gebhart/patrepeval huggingface dataset:
Lanadelumab for the Prophylactic Treatment of Hereditary Angioedema with C1 Inhibitor Deficiency: A Review of Preclinical and Phase I Studies (2018)

Hereditary angioedema (HAE) with C1 esterase inhibitor (C1-INH) deficiency (C1-INH-HAE) is a rare disease characterized by diminished levels or dysfunctional activity of C1-INH, leading to dysregulated plasma kallikrein activity within the kallikrein-kinin pathway. Symptoms manifest as painful, potentially life-threatening swelling of subcutaneous tissues throughout the body and/or submucosal edema in the upper airway or gastrointestinal tract. Attacks recur with unpredictable frequency, intensity, and duration, placing a heavy burden on patients' daily lives. Despite improved availability of medications for on-demand treatment during attacks and prophylaxis of future attacks, unmet needs remain. Lanadelumab, a fully human monoclonal antibody, may help address some of the limitations of existing prophylactic options (e.g., the need for intravenous administration or frequent dosing). Preclinical studies demonstrate that it is highly potent and specifically inhibits plasma kallikrein, and findings from phase Ia and Ib studies suggest this agent is well tolerated and provides sustained inhibition of plasma kallikrein, allowing for less frequent dosing. The phase III HELP Study (NCT02586805) evaluating the efficacy and safety of lanadelumab in preventing HAE attacks has been completed, and its open-label extension (NCT02741596) is ongoing. Lanadelumab is now approved in the USA and Canada for prophylaxis to prevent attacks of HAE in patients aged ≥ 12 years. This review provides an overview of the discovery and clinical development of lanadelumab, from preclinical through phase Ib studies, characterizing its safety/tolerability, efficacy, and pharmacokinetic and pharmacodynamic profiles. It also highlights how this agent may positively impact clinical care of patients with C1-INH-HAE.
Peripheral blood CD38 expression predicts time to progression in B-cell chronic lymphocytic leukemia after first-line therapy with high-dose chlorambucil. (2002)

CD38 expression by B-cell chronic lymphocytic leukemia (B-CLL) cells has been the focus of several recent studies. The aim of this study was to evaluate the prognostic impact of CD38 expression by peripheral blood lymphocytes on progression-free survival after first-line therapy with high-dose chlorambucil in 53 previously untreated patients affected by typical CD5+ CD23+ B-CLL.
Continuous versus intermittent oral administration of levodopa in Parkinson's disease patients with motor fluctuations: A pharmacokinetics, safety, and efficacy study (2019)

Continuous oral delivery of l-dopa/carbidopa was associated with less plasma variability and reduced off time in comparison to standard intermittent oral l-dopa/carbidopa therapy. © 2019 International Parkinson and Movement Disorder Society.
Enhancing Collaborative Spam Detection with Bloom Filters (2006)

Signature-based collaborative spam detection (SCSD) systems provide a promising solution addressing many problems facing statistical spam filters, the most widely adopted technology for detecting junk emails. In particular, some SCSD systems can identify previously unseen spam messages as such, although intuitively this would appear to be impossible. However, the SCSD approach usually relies on huge databases of email signatures, demanding lots of resource in signature lookup, storage, transmission and merging. In this paper, we report our enhancements to two representative SCSD systems. In our enhancements, signature lookups can be performed in constant time, independent of the number of signatures in the database. Space-efficient representation can significantly reduce signature database size. A simple but fast algorithm for merging different signature databases is also supported. We use the Bloom filter technique and a novel variant of this technique to achieve all this.
Crystal Structure of Anti-polysialic Acid Antibody Single Chain Fv Fragment Complexed with Octasialic Acid (2013)

