gebhart/patrepeval huggingface dataset:
1743-P: Engineering Erythrocytes with the SQZ Cell Therapy Platform to Enhance Immunotolerance (2019)

Current treatments for autoimmune disorders typically rely on the use of broadly immunosuppressive agents that increase the risk of adverse events in patients, such as cancer and opportunistic infections. Antigen (Ag)-specific immunotherapies have the potential to minimize these risks and improve efficacy by generating Ag-specific suppression to maintain immunohomeostasis. Several studies have established Ag-specific tolerance using red blood cells (RBCs) as a platform for delivery and Ag presentation in the context of eryptosis, a mechanism of RBC clearance. Here, we used the SQZ cell therapy platform to create Agloaded, pro-eryptotic RBCs to induce tolerance. In this approach, cells pass through constricted channels that cause transient permeation of the cell membrane and permit diffusion of cargo before the membrane reseals. In mice, we demonstrated that these highly delivered RBCs are rapidly cleared from circulation by splenic and liver-resident macrophages. The administration of ovalbumin (OVA)-SQZ’d RBCs led to a reduction of OVA-specific T cell proliferation and cytokine production in an OVA immunization model. In an autoimmune diabetes BDC2.5 T cell transfer model, mice treated with RBCs SQZ’d with 1040-p31 peptide mimetope delayed the onset of hyperglycemia in 80% of mice. Additionally, we developed mouse models for adenoassociated virus (AAV)-gene therapy and anti-drug antibody (ADA) to examine immunemediated clearance of exogenous Ag. In the AAV vector-specific model, mice treated with RBCs loaded with AAV-derived peptides abrogated the effector responses of AAV-specific CD8+ T cells upon restimulation. In a model of ADA responses, RBCs SQZ’d with a model drug also led to potent inhibition of ADA responses and preserved drug levels in circulation. In summary, SQZ’d RBCs are a potentially exciting allogeneic cell therapy strategy to induce Ag-specific tolerance across a range of disease mechanisms and indications. Disclosure A. Ramakrishnan: None. T. Lee: None. L.J. Moore: None. A. Vicente Suarez: None. F. Moore: None. H. Bernstein: Employee; Self; SQZ Biotechnologies. Funding JDRF
Human high molecular weight-melanoma associated antigen mimicry by an anti-idiotypic antibody: characterization of the immunogenicity and the immune response to the mouse monoclonal antibody IMel-1. (1991)

The mouse anti-idiotype (anti-id) monoclonal antibody (mAb) IMel-1 recognizes an idiotope in the antigen combining site of the immunizing anti-human high molecular weight melanoma-associated antigen (HMW-MAA) mAb 225.28. The mAb IMel-1 is able to induce an immune response against self cross-reacting HMW-MAA in rabbits that express HMW-MAA in normal tissues. Most of the rabbit anti-anti-id antibodies recognize a spatially distant determinant(s) from that defined by anti-HMW-MAA mAb 225.28. The immunogenicity of mAb IMel-1 is enhanced by its administration with the muramyl dipeptide-derived adjuvant. Anti-HMW-MAA antibodies were not detected in sera from rabbits immunized with HMW-MAA bearing cultured human melanoma cells. The differential immunogenicity of mAb IMel-1 and cell membrane bound HMW-MAA may account for the ability of anti-id mAb to induce anti-HMW-MAA immunity in patients who have not mounted such a response to HMW-MAA present in their lesions. Rabbit anti-HMW-MAA antibodies induced by anti-id mAb IMel-1 inhibited interactions of melanoma cells with elements of extracellular matrix. This may represent an additional mechanism by which anti-HMW-MAA immunity may affect the biology of melanoma cells in patients with melanoma immunized with anti-id mAb IMel-1.
Clinical and Neuropathological Correlates of Apolipoprotein E Genotype in Dementia with Lewy Bodies (2002)

