gebhart/patrepeval huggingface dataset:
HSP90 Inhibitors: Multi-Targeted Antitumor Effects and Novel Combinatorial Therapeutic Approaches in Cancer Therapy (2009)

With the rapid rise of tumor resistance, combinatorial anticancer therapies have gained favor over single-molecule inhibition to maximize the suppression of oncogenic pathways. In this regard, HSP90 inhibitors have rapidly emerged as a class of promising drugs that can target multiple oncogenic pathways simultaneously. HSP90 is a highly conserved protein chaperone involved in essential cellular functions such as protein folding and cell signaling in both stressed and unstressed cells. In the last decade, a large number of oncogenic client proteins have been identified to associate with HSP90 and contribute to malignant transformation. Development of HSP90 inhibitors, derived from the natural compound geldanamycin that mimics the ATP binding site of HSP90, was designed to target HSP90 and allow degradation of these client proteins. Preclinical and clinical data with HSP90 inhibitors in various cancer models are promising, and evidences also hint at the potential for tumor-selective cytotoxicity as well as enhanced sensitization to chemo- and radiotherapy. This review will discuss the effects of HSP90 inhibition in cancer, the known mechanistic basis for the oncogenic toxicity and selectivity, as well as the current progress on single or combinatorial therapies with HSP90 inhibitors.
Cell-mediated Immunity in Legionnaires' Disease (1983)

Previous studies from this laboratory have suggested a role for cell-mediated immunity in host defense against Legionella pneumophila. In this paper, cell-mediated immunity to L. pneumophila in patients recovered from Legionnaires' disease was studied by examining patient mononuclear cell responses to L. pneumophila antigens. Patient mononuclear cells were assayed both for their capacity to respond to L. pneumophila antigens with the production of cytokines that activate monocytes, as measured by monocyte inhibition of L. pneumophila multiplication, and for their capacity to respond with proliferation, as measured by [(3)H]thymidine incorporation. Patient mononuclear cells incubated with formalin-killed L. pneumophila generated cytokines (supernatants) that were capable of activating in vitro freshly explanted monocytes from a person without historical or serological evidence of L. pneumophila infection (nonpatient). Such activated nonpatient monocytes inhibited the intracellular multiplication of L. pneumophila, and the degree of inhibition was proportional to the concentration of supernatant added. Patient mononuclear cells incubated with 5 x 10(6) - 5 x 10(8) formalin-killed L. pneumophila/ml for 4 d produced maximally potent supernatants; supernatants generated in flat-bottomed wells were equivalent in potency to supernatants generated in cone-shaped wells. Patient L. pneumophila-induced mononuclear cell supernatants were less potent than patient concanavalin A-induced mononuclear cell supernatants. Patient mononuclear cells also responded to formalin-killed L. pneumophila with proliferation (lymphoproliferation). Patient mononuclear cells responded more strongly to L. pneumophila antigens than mononuclear cells of age- and sex-matched nonpatients, as measured by both assays; responses to concanavalin A were comparable. Mononuclear cells from patients recovered from Legionnaires' disease responded more strongly to L. pneumophila than to Mycobacterium leprae antigens, whereas mononuclear cells from patients with tuberculoid leprosy responded more strongly to M. leprae antigens. These findings indicate that cell-mediated immunity to L. pneumophila develops in patients with Legionnaires' disease and, taken together with previously reported findings, that cell-mediated immunity plays a major role in host defense against L. pneumophila. The monocyte activation assay described in this paper has general applicability for the study of monocyte and mononuclear cell effector functions in selected patients. The assay may be used to study (a) the capacity of a patient's monocytes to be activated to an antimicrobial potential by a standard preparation of cytokines and (b) the capacity of a patient's mononuclear cells to generate such monocyte-activating cytokines in response to a mitogen or antigen.
The APC Protein and E-cadherin Form Similar but Independent Complexes with α-Catenin, β-Catenin, and Plakoglobin (1995)

The tumor suppressor APC protein associates with the cadherin-binding proteins alpha- and beta-catenin. To examine the relationship between cadherin, catenins, and APC, we have tested combinatorial protein-protein interactions in vivo, using a yeast two-hybrid system, and in vitro, using purified proteins. beta-Catenin directly binds to APC at high and low affinity sites. alpha-Catenin cannot directly bind APC but associates with it by binding to beta-catenin. Plakoglobin, also known as gamma-catenin, directly binds to both APC and alpha-catenin and also to the APC-beta-catenin complex, but not directly to beta-catenin. beta-Catenin binds to multiple independent regions of APC, some of which include a previously identified consensus motif and others which contain the centrally located 20 amino acid repeat sequences. The APC binding site on beta-catenin may be discontinuous since neither the carboxyl- nor amino-terminal halves of beta-catenin will independently associate with APC, although the amino-terminal half independently binds alpha-catenin. The catenins bind to APC and E-cadherin in a similar fashion, but APC and E-cadherin do not associate with each other either in the presence or absence of catenins. Thus, APC forms distinct heteromeric complexes containing combinations of alpha-catenin, beta-catenin, and plakoglobin which are independent from the cadherin-catenin complexes.
A Regulatory SNP Causes a Human Genetic Disease by Creating a New Transcriptional Promoter (2006)

We describe a pathogenetic mechanism underlying a variant form of the inherited blood disorder alpha thalassemia. Association studies of affected individuals from Melanesia localized the disease trait to the telomeric region of human chromosome 16, which includes the alpha-globin gene cluster, but no molecular defects were detected by conventional approaches. After resequencing and using a combination of chromatin immunoprecipitation and expression analysis on a tiled oligonucleotide array, we identified a gain-of-function regulatory single-nucleotide polymorphism (rSNP) in a nongenic region between the alpha-globin genes and their upstream regulatory elements. The rSNP creates a new promoterlike element that interferes with normal activation of all downstream alpha-like globin genes. Thus, our work illustrates a strategy for distinguishing between neutral and functionally important rSNPs, and it also identifies a pathogenetic mechanism that could potentially underlie other genetic diseases.
Menaquinone (vitamin K2) biosynthesis: nucleotide sequence and expression of the menB gene from Escherichia coli (1992)

In Escherichia coli, the biosynthesis of the electron carrier menaquinone (vitamin K2) involves at least seven identified enzymes. One of these, naphthoate synthase, forms the bicyclic ring system by catalyzing the conversion of o-succinylbenzoyl-coenzyme A to 1,4-dihydroxy-2-naphthoic acid. The gene for this enzyme has been previously identified as menB. By genetic and biochemical tests, a 1.349-kb DNA fragment from the E. coli men locus complements menB mutants. This fragment contains a single 285-codon open reading frame (ORF). Recombinant plasmids containing deletions of either the amino or the carboxy region of the ORF fail to complement the mutants. The ORF is preceded by consensus sequences for a ribosomal binding site and a sigma 70 promoter. menB transcription sufficient to complement the menB mutant in vivo and in vitro can be initiated from the identified putative promoter, and that in the constructs, menB expression, can be made independent of read-through transcription from the lac promoter. However, multicopy plasmids containing menB fail to generate the expected levels of enzymatic activity.
Sequence determinants of cytosolic N-terminal protein processing (1986)

N-terminal methionine removal has been analyzed statistically in a large sample of prokaryotic and eukaryotic cytosolic proteins in an attempt to uncover common sequence determinants. We find that the residue next to the initiator Met is the most important determinant of N-terminal processing: Lys, Arg, Leu and (in prokaryotes) Phe and Ile protect the initiator Met from being removed when next to it in the sequence; Ala, Gly, Pro, Ser, Thr and (in eukaryotes) Val in this position cause its removal. Subsequent acetylation is confirmed to be strongly biased towards Ala, Met and Ser residues; when Met is acetylated, Asp is the predominant penultimate residue in eukaryotes. Also, we find major differences in the relative abundance of the various residues next to the initiator Met between prokaryotes and eukaryotes: prokaryotic proteins are much more biased towards Lys as the Met-protecting residue, and towards Ala when met is to be removed, than eukaryotic ones. Finally, we show that our results can explain a part of the mRNA 'consensus sequence' found around eukaryotic initiator AUG codons.
A potential role for bacterial endophytes in phytoremediation of heavy metal contaminated soils (2016)

This thesis aims to study the potential contribution of heavy metal resistant endophytic bacteria on heavy metal uptake and translocation processes by their host plant. The extensive study of bacterial heavy metal resistance mechanisms showed that metal bioprecipitation processes near the bacterial cell wall are often found to be a consequence of efflux based systems that reduce the bioavailable metal concentration present. Heavy metal resistant endophytic bacteria with a similar behaviour would possibly result in a lowered heavy metal bioavailability that consequently would lead to a lowered heavy metal toxicity or an improved heavy metal accumulation within the host plant. Based on this concept, new strategies to improve phytoremediation would be developed.
Shiver Motion and Core Body Temperature Classification for Wearable Soldier Health Monitoring Systems (2004)

We present a wearable real-time shiver monitor based on the MIThril LiveNet system, a flexible distributed mobile platform that can be used for a variety of proactive healthcare applications. In this exploratory study, we demonstrate that shivering can be accurately determined from continuous accelerometer sensing. Our preliminary results also indicate that shivering characteristics may be correlated with core body temperature, indicating the potential for creating a real-world cold exposure monitoring and classification wearable system.
Murine monoclonal anti-idiotope antibody breaks unresponsiveness and induces a specific antibody response to human melanoma-associated proteoglycan antigen in cynomolgus monkeys. (1992)

The mouse monoclonal antibody MEM136 (mAb1) is directed against an epitope on human melanoma-associated proteoglycan antigen (MPG). This epitope is also present on various normal human and subhuman tissues. A monoclonal murine anti-idiotope (anti-Id) antibody (mAb2), designated I-Mel-2, was generated against MEM136 and used as a surrogate antigen for the MPG molecule. I-Mel-2 was tested in cynomolgus monkeys (Macaca fascicularis) for its ability to induce anti-MPG humoral responses. All monkeys immunized with Ab2 developed specific anti-anti-idiotype (Ab3) responses that were capable of inhibiting binding of Ab2 to Ab1. Furthermore, I-Mel-2 immune monkey serum contained anti-MPG antibodies (Ab1') that bound to MPG-positive but not to MPG-negative melanoma cell lines. Monkeys immunized with Colo38 melanoma cells (membrane-bound MPG antigen) did not contain anti-MPG antibodies that inhibited the binding of two distinct anti-MPG mAb 125I-labeled MEM136 or 125I-labeled 225.28 to Colo38 cells. The induction of anti-MPG responses in monkeys did not cause any apparent side effects in animals, despite the fact that the MPG antigen is expressed by many normal tissues. The affinity-purified, I-Mel-2 idiotype-specific, Ab3 immunoprecipitated MPG antigen from melanoma cells. Furthermore, the I-Mel-2-induced Ab3 inhibited melanoma cell invasion in an in vitro assay, implying that these antibodies have biological significance.
Molecular Biology and Pathogenicity of Mycoplasmas (1998)

The recent sequencing of the entire genomes of Mycoplasma genitalium and M. pneumoniae has attracted considerable attention to the molecular biology of mycoplasmas, the smallest self-replicating organisms. It appears that we are now much closer to the goal of defining, in molecular terms, the entire machinery of a self-replicating cell. Comparative genomics based on comparison of the genomic makeup of mycoplasmal genomes with those of other bacteria, has opened new ways of looking at the evolutionary history of the mycoplasmas. There is now solid genetic support for the hypothesis that mycoplasmas have evolved as a branch of gram-positive bacteria by a process of reductive evolution. During this process, the mycoplasmas lost considerable portions of their ancestors' chromosomes but retained the genes essential for life. Thus, the mycoplasmal genomes carry a high percentage of conserved genes, greatly facilitating gene annotation. The significant genome compaction that occurred in mycoplasmas was made possible by adopting a parasitic mode of life. The supply of nutrients from their hosts apparently enabled mycoplasmas to lose, during evolution, the genes for many assimilative processes. During their evolution and adaptation to a parasitic mode of life, the mycoplasmas have developed various genetic systems providing a highly plastic set of variable surface proteins to evade the host immune system. The uniqueness of the mycoplasmal systems is manifested by the presence of highly mutable modules combined with an ability to expand the antigenic repertoire by generating structural alternatives, all compressed into limited genomic sequences. In the absence of a cell wall and a periplasmic space, the majority of surface variable antigens in mycoplasmas are lipoproteins. Apart from providing specific antimycoplasmal defense, the host immune system is also involved in the development of pathogenic lesions and exacerbation of mycoplasma induced diseases. Mycoplasmas are able to stimulate as well as suppress lymphocytes in a nonspecific, polyclonal manner, both in vitro and in vivo. As well as to affecting various subsets of lymphocytes, mycoplasmas and mycoplasma-derived cell components modulate the activities of monocytes/macrophages and NK cells and trigger the production of a wide variety of up-regulating and down-regulating cytokines and chemokines. Mycoplasma-mediated secretion of proinflammatory cytokines, such as tumor necrosis factor alpha, interleukin-1 (IL-1), and IL-6, by macrophages and of up-regulating cytokines by mitogenically stimulated lymphocytes plays a major role in mycoplasma-induced immune system modulation and inflammatory responses.
A clustering scheme (1983)

In this paper, a new clustering algorithm has been described. The algorithm proposed determines both the number of clusters in a collection, and the number of elements in each cluster before beginning the final clustering process. The complexity assessment of the algorithm and the implementation issues are also emphasized.
Dispersed human lung mast cells. Pharmacologic aspects and comparison with human lung tissue fragments. (1982)

The present investigation was designed to study the histamine release and pharmacologic characteristics of dispersed human lung mast cells, particularly in comparison with parenchymal tissue fragments. Dispersed human lung mast cells were prepared by enzymatic treatment (yield, 0.5 to 2 x 10(6) mast cells/g tissue). Purity was 1 to 8% (mean, 3.6% +/- 0.7%), and histamine content varied from 2 to 6 pg/cell (mean, 3.6 +/- 0.5 pg/cell). Release, studied using anti-IgE as the stimulus, was relatively rapid, being essentially complete within 15 min when high concentrations of anti-IgE (greater than or equal to 0.3 microgram/ml) were used and was not enhanced by phosphatidyl serine. The concentration of drug required to inhibit histamine release by 50% in dispersed cells for a series of pharmacologic agents, including the beta-adrenergic agent fenoterol, the prostaglandin E2, and the phosphodiesterase inhibitor isobutylmethylxanthine, were 0.1 to 1 microM, 50 microM, and 0.5 mM, respectively; similar results were obtained in simultaneous experiments performed using tissue fragments. Adenosine enhanced release (19 +/- 3.4%) at low concentrations (10 microM) and inhibited release (61 +/- 5.1%) at high concentrations (1mM). The H2 agonist, dimaprit (at 10(-5) to 10(-7) M) and prostaglandin D2 (at 10(-4) to 10(-6) M) had no effect on histamine release, whereas deuterium oxide potentiated histamine release. This study serves to quantitate the pharmacologic effects of several agents on anti-IgE-mediated histamine release from dispersed human lung mast cells and has further suggested that the dispersed cell system is similar to the standard chopped lung system in dose-response relationships, kinetics, and pharmacologic modulation. It also indicates that the enzymatic treatment of the cells does not affect the release characteristics or functional capacity of several different receptors, and that this preparation, therefore, appears suitable as an in vitro human model of mediator release that can be used for the evaluation of pharmacologic agents and for further mast cell purification.
Microarray Technology as a Universal Tool for High-Throughput Analysis of Biological Systems (2006)

Over the last years microarray technology has become one of the principal platform technologies for the high-throughput analysis of biological systems. Starting with the construction of first DNA microarrays in the 1990s, microarray technology has flourished in the last years and many different new formats have been developed. Peptide and protein microarrays are now applied for the elucidation of interaction partners, modification sites and enzyme substrates. Antibody microarrays are envisaged to be of high importance for the high-throughput determination of protein abundances in translational profiling approaches. First cell microarrays have been constructed to transform microarray technology from an in vitro technology to an in vivo functional analysis tool. All of these approaches share a common prerequisite: the solid support on which they are generated. The demands on this solid support are thereby as manifold as the applications themselves. This review is aimed to display the recent developments in surface chemistry and derivatization, and to summarize the latest developments in the different application areas of microarray technology.
An enzymatic mutant of Shiga-like toxin II variant is a vaccine candidate for edema disease of swine (1992)

Edema disease (ED) of weanling pigs is caused by an infection with Escherichia coli that produces Shiga-like toxin II variant (SLT-IIv). Pathology identical to that caused by ED can be duplicated in pigs that are injected with less than 10 ng of purified SLT-IIv per kg of body weight. Therefore, SLT-IIv was mutated to create an immunoreactive form of the toxin that was significantly reduced in enzymatic activity. Initially, purified SLT-IIv was treated with formaldehyde which abrogated cytotoxic activity. Pigs were vaccinated with the toxoid (100 micrograms) to determine whether a toxoid was a viable vaccine candidate and whether young pigs were capable of mounting an immune response. Although the pigs developed a neutralizing antibody titer (1:128 to 1:512) 28 days postinjection, they also lost weight and developed ED lesions. The deleterious effect of the toxoid appeared to result from residual enzymatic activity or a reversion to a toxic form. An alternative method, site-directed mutagenesis, was employed to consistently reduce the enzymatic activity of SLT-IIv. Glutamate at position 167 of the mature A subunit was replaced by aspartate (E167D), and arginine at position 170 was replaced by lysine (R170K). These mutations reduced cytotoxic activity 10(4)-fold and 10-fold, respectively, while the enzymatic activities were decreased 400-fold and 5-fold, respectively. The activity of a toxin that contained both mutations (SLT-IIvE167D/R170K) closely resembled that of SLT-IIvE167D. When position 167 was replaced by glutamine (E167Q), the cytotoxic activity decreased 10(6)-fold and the enzymatic activity decreased approximately 1,500-fold. Pigs that were vaccinated with purified, mutant toxin designated SLT-IIvE167Q developed a neutralizing antibody titer of 1:512 21 days postinjection, and their tissues were free of ED lesions. These data suggest that SLT-IIvE167Q may represent an effective vaccine against ED.
Functional activation of the long terminal repeat of human T-cell leukemia virus type I by a trans-acting factor. (1985)

Promoter function for gene expression of the long terminal repeat (LTR) of human T-cell leukemia virus type I (HTLV-I) was studied by constructing plasmids containing the LTR sequence. The gene encoding chloramphenicol acetyltransferase (CATase) was linked to an HTLV-I LTR sequence (pLTR-CAT) by replacing the simian virus 40 promoter in plasmid pSV2-CAT with the LTR sequence. The transient CATase activities of cells transfected with the plasmids were compared. The results are summarized as follows: The HTLV LTR was active even in an epithelial cell line, with efficiency similar to that of the simian virus 40 promoter. pLTR-CAT expressed high CATase activity, 40-200 times that expressed by pSV2-CAT, in HTLV-I-infected T-cell lines, such as the human cell lines MT-2 and HUT-102, or in HTLV-I-infected rat cell lines. This enhanced activity of the LTR seems to be associated with HTLV gene expression, since only low activity of pLTR-CAT was observed in the HTLV-infected cell line MT-1, in which only a small percent of cells express viral antigens. In HTLV-infected rat cell lines, the pX-encoded protein p40x was the only viral protein detected. Thus, we suggest that p40x is the factor associated directly or indirectly with the enhanced activity of the LTR.
Sterile Endophthalmitis after Intravitreal Injections (2012)

Sterile endophthalmitis appears as an infrequent complication of intravitreal injections and seems to develop mainly in the context of the off-label use of drugs that have not been conceived for intravitreous administration. The aetiology of sterile endophthalmitis, independently of the administered drug, remains uncertain and a multifactorial origin cannot be discarded. Sterile inflammation secondary both to intravitreal triamcinolone acetonide and to intravitreal bevacizumab share many characteristics such as the acute and painless vision loss present in the big majority of the cases. Dense vitreous opacity is a common factor, while anterior segment inflammation appears to be mild to moderate. In eyes with sterile endophthalmitis, visual acuity improves progressively as the intraocular inflammation reduces without any specific treatment. If by any chance the ophthalmologist is not convinced by the sterile origin of the inflammation, this complication must be treated as an acute endophthalmitis because of the devastating visual prognosis of this intraocular infection in the absence of therapy.