gebhart/patrepeval huggingface dataset:
Antileukemia activity of the novel peptidic CXCR4 antagonist LY2510924 as monotherapy and in combination with chemotherapy (2015)

Targeting the stromal cell-derived factor 1α (SDF-1α)/C-X-C chemokine receptor type 4 (CXCR4) axis has been shown to be a promising therapeutic approach to overcome chemoresistance in acute myeloid leukemia (AML). We investigated the antileukemia efficacy of a novel peptidic CXCR4 antagonist, LY2510924, in preclinical models of AML. LY2510924 rapidly and durably blocked surface CXCR4 and inhibited stromal cell-derived factor 1 (SDF-1)α-induced chemotaxis and prosurvival signals of AML cells at nanomolar concentrations more effectively than the small-molecule CXCR4 antagonist AMD3100. In vitro, LY2510924 chiefly inhibited the proliferation of AML cells with little induction of cell death and reduced protection against chemotherapy by stromal cells. In mice with established AML, LY2510924 caused initial mobilization of leukemic cells into the circulation followed by reduction in total tumor burden. LY2510924 had antileukemia effects as monotherapy as well as in combination with chemotherapy. Gene expression profiling of AML cells isolated from LY2510924-treated mice demonstrated changes consistent with loss of SDF-1α/CXCR4 signaling and suggested reduced proliferation and induction of differentiation, which was proved by showing the attenuation of multiple prosurvival pathways such as PI3K/AKT, MAPK, and β-catenin and myeloid differentiation in vivo. Effective disruption of the SDF-1α/CXCR4 axis by LY2510924 may translate into effective antileukemia therapy in future clinical applications.
Chemical probes for anion transporters of mammalian cell membranes (1992)

Mammalian cell membranes harbor several types of chloride channels, chloride-cation symporters/cotransporters, and several classes of anion exchangers/antiporters. These transport systems subserve different cellular or organismic functions, depending on the nature of the cell, the spatial organization of transporters, and their functional interplay. Chemical probing has played a central role in the structural and functional delineation of the various anion transport systems. The design of specific probes or their selection from existing sources coupled with their judicious application to the most appropriate biological system had led to the identification of specific anion transporters and to the elucidation of the underlying molecular transport mechanism. In many instances, chemical probing has remained the major or exclusive analytical tool for the functional definition or identification of a given transport system, particularly for discerning among the various anion transporters which operate in highly heterogeneous cell membrane systems. This work critically reviews the present state of the chemical armamentarium available for the most common anion transporters found in mammalian cell membranes. It encompasses the description of the most useful or commonly used probes in terms of their chemical, biochemical, physiological, and pharmacological properties. The review deals primarily with what chemical probes tell about anion transporters and, most importantly, with the limitations inherent in the use of probes in transport studies.
The CD28-B7 Family in Anti-Tumor Immunity: Emerging Concepts in Cancer Immunotherapy (2014)

The interactions between B7 molecules and CD28-family receptors are crucial in the regulation of adaptive cellular immunity. In cancer, the aberrant expression of co-inhibitory B7 molecules has been attributed to reduced anti-tumor immunity and cancer immune evasion, prompting the development of cancer therapeutics that can restore T cell function. Murine tumor models have provided significant support for the targeting of multiple immune checkpoints involving CTLA-4, PD-1, ICOS, B7-H3 and B7-H4 during tumor growth, and clinical studies investigating the therapeutic effects of CTLA-4 and PD-1 blockade have shown exceptionally promising results in patients with advanced melanoma and other cancers. The expression pattern of co-inhibitory B7 ligands in the tumor microenvironment has also been largely correlated with poor patient prognosis, and recent evidence suggests that the presence of several B7 molecules may predict the responsiveness of immunotherapies that rely on pre-existing tumor-associated immune responses. While monotherapies blocking T cell co-inhibition have beneficial effects in reducing tumor burden, combinatorial immunotherapy targeting multiple immune checkpoints involved in various stages of the anti-tumor response has led to the most substantial impact on tumor reduction. In this review, we will examine the contributions of B7- and CD28-family members in the context of cancer development, and discuss the implications of current human findings in cancer immunotherapy.
Enhanced Immune Responses in Transgenic Mice Expressing a Truncated Form of the Lymphocyte Semaphorin CD100 (2001)

Abstract CD100/Sema4D is a 150-kDa transmembrane protein that belongs to the semaphorin family. Binding of CD100 to CD72 enhances the immune response by turning off the negative signaling effects of CD72. To investigate the physiological functions of CD100 in vivo, we generated transgenic mice expressing a truncated form of CD100. A large amount of the soluble form of CD100 was detected in the sera of mice expressing a truncated form of CD100, although the amount of CD100 was only slightly elevated on the surface of B cells. In the mutant mice the development of conventional B and T cells appeared normal in terms of the surface marker phenotypes, while the number of CD5+ B-1 cells in the peritoneal cavity increased in comparison with wild-type mice. In vitro proliferation and Ig production of B cells in response to CD40 stimulation were considerably enhanced in mice expressing a truncated form of CD100. Additionally, in vivo both Ab responses against T cell-dependent Ags and generation of Ag-specific T cells were enhanced. Furthermore, introduction of the CD100-transgene could restore in vitro B cell responses as well as in vivo Ab production against T cell-dependent Ag in CD100-deficient mice. Collectively, these results not only indicate that CD100 has an important role in the immune system, but also that the soluble form of CD100 released from the cell surface can exert functions in vivo.
Neoadjuvant hormonal manipulation: A strategy for chemoprevention trials (1992)

Androgen ablation using hormonal manipulation is used extensively in metastatic prostate cancer; however, its use in localized disease combined with surgical extirpation of the gland has not been thoroughly and systematically investigated. The rationale for neoadjuvant therapy stems from the demonstrated effectiveness of androgen ablative therapy in metastatic disease and the high rate of "positive" surgical margins, especially in patients with Stage B2 disease. In addition, the essentially anecdotal clinical report of Scott and Boyd [1], using endocrine therapy plus radical prostatectomy in patients with Stage C disease, gives 15 year survival results comparable to those obtained by Jewett [2] in Stage 1 patients treated by radical prostatectomy. Finally, experimental observations in the androgen-sensitive mammary tumor (Shionogi) lend support to the concept of neoadjuvant hormonal manipulation. A pilot study of neoadjuvant endocrine therapy in 55 patients treated at Memorial Sloan-Kettering Cancer Center with 3 months of diethylstilbestrol (DES) (3 mg/day) prior to radical prostatectomy indicates marked reductions in prostate-specific antigen (PSA), although persistent evidence of adverse local tumor features was common. Some patients, however, exhibited evidence of significant downstaging. Whether or not any alteration in disease progression will accrue from demonstrated local downstaging is, of course, uncertain. However, clinical and laboratory effects of such treatment may provide a means for correlation with subsequent tumor behavior, and may prove useful in treatment decisions. Additionally, a decrease in the number of foci of grade 3 prostatic intraepithelial neoplasia (PIN-3) was noted in a small number of patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Proteases Involved in Erythrocyte Invasion by the Malaria Parasite Function and Potential as Chemotherapeutic Targets (2000)

Malaria places an increasing burden on global public health resources. In the face of growing resistance of the malaria parasite to available antimalarial drugs, there is a need for new drugs and the identification of new chemotherapeutic targets. The malaria parasite has a complex life cycle which includes a number of obligate intracellular stages. Clinical malaria results from cyclic asexual replication of the blood-stage parasite in circulating erythrocytes of the human host. Erythrocyte entry and host cell rupture require the activity of parasite proteases, and these enzymes are, therefore, attractive targets for rational approaches to new drug development. Malarial proteases play a role in at least two distinct aspects of host cell invasion; modification of parasite proteins involved in host cell recognition and entry; and restructuring of the host cell itself, during and following invasion, and in order to allow parasite release from the host cell. This review details recent advances in the identification of these proteases, describes current understanding of their activation and functional role, and discusses their potential as targets for protease inhibitor-based drugs.
A novel erasing technology for 3.3 V flash memory with 64 Mb capacity and beyond (1992)

A novel erasing scheme has been developed to suppress the distribution of the erased cell threshold voltage (erased-V). The new 2-step erasing scheme consists of two steps of the cell gate bias conditions, that is to apply 1) negative high voltage on the control gate to erase the cell data, and successive 2) positive high voltage to inject a few electrons from the substrate back to the floating gate. The suppressing effect of the erased-V distribution was also confirmed using a 16 Kbit flash memory cell array, the erased-V/sub /distribution drastically decreases from 2.0 V by the conventional erasing scheme to 0.9 V using the 2-step erasing scheme.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Signal and noise in magneto-optical readout (1982)

For a magneto-optical readout system which uses the Kerr effect, the power spectral density of the read signal has been derived. The noise components originating in the photodetection and amplification stages appear as additive terms in the expression for the overall spectral density, enabling us to define a signal to noise ratio for the readout system. Adjustable parameters of the system are then optimized and a multilayer disk structure is introduced which enhances the Kerr effect and, consequently, results in an increased signal to noise ratio.
Biocompatibility of Gold Nanoparticles and Their Endocytotic Fate Inside the Cellular Compartment: A Microscopic Overview (2005)

Macrophages are one of the principal immune effector cells that play essential roles as secretory, phagocytic, and antigen-presenting cells in the immune system. In this study, we address the issue of cytotoxicity and immunogenic effects of gold nanoparticles on RAW264.7 macrophage cells. The cytotoxicity of gold nanoparticles has been correlated with a detailed study of their endocytotic uptake using various microscopy tools such as atomic force microscopy (AFM), confocal-laser-scanning microscopy (CFLSM), and transmission electron microscopy (TEM). Our findings suggest that Au(0) nanoparticles are not cytotoxic, reduce the production of reactive oxygen and nitrite species, and do not elicit secretion of proinflammatory cytokines TNF-alpha and IL1-beta, making them suitable candidates for nanomedicine. AFM measurements suggest that gold nanoparticles are internalized inside the cell via a mechanism involving pinocytosis, while CFLSM and TEM studies indicate their internalization in lysosomal bodies arranged in perinuclear fashion. Our studies thus underline the noncytotoxic, nonimmunogenic, and biocompatible properties of gold nanoparticles with the potential for application in nanoimmunology, nanomedicine, and nanobiotechnology.
Sustained Release Intravitreal Dexamethasone (1996)

Sustained intravitreal levels of dexamethasone may be useful in the treatment of proliferative vitreoretinopathy (PVR). The preparation and evaluation of an implantable system for intravitreal sustained release of dexamethasone is described. Pellets of dexamethasone were coated in biocompatible, nonerodible polymers and the release rate tested in vitro. Devices were then implanted in the rabbit vitreous and the in vivo release rate and corresponding steady state vitreous concentration determined. Toxicity was also evaluated by histopathology and electrographic examination. Devices released dexamethasone at approximately 1 ug/hr in vitro and 1.5 ug/hr in vivo. When implanted into the vitreous intravitreal concentrations of approximately 2.5 +/- 1.2 ug/hr were maintained for over 3 months. Devices were well tolerated with no evidence of inflammation or retinal abnormalities.
C‐type lectin‐like receptors on myeloid cells (2006)

Host defence against pathogens requires the recognition of conserved microbial molecules, or 'pathogen-associated molecular patterns' (PAMPs), by their receptors termed 'pattern recognition receptors' (PRRs), represented most notably by toll-like receptors (TLRs) and C-type lectins. The 'non-classical' C-type lectins (these that lack the residues involved in calcium binding, required for carbohydrate binding) are traditionally thought of as being restricted to natural killer (NK) or T cells, playing important roles in immune surveillance. In recent years, however, a growing number of these receptors have been identified on myeloid cells, both of human and mouse origin. In contrast to their NK counterparts that primarily control cellular activation through recognition of major histocompatibility antigen (MHC) class I and related molecules, the myeloid-expressed receptors appear to have a far more diverse range of functions and ligands, including those of exogenous origin. Some of C-type lectin-like molecules possess activating/inhibitory signalling motifs that trigger downstream signalling events, suggesting the role for these receptors as positive/negative regulators of granulocyte and monocyte functions. With the exception of a few myeloid NK-like lectins, the natural ligands for most of these receptors remain unidentified, making it difficult to define their functions in normal physiological, inflammatory or pathological conditions. Importantly, in some cases, these novel C-type lectin-like lectins, encoded by genes from the same gene cluster, can act as receptor/ligand pairs, additionally contributing to the regulation of myeloid cell functions or their interaction with other (like NK) cell types. However, the relevance and importance of such interactions still needs to be assessed. Although few of the myeloid-expressed C-type lectins have been characterized in detail, we review here each of these receptors and highlight their prospective roles in innate and adaptive immunity.
Iodine-Mediated Guanidine Formation through Arylsulfonyl-Activated Thioureas (2009)

Reaction of arylsulfonyl thioureas with amines to form guanidines can be efficiently promoted through the use of iodine, instead of conventional reagents such as the Mukaiyama reagent or EDC. The general scope and limitations of the reaction are probed.
Notch1-Induced Delay of Human Hematopoietic Progenitor Cell Differentiation Is Associated With Altered Cell Cycle Kinetics (1999)

Hematopoiesis is a balance between proliferation and differentiation that may be modulated by environmental signals. Notch receptors and their ligands are highly conserved during evolution and have been shown to regulate cell fate decisions in multiple developmental systems. To assess whether Notch1 signaling may regulate human hematopoiesis to maintain cells in an immature state, we transduced a vesicular stomatitis virus G-protein (VSV-G) pseudo-typed bicistronic murine stem cell virus (MSCV)-based retroviral vector expressing a constitutively active form of Notch1 (ICN) and green fluorescence protein into the differentiation competent HL-60 cell line and primary cord blood-derived CD34(+) cells. In addition, we observed endogenous Notch1 expression on the surface of both HL-60 cells and primary CD34(+) cells, and therefore exposed cells to Notch ligand Jagged2, expressed on NIH3T3 cells. Both ligand-independent and ligand-dependent activation of Notch resulted in delayed acquisition of differentiation markers by HL-60 cells and cord blood CD34(+) cells. In addition, primary CD34(+) cells retained their ability to form immature colonies, colony-forming unit-mix (CFU-mix), whereas control cells lost this capacity. Activation of Notch1 correlated with a decrease in the fraction of HL-60 cells that were in G0/G1 phase before acquisition of a mature cell phenotype. This enhanced progression through G1 was noted despite preservation of the proliferative rate of the cells and the overall length of the cell cycle. These findings show that Notch1 activation delays human hematopoietic differentiation and suggest a link of Notch differentiation effects with altered cell cycle kinetics.
A mechanism for the proarrhythmic effects of cisapride (Propulsid): high affinity blockade of the human cardiac potassium channel HERG (1997)

Cisapride (Propulsid) is a gastrointestinal prokinetic agent commonly used to treat nocturnal heartburn as well as a variety of other gastrointestinal disorders. The use of cisapride has been associated with acquired long QT syndrome and ventricular arrhythmias such as torsades de pointes which produces sudden cardiac death. These cardiotoxic effects can be due to blockade of one or more types of K+ channel currents in the human heart. For this reason we compared the effects of cisapride on two cloned human cardiac K+ channels, Kv1.5 and the human ether-a-go-go-related gene (HERG) stably transfected into mammalian cells. Using patch clamp electrophysiology, we found that cisapride was a potent inhibitor of HERG displaying an IC50 value of 44.5 nmol/l when tail currents at -40 mV were measured following a 2 s test depolarization to +20 mV. When HERG currents were measured at the end of prolonged (20 s) depolarizing steps to +20 mV, the apparent affinity of cisapride was increased and measured 6.70 nmol/l. The main effect of cisapride was to enhance the rate of HERG current decay thereby reducing current at the end of the voltage clamp pulse. Furthermore, the potency of cisapride for the HERG channel was similar to that observed for the class III antiarrhythmic agent dofetilide (IC50 = 15.3 nmol/l) and the nonsedating antihistamine terfenadine (IC50 = 56.0 nmol/l). In contrast to its effects on HERG, cisapride inhibited Kv1.5 channel currents weakly displaying an IC50 value of 21.2 micromol/l. It is concluded that cisapride displays specific, high affinity block of the human cardiac K+ channel HERG. It is likely that this interaction underlies the proarrhythmic effects of the drug observed under certain clinical settings.
Extracellular matrix and its receptors during development (1995)