Polysialic acid is a linear homopolymer of α2-8-linked sialic acids attached mainly onto glycoproteins. Cell surface polysialic acid plays roles in cell adhesion and differentiation events in a manner that is often dependent on the degree of polymerization (DP). Anti-oligo/polysialic acid antibodies have DP-dependent antigenic specificity, and such antibodies are widely utilized in biological studies for detecting and distinguishing between different oligo/polysialic acids. A murine monoclonal antibody mAb735 has a unique preference for longer polymers of polysialic acid (DP >10), yet the mechanism of recognition at the atomic level remains unclear. Here, we report the crystal structure of mAb735 single chain variable fragment (scFv735) in complex with octasialic acid at 1.8 Å resolution. In the asymmetric unit, two scFv735 molecules associate with one octasialic acid. In both complexes of the unit, all the complementarity-determining regions except for L3 interact with three consecutive sialic acid residues out of the eight. A striking feature of the complex is that 11 ordered water molecules bridge the gap between antibody and ligand, whereas the direct antibody-ligand interaction is less extensive. The dihedral angles of the trisialic acid unit directly interacting with scFv735 are not uniform, indicating that mAb735 does not strictly favor the previously proposed helical conformation. Importantly, both reducing and nonreducing ends of the bound ligand are completely exposed to solvent. We suggest that mAb735 gains its apparent high affinity for a longer polysialic acid chain by recognizing every three sialic acid units in a paired manner.
Effects of troxerutin on anxiety- and depressive-like behaviors induced by chronic mild stress in adult male rats. (2018)

Troxerutin demonstrated anxiolytic- and antidepressant-like activities in rodents, which supports the use of herbal medicine in the mood disorders.
Increasing antimicrobial resistance of Shigella isolates in Israel during the period 1984 to 1992 (1995)

Recent (1984 to 1992) trends in the antimicrobial resistance of Shigella isolates in Israel were studied by analyzing the results of 106,000 stool cultures, 3,511 of which yielded Shigella spp. Over the study period, resistance to trimethoprim-sulfamethoxazole (TMP-SMX) increased from 59 to 92% (P = 0.0038) and that to ampicillin increased from 13 to 86% (P &lt; 0.0001). Resistances to nalidixic acid, chloramphenicol, and broad-spectrum cephalosporins remained low. Shigella sonnei, which currently accounts for 90% of Shigella infections, was more resistant than S. flexneri to TMP-SMX (81 versus 57%, P &lt; 10(-6)), ampicillin (42 versus 32%, P &lt; 10(-5)), and tetracycline (38 versus 28%, P &lt; 10(-5)). S. boydii and S. dysenteriae were relatively rare. Seasonality in antimicrobial resistance was found, with summer isolates being less resistant to TMP-SMX, ampicillin, or both than isolates obtained over the rest of the year (P &lt; 10(-5)). We conclude that the resistance of shigellae, especially S. sonnei, to TMP-SMX and ampicillin is increasing to approximately 90%. Resistance should be recorded locally, and empiric therapy for suspected shigellosis should be changed accordingly.
Proteome analysis ofCorynebacterium glutamicum (2001)

By the use of different Corynebacterium glutamicum strains more than 1.4 million tons of amino acids, mainly L-glutamate and L-lysine, are produced per year. A project was started recently to elucidate the complete DNA sequence of this bacterium. In this communication we describe an approach to analyze the C. glutamicum proteome, based on this genetic information, by a combination of two-dimensional (2-D) gel electrophoresis and protein identification via microsequencing or mass spectrometry. We used these techniques to resolve proteins of C. glutamicum with the aim to establish 2-D protein maps as a tool for basic microbiology and for strain improvement. In order to analyze the C. glutamicum proteome, methods were established to fractionate the C. glutamicum proteins according to functional entities, i.e., cytoplasm, membranes, and cell wall. Protein spots of the cytoplasmic and membrane fraction were identified by N-terminal sequencing, immunodetection, matrix assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS) and electrospray ionization-mass spectrometry (ESI-MS). Additionally, a protocol to analyze proteins secreted by C. glutamicum was established. Approximately 40 protein spots were observed on silver-stained 2-D gels, 12 of which were identified.
Elevated Serum Pancreatic Enzyme Levels After Hemorrhagic Shock Predict Organ Failure and Death (2009)

: Serum levels of pancreatic enzymes are elevated in patients who present in shock or require a massive transfusion and are independent predictors of organ failure. Whether these elevations are caused by ischemic pancreatitis or the translocation of intraluminal enteric pancreatic enzymes is uncertain and future studies are needed. Trauma patients with elevated pancreatic enzymes in the absence of a pancreatic injury have an increased risk of morbidity and mortality.
α1‐Antichymotrypsin activity correlates with and may modulate matrix metalloproteinase‐9 in human acute wounds (2009)

Matrix metalloproteinase-9 (MMP-9) plays a central role in many physiologic processes including acute and the chronic wounds. MMP-9 is not routinely expressed in healthy tissues but is promptly expressed as a proenzyme and converted into active enzyme after tissue injury. The mechanisms involved, including the activators and inhibitors for this enzyme in human tissue remain largely obscure. We recently identified alpha1-antichymotrypsin (alpha1-ACT), an acute phase factor, as a potent inhibitor controlling activation of pro-MMP-9 by human skin. The aim of this study is to establish the clinical relevance of the inhibitor in cutaneous wound healing. Fluids from acute burn blisters and conditioned media from skin explants of burn patients were analyzed. We observed that the presence pro-MMP-9 and its activation correlated with the proximity to and degree of injury. Early after trauma, massive levels of wound alpha1-ACT were associated with an absence of pro-MMP-9 activation. Conversely, the active MMP-9 occurs simultaneously with inactivation of alpha1-ACT. Our results suggest a role for alpha1-ACT as a physiologic inhibitor of MMP-9 activation in human wound healing.
Controlled Release of rhBMP-2 Loaded Poly(DL-lactic-co-glycolic Acid)/ Calcium Phosphate Cement Composites In Vivo (2006)

The release kinetics of recombinant human bone morphogenetic protein-2 (rhBMP-2) loaded poly(DL-lactic-co-glycolic acid)/calcium phosphate cement (PLGA/Ca-P cement) composites were studied in vivo. RhBMP-2 was radiolabeled with 131I and entrapped within PLGA microparticles or adsorbed onto the microparticle surface. PLGA microparticles were prepared of high molecular weight (HMW) PLGA (weight average molecular weight [Mw] 49,100 ± 1,700) or low molecular weight (LMW) PLGA (Mw 5,900 ± 300) and used for preparation of 30:70 wt% PLGA/Ca-P cement composite discs. Release of 131I-rhBMP-2 loaded composites was assessed by scintigraphic imaging according to a 22 two-level full factorial design in the rat ectopic model during four weeks. In vivo release kinetics varied among formulations. All formulations showed slow release without initial burst, and displayed a linear release from 3 to 28 days. Release of LMW entrapped rhBMP-2 composites (1.7 ± 0.3%/day) was significantly faster than release from other formulations (p &lt; 0.01). After 28 days, retention within the composites was 65 ± 5%, 75 ± 4%, 50 ± 4% and 70 ± 6% of the initial rhBMP-2 for HMW entrapped, HMW adsorbed, LMW entrapped and LMW adsorbed rhBMP-2 composites, respectively. Release from the composite was probably slowed down by an interaction of rhBMP-2 and Ca-P cement after rhBMP-2 release from PLGA microparticles. We conclude that PLGA/Ca-P cement composites can be considered as sustained slow release vehicles and that the release and retention of rhBMP-2 can be modified according to the desired profile to a limited extent.
[Disordered peripapillary microcirculation in glaucoma patients]. (1993)

To study the haemodynamics of the peripapillary choroid, perfusion pressure videoangiography (PVA) was performed in six healthy subjects and in seven patients with primary open-angle glaucoma (poag). In healthy subjects the peripapillary part of the choroid starts filling at distinctly lower ocular perfusion pressures than other parts of the choroid. The mean difference in perfusion pressure between peripapillary and perimacular filling was 13.6 mmHg in the six healthy subjects. A different filling pattern of the choroid was found in the seven glaucoma patients. The mean difference in perfusion pressure between the beginning of peripapillary and the beginning of perimacular perfusion of the choroid was found to be as small as 1.9 mmHg. That the filling of the peripapillary choroid observed by PVA in healthy subjects is found to start at lower perfusion pressures than in the other parts is explained by autoregulative dilatation of the peripapillary choroidal arterioles resulting from artificially raised intraocular pressure during the PVA examination. In the poag patients the peripapillary choroidal arterioles were dilated either insufficiently or not at all. The following conclusions are drawn: (1) The peripapillary choroid of healthy persons shows effective autoregulation securing the blood supply to the prelaminar part of the optic nerve. (2) In poag the peripapillary choroid has lost the capability of effective autoregulation.
Profound Impairment of Adaptive Immune Responses by Alkylating Chemotherapy (2013)

Overall, cancer vaccines have had a record of failure as an adjuvant therapy for malignancies that are treated with alkylating chemotherapy, and the contribution of standard treatment to that failure remains unclear. Vaccines aim to harness the proliferative potential of the immune system by expanding a small number of tumor-specific lymphocytes into a large number of antitumor effectors. Clinical trials are often conducted after treatment with alkylating chemotherapy, given either as standard therapy or for immunomodulatory effect. There is mounting evidence for synergy between chemotherapy and adoptive immunotherapy or vaccination against self-Ags; however, the impact of chemotherapy on lymphocytes primed against tumor neoantigens remains poorly defined. We report that clinically relevant dosages of standard alkylating chemotherapies, such as temozolomide and cyclophosphamide, significantly inhibit the proliferative abilities of lymphocytes in mice. This proliferative impairment was long-lasting and led to quantitative and qualitative defects in B and T cell responses to neoantigen vaccines. High-affinity responder lymphocytes receiving the strongest proliferative signals from vaccines experienced the greatest DNA damage responses, skewing the response toward lower-affinity responders with inferior functional characteristics. Together, these defects lead to inferior efficacy and overall survival in murine tumor models treated by neoantigen vaccines. These results suggest that clinical protocols for cancer vaccines should be designed to avoid exposing responder lymphocytes to alkylating chemotherapy.
Tissue inhibitor of matrix metalloproteinase-1 in the plasma of patients with gastric carcinoma (1999)

In patients with gastric carcinoma, plasma concentration of TIMP-1 appears to correlate with both serosal invasion and metastasis.
Using a baculovirus display library to identify MHC class I mimotopes (2005)

We have developed a baculovirus-based display system for identifying antigen mimotopes for MHC class I-specific T cells. The mouse MHC class I molecule, Dd, was displayed on baculovirus-infected insect cells with a library of 9- and 10-mer peptides tethered via a flexible linker to the N terminus of beta2 microglobulin. As a test case, the library was screened by flow cytometry by using a multimeric fluorescent alphabetaTCR from a mouse T cell specific for Dd plus an unknown self peptide. A mimotope was identified that, when bound to Dd, stimulated the T cell to secret IL-2. The sequence of the mimotope was used to identify a self peptide present in a mouse protein, Spin. The Spin peptide, when complexed with Dd, also activated the T cell. This technique should be generally useful in identifying and manipulating MHC class I peptide mimotopes and epitopes.
The Clinical Effect of the Dual-Targeting Strategy Involving PI3K/AKT/mTOR and RAS/MEK/ERK Pathways in Patients with Advanced Cancer (2012)

These results suggest that dual inhibition of both pathways may potentially exhibit favorable efficacy compared with inhibition of either pathway, at the expense of greater toxicity. Furthermore, this parallel pathway targeting strategy may be especially important in patients with coexisting PI3K pathway genetic alterations and KRAS or BRAF mutations and suggests that molecular profiling and matching patients with combinations of these targeted drugs will need to be investigated in depth.
Tuning the Amphiphilicity of Building Blocks: Controlled Self‐Assembly and Disassembly for Functional Supramolecular Materials (2009)

Abstract Amphiphilicity is one of the molecular bases for self‐assembly. By tuning the amphiphilicity of building blocks, controllable self‐assembly can be realized. This article reviews different routes for tuning amphiphilicity and discusses different possibilities for self‐assembly and disassembly in a controlled manner. In general, this includes irreversible and reversible routes. The irreversible routes concern irreversible reactions taking place on the building blocks and changing their molecular amphiphilicity. The building blocks are then able to self‐assemble to form different supramolecular structures, but cannot remain stable upon loss of amphiphilicity. Compared to the irreversible routes, the reversible routes are more attractive due to the good control over the assembly and disassembly of the supramolecular structure formed via tuning of the amphiphilicity. These routes involve reversible chemical reactions and supramolecular approaches, and different external stimuli can be used to trigger reversible changes of amphiphilicity, including light, redox, pH, and enzymes. It is anticipated that this line of research can lead to the fabrication of new functional supramolecular assemblies and materials.
Direct Observation of Nanoparticle–Cancer Cell Nucleus Interactions (2012)

We report the direct visualization of interactions between drug-loaded nanoparticles and the cancer cell nucleus. Nanoconstructs composed of nucleolin-specific aptamers and gold nanostars were actively transported to the nucleus and induced major changes to the nuclear phenotype via nuclear envelope invaginations near the site of the construct. The number of local deformations could be increased by ultrafast, light-triggered release of the aptamers from the surface of the gold nanostars. Cancer cells with more nuclear envelope folding showed increased caspase 3 and 7 activity (apoptosis) as well as decreased cell viability. This newly revealed correlation between drug-induced changes in nuclear phenotype and increased therapeutic efficacy could provide new insight for nuclear-targeted cancer therapy.
Cloning and Expression of cDNAs from Enterically‐Transmitted Non‐A, Non‐B Hepatitis Virus (1991)

The fragment gene of enterically-transmitted non-A, non-B hepatitis virus (ET-NANBHV) was cloned as a cDNA and inserted into an expression vector pUEX2. The recombinant protein was expressed in Escherichia coli HB101 as a fusion protein with beta-galactosidase (beta-Gal). The fusion protein reacted with the sera of infected cynomolgus monkeys and of patients from Myanmar. This reaction was highly related with ET-NANBHV infection, and obviously demonstrates in that the recombinant protein can be used for the detection of ET-NANBHV infection.
DNA-mediated transfer of the adenine phosphoribosyltransferase locus into mammalian cells. (1979)

In this report, we demonstrate the feasibility of transforming mouse cells deficient in adenine phosphoribosyltransferase (aprt; AMP:pyrophosphate phosphoribosyltransferase, EC 2.4.2.7) to the aprt+ phenotype by means of DNA-mediated gene transfer. Transformation was effected by using unfractionated high molecular weight genomic DNA from Chinese hamster, human, and mouse cells and restriction endonuclease-digested DNA from rabbit liver. The transformation frequency observed was between 1 and 10 colonies per 10(6) cells per 20 microgram of donor DNA. Transformants displayed enzymatic activity that was donor derived as demonstrated by isoelectric focusing of cytoplasmic extracts. These transformants fall into two classes: those that are phenotypically stable when grown in the absence of selective pressure and those that are phenotypically unstable under the same conditions.
Analyses of p53 Target Genes in the Human Genome by Bioinformatic and Microarray Approaches (2001)

The completion of the human genome sequence (International Human Genome Sequence Consortium (2001) Nature 409, 860-921; Venter, J. C., et al. (2001) Science 291, 1304-1351) allows for new ways to analyze global cellular regulatory mechanisms. Here we present a strategy to identify genes regulated by specific transcription factors in the human genome, and apply it to p53. We first collected promoters or introns of all genes available using two methods: GenBank(TM) annotation and a computationally derived transcript map. 4,852 genes analyzed in this way contained at least one p53 consensus binding sequence. Of 13 genes randomly selected for mRNA analysis, 11 were shown to respond to p53 expression. Five promoters were analyzed by chromatin immunoprecipitation, which revealed that all were bound by p53 in vivo. We then analyzed 33,615 unique human genes on cDNA microarrays, identifying 1,501 genes that respond to p53 expression. A parameter was derived that demonstrates that in silico prediction greatly enriches for genes that are activated and repressed by p53 and assists us to suggest other signaling pathways that may be connected to p53. The methods shown here illustrate a novel approach to analysis of global gene regulatory network through the integration of human genomic sequence information and genome-wide gene expression analysis.
Clinical, biochemical and molecular genetic correlations in Friedreich's ataxia (2000)

Friedreich's ataxia (FRDA) is an autosomal recessive disorder with a frequency of 1 in 50 000 live births. In 97% of patients it is caused by the abnormal expansion of a GAA repeat in intron 1 of the FRDA gene on chromosome 9, which encodes a 210 amino acid protein called frataxin. Frataxin is widely expressed and has been localized to mitochondria although its function is unknown. We have investigated mitochondrial function, mitochondrial DNA levels, aconitase activity and iron content in tissues from FRDA patients. There were significant reductions in the activities of complex I, complex II/III and aconitase in FRDA heart. Respiratory chain and aconitase activities were decreased although not significantly in skeletal muscle, but were normal in FRDA cerebellum and dorsal root ganglia, although there was a mild decrease in aconitase activity in the latter. Mitochondrial DNA levels were reduced in FRDA heart and skeletal muscle, although in skeletal muscle this was paralleled by a decline in citrate synthase activity. Increased iron deposition was seen in FRDA heart, liver and spleen in a pattern consistent with a mitochondrial location. The iron accumulation, mitochondrial respiratory chain and aconitase dysfunction and mitochondrial DNA depletion in FRDA heart samples largely paralleled those in the yeast YFH1 knockout model, suggesting that frataxin may be involved in mitochondrial iron regulation or iron sulphur centre synthesis. However, the severe deficiency in aconitase activity also suggests that oxidant stress may induce a self-amplifying cycle of oxidative damage and mitochondrial dysfunction, which may contribute to cellular toxicity.