Dementia with Lewy bodies (DLB) represents the second commonest cause of dementia in the elderly following Alzheimer's disease (AD). Whilst the presence of Lewy bodies is essential, DLB shares with AD the presence of senile plaques (SP), but neurofibrillary tangles (NFT) are not a necessary feature. The apolipoprotein E (APO E) epsilon4 allele is the most consistently associated genetic risk factor for AD and has also been shown to associate with DLB. We have therefore analysed the APO E epsilon4 allele in a large series of DLB cases coming to autopsy to: (1) determine if the epsilon4 allele describes a similar risk in DLB development as in AD and (2) determine how APO E epsilon4 allele status correlates with clinical and neuropathological findings in DLB, and in AD, as an indication of the role of APO E in underlying disease biology. Both DLB and AD share an increased epsilon4 allele frequency, though in DLB the epsilon2 allele frequency is not reduced and there is a relative lack of epsilon4 homozygotes. In contrast to previous studies, no association of the epsilon4 allele with age at onset or duration of disease was found in either disorders. In DLB cases, overall a significantly shorter duration of illness was observed when compared with AD cases, though no significant effect of the epsilon4 allele on disease onset or duration was seen. The survival rate was reduced by the presence of the epsilon4 allele in DLB, as with AD. No effect on SP or NFT counts was seen with the epsilon4 allele, though DLB cases showed a lower SP burden in addition to the expected lower NFT counts. This study demonstrates that DLB shares the APO epsilon4 allele with AD as a common risk factor, but that there are differences in the way the epsilon4 allele affects the phenotypic expression of disease.
Advances in biological markers for cancer. (1983)

The following serum tumor markers are elevated above normal levels in 50 percent or more of patients with various malignant neoplasms: Alpha-fetoprotein in yolk sac tumors, hepatomas, retinoblastomas, embryonal carcinomas, breast carcinomas, and carcinomas of uterine cervix; Carcinoembryonic antigen in colon carcinomas, choriocarcinomas, pancreatic carcinomas, medullary thyroid carcinomas, osteosarcomas, retinoblastomas, ovarian cystadenocarcinomas, mycosis fungoides, hepatomas, esophageal carcinomas, adenocarcinomas of uterine cervix, lung carcinomas, carcinomas of small intestine, urinary bladder carcinomas, and renal cell carcinomas; Human chorionic gonadotrophin in choriocarcinomas, malignant interstitial cell tumors of testis, non seminomatous tumors of testis, embryonal carcinomas, and pancreatic carcinomas. Combined use of these three markers increases the probability of finding one of them to be elevated in selected cases of malignancy. There will be further advances in biological markers for cancer, but the existence of a specific marker is questionable.
Activation of antigen-presenting cells by microbial products breaks self tolerance and induces autoimmune disease (2004)

We describe the generation of mice that express a transgenic T cell receptor (TCR) (5B6) specific for the encephalitogenic myelin proteolipid protein (PLP) peptide 139-151, on the experimental autoimmune encephalomyelitis-resistant (EAE-resistant) B10.S background. Despite harboring a high frequency of self-reactive T cells, 5B6 transgenic mice on the B10.S background rarely develop spontaneous EAE, which is in striking contrast to 5B6 transgenic mice on the EAE-susceptible SJL background. The relative resistance to spontaneous EAE in transgenic B10.S mice is not due to deletion or anergy of T cells, but appears to be controlled by APCs. Analysis of APCs revealed a lower activation state and a lower T cell-activating capacity for APCs from B10.S mice than for those from EAE-susceptible SJL mice. When APCs in 5B6 transgenic B10.S mice were activated, for example, via TLR9 or TLR4, T cell tolerance was broken, resulting in EAE. Our findings demonstrate that activation of APCs via innate immune receptors can break self tolerance and trigger the development of autoimmunity even in a genetically resistant strain. These findings suggest that the development of autoimmune diseases such as multiple sclerosis is determined at least partly by the endogenous activation state of APCs.
Changes in urinary metabolomic profile during relapsing renal vasculitis (2016)

Current biomarkers of renal disease in systemic vasculitis lack predictive value and are insensitive to early damage. To identify novel biomarkers of renal vasculitis flare, we analysed the longitudinal urinary metabolomic profile of a rat model of anti-neutrophil cytoplasmic antibody (ANCA) vasculitis. Wistar-Kyoto (WKY) rats were immunised with human myeloperoxidase (MPO). Urine was obtained at regular intervals for 181 days, after which relapse was induced by re-challenge with MPO. Urinary metabolites were assessed in an unbiased fashion using nuclear magnetic resonance (NMR) spectroscopy, and analysed using partial least squares discriminant analysis (PLS-DA) and partial least squares regression (PLS-R). At 56 days post-immunisation, we found that rats with vasculitis had a significantly different urinary metabolite profile than control animals; the observed PLS-DA clusters dissipated between 56 and 181 days, and re-emerged with relapse. The metabolites most altered in rats with active or relapsing vasculitis were trimethylamine N-oxide (TMAO), citrate and 2-oxoglutarate. Myo-inositol was also moderately predictive. The key urine metabolites identified in rats were confirmed in a large cohort of patients using liquid chromatography-mass spectrometry (LC-MS). Hypocitraturia and elevated urinary myo-inositol remained associated with active disease, with the urine myo-inositol:citrate ratio being tightly correlated with active renal vasculitis.
Tunable digital material properties for 3D voxel printers (2010)

