gebhart/patrepeval huggingface dataset:
New Approaches for Inner Ear Therapy with Glutamate Antagonists (1999)

In the mammalian cochlea neurotransmission between inner hair cells and afferent auditory neurons is probably mediated by glutamate or another related excitatory amino acid. Neurotoxicity induced by excessive glutamate release seems to play a crucial role in some pathological conditions of the cochlea, such as ischaemia or noise trauma. Thus, glutamate antagonists may be a new therapeutic strategy for different inner ear diseases. Because of their potential severe side-effects only a few glutamate antagonists have so far been adopted for clinical use. We used microiontophoretic techniques to compare the effects of memantine and caroverine on the glutamatergic transmission of inner hair cells of the guinea pig and tested the possibility of a local administration of memantine to the cochlea with a micropump. Memantine selectively inhibited the NMDA (N-methyl-D-aspartate) stimulated activity while caroverine blocked NMDA as well as AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) induced activity of inner hair cell afferents. With a flow rate of 1 microl/h the local administration of memantine via a cochleotomy was succeeded in a reversible blockade of the spontaneous and the NMDA induced firing of inner hair cell afferents. These results suggest that local application to the cochlea could be a feasible way to administer glutamate antagonists in sufficient amounts while avoiding systemic side-effects.
Tumor treating fields inhibit glioblastoma cell migration, invasion and angiogenesis (2016)

Treatment with alternating electric fields at an intermediate frequency (100-300 kHz), referred to as tumor treating fields (TTF) therapy, inhibits cancer cell proliferation. In the present study, we demonstrated that TTF application suppressed the metastatic potential of U87 and U373 glioblastoma cell lines via the NF-kB, MAPK and PI3K/AKT signaling pathways. Wound-healing and transwell assays showed that TTF suppressed cell migration and invasion compared with controls. Soft agar and three-dimensional culture assays showed that TTF inhibited both anchorage-dependent (cell proliferation) and anchorage-independent (colony formation) GBM cell growth. TTF dysregulated epithelial-to-mesenchymal transition-related genes, such as vimentin and E-cadherin, which partially accounted for TTF inhibition of cell migration and invasion. We further demonstrated that TTF application suppressed angiogenesis by downregulating VEGF, HIF1α and matrix metalloproteinases 2 and 9. TTF also inhibited NF-kB transcriptional activity. Collectively, our findings show that TTF represents a promising novel anti-invasion and anti-angiogenesis therapeutic strategy for use in GBM patients.
Is It Time to Introduce HPV Self-Sampling for Primary Cervical Cancer Screening? (2012)

Regular Papanicolaou (Pap) testing has been the backbone of the most successful cancer reduction program in the public health system. However, it is not perfect. In high-income countries, more than half of the women who are diagnosed with cervical cancer had never had a Pap test or were infrequently screened (1). In the United Kingdom, recent studies have suggested a decline in the routine screening program participation to below its target rate of 80%, particularly among women aged 25–29 years (2). Factors that may discourage women from going for regular screening are lack of time, discomfort, inconvenience, cultural objections, and poor socioeconomic status. In low-resource regions, additional barriers include lack of knowledge and lack of accessible or appropriate screening facilities as well as the prohibitively high cost of screening. Offering a simple, inexpensive, and convenient self-test that respects individual privacy may improve the participation of women who might be otherwise reluctant to undergo screening and those who live in areas with poor access to health care. In the last few years, we have learned that self-collected vaginal specimens from women who have received appropriate instruction produce human papillomavirus (HPV) test results similar to cervical specimens collected by health-care professionals (3). This congruence has supported the concept of introducing HPV selfsampling (Self-HPV) as an alternative means for cervical cancer screening. However, screening is a complex process, and the introduction of a new screening scenario should be carefully evaluated. Fundamental issues that must be addressed regarding the future of Self-HPV as a primary screening method are 1) whether the performance for the detection of cervical intraepithelial neoplasia (CIN) grade 2–3 and cervical cancer (CIN2+) by Self-HPV is (at least) equal or superior to that of the Pap test, 2) whether screening participation rate with Self-HPV will be sufficiently high, and 3) whether comparable results would be obtained outside a research setting.
Design considerations of new six degrees-of-freedom parallel robots (2002)

