bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted Delivery of Gemcitabine to Pancreatic Adenocarcinoma Using Cetuximab as a Targeting Agent
Authors: Patra Chitta Ranjan , Bhattacharya Resham , Wang Enfeng , Katarya Aaron , Lau Julie S. , Dutta Shamit , Muders Michael , Wang Shanfeng , Buhrow Sarah A. , Safgren Stephanie L. , Yaszemski Michael J. , Reid Joel M. , Ames Matthew M. , Mukherjee Priyabrata , Mukhopadhyay Debabrata 
Published: March 2008

Abstract
One of the key challenges in anticancer therapy is the toxicity and poor bioavailability of the anticancer drugs. Nanotechnology can play a pivotal role by delivering drugs in a targeted fashion to the malignant cells that will reduce the systemic toxicity of the anticancer drug. In this report, we show a stepwise development of a nanoparticle-based targeted delivery system for in vitro and in vivo therapeutic application in pancreatic cancer. In the first part of the study, we have shown the fabrication and characterization of the delivery system containing gold nanoparticle as a delivery vehicle, cetuximab as a targeting agent, and gemcitabine as an anticancer drug for in vitro application. Nanoconjugate was first characterized physico-chemically. In vitro targeting efficacy, tested against three pancreatic cancer cell lines (PANC-1, AsPC-1, and MIA Paca2) with variable epidermal growth factor receptor (EGFR) expression, showed that gold uptake correlated with EGFR expression. In the second part, we showed the in vivo therapeutic efficacy of the targeted delivery system. Administration of this targeted delivery system resulted in significant inhibition of pancreatic tumor cell proliferation in vitro and orthotopic pancreatic tumor growth in vivo. Tumor progression was monitored noninvasively by measuring bioluminescence of the implanted tumor cells. Pharmacokinetic experiments along with the quantitation of gold both in vitro and in vivo further confirmed that the inhibition of tumor growth was due to targeted delivery. This strategy could be used as a generalized approach for the treatment of a variety of cancers characterized by overexpression of EGFR. [Cancer Res 2008;68(6):1970–8]
Nonlinear Optimization Using Generalized Hopfield Networks
Authors: Tsirukis Athanasios G. , Reklaitis Gintaras V. , Tenorio Manoel F. 
Published: March 2008

A nonlinear neural framework, called the generalized Hopfield network (GHN), is proposed, which is able to solve in a parallel distributed manner systems of nonlinear equations. The method is applied to the general nonlinear optimization problem. We demonstrate GHNs implementing the three most important optimization algorithms, namely the augmented Lagrangian, generalized reduced gradient, and successive quadratic programming methods. The study results in a dynamic view of the optimization problem and offers a straightforward model for the parallelization of the optimization computations, thus significantly extending the practical limits of problems that can be formulated as an optimization problem and that can gain from the introduction of nonlinearities in their structure (e.g., pattern recognition, supervised learning, and design of content-addressable memories).
Stimulus-Dependent Assembly Formation of Oscillatory Responses: II. Desynchronization
Authors: Schillen Thomas B. , König Peter 
Published: March 2008

Recent theoretical and experimental work suggests a temporal structure of neuronal spike activity as a potential mechanism for solving the binding problem in the brain. In particular, recordings from cat visual cortex demonstrate the possibility that stimulus coherency is coded by synchronization of oscillatory neuronal responses. Coding by synchronized oscillatory activity has to avoid bulk synchronization within entire cortical areas. Recent experimental evidence indicates that incoherent stimuli can activate coherently oscillating assemblies of cells that are not synchronized among one another. In this paper we show that appropriately designed excitatory delay connections can support the desynchronization of two-dimensional layers of delayed nonlinear oscillators. Closely following experimental observations, we then present two examples of stimulus-dependent assembly formation in oscillatory layers that employ both synchronizing and desynchronizing delay connections: First, we demonstrate the segregation of oscillatory responses to two overlapping but incoherently moving stimuli. Second, we show that the coherence of movement and location of two stimulus bar segments can be coded by the correlation of oscillatory activity.
A Resource-Allocating Network for Function Interpolation
Authors: Platt John 
Published: March 2008

We have created a network that allocates a new computational unit whenever an unusual pattern is presented to the network. This network forms compact representations, yet learns easily and rapidly. The network can be used at any time in the learning process and the learning patterns do not have to be repeated. The units in this network respond to only a local region of the space of input values. The network learns by allocating new units and adjusting the parameters of existing units. If the network performs poorly on a presented pattern, then a new unit is allocated that corrects the response to the presented pattern. If the network performs well on a presented pattern, then the network parameters are updated using standard LMS gradient descent. We have obtained good results with our resource-allocating network (RAN). For predicting the Mackey-Glass chaotic time series, RAN learns much faster than do those using backpropagation networks and uses a comparable number of synapses.
Symmetric Neural Networks and Propositional Logic Satisfiability
Authors: Pinkas Gadi 
Published: March 2008

Connectionist networks with symmetric weights (like Hopfield networks and Boltzmann Machines) use gradient descent to find a minimum for quadratic energy functions. We show equivalence between the problem of satisfiability in propositional calculus and the problem of minimizing those energy functions. The equivalence is in the sense that for any satisfiable well-formed formula (WFF) we can find a quadratic function that describes it, such that the set of solutions that minimizes the function is equal to the set of truth assignments that satisfy the WFF. We also show that in the same sense every quadratic energy function describes some satisfiable WFF. Algorithms are given to transform any propositional WFF into an energy function that describes it and vice versa. High-order models that use sigma-pi units are shown to be equivalent to the standard quadratic models with additional hidden units. An algorithm to convert high-order networks to low-order ones is used to implement a satisfiability problem-solver on a connectionist network. The results give better understanding of the role of hidden units and of the limitations and capabilities of symmetric connectionist models. The techniques developed for the satisfiability problem may be applied to a wide range of other problems, such as associative memories, finding maximal consistent subsets, automatic deduction, and even nonmonotonic reasoning.
Role of the Vastus Medialis Obliquus in Repositioning the Patella
Authors: Un Yeong-Fwu , Lin Jiu-Jenq , Jan Mei-Hwa , Wei Tung-Ching , Shin Hsin-Yen , Cheng Cheng-Kung 
Published: March 2008

Background It has been assumed that patellofemoral pain syndrome results from patellar malalignment. The precise role the vastus medialis obliquus plays in mediating the underlying pathologic abnormality is unclear. Hypothesis The morphologic characteristics of the vastus medialis obliquus correlate to patellar malalignment in patients with patellofemoral pain syndrome. Study Design Cross-sectional study; Level of evidence, 3. Methods One hundred twelve patients with patellofemoral pain syndrome were studied. Six sets of computed tomography axial images were assessed in which knee flexion was 0°, 15°, or 30° and the quadriceps muscle either relaxed or contracted. Measurements of serial cross-sectional areas of the vastus medialis obliquus and patellar malalignment were made. Correlation and stepwise regression models between the vastus medialis obliquus variables and patellar malalignment (lateral shift and patellar tilt) were calculated. Statistics were calculated on 4 subgroups depending on patellofemoral malalignment type. Results Significant correlations were found between measures of cross-sectional areas of vastus medialis obliquus and patellar tilt at 0° and 30° of knee flexion. Using a regression model, it was determined that vastus medialis obliquus is predictive of patellar tilt ( R 2 = 0.078–0.130). This explanation was most apparent in the subgroup of patients with extreme patellar tilt and lateral shift malalignments ( R 2 up to 0.824). Conclusion There are significant correlations between vastus medialis obliquus variables and patellar malalignments in extended knees of patients with patellofemoral pain syndrome. Clinical Relevance Vastus medialis obliquus muscle function is important to consider in the rehabilitation of patients with patellofemoral pain syndrome, especially those with extreme patellar tilt and lateral shift malalignments.
Prevention of Overuse Injuries by a Concurrent Exercise Program in Subjects Exposed to an Increase in Training Load
Authors: Brushøj Christoffer , Larsen Klaus , Albrecht-Beste Elisabeth , Nielsen Michael Bachmann , Løye Finn , Hölmich Per 
Published: March 2008

Background It is unknown whether an exercise program can prevent overuse injuries in the lower extremity. An often encountered and important risk factor for the development of lower extremity overuse injuries is an abrupt increase in activity level. Hypothesis A preventive training program based on a literature review of intrinsic risk factors, and performed concurrent with an increase in physical activity, can reduce the incidence of overuse knee injuries and medial tibial stress syndrome, as well as increase running distance. Study Design Randomized controlled trial; Level of evidence, 1. Methods A total of 1020 soldiers aged 20.9 years (range, 19–26 years) undergoing 3 months of basic military training consecutively enrolled from December 2004 to December 2005. The prevention program consisted of an exercise program of 15 minutes’ duration 3 times a week, including 5 exercises for strength, flexibility, and coordination; the placebo program consisted of 5 exercises for the upper body. Results During the observation period, 223 subjects sustained an injury, with 50 and 48 of these fulfilling the study criteria for overuse knee injuries or medial tibial stress syndrome, respectively. There were no significant differences in incidence of injury between the prevention group and the placebo group (incidence, 0.22 vs 0.19; P = .162; relative risk = 1.05 [range, 0.98–1.11]). The soldiers in the prevention group had the greater improvement in running distance in 12-minute run tests (82 vs 43 m; P = .037). Conclusion An exercise program with an emphasis on muscular strengthening, coordination, and flexibility based on intrinsic risk factors identified through a literature review did not influence the risk of developing overuse knee injuries or medial tibial stress syndrome in subjects undergoing an increase in physical activity. The program increased maximal running distance in a 12-minute test.
Nuclear translocation of urokinase-type plasminogen activator
Authors: Stepanova Victoria , Lebedeva Tatiana , Kuo Alice , Yarovoi Serge , Tkachuk Sergei , Zaitsev Sergei , Bdeir Khalil , Dumler Inna , Marks Michael S. , Parfyonova Yelena , Tkachuk Vsevolod A. , Higazi Abd Al-Roof , Cines Douglas B. 
Published: March 2008

AbstractUrokinase-type plasminogen activator (uPA) participates in diverse (patho)physiological processes through intracellular signaling events that affect cell adhesion, migration, and proliferation, although the mechanisms by which these occur are only partially understood. Here we report that upon cell binding and internalization, single-chain uPA (scuPA) translocates to the nucleus within minutes. Nuclear translocation does not involve proteolytic activation or degradation of scuPA. Neither the urokinase receptor (uPAR) nor the low-density lipoprotein-related receptor (LRP) is required for nuclear targeting. Rather, translocation involves the binding of scuPA to the nucleocytoplasmic shuttle protein nucleolin through a region containing the kringle domain. RNA interference and mutational analysis demonstrate that nucleolin is required for the nuclear transport of scuPA. Furthermore, nucleolin is required for the induction smooth muscle α-actin (α-SMA) by scuPA. These data reveal a novel pathway by which uPA is rapidly translocated to the nucleus where it might participate in regulating gene expression.
Enhanced NK-cell development and function in BCAP-deficient mice
Authors: MacFarlane Alexander W. , Yamazaki Tetsuo , Fang Min , Sigal Luis J. , Kurosaki Tomohiro , Campbell Kerry S. 
Published: March 2008

AbstractIn B lymphocytes, the B-cell adaptor for phosphatidylinositol 3-kinase (BCAP) facilitates signaling from the antigen receptor. Mice lacking BCAP have a predominantly immature pool of B cells with impaired immune function and increased susceptibility to apoptosis. Unexpectedly, we have found that natural killer (NK) cells from BCAP-deficient mice are more mature, more long-lived, more resistant to apoptosis, and exhibit enhanced functional activity compared with NK cells from wild-type mice. Surprisingly, these effects are evident despite a severe impairment of the immunoreceptor tyrosine-based activation motif-mediated Akt signaling pathway. The seemingly paradoxical phenotype reveals inherent differences in the signals controlling the final maturation of B cells and NK cells, which depend on positive and negative signals, respectively. Both enhanced interferon-γ responses and augmented maturation of NK cells in BCAP-deficient mice are independent of available MHC class I ligands. Our data support a model in which blunting of BCAP-mediated activation signaling in developing NK cells promotes functionality, terminal maturation, and long-term survival.
TNF primes endothelial cells for angiogenic sprouting by inducing a tip cell phenotype
Authors: Sainson Richard C. A. , Johnston Douglas A. , Chu Henry C. , Holderfield Matthew T. , Nakatsu Martin N. , Crampton Steven P. , Davis Jaeger , Conn Erin , Hughes Christopher C. W. 
Published: March 2008