Purpose Digital materials are composed of many discrete voxels placed in a massively parallel layer deposition process, as opposed to continuous (analog) deposition techniques. The purpose of this paper is to explore the wide range of material properties attainable using a voxel‐based freeform fabrication process, and demonstrate in simulation the versatility of fabricating with multiple materials in this manner. Design/methodology/approach A representative interlocking voxel geometry was selected, and a nonlinear physics simulator was implemented to perform virtual tensile tests on blocks of assembled voxels of varying materials. Surface contact between tiles, plastic deformation of the individual voxels, and varying manufacturing precision were all modeled. Findings By varying the precision, geometry, and material of the individual voxels, continuous control over the density, elastic modulus, coefficient of thermal expansion, ductility, and failure mode of the material is obtained. Also, the effects of several hierarchical voxel “microstructures” are demonstrated, resulting in interesting properties such as negative Poisson's ratio. Research limitations/implications This analysis is a case study of a specific voxel geometry, which is representative of 2.5D interlocking shapes but not necessarily all types of interlocking voxels. Practical implications The results imply that digital materials can exhibit widely varying and tunable properties in a single desktop fabrication process. Originality/value The paper explores the vast potential of tunable materials, especially using the concept of voxel microstructure, applicable primarily to 3D voxel printers but also to other multi‐material freeform fabrication processes.
Intracranially administered anti-Abeta antibodies reduce beta-amyloid deposition by mechanisms both independent of and associated with microglial activation. (2003)

Active immunization against the beta-amyloid peptide (Alphabeta) with vaccines or passive immunization with systemic monoclonal anti-Abeta antibodies reduces amyloid deposition and improves cognition in APP transgenic mice. In this report, intracranial administration of anti-Alphabeta antibodies into frontal cortex and hippocampus of Tg2576 transgenic APP mice is described. The antibody injection resulted initially in a broad distribution of staining for the antibody, which diminished over 7 d. Although no loss of immunostaining for deposited Abeta was apparent at 4 hr, a dramatic reduction in the Alphabeta load was discernible at 24 hr and was maintained at 3 and 7 d. A reduction in the thioflavine-S-positive compact plaque load was delayed until 3 d, at which time microglial activation also became apparent. At 1 week after the injection, microglial activation returned to control levels, whereas Alphabeta and thioflavine-S staining remained reduced. The results from this study suggest a two-phase mechanism of anti-Alphabeta antibody action. The first phase occurs between 4 and 24 hr, clears primarily diffuse Alphabeta deposits, and is not associated with observable microglial activation. The second phase occurs between 1 and 3 d, is responsible for clearance of compact amyloid deposits, and is associated with microglial activation. The results are discussed in the context of other studies identifying coincident microglial activation and amyloid removal in APP transgenic animals.
Lipoid proteinosis maps to 1q21 and is caused by mutations in the extracellular matrix protein 1 gene (ECM1) (2002)

Lipoid proteinosis (LP), also known as hyalinosis cutis et mucosae or Urbach-Wiethe disease (OMIM 247100) is a rare, autosomal recessive disorder typified by generalized thickening of skin, mucosae and certain viscera. Classical features include beaded eyelid papules and laryngeal infiltration leading to hoarseness. Histologically, there is widespread deposition of hyaline (glycoprotein) material and disruption/reduplication of basement membrane. The aetiology of LP is currently unknown. Using DNA from three affected siblings in a consanguineous Saudi Arabian family we performed genome-wide linkage and mapped the disorder to 1q21 (marker D1S498) with a two-point LOD score of 3.45 at theta = 0. A further 28 affected individuals from five other unrelated consanguineous family groups from different geographical regions also showed complete linkage and resulted in a maximum two-point LOD score of 21.85 at theta = 0. Using available markers in the interval between D1S442 and D1S305, the observed recombinants placed the gene in a 2.3 cM critical interval between D1S2344 and D1S2343 (Marshfield genetic map) corresponding to an approximately 6.5 Mb region on the UCSC physical map. Using a candidate gene approach (comparison of control versus LP gene expression in cultured fibroblasts) and subsequent direct sequencing of genomic DNA, we identified six different homozygous loss-of-function mutations in the extracellular matrix protein 1 gene (ECM1). Although the precise function of ECM1 is not known, our findings provide the first clinical indication of its relevance to skin adhesion, epidermal differentiation, wound healing, scarring, angiogenesis/angiopathy and basement membrane physiology, as well as defining the molecular basis of this inherited disorder.
A Precisely Regulated Gene Expression Cassette Potently Modulates Metastasis and Survival in Multiple Solid Cancers (2008)