Extracellular matrix (ECM) components are essential for morphogenesis of virtually all tissues. The ECM interacts with the cell surface by binding to specific receptors. The first family of receptors for the ECM that was identified was the integrin family. Integrins are composed of an alpha and a beta-chain, both of which are single pass transmembrane proteins. In muscle cells the dystroglycan complex forms another important receptor system for ECM. It is a complex composed of many proteins. Recent studies have shown that dystroglycan is expressed by embryonic epithelial cells as well. The nature of constituents of the dystroglycan complex is well known for muscle, whereas the detailed composition of the dystroglycan complex in embryonic epithelium is not yet well known. We here review the evidence that binding of ECM to integrins and the dystroglycan complex could be essential for muscle and epithelial cell development and function. It is likely that integrins and the dystroglycan complex have distinct roles during development. It will be an interesting task to study the signal transduction pathways elicited by the interactions between ECM and the two receptor systems during muscle and epithelial morphogenesis.
Mapping Nanoscale Electrochemistry of Individual Single-Walled Carbon Nanotubes (2013)

We introduce a multiprobe platform for the investigation of single-walled carbon nanotubes (SWNTs) that allows the electrochemical response of an individual SWNT to be mapped at high spatial resolution and correlated directly with the intrinsic electronic and structural properties. With this approach, we develop a detailed picture of the factors controlling electrochemistry at SWNTs and propose a definitive model that has major implications for future architectures of SWNT electrode devices.
Hematin-Catalyzed Polymerization of Phenol Compounds (2000)

The oxidative dehydrogenation of phenol compounds, as well as polymer formation from these monomers, was studied by UV−vis and Mössbauer spectroscopy using a novel biological catalyst hematin. The mechanism of the polymerization reaction was also followed in various pH environments. Phenol radicals were formed by a two-step electron transfer reaction catalyzed by hematin in the presence of peroxide, and polymer was formed from phenol radicals by a noncatalytic reaction. This mechanism partially explains the analogous catalytic polymerization activity of horseradish peroxidase.
A Partial Failure of Membrane Protein Turnover May Cause Alzheimers Disease: A New Hypothesis (2006)

The amyloid hypothesis has dominated the thinking in our attempts to understand, diagnose and develop drugs for Alzheimer's disease (AD). This article presents a new hypothesis that takes into account the numerous familial AD (FAD) mutations in the amyloid precursor protein (APP) and its processing pathways, but suggests a new perspective beyond toxicity of forms of the amyloid beta-peptide (Abeta). Clearly, amyloid deposits are an invariable feature of AD. Moreover, although APP is normally processed to secreted and membrane-bound fragments, sAPPbeta and CTFbeta, by BACE, and the latter is subsequently processed by gamma-secretase to Abeta and CTFgamma, this pathway mostly yields Abeta of 40 residues, and increases in the levels of the amyloidogenic 42-residue Abeta (Abeta42) are seen in the majority of the mutations linked to the disease. The resulting theory is that the disease is caused by amyloid toxicity, which impairs memory and triggers deposition of the microtubule associated protein, Tau, as neurofibrillary tangles. Nevertheless, a few exceptional FAD mutations and the presence of large amounts of amyloid deposits in a group of cognitively normal elderly patients suggest that the disease process is more complex. Indeed, it has been hard to demonstrate the toxicity of Abeta42 and the actual target has been shifted to small oligomers of the peptide, named Abeta derived diffusible ligands (ADDLs). Our hypothesis is that the disease is more complex and caused by a failure of APP metabolism or clearance, which simultaneously affects several other membrane proteins. Thus, a traffic jam is created by failure of important pathways such as gamma-secretase processing of residual intramembrane domains released from the metabolism of multiple membrane proteins, which ultimately leads to a multiple system failure. In this theory, toxicity of Abeta42 will only contribute partially, if at all, to neurodegeneration in AD. More significantly, this theory would predict that focussing on specific reagents such as gamma-secretase inhibitors that hamper metabolism of APP, may initially show some beneficial effects on cognitive performance by elimination of acutely toxic ADDLs, but over the longer term may exacerbate the disease process by reducing membrane protein turnover.