AbstractPathological angiogenesis associated with wound healing often occurs subsequent to an inflammatory response that includes the secretion of cytokines such as tumor necrosis factor (TNF). Controversy exists on the angiogenic actions of TNF, with it being generally proangiogenic in vivo, but antiangiogenic in vitro. We find that whereas continuous administration of TNF in vitro or in vivo inhibits angiogenic sprouting, a 2- to 3-day pulse stimulates angiogenesis by inducing an endothelial “tip cell” phenotype. TNF induces the known tip cell genes platelet-derived growth factor B (PDGFB) and vascular endothelial cell growth factor receptor-2 (VEGFR2), while at the same time blocking signaling through VEGFR2, thus delaying the VEGF-driven angiogenic response. Notch signaling regulates tip cell function, and we find that TNF also induces the notch ligand jagged-1, through an NFκB-dependent mechanism. Enrichment of jagged-1 in tip cells was confirmed by immunofluorescent staining as well as by laser capture microdissection/quantitative reverse-transcription–polymerase chain reaction (qRT-PCR) of tip cells sprouting in vitro. Thus, in angiogenesis, the temporal expression of TNF is critical: it delays angiogenesis initially by blocking signaling through VEGFR2, but in addition by inducing a tip cell phenotype through an NFκB-dependent pathway, it concomitantly primes endothelial cells (ECs) for sprouting once the initial inflammatory wave has passed.
Association between the proliferative rate of neoplastic B cells, their maturation stage, and underlying cytogenetic abnormalities in B-cell chronic lymphoproliferative disorders: analysis of a series of 432 patients
Authors: Quijano Sandra , López Antonio , Rasillo Ana , Barrena Susana , Luz Sánchez Maria , Flores Juan , Fernández Carlos , Sayagués José María , Osuna Carlos Salvador , Fernández Nuria , González Marcos , Giraldo Pilar , Giralt Manuel , Pérez Maria Carmen , Martin-Antoran José Manuel , Gutiérrez Oliver , Perdiguer Luis , Díaz Mediavilla Joaquín , González Silva Manuel , Asensio del Rio Agustín , Cerveró Carlos , Guerra José Luis , Butrón Rosario , del Carmen García Maria , Almeida Julia , Orfao Alberto 
Published: March 2008

Abstract
Limited knowledge exists about the impact of specific genetic abnormalities on the proliferation of neoplastic B cells from chronic lymphoproliferative disorders (B-CLPDs). Here we analyze the impact of cytogenetic abnormalities on the proliferation of neoplastic B cells in 432 B-CLPD patients, grouped according to diagnosis and site of sampling, versus their normal counterparts. Overall, proliferation of neoplastic B cells highly varied among the different B-CLPD subtypes, the greatest numbers of proliferating cells being identified in diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). Compared with normal B cells, neoplastic B-CLPD cells showed significantly increased S + G2/M-phase values in mantle cell lymphoma (MCL), B-chronic lymphocytic leukemia (B-CLL), BL, and some DLBCL cases. Conversely, decreased proliferation was observed in follicular lymphoma, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM), and some DLBCL patients; hairy cell leukemia, splenic marginal zone, and MALT-lymphoma patients showed S + G2/M phase values similar to normal mature B lymphocytes from LN. Interestingly, in B-CLL and MCL significantly higher percentages of S + G2/M cells were detected in BM versus PB and in LN versus BM and PB samples, respectively. In turn, presence of 14q32.3 gene rearrangements and DNA aneuploidy, was associated with a higher percentage of S + G2/M-phase cells among LPL/WM and B-CLL cases, respectively.
Novel HAX1 mutations in patients with severe congenital neutropenia reveal isoform-dependent genotype-phenotype associations
Authors: Germeshausen Manuela , Grudzien Magda , Zeidler Cornelia , Abdollahpour Hengameh , Yetgin Sevgi , Rezaei Nima , Ballmaier Matthias , Grimbacher Bodo , Welte Karl , Klein Christoph 
Published: March 2008

AbstractHomozygous mutations in HAX1 cause an autosomal recessive form of severe congenital neutropenia (CN). By screening 88 patients with CN, we identified 6 additional patients with HAX1 mutations carrying 4 novel mutations. Of these, 2 affect both published transcript variants of HAX1; the other 2 mutations affect only transcript variant 1. Analysis of the patients' genotypes and phenotypes revealed a striking correlation: Mutations affecting transcript variant 1 only were associated with CN (23 of 23 patients), whereas mutations affecting both transcript variants caused CN and neurologic symptoms, including epilepsy and neurodevelopmental delay (6 of 6 patients). In contrast to peripheral blood, transcript variant 2 was markedly expressed in human brain tissue. The clinical phenotype of HAX1 deficiency appears to depend on the localization of the mutation and their influence on the transcript variants. Therefore, our findings suggest that HAX1 isoforms may play a distinctive role in the neuronal system.
CCL5-mediated T-cell chemotaxis involves the initiation of mRNA translation through mTOR/4E-BP1
Authors: Murooka Thomas T. , Rahbar Ramtin , Platanias Leonidas C. , Fish Eleanor N. 
Published: March 2008

AbstractThe multistep, coordinated process of T-cell chemotaxis requires chemokines, and their chemokine receptors, to invoke signaling events to direct cell migration. Here, we examined the role for CCL5-mediated initiation of mRNA translation in CD4+ T-cell chemotaxis. Using rapamycin, an inhibitor of mTOR, our data show the importance of mTOR in CCL5-mediated T-cell migration. Cycloheximide, but not actinomycin D, significantly reduced chemotaxis, suggesting a possible role for mRNA translation in T-cell migration. CCL5 induced phosphorylation/activation of mTOR, p70 S6K1, and ribosomal protein S6. In addition, CCL5 induced PI-3′K–, phospholipase D (PLD)–, and mTOR-dependent phosphorylation and deactivation of the transcriptional repressor 4E-BP1, which resulted in its dissociation from the eukaryotic initiation factor-4E (eIF4E). Subsequently, eIF4E associated with scaffold protein eIF4G, forming the eIF4F translation initiation complex. Indeed, CCL5 initiated active translation of mRNA, shown by the increased presence of high-molecular-weight polysomes that were significantly reduced by rapamycin treatment. Notably, CCL5 induced protein translation of cyclin D1 and MMP-9, known mediators of migration. Taken together, we describe a novel mechanism by which CCL5 influences translation of rapamycin-sensitive mRNAs and “primes” CD4+ T cells for efficient chemotaxis.
MicroRNA expression profiling in relation to the genetic heterogeneity of acute myeloid leukemia
Authors: Jongen-Lavrencic Mojca , Sun Su Ming , Dijkstra Menno K. , Valk Peter J. M. , Löwenberg Bob 
Published: March 2008

Abstract
Acute myeloid leukemia (AML) is a highly diverse disease characterized by various cytogenetic and molecular abnormalities. MicroRNAs are small noncoding RNAs that show variable expression during myeloid differentiation. MicroRNA expression in marrow blasts in 215 cases of newly diagnosed and (cyto)genetically defined AML was assessed using quantitative reverse-transcription–polymerase chain reaction (RT-PCR) for 260 human microRNAs. In the same series, mRNA gene expression profiles were established, allowing a direct comparison between microRNA and mRNA expression. We show that microRNA expression profiling following unsupervised analysis reveals distinctive microRNA signatures that correlate with cytogenetic and molecular subtypes of AML (ie, AMLs with t(8;21), t(15;17), inv(16), NPM1, and CEBPA mutations). Significantly differentially expressed microRNAs for genetic subtypes of AML were identified. Specific microRNAs with established oncogenic and tumor suppressor functions, such as microRNA-155, microRNA-21, and let-7, appear to be associated with particular subtypes. Combinations of selected sets of microRNAs could predict cytogenetically normal AML with mutations in the genes of NPM1 and CEBPA and FLT3-ITD with similar accuracy as mRNA probe set combinations defined by gene expression profiling. MicroRNA expression apparently bears specific relationships to the heterogeneous pathobiology of AML. Distinctive microRNA signatures appear of potential value in the clinical diagnosis of AML.