Successful tumor development and progression involves the complex interplay of both pro- and anti-oncogenic signaling pathways. Genetic components balancing these opposing activities are likely to require tight regulation, because even subtle alterations in their expression may disrupt this balance with major consequences for various cancer-associated phenotypes. Here, we describe a cassette of cancer-specific genes exhibiting precise transcriptional control in solid tumors. Mining a database of tumor gene expression profiles from six different tissues, we identified 48 genes exhibiting highly restricted levels of gene expression variation in tumors (n = 270) compared to nonmalignant tissues (n = 71). Comprising genes linked to multiple cancer-related pathways, the restricted expression of this "Poised Gene Cassette" (PGC) was robustly validated across 11 independent cohorts of approximately 1,300 samples from multiple cancer types. In three separate experimental models, subtle alterations in PGC expression were consistently associated with significant differences in metastatic and invasive potential. We functionally confirmed this association in siRNA knockdown experiments of five PGC genes (p53CSV, MAP3K11, MTCH2, CPSF6, and SKIP), which either directly enhanced the invasive capacities or inhibited the proliferation of AGS cancer cells. In primary tumors, similar subtle alterations in PGC expression were also repeatedly associated with clinical outcome in multiple cohorts. Taken collectively, these findings support the existence of a common set of precisely controlled genes in solid tumors. Since inducing small activity changes in these genes may prove sufficient to potently influence various tumor phenotypes such as metastasis, targeting such precisely regulated genes may represent a promising avenue for novel anti-cancer therapies.
Fatty Acid Composition of the Complex Lipids ofStaphylococcus aureusDuring the Formation of the Membrane-bound Electron Transport System (1968)

In Staphylococcus aureus, 64 fatty acids could be separated by gas-liquid chromatography. The fatty acids consisted of normal, iso, and anteiso saturated fatty acids of from 10 to 21 carbon atoms. Of the total fatty acids, 2 to 4% were normal, iso, and anteiso monoenoic fatty acids. Positional isomers of the normal monoenoic fatty acids could be detected. The fatty acids could be extracted, leaving 1 to 2% of the total fatty acids in the residue. The proportions of the fatty acids in the residue and the total lipids differed significantly. The lipid extract contained less than 0.12% free fatty acid. Between 5 and 10% of the lipid fatty acids were associated with neutral lipids. The majority of the fatty acids were associated with the complex lipids: mono- and diglucosyl diglyceride, phosphatidyl glycerol, lysyl phosphatidyl glycerol, and cardiolipin. The proportions of the fatty acids changed markedly between bacteria grown anaerobically (no membrane-bound electron transport system) and those grown aerobically (containing a functional electron transport system). In each of the complex lipids, the proportions of the fatty acids, as well as the magnitude and direction of change in the molar quantity of the fatty acids per bacterium, changed dramatically between these growth conditions. Since the glucosyl diglycerides and phospholipids were formed from the same pool of diglyceride intermediates, the marked differences in fatty acids indicate that acyl transferase activities must be an important part of complex lipid metabolism in S. aureus.
Children with Persistent Cough – Outcome with Treatment and Role of Moraxella catarrhalis? (1994)

52 children with severe cough persisting for more than 10 days were randomized to treatment with amoxycillin/clavulanic acid or placebo in a prospective double-blinded study. Clinically suspected cases of pertussis were excluded, yet 12 (23%) of the children had laboratory verified pertussis infection. The nasopharyngeal colonization showed a predominance of Moraxella catarrhalis which was isolated in 37 (71%) children. Streptococcus pneumoniae and Haemophilus influenzae were isolated in 11 (20%) and 16 (30%) children, respectively. The antibiotic-treated group had a significantly better recovery in both the pediatrician's estimation (p = 0.02) and the independent parental judgement (p = 0.002). These findings are consistent with the view that Moraxella catarrhalis could be directly involved in the pathogenesis of persistent cough in children.
Novel Caprine Adeno-Associated Virus (AAV) Capsid (AAV-Go.1) Is Closely Related to the Primate AAV-5 and Has Unique Tropism and Neutralization Properties (2005)

Preexisting humoral immunity to adeno-associated virus (AAV) vectors may limit their clinical utility in gene delivery. We describe a novel caprine AAV (AAV-Go.1) capsid with unique biological properties. AAV-Go.1 capsid was cloned from goat-derived adenovirus preparations. Surprisingly, AