gebhart/patrepeval huggingface dataset:
Cancer immunotherapy (2006)

Cancer is the second leading cause of death in the industrialized world. Most cancer patients are treated by a combination of surgery, radiation and/or chemotherapy. Whereas the primary tumor can, in most cases, be efficiently treated by a combination of these standard therapies, preventing the metastatic spread of the disease through disseminated tumor cells is often not effective. The eradication of disseminated tumor cells present in the blood circulation and micro-metastases in distant organs therefore represents another promising approach in cancer immunotherapy. Main strategies of cancer immunotherapy aim at exploiting the therapeutic potential of tumor-specific antibodies and cellular immune effector mechanisms. Whereas passive antibody therapy relies on the repeated application of large quantities of tumor antigen-specific antibodies, active immunotherapy aims at the generation of a tumor-specific immune response combining both humoral and cytotoxic T cell effector mechanisms by the host's immune system following vaccination. In the first part of this review, concurrent developments in active and passive cancer immunotherapy are discussed. In the second part, the various approaches for the production of optimized monoclonal antibodies used for anti-cancer vaccination are summarized.
Results of a Low-Background Measurement of the Fission Neutron Spectrum from252Cf in the 9- to 29-MeV Energy Range (1990)

AbstractBy means of a time-of-flight experiment, the high-energy part of the 252Cf fission neutron spectrum is investigated with excellent shielding against cosmic radiation. Data analysis was performed with four different bias settings and results in the 9- to 29-MeV energy range were obtained. Small deviations from the Maxwellian shape (T = 1.42 MeV) were found; however, no indication of any neutron excess above 20 MeV was found.
Synthesis and characterization of a hyper-branched water-soluble β-cyclodextrin polymer (2014)

A new hyper-branched water-soluble polymer was synthesized by reacting β-cyclodextrin with pyromellitic dianhydride beyond the critical conditions that allow the phenomenon of gelation to occur. The molar ratio between the monomers is a crucial parameter that rules the gelation process. Nevertheless, the concentration of monomers in the solvent phase plays a key role as well. Hyper-branched β-cyclodextrin-based polymers were obtained performing the syntheses with excess of solvent and cross-linking agent, and the conditions for critical dilution were determined experimentally. A hyper-branched polymer with very high water solubility was obtained and fully characterized both as for its chemical structure and for its capability to encapsulate substances. Fluorescein was used as probe molecule to test the complexation properties of the new material.
Studies of Cytokinin Action and Metabolism Using Tobacco Plants Expressing either the ipt or the GUS Gene Controlled by a Chalcone Synthase Promoter. II ipt and GUS Gene Expression, Cytokinin Levels and Metabolism (1997)

The expression of GUS and ipt genes under control of a chalcone synthase ( chs ) promoter (PCHS) has been determined in tobacco ( Nicotiana tabacum L.) plants and related to the development of plants expressing the chimaeric PCHS - ipt gene. GUS gene expression, which served as a model for the expression of the ipt gene, was highest in the internal phloem tissue of stems, in mature leaf laminae and in the upper part of corollas when fully open. Expression of the PCHS - ipt gene was assessed by quantifying the cytokinins produced, by determining incorporation of [3H]adenine into cytokinins and by quantifying ipt mRNA. Results from these studies were in general agreement with those based on expression of the PCHS - GUS gene. The chs promoter controlled expression of the ipt gene with some degree of tissue and temporal specificity. Expression of the ipt gene markedly elevated the cytokinin level in mature leaf laminae and the upper stems of flowering plants. The former was associated with retardation of leaf senescence and increased rates of transpiration due to changes in number, size and aperture of stomata, while the latter was associated with development of lateral shoots. In shoot tip cultures, 2-fold elevations in endogenous cytokinin level caused clear changes in development and this is discussed in relation to current concepts concerning the hormonal control of plant development. Using the transgenic tobacco tissues, it was shown that cis -zeatin is a substrate for cytokinin oxidase, that cis -zeatin is not converted to trans -zeatin in these tissues and that the endogenous cytokinin level influences the level of cytokinin oxidase activity in tissue and the rate of degradation of exogenous zeatin riboside to adenosine.
Recognition of Membrane-Bound Fusion-Peptide/MPER Complexes by the HIV-1 Neutralizing 2F5 Antibody: Implications for Anti-2F5 Immunogenicity (2012)

The membrane proximal external region (MPER) of the fusogenic HIV-1 glycoprotein-41 harbors the epitope sequence recognized by 2F5, a broadly neutralizing antibody isolated from an infected individual. Structural mimicry of the conserved MPER 2F5 epitope constitutes a pursued goal in the field of anti-HIV vaccine development. It has been proposed that 2F5 epitope folding into its native state is attained in the vicinity of the membrane interface and might involve interactions with other viral structures. Here we present results indicating that oligomeric complexes established between MPER and the conserved amino-terminal fusion peptide (FP) can partition into lipid vesicles and be specifically bound by the 2F5 antibody at their surfaces. Cryo-transmission electron microscopy of liposomes doped with MPER:FP peptide mixtures provided the structural grounds for complex recognition by antibody at lipid bilayer surfaces. Supporting the immunogenicity of the membrane-bound complex, these MPER:FP peptide-vesicle formulations could trigger cross-reactive anti-MPER antibodies in rabbits. Thus, our observations suggest that contacts with N-terminal regions of gp41 may stabilize the 2F5 epitope as a membrane-surface antigen.
Mitochondria and apoptosis: emerging concepts (2015)

As mitochondria are the powerhouses of the cell, their damage during the cell suicide process of apoptosis is essentially responsible for cellular demise in most cells. A key family of proteins, the B-cell lymphoma-2 (BCL-2) family, determines the integrity of mitochondria in the face of apoptotic insult. A comprehensive understanding of the molecular details of how apoptosis is initiated and how it culminates is essential if apoptosis is to fulfil its undoubted potential as a therapeutic target to treat diseases ranging from cancer to neurodegenerative conditions. Recent advances have provided significant insight into the control of this fundamental process while prompting a re-evaluation of what was considered dogma in the field. Emerging evidence also points to a potential overarching control network that governs not only apoptosis but other fundamental mitochondrial processes, including mitochondrial fission/fusion and quality control.
Ventriculostomy infections: the effect of monitoring duration and catheter exchange in 584 patients (1996)

The investigators undertook a retrospective analysis of ventriculostomy infections to evaluate their relationship to monitoring duration and prophylactic catheter exchange. In 1984, the results of an epidemiological study of ventriculostomy-related infection were published. One of the conclusions of the paper was that the incidence of ventriculostomy-related infections rose after 5 days of monitoring. This led to the recommendation that catheters be prophylactically changed at 5-day intervals if prolonged monitoring was required. A recent randomized prospective study on central venous catheters showed no reduction in infection with prophylactic catheter exchanges. This has led the authors to reexamine their experience with ventriculostomy infections. Data on 584 severely head injured patients with ventriculostomies were prospectively collected in two data banks, The Traumatic Coma Data Bank and The Medical College of Virginia Neurocore Data Bank. These data were retrospectively analyzed for factors associated with ventriculostomy related infections. It was found that there is a relationship of ventriculitis to monitoring duration but it is not simple or linear. There is a rising risk of infection over the first 10 days, but infection then becomes very unlikely despite a population that continues to be at risk. Patients in whom catheters were replaced prior to 5 days did not have a lower infection rate than those whose catheters were exchanged at more than 5-day intervals. Based on these data, it is recommended that ventriculostomy catheters for intracranial pressure monitoring be removed as quickly as possible, and in circumstances in which prolonged monitoring is required, there appears to be no benefit from catheter exchange.
Nucleation of microcellular foam: Theory and practice (1987)

Abstract Microcellular polymer foams exhibit greatly improved mechanical properties as compared to standard foams due to the formers' small bubble size. Microcellular foams have bubbles with diameters on the order of 10 microns, volume reductions of 30 to 40 percent, and six or seven times the impact strength of solid parts. They are produced through the use of thermodynamic instabilities without the use of foaming agents. This method leads to a very uniform cell size throughout a part's cross section. A theoretical model for the nucleation of microcellular foams in thermoplastic polymers has been developed and experimentally confirmed. This model explains the effect of various additives and processing conditions on the number of bubbles nucleated. At levels of secondary constituents below their solubility limits, an increase in the concentration of the additive or the concentration of gas in solution with the polymer increases the number of bubbles nucleated. Nucleation in this region is homogeneous. Above the solubility limit of additives, nucleation is heterogeneous and takes place at the interface between second phase inclusions and the polymer. The number of bubbles nucleated is dependent on the concentration of heterogeneous nucleation sites and their relative effect on the activation energy barrier to nucleation. In the vicinity of the solubility limit, the two mechanisms compete.
Studies of Ebola Virus Glycoprotein-Mediated Entry and Fusion by Using Pseudotyped Human Immunodeficiency Virus Type 1 Virions: Involvement of Cytoskeletal Proteins and Enhancement by Tumor Necrosis Factor Alpha (2004)

The Ebola filoviruses are aggressive pathogens that cause severe and often lethal hemorrhagic fever syndromes in humans and nonhuman primates. To date, no effective therapies have been identified. To analyze the entry and fusion properties of Ebola virus, we adapted a human immunodeficiency virus type 1 (HIV-1) virion-based fusion assay by substituting Ebola virus glycoprotein (GP) for the HIV-1 envelope. Fusion was detected by cleavage of the fluorogenic substrate CCF2 by beta-lactamase-Vpr incorporated into virions and released as a result of virion fusion. Entry and fusion induced by the Ebola virus GP occurred with much slower kinetics than with vesicular stomatitis virus G protein (VSV-G) and were blocked by depletion of membrane cholesterol and by inhibition of vesicular acidification with bafilomycin A1. These properties confirmed earlier studies and validated the assay for exploring other properties of Ebola virus GP-mediated entry and fusion. Entry and fusion of Ebola virus GP pseudotypes, but not VSV-G or HIV-1 Env pseudotypes, were impaired in the presence of the microtubule-disrupting agent nocodazole but were enhanced in the presence of the microtubule-stabilizing agent paclitaxel (Taxol). Agents that impaired microfilament function, including cytochalasin B, cytochalasin D, latrunculin A, and jasplakinolide, also inhibited Ebola virus GP-mediated entry and fusion. Together, these findings suggest that both microtubules and microfilaments may play a role in the effective trafficking of vesicles containing Ebola virions from the cell surface to the appropriate acidified vesicular compartment where fusion occurs. In terms of Ebola virus GP-mediated entry and fusion to various target cells, primary macrophages proved highly sensitive, while monocytes from the same donors displayed greatly reduced levels of entry and fusion. We further observed that tumor necrosis factor alpha, which is released by Ebola virus-infected monocytes/macrophages, enhanced Ebola virus GP-mediated entry and fusion to human umbilical vein endothelial cells. Thus, Ebola virus infection of one target cell may induce biological changes that facilitate infection of secondary target cells that play a key role in filovirus pathogenesis. Finally, these studies indicate that pseudotyping in the HIV-1 virion-based fusion assay may be a valuable approach to the study of entry and fusion properties mediated through the envelopes of other viral pathogens.
Has the rising placebo response impacted antidepressant clinical trial outcome? Data from the US Food and Drug Administration 1987‐2013 (2017)

More than fifteen years ago, it was noted that the failure rate of antidepressant clinical trials was high, and such negative outcomes were thought to be related to the increasing magnitude of placebo response. However, there is considerable debate regarding this phenomenon and its relationship to outcomes in more recent antidepressant clinical trials. To investigate this, we accessed the US Food and Drug Administration (FDA) reviews for sixteen antidepressants (85 trials, 115 trial arms, 23,109 patients) approved between 1987 and 2013. We calculated the magnitude of placebo and antidepressant responses, antidepressant-placebo differences, as well as the effect sizes and success rates, and compared these measures over time. Exploratory analysis investigated potential changes in trial design and conduct over time. As expected, the magnitude of placebo response has steadily grown in the past 30 years, increasing since 2000 by 6.4% (r=0.46, p<0.001). Contrary to expectations, a similar increase has occurred in the magnitude of antidepressant response (6.0%, r=0.37, p<0.001). Thus, the effect sizes (0.30 vs. 0.29, p=0.42) and the magnitude of antidepressant-placebo differences (10.5% vs. 10.3%, p=0.37) have remained statistically equivalent. Furthermore, the frequency of positive trial arms has gone up in the past 15 years (from 47.8% to 63.8%), but this difference in frequency has not reached statistical significance. Trial design features that were previously associated with a possible lower magnitude of placebo response were not implemented, and their relationship to the magnitude of placebo response could not be replicated. Of the 34 recent trials, two implemented enhanced interview techniques, but both of them were unsuccessful. The results of this study suggest that the relationship between the magnitude of placebo response and the outcome of antidepressant clinical trials is weak at best. These data further indicate that antidepressant-placebo differences are about the same for all of the sixteen antidepressants approved by the FDA in the past thirty years.
Brain and gastrointestinal cholecystokinin receptor family: structure and functional expression. (1992)

Cholecystokinin was one of the first gastrointestinal peptides discovered in the mammalian brain. In the central nervous system there is evidence for CCKA and CCKB receptor subtypes. The CCKA receptors occur in a few localized areas of the central and peripheral nervous systems where they modulate feeding and dopamine-induced behavior. CCKB receptors occur throughout the central nervous system where they modulate anxiety, analgesia, arousal, and neuroleptic activity. We have recently purified and cloned a CCKA receptor cDNA from rat pancreas that allowed isolation of an identical cDNA from rat brain by using the polymerase chain reaction. Using low-stringency hybridization screening of cDNA libraries from rat brain and AR42-J cells, which possess large numbers of CCKB receptors, we identified previously unreported cDNAs, the sequence of which were identical in both tissues. The cDNA sequence encodes a 452-amino acid protein that is 48% identical to the CCKA receptor and contains seven transmembrane domains characteristics of guanine nucleotide-binding regulatory protein-coupled receptors. COS-7 cells transfected with this cDNA expressed binding sites for agonists and antagonists characteristic of a CCKB receptor subtype. We conclude that this cDNA isolated from rat brain and AR42-J cells is a receptor of the CCKB subtype and that the respective cDNAs for both CCKA and CCKB are identical in the brain and gastrointestinal system.
The Natriuretic Peptides in Heart Failure: Diagnostic and Therapeutic Potentials (1999)

The natriuretic peptides are a group of structurally similar but genetically distinct peptides that have diverse actions in cardiovascular, renal, and endocrine homeostasis. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are of myocardial cell origin and C-type natriuretic peptide (CNP) is of endothelial origin. ANP and BNP bind to the natriuretic peptide-A receptor (NPR-A), which, via 3',5'-cyclic guanosine monophosphate (cGMP), mediates natriuresis, vasodilation, renin inhibition, antimitogenesis, and lusitropic properties. CNP lacks natriuretic actions but possesses vasodilating and growth-inhibiting actions via the guanylyl cyclase-linked natriuretic peptide-B receptor (NPR-B). All three peptides are cleared by the natriuretic peptide-C receptor (NPR-C) and are degraded by the ectoenzyme neutral endopeptidase 24.11 (NEP), both of which are widely expressed in the kidneys, lungs, and the vascular wall. Congestive heart failure (CHF) represents a pathological state in which the activation of the natriuretic peptides exceeds those of all other states. In this brief review, we will attempt to provide an update on important issues regarding natriuretic peptides in CHF, with a focus on their functional importance as a beneficial humoral response in asymptomatic left ventricular dysfunction (LVD), the mechanisms of natriuretic peptide hyporesponsiveness in severe heart failure, the diagnostic and prognostic significance of the natriuretic peptides in CHF, and the therapeutic potential of the natriuretic peptides in this multiorgan syndrome.
Cytokine expression during early and late phase of acute Puumala hantavirus infection (2011)

High expression of cytokines activating T-lymphocytes, monocytes and macrophages in the early phase of disease supports the hypothesis of an immune-mediated pathogenesis. In the late phase of disease, immunosuppressive TGF-β1 level increase significantly. We suggest that delayed induction of a protective immune mechanism to downregulate a massive early pro-inflammatory immune response might contribute to the pathologies characteristic of human hantavirus infection.
Nonstoquastic Hamiltonians and quantum annealing of an Ising spin glass (2017)

Quantum annealers are computing machines that utilize quantum effects to solve hard optimization problems. Understanding the circumstances under which quantum annealers are more efficient than other optimization methods is a challenging open problem. A clue to this conundrum comes from studying the complexity of quantum annealers. In general, the complexity of a physical system relates to how efficiently the system can be simulated by classical algorithms. One then asks: if some class of quantum annealers are hard to simulate classically, are they also more powerful optimization machines? Here, the authors study quantum annealers belonging to two different complexity classes: the so-called ``stoquastic'' systems, which can be efficiently simulated with classical algorithms, and ``nonstoquastic'' systems, currently with no efficient classical treatment. Applied to a prototypical optimization problem, the authors observe that, on average, the stoquastic systems perform better on easier instances of the problem, while the more complex nonstoquastic annealers show significant advantage when applied to the hardest instances. The authors conjecture that the performance of the nonstoquastic Hamiltonians is closely related to their internal structure during the annealing process and elucidate how properties such as magnetic frustration can play a key role in devising more powerful quantum annealers.
The diagnosis of multiple sclerosis and the clinical subtypes (2009)

The diagnosis of multiple sclerosis (MS) requires objective findings referable to the central nervous system. A wide differential diagnosis often has to be considered. Magnetic resonance imaging and electrophysiologic and cerebrospinal fluid studies can all contribute to an early definitive diagnosis. The McDonald diagnostic criteria for MS (2005) are the currently recognized MS diagnostic criteria. The clinical subtypes of MS and their diagnosis are discussed in this article. Being informed of the diagnosis may be a stressful experience for the patient and this is also dealt with.
Mini‐review: The nuclear protein HMGB1 as a proinflammatory mediator (2004)

Abstract The intranuclear architectural protein that is termed high mobility group box chromosomal protein 1 (HMGB1) was recently identified as a potent proinflammatory mediator when present extracellularly. HMGB1 has been demonstrated to be a long‐searched‐for nuclear danger signal passively released by necrotic, as opposed to apoptotic, cells that will induce inflammation. Furthermore, HMGB1 can also be actively secreted by stimulated macrophages or monocytes in a process requiring acetylation of the molecule, which enables translocation from the nucleus to secretory lysosomes. Subsequenttransport out of the cells depends on a secretion signal mediated by either extracellular lysophophatidyl‐choline or ATP. HMGB1 passively released from necrotic cells and HMGB1 actively secreted byinflammatory cells are thus molecularly different. Extracellular HMGB1 acts as a cytokine by signaling via the receptor for advanced glycated end‐products and via members of the Toll‐like receptor family. The initiated inflammatory responses include the production of multiple cytokines, chemoattraction of certain stem cells, induction of vascular adhesion molecules and impaired function of intestinalepithelial cells. Therapeutic administration of HMGB1 antagonists rescues mice from lethal sepsis, even when initial treatment is delayed for 24 h after the onset of infection, establishing a clinically relevant therapeutic window that is significantly wider than for other known cytokines.
The eye in focus: accommodation and presbyopia (2008)

Current understanding of the anatomy, function and performance of the accommodative system of the young, adult human eye is outlined. Most major current models of the accommodative mechanism are based on Helmholtz's original ideas but, despite of a growing volume of related research, uncertainty continues over the relative contributions made to the overall mechanism by different ocular structures. The changes with age are then discussed. Although the amplitude of accommodation decreases steadily from later childhood, the speed and accuracy of the system within the available amplitude are little impaired until the age of about 40, when the amplitude falls below that needed for normal near work. A review of the available evidence on age-related change in the lens, capsule, ciliary body and other relevant ocular structures confirms that geometric and viscoelastic lenticular changes play major roles in the progressive loss of accommodation. Other factors may also contribute in an, as yet, unquantified way and a full understanding of the origins of presbyopic change remains elusive.