This paper describes the structure of three types of parallel robots and compares their performances in the sense of size and static forces. The motivation for this investigation is to construct a robot that best fits a given medical application. The requirements are to cover a given work volume with a given orientation and to maintain the robot within the smallest cube possible. Among the structures examined, three are presented since two are modifications of known structures and the third is a new one.
Demonstration of burst-promoting activity of recombinant human GM-CSF on circulating erythroid progenitors using an assay involving the delayed addition of erythropoietin (1985)

We demonstrate through the use of an in vitro assay involving the delayed addition of erythropoietin that human recombinant GM-CSF, cloned from a mature T cell line, Mo, clearly has burst-promoting activity (BPA) on peripheral blood erythroid progenitors at picomolar concentrations. Delay for up to 72 hours of the addition of erythropoietin to semi-solid methylcellulose cultures of concentrated peripheral blood progenitors minimizes or eliminates BPA-independent erythroid colony formation with little loss of BPA-dependent erythroid colony formation. This assay will prove useful in accurately detecting sources of BPA.
Boosting with recombinant vaccinia increases HPV-16 E7-specific T cell precursor frequencies of HPV-16 E7-expressing DNA vaccines (2000)

We have previously linked the sorting signals of the lysosome-associated membrane protein-1 (LAMP-1) to HPV-16 E7 antigen, creating a chimera, Sig/E7/LAMP-1. We found that both Sig/E7/LAMP-1-containing recombinant vaccinia virus (Vac-Sig/E7/LAMP-1) and Sig/E7/LAMP-1 DNA can generate strong antitumor immunity. To determine whether combination of Sig/E7/LAMP-1 DNA and Vac-Sig/E7/LAMP-1 can further enhance immune responses, sequential vaccination with Sig/E7/LAMP-1 DNA and Vac-Sig/E7/LAMP-1 was given. We found that priming with Sig/E7/LAMP-1 DNA and boosting with Vac-Sig/E7/LAMP-1 generated the strongest E7-specific CD8(+) T cell responses. Our results encourage the use of the DNA prime/vaccinia booster regimen in future clinical trials.
Compensation Indices of Radiation‐Induced Wheat‐Agropyron elongatum Translocations Conferring Resistance to Leaf Rust and Stem Rust (1994)

Species belonging to the genus Agropyron are an important source of disease resistance for bread wheat. Several resistance genes have been transferred. C‐banding and in situ hybridization are the methods of choice for analyzing introgressed alien chromatin. Using these methods, we characterized radiation‐induced wheat‐ Agropyron elongatum chromosome translocation lines carrying the rust resistance genes Sr26 and Sr25/Lr19 . Data show that Sr26 is located on the translocation chromosome T6AS. 6AL‐6Ae#1L. The Ag. elongatum segment in this translocation has a length of 2.48 μm. The Sr25/Lr19 genes in cultivar ‘Agatha’ are located on a 2.55 μm long Ag. elongatum segment present in the translocation chromosome T7DS. 7DL‐7Ae#1L. The wheat‐ Ag. elongatum translocation chromosome present in the ethyl methane‐sulfonate (EMS) treated derivative ‘Agatha‐28’ is similar to that present in Agatha. The Ag. elongatum segment present in the EMS treated derivative ‘Agatha‐235’ has a length of 1.99 pm and is inserted intercalary in the long arm of wheat chromosome 7D, resulting in the translocation chromosome T7DS‐7DL‐7Ae#1L‐7DL. A compensation (CI) index was calculated as the ratio of the length of the missing wheat segment as percent of the corresponding wheat arm divided by the length of the transferred alien segment as percent of the corresponding alien chromosome arm. The CIs in T6AS‐6AL‐6Ae#1L and T7DS‐7DL‐7Ae#1L are 1.15 and 0.95, respectively. These are close to the desirable value of I and indicate good compensation ability. The CI in T7DS. 7DL‐7Ae#1L‐7DL is 0.60 and indicates poor compensation ability. This index may allow the prediction of the performance of any compensating wheat‐alien chromosome translocation.
Ultrathin Functional Star PEG Coatings for DNA Microarrays (2005)

In this study, star PEG coatings on glass substrates have been used as support material for oligonucleotide microarrays. These coatings are prepared from solutions of six armed star shaped prepolymers that carry reactive isocyanate endgroups. As described earlier, such films prevent the adsorption of proteins and the adhesion of cells but can easily be functionalized for specific biological recognition. Here we used the high functionality of these coatings for the covalent immobilization of amino terminated 20mer oligonucleotides, both by microcontact printing and spotting techniques. The permanent immobilization of fluorescently labeled DNA as well as hybridization of 20mer oligonucleotides have been monitored by fluorescence microscopy. The hybridization efficiency as determined by fluorescence intensity varied from 30% to 80% depending on the way of layer preparation. The direct spotting without additional activation and blocking steps of the surface demonstrates the potential of star PEG coatings as ultrathin surface modification for microarrays.
Synthesizing a protocol converter from executable protocol traces (1991)

Communicating finite state machines (CFSM's) with FIFO (first in, first out) queues are used to model a protocol converter. A protocol conversion algorithm is developed and presented for the CSFM model of the protocols A and B. A converter H for protocols A=(A/sub 0/, A/sub 1/) and B=(B/sub 0/, B/sub 1/) is viewed as a black box such that H is between sender A/sub 0/ and receiver B/sub 1/. This gives a resulting protocol X=(A/sub 0/, H, B/sub 1/). The conversion algorithm requires a specification of the message relationships between the messages of protocols A and B. It is assumed that protocols A and B have the required progress properties. The algorithm includes a search for related messages from the two protocols in an FIFO from a composite space formed by a Cartesian cross-product of state spaces A/sub 1/ and B/sub 0/. The search produces finite-length traces which are combined to form a state machine H, which is examined for freedom from unspecified receptions, deadlocks, and livelocks. A protocol conversion example demonstrates the applicability of the algorithm.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Bridging a Complete Transection Lesion of Adult Rat Spinal Cord with Growth Factor‐Treated Nitrocellulose Implants (1994)

The ability of a substrate bound neurotrophic factor to promote growth of ascending sensory axons across a complete transection lesion of the rat spinal cord was examined in a transplantation model. Aspiration lesions created a 3 mm long cavity in the upper lumbar spinal cord of adult rats. Five weeks after injury two strips of nerve growth factor-treated nitrocellulose were implanted, each in a medio-lateral position, and apposed to the rostral and caudal surfaces of the cavity. Control animals received untreated nitrocellulose implants. Fetal spinal cord tissue was transplanted alongside and between these strips. Six weeks post transplantation, animals were sacrificed and vibratome sections through the grafts were processed for immunocytochemical demonstration of ingrowing axons expressing calcitonin gene-related peptide (CGRP-IR). Immunolabeled axons were abundant at the caudal interface between host tissue and the NGF-treated nitrocellulose implants, with dense fascicles of fibers abutting the grafts. As the distance from the caudal surface increased some CGRP-IR fibers extended into the fetal tissue although most appeared to remain oriented in a longitudinal course adjacent to the nitrocellulose. Labeled axons were evident along the entire length of the nitrocellulose and appeared to aggregate at the rostral tip of the implant, with many fibers extending into the host spinal cord rostral to the lesion/transplant site. When untreated nitrocellulose was implanted, fewer labeled axons appeared to extend beyond the caudal host-graft interface. Most CGRP-IR axons displayed limited association or contact with the untreated nitrocellulose in this condition. Computer-assisted quantitative analysis indicated that NGF-treated nitrocellulose supported regrowing host axons for nearly three times the length exhibited by axons associated with non-treated nitrocellulose implants. These results indicate that substrate bound nerve growth factor has the capacity to enhance the regrowth of ascending sensory axons across a traumatic spinal cord injury site. The potential to reestablish functional contacts across such a lesion may be heightened by the ability of neurotrophic factors to promote more extensive axonal regrowth.
Promotion of Trophoblast Stem Cell Proliferation by FGF4 (1998)

The trophoblast cell lineage is essential for the survival of the mammalian embryo in utero. This lineage is specified before implantation into the uterus and is restricted to form the fetal portion of the placenta. A culture of mouse blastocysts or early postimplantation trophoblasts in the presence of fibroblast growth factor 4 (FGF4) permitted the isolation of permanent trophoblast stem cell lines. These cell lines differentiated to other trophoblast subtypes in vitro in the absence of FGF4 and exclusively contributed to the trophoblast lineage in vivo in chimeras.
Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma (2013)

Acute myeloid leukemia (AML) represents a clonal disease of hematopoietic progenitors characterized by acquired heterogenous genetic changes that alter normal mechanisms of proliferation, self-renewal, and differentiation.(1) Although 40% to 45% of patients younger than 65 years of age can be cured with current therapies, only 10% of older patients reach long-term survival.(1) Because only very few novel AML drugs were approved in the past 2 decades, there is an urgent need to identify novel targets and therapeutic strategies to treat underserved AML patients. We report here that Axl, a member of the Tyro3, Axl, Mer receptor tyrosine kinase family,(2-4) represents an independent prognostic marker and therapeutic target in AML. AML cells induce expression and secretion of the Axl ligand growth arrest-specific gene 6 (Gas6) by bone marrow-derived stromal cells (BMDSCs). Gas6 in turn mediates proliferation, survival, and chemoresistance of Axl-expressing AML cells. This Gas6-Axl paracrine axis between AML cells and BMDSCs establishes a chemoprotective tumor cell niche that can be abrogated by Axl-targeting approaches. Axl inhibition is active in FLT3-mutated and FLT3 wild-type AML, improves clinically relevant end points, and its efficacy depends on presence of Gas6 and Axl. Axl inhibition alone or in combination with chemotherapy might represent a novel therapeutic avenue for AML.
Engraftment of a Galactose Receptor Footprint onto Adeno-associated Viral Capsids Improves Transduction Efficiency (2013)

New viral strains can be evolved to recognize different host glycans through mutagenesis and experimental adaptation. However, such mutants generally harbor amino acid changes that affect viral binding to a single class of carbohydrate receptors. We describe the rational design and synthesis of novel, chimeric adeno-associated virus (AAV) strains that exploit an orthogonal glycan receptor for transduction. A dual glycan-binding AAV strain was first engineered as proof of concept by grafting a galactose (Gal)-binding footprint from AAV serotype 9 onto the heparan sulfate-binding AAV serotype 2. The resulting chimera, AAV2G9, continues to bind heparin affinity columns but interchangeably exploits Gal and heparan sulfate receptors for infection, as evidenced by competitive inhibition assays with lectins, glycans, and parental AAV strains. Although remaining hepatotropic like AAV2, the AAV2G9 chimera mediates rapid onset and higher transgene expression in mice. Similarly, engraftment of the Gal footprint onto the laboratory-derived strain AAV2i8 yielded an enhanced AAV2i8G9 chimera. This new strain remains liver-detargeted like AAV2i8 while selectively transducing muscle tissues at high efficiency, comparable with AAV9. The AAV2i8G9 chimera is a promising vector candidate for targeted gene therapy of cardiac and musculoskeletal diseases. In addition to demonstrating the modularity of glycan receptor footprints on viral capsids, our approach provides design strategies to expand the AAV vector toolkit.
High-throughput screening for developability during early-stage antibody discovery using self-interaction nanoparticle spectroscopy (2013)

The discovery of monoclonal antibodies (mAbs) that bind to a particular molecular target is now regarded a routine exercise. However, the successful development of mAbs that (1) express well, (2) elicit a desirable biological effect upon binding, and (3) remain soluble and display low viscosity at high concentrations is often far more challenging. Therefore, high throughput screening assays that assess self-association and aggregation early in the selection process are likely to yield mAbs with superior biophysical properties. Here, we report an improved version of affinity-capture self-interaction nanoparticle spectroscopy (AC-SINS) that is capable of screening large panels of antibodies for their propensity to self-associate. AC-SINS is based on concentrating mAbs from dilute solutions around gold nanoparticles pre-coated with polyclonal capture (e.g., anti-Fc) antibodies. Interactions between immobilized mAbs lead to reduced inter-particle distances and increased plasmon wavelengths (wavelengths of maximum absorbance), which can be readily measured by optical means. This method is attractive because it is compatible with dilute and unpurified mAb solutions that are typical during early antibody discovery. In addition, we have improved multiple aspects of this assay for increased throughput and reproducibility. A data set comprising over 400 mAbs suggests that our modified assay yields self-interaction measurements that are well-correlated with other lower throughput assays such as cross-interaction chromatography. We expect that the simplicity and throughput of our improved AC-SINS method will lead to improved selection of mAbs with excellent biophysical properties during early antibody discovery.
Effect of genetic background on phenotype variability in transgenic mouse models of amyotrophic lateral sclerosis: A window of opportunity in the search for genetic modifiers (2011)

Transgenic (Tg) mouse models of FALS containing mutant human SOD1 genes (G37R, G85R, D90A, or G93A missense mutations or truncated SOD1) exhibit progressive neurodegeneration of the motor system that bears a striking resemblance to ALS, both clinically and pathologically. The most utilized and best characterized Tg mice are the G93A mutant hSOD1 (Tg(hSOD1-G93A)1GUR mice), abbreviated G93A. In this review we highlight what is known about background-dependent differences in disease phenotype in transgenic mice that carry mutated human or mouse SOD1. Expression of G93A-hSOD1Tg in congenic lines with ALR, NOD.Rag1KO, SJL or C3H backgrounds show a more severe phenotype than in the mixed (B6xSJL) hSOD1Tg mice, whereas a milder phenotype is observed in B6, B10, BALB/c and DBA inbred lines. We hypothesize that the background differences are due to disease-modifying genes. Identification of modifier genes can highlight intracellular pathways already suspected to be involved in motor neuron degeneration; it may also point to new pathways and processes that have not yet been considered. Most importantly, identified modifier genes provide new targets for the development of therapies.
The human immunodeficiency virus type 1 polyadenylylation signal: a 3' long terminal repeat element upstream of the AAUAAA necessary for efficient polyadenylylation. (1991)

Several polyadenylylation (PA) signals containing elements upstream of the AAUAAA have recently been characterized. Similar to PA elements found downstream of the AAUAAA, the upstream elements function to increase efficiency of AAUAAA use as a signal for cleavage and PA. Using deletion and linker scanning mutations we show that the PA signal of human immunodeficiency virus type 1 contains upstream elements transcribed from the U3 region of the 3' long terminal repeat. The element that has the greatest effect on PA site use lies 77 to 94 nucleotides upstream of the AAUAAA, between the TATA element and the transcriptional initiation site. Mutations in the adjacent region, between 59 and 76 nucleotides upstream of the AAUAAA, have a smaller effect on PA efficiency. Mutations in a region further upstream, between 141 and 176 nucleotides upstream of the AAUAAA, also affected PA modestly. Functional similarity between upstream elements was indicated by the ability of the human immunodeficiency virus upstream region to replace the upstream region of the simian virus 40 late PA signal. The sequence of the major upstream element of human immunodeficiency virus is uracil-rich, analogous to many defined downstream PA elements. This fact may imply that upstream and downstream elements have similar mechanisms of action.
Dynamics of blood flow and oxygenation changes during brain activation: The balloon model (1998)

A biomechanical model is presented for the dynamic changes in deoxyhemoglobin content during brain activation. The model incorporates the conflicting effects of dynamic changes in both blood oxygenation and blood volume. Calculations based on the model show pronounced transients in the deoxyhemoglobin content and the blood oxygenation level dependent (BOLD) signal measured with functional MRI, including initial dips and overshoots and a prolonged poststimulus undershoot of the BOLD signal. Furthermore, these transient effects can occur in the presence of tight coupling of cerebral blood flow and oxygen metabolism throughout the activation period. An initial test of the model against experimental measurements of flow and BOLD changes during a finger-tapping task showed good agreement.
Rapid and Sensitive Detection of Severe Acute Respiratory Syndrome Coronavirus by Rolling Circle Amplification (2005)

The severe acute respiratory syndrome (SARS) epidemic of 2003 was responsible for 774 deaths and caused significant economic damage worldwide. Since July 2003, a number of SARS cases have occurred in China, raising the possibility of future epidemics. We describe here a rapid, sensitive, and highly efficient assay for the detection of SARS coronavirus (SARS-CoV) in cultured material and a small number (n = 7) of clinical samples. Using rolling circle amplification (RCA), we were able to achieve sensitive detection levels of SARS-CoV RNA in both solid and liquid phases. The main advantage of RCA is that it can be performed under isothermal conditions with minimal reagents and avoids the generation of false-positive results, a problem that is frequently encountered in PCR-based assays. Furthermore, the RCA technology provides a faster, more sensitive, and economical option to currently available PCR-based methods.