococcal carriage. The broth enrichment, conventional multiplex PCR, and real-time PCR approaches used in this study were effective in detecting pneumococcal carriage in the 50 specimens that were negative by conventional direct plating from transport medium (range of numbers of positive specimens, 8/50 to 22/50 [16 to 44%]), and the three different serotyping approaches that used broth enrichment increased the number of serotype identifications from the 100 specimens (12 to 29 additional serotype identifications to be positive). A PCR-based approach that employed a broth enrichment step appeared to best enhance the detection of mixed serotypes and low-density pneumococcal carriage.
Rapid Detection of Influenza A Pandemic (H1N1) 2009 Virus Neuraminidase Resistance Mutation H275Y by Real-Time Reverse Transcriptase PCR
Authors: Hindiyeh Musa , Ram Daniela , Mandelboim Michal , Meningher Tal , Hirsh Shira , Robinov Jana , Levy Virginia , Orzitzer Sara , Azar Roberto , Grossman Zehava , Mendelson Ella 
Published: March 2010

ABSTRACT
The emergence of oseltamivir-resistant influenza A pandemic (H1N1) 2009 virus highlights the need for rapid oseltamivir resistance screening. We report the development and validation of high-throughput real-time reverse transcriptase PCR assays for the detection of the H275Y substitution in the neuraminidase 1 gene that can be accomplished in 3 to 4 h.
The Human Cytomegalovirus UL36 Gene Controls Caspase-Dependent and -Independent Cell Death Programs Activated by Infection of Monocytes Differentiating to Macrophages
Authors: McCormick A. Louise , Roback Linda , Livingston-Rosanoff Devon , St. Clair Courtney 
Published: March 2010

ABSTRACTThe cellular protease caspase-8 activates extrinsic apoptosis and also functions to promote monocyte-to-macrophage differentiation. Differentiation-induced alterations to antiviral caspase-8-dependent cell death pathways are unclear. Here, we show THP-1 monocyte-to-macrophage differentiation alters the specific cell death pathways activated in response to human cytomegalovirus (HCMV) infection. Employing viruses with mutations in UL36, the gene that encodes theviralinhibitor ofcaspase-8activation (vICA), our data indicate that both caspase-dependent and -independent death pathways are activated in response to infection. Activation of caspase-dependent and -independent cell death responses restricted growth of vICA-deficient viruses, and vICA/pUL36 inhibited either response. Thus, these studies also reveal that the UL36 gene controls a caspase-independent cell death pathway. The impact of caspases on control of antiviral responses differed at early and late stages of macrophage differentiation. Early in differentiation, vICA-deficient virus-induced cell death was dependent on caspases and inhibited by the pan-caspase inhibitor z-VAD(OMe)-fluoromethyl ketone. In contrast, virus-induced death at late times of differentiation was caspase independent. Additional unlabeled and fluorescent inhibitors indicated that caspase-8 promoted death from within infected cells at early but not late stages of differentiation. These data highlight the multifunctional role of vICA/pUL36 as HCMV encounters various antiviral responses during macrophage differentiation.
B Cells and Platelets Harbor Prion Infectivity in the Blood of Deer Infected with Chronic Wasting Disease
Authors: Mathiason Candace K. , Hayes-Klug Jeanette , Hays Sheila A. , Powers Jenny , Osborn David A. , Dahmes Sallie J. , Miller Karl V. , Warren Robert J. , Mason Gary L. , Telling Glenn C. , Young Alan J. , Hoover Edward A. 
Published: March 2010

ABSTRACT

Substantial evidence for prion transmission via blood transfusion exists for many transmissible spongiform encephalopathy (TSE) diseases. Determining which cell phenotype(s) is responsible for trafficking infectivity has important implications for our understanding of the dissemination of prions, as well as their detection and elimination from blood products. We used bioassay studies of native white-tailed deer and transgenic cervidized mice to determine (i) if chronic wasting disease (CWD) blood infectivity is associated with the cellular versus the cell-free/plasma fraction of blood and (ii) in particular if B-cell (MAb 2-104
+
), platelet (CD41/61
+
), or CD14
+
monocyte blood cell phenotypes harbor infectious prions. All four deer transfused with the blood mononuclear cell fraction from CWD
+
donor deer became PrP
CWD
positive by 19 months postinoculation, whereas none of the four deer inoculated with cell-free plasma from the same source developed prion infection. All four of the deer injected with B cells and three of four deer receiving platelets from CWD
+
donor deer became PrP
CWD
positive in as little as 6 months postinoculation, whereas none of the four deer receiving blood CD14
+
monocytes developed evidence of CWD infection (immunohistochemistry and Western blot analysis) after 19 months of observation. Results of the Tg(CerPrP) mouse bioassays mirrored those of the native cervid host. These results indicate that CWD blood infectivity is cell associated and suggest a significant role for B cells and platelets in trafficking CWD infectivity
in vivo
and support earlier tissue-based studies associating putative follicular B cells with PrP
CWD
. Localization of CWD infectivity with leukocyte subpopulations may aid in enhancing the sensitivity of blood-based diagnostic assays for CWD and other TSEs.
The Specificity of TRIM5α-Mediated Restriction Is Influenced by Its Coiled-Coil Domain
Authors: Maillard Pierre V. , Ecco Gabriela , Ortiz Millán , Trono Didier 
Published: March 2010

ABSTRACT
Retroviruses are both powerful evolutionary forces and dangerous threats to genome integrity. As such, they have imposed strong selective pressure on their hosts, notably triggering the emergence of restriction factors, such as TRIM5α, that act as potent barriers to their cross-species transmission. TRIM5α orthologues from different primates have distinct retroviral restriction patterns, largely dictated by the sequence of their C-terminal PRYSPRY domain, which binds the capsid protein of incoming virions. Here, by combining genetic and functional analyses of human and squirrel monkey TRIM5α, we demonstrate that the coiled-coil domain of this protein, thus far essentially known for mediating oligomerization, also conditions the spectrum of antiretroviral activity. Furthermore, we identify three coiled-coil residues responsible for this effect, one of which has been under positive selection during primate evolution, notably in New World monkeys. These results indicate that the PRYSPRY and coiled-coil domains cooperate to determine the specificity of TRIM5α-mediated capture of retroviral capsids, shedding new light on this complex event.
Autographa californica
Multicapsid Nucleopolyhedrovirus Efficiently Infects Sf9 Cells and Transduces Mammalian Cells via Direct Fusion with the Plasma Membrane at Low pH
Authors: Dong Sicong , Wang Manli , Qiu Zhijuan , Deng Fei , Vlak Just M. , Hu Zhihong , Wang Hualin 
Published: March 2010

ABSTRACT

The budded virus (BV) of the
Autographa californica
multicapsid nucleopolyhedrovirus (AcMNPV) infects insect cells and transduces mammalian cells mainly through the endocytosis pathway. However, this study revealed that the treatment of the virus bound to Sf9 cells at low pH could efficiently rescue the infectivity of AcMNPV in the presence of endocytosis pathway inhibitors. A colocalization assay of the major capsid protein VP39 with the early endosome marker EEA1 showed that at low pH, AcMNPV entered Sf9 cells via an endosome-independent pathway. Using a fluorescent probe (R18), we showed that at low pH, the viral nucleocapsid entered Sf9 cells via direct fusion at the cell surface. By using the myosin-specific inhibitor 2,3-butanedione monoxime (BDM) and the microtubule inhibitor nocodazole, the low pH-triggered direct fusion was demonstrated to be dependent on myosin-like proteins and independent of microtubules. The reverse transcription-PCR of the IE1 gene as a marker for viral entry showed that the kinetics of AcMNPV in cells triggered by low pH was similar to that of the normal entry via endocytosis. The low pH-mediated infection assay and VP39 and EEA1 colocalization assay also demonstrated that AcMNPV could efficiently transduce mammalian cells via direct membrane fusion at the cell surface. More importantly, we found that a low-pH trigger could significantly improve the transduction efficiency of AcMNPV in mammalian cells, leading to the potential application of this method when using baculovirus as a vector for heterologous gene expression and for gene therapy.
Targeting Cancer Cell Metabolism: The Combination of Metformin and 2-Deoxyglucose Induces p53-Dependent Apoptosis in Prostate Cancer Cells
Authors: Ben Sahra Issam , Laurent Kathiane , Giuliano Sandy , Larbret Frédéric , Ponzio Gilles , Gounon Pierre , Le Marchand-Brustel Yannick , Giorgetti-Peraldi Sophie , Cormont Mireille , Bertolotto Corine , Deckert Marcel , Auberger Patrick , Tanti Jean-François , Bost Frédéric 
Published: March 2010

Abstract
Targeting cancer cell metabolism is a new promising strategy to fight cancer. Metformin, a widely used antidiabetic agent, exerts antitumoral and antiproliferative action. In this study, the addition of metformin to 2-deoxyglucose (2DG) inhibited mitochondrial respiration and glycolysis in prostate cancer cells leading to a severe depletion in ATP. The combination of the two drugs was much more harmful for cancer cells than the treatment with metformin or 2DG alone, leading to 96% inhibition of cell viability in LNCaP prostate cancer cells. In contrast, a moderate effect on cell viability was observed in normal prostate epithelial cells. At the cellular level, the combination of metformin and 2DG induced p53-dependent apoptosis via the energy sensor pathway AMP kinase, and the reexpression of a functional p53 in p53-deficient prostate cancer cells restored caspase-3 activity. In addition to apoptosis, the combination of metformin and 2DG arrested prostate cancer cells in G2-M. This G2-M arrest was independent of p53 and correlated with a stronger decrease in cell viability than obtained with either drug. Finally, metformin inhibited 2DG-induced autophagy, decreased beclin 1 expression, and triggered a switch from a survival process to cell death. Our study reinforces the growing interest of metabolic perturbators in cancer therapy and highlights the potential use of the combination of metformin and 2DG as an anticancerous treatment. Cancer Res; 70(6); 2465–75
Local Radiation Therapy Inhibits Tumor Growth through the Generation of Tumor-Specific CTL: Its Potentiation by Combination with Th1 Cell Therapy
Authors: Takeshima Tsuguhide , Chamoto Kenji , Wakita Daiko , Ohkuri Takayuki , Togashi Yuji , Shirato Hiroki , Kitamura Hidemitsu , Nishimura Takashi 
Published: March 2010

AbstractRadiation therapy is one of the primary treatment modalities for cancer along with chemotherapy and surgical therapy. The main mechanism of the tumor reduction after irradiation has been considered to be damage to the tumor DNA. However, we found that tumor-specific CTL, which were induced in the draining lymph nodes (DLN) and tumor tissue of tumor-bearing mice, play a crucial role in the inhibition of tumor growth by radiation. Indeed, the therapeutic effect of irradiation was almost completely abolished in tumor-bearing mice by depleting CD8+ T cells through anti-CD8 monoclonal antibody administration. In mice whose DLN were surgically ablated or genetically defective (Aly/Aly mice), the generation of tetramer+ tumor-specific CTL at the tumor site was greatly reduced in parallel with the attenuation of the radiation-induced therapeutic effect against the tumor. This indicates that DLN are essential for the activation and accumulation of radiation-induced CTL, which are essential for inhibition of the tumor. A combined therapy of local radiation with Th1 cell therapy augmented the generation of tumor-specific CTL at the tumor site and induced a complete regression of the tumor, although radiation therapy alone did not exhibit such a pronounced therapeutic effect. Thus, we conclude that the combination treatment of local radiation therapy and Th1 cell therapy is a rational strategy to augment antitumor activity mediated by tumor-specific CTL. Cancer Res; 70(7); 2697–706
Matrix Metalloproteinases Contribute Distinct Roles in Neuroendocrine Prostate Carcinogenesis, Metastasis, and Angiogenesis Progression
Authors: Littlepage Laurie E. , Sternlicht Mark D. , Rougier Nathalie , Phillips Joanna , Gallo Eugenio , Yu Ying , Williams Kurt , Brenot Audrey , Gordon Jeffrey I. , Werb Zena 
Published: March 2010

Abstract
Prostate cancer is the leading form of cancer in men. Prostate tumors often contain neuroendocrine differentiation, which correlates with androgen-independent progression and poor prognosis. Matrix metalloproteinases (MMP), a family of enzymes that remodel the microenvironment, are associated with tumorigenesis and metastasis. To evaluate MMPs during metastatic prostatic neuroendocrine cancer development, we used transgenic mice expressing SV40 large T antigen in their prostatic neuroendocrine cells, under the control of transcriptional regulatory elements from the mouse cryptdin-2 gene (CR2-TAg). These mice have a stereotypical pattern of tumorigenesis and metastasis. MMP-2, MMP-7, and MMP-9 activities increased concurrently with the transition to invasive metastatic carcinoma, but they were expressed in different prostatic cell types: stromal, luminal epithelium, and macrophages, respectively. CR2-TAg mice treated with AG3340/Prinomastat, an MMP inhibitor that blocks activity of MMP-2, MMP-9, MMP-13, and MMP-14, had reduced tumor burden. CR2-TAg animals were crossed to mice homozygous for null alleles of MMP-2, MMP-7, or MMP-9 genes. At 24 weeks CR2-TAg; MMP-2−/− mice showed reduced tumor burden, prolonged survival, decreased lung metastasis, and decreased blood vessel density, whereas deficiencies in MMP-7 or MMP-9 did not influence tumor growth or survival. Mice deficient for MMP-7 had reduced endothelial area coverage and decreased vessel size, and mice lacking MMP-9 had increased numbers of invasive foci and increased perivascular invasion, as well as decreased tumor blood vessel size. Together, these results suggest distinct contributions by MMPs to the progression of aggressive prostate tumor and to helping tumors cleverly find alternative routes to malignant progression. Cancer Res; 70(6); 2224–34
Randomized Phase II Multicenter Trial of Two Schedules of Lapatinib as First- or Second-Line Monotherapy in Patients with Advanced or Metastatic Non–Small Cell Lung Cancer
Authors: Ross Helen J. , Blumenschein, George R. , Aisner Joseph , Damjanov Nevena , Dowlati Afshin , Garst Jennifer , Rigas James R. , Smylie Michael , Hassani Habib , Allen Kimberly E. , Leopold Lance , Zaks Tal Z. , Shepherd Frances A. 
Published: March 2010

Abstract
Purpose: This randomized phase II study was initially designed to test the activity of two dose schedules of lapatinib (GW572016H), an oral, reversible, dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2/neu; HER2), in chemotherapy-naive patients with non–small cell lung cancer (NSCLC); it was later amended to target patients with bronchioloalveolar carcinoma or no smoking history.
Experimental Design: Patients with good performance status and recurrent or metastatic NSCLC were randomized to lapatinib (orally, 1,500 mg once daily or 500 mg twice daily) until progression or intolerance. Patients could have had a maximum of one prior systemic therapy (chemotherapy or biological therapy) for NSCLC. Safety and activity were assessed every 4 and 8 weeks, respectively. Tumors were analyzed for EGFR and HER2 mutations and/or amplifications.
Results: Of 75 patients in the nontargeted population, 1 (1.3%) had partial response and 16 (21%) had stable disease of ≥24 weeks. No complete or partial responses were observed in 56 patients in the targeted population; 14 (25%) had stable disease of ≥24 weeks. No responses were seen in three patients with EGFR mutations and five with EGFR gene amplification. No mutations in HER2 were found. One of two patients with HER2 amplification had a 51% decrease in tumor size; however, this response was unconfirmed. The most common adverse events were grade 1 or 2 diarrhea, rash, fatigue, nausea, and anorexia. Adverse events were similar across dosing regimens.
Conclusions: Lapatinib was well tolerated, with no notable difference in toxicity between treatment groups. Lapatinib monotherapy did not induce a significant number of tumor regressions in NSCLC. Further studies may be warranted to determine whether lapatinib is active in combination with other agents in the treatment of NSCLC. Clin Cancer Res; 16(6); 1938–49
Overexpression of Smoothened Activates the Sonic Hedgehog Signaling Pathway in Pancreatic Cancer–Associated Fibroblasts
Authors: Walter Kimberly , Omura Noriyuki , Hong Seung-Mo , Griffith Margaret , Vincent Audrey , Borges Michael , Goggins Michael 
Published: March 2010

Abstract
Purpose: Accumulating evidence suggests that cancer-associated stromal fibroblasts (CAF) contribute to tumor growth by actively communicating with cancer cells. Our aim is to identify signaling pathways involved in tumor-stromal cell interactions in human pancreatic cancer.
Experimental Design: We established primary fibroblast cultures from human pancreatic adenocarcinomas and nonneoplastic pancreas tissues. To identify differentially expressed genes in CAFs, we did gene expression profiling of human pancreatic CAFs and nonneoplastic pancreatic fibroblasts.
Results: The Hedgehog receptor Smoothened (SMO) was upregulated in CAFs relative to control fibroblasts. CAFs expressing SMO could transduce the Sonic hedgehog signal to activate Gli1 expression, and small interfering RNA knockdown of SMO blocked the induction of Gli1 in these cells. Stromal fibroblasts of human primary pancreatic adenocarcinomas overexpressed Smo compared with normal pancreatic fibroblasts.
Conclusions: These findings implicate overexpression of Smo as a mechanism for the activation of Hedgehog signaling in human pancreatic CAFs and suggest that stromal cells may be a therapeutic target for Smo antagonists in pancreatic cancer. Clin Cancer Res; 16(6); 1781–9
An Overview of the Optimal Planning, Design, and Conduct of Phase I Studies of New Therapeutics
Authors: LoRusso Patricia M. , Boerner Scott A. , Seymour Lesley 
Published: March 2010

Abstract
Phase I clinical trials represent the first step in bringing promising new treatments from the laboratory to the clinic. Although the importance of phase I clinical trials is widely recognized, there is currently no consensus among the scientific, medical, and statistical communities on how best to do these studies in humans. With the advent of targeted therapies, it has become evident that we need to tailor the design of phase I studies for the particular drug class under investigation and any endpoints that are being defined.
The National Cancer Institute (NCI) Investigational Drug Steering Committee (IDSC) provides broad external scientific and clinical input on the design and prioritization of early-phase clinical trials with agents for which the NCI Cancer Therapy Evaluation Program (CTEP) holds an Investigational New Drug (IND) application through the U.S. Food and Drug Administration (FDA). The IDSC has formed a number of task forces and working groups, including the Clinical Trial Design Task Force and the Biomarker Working Group, many with membership from within the IDSC as well as external experts, including participants from academia, the pharmaceutical industry, and regulatory authorities.
The Clinical Trials Design Taskforce sponsored a Phase I Workshop with the primary goal being to develop consensus recommendations for the optimal design of phase I studies. The primary focus included (1) efficient trial designs, (2) phase I drug combinations, and (3) appropriate statistical and correlative endpoints.
In this CCR Focus series, articles summarize key aspects and recommendations on phase I studies (including combination trials), such as design, use of biomarkers, the European Union and Japanese perspectives on design, requirements for first-in-human and other phase I studies, and ensuring regulatory and International Conference on Harmonization (ICH) compliance. A final article summarizes recommendations for the design and conduct of phase II studies. Clin Cancer Res; 16(6); 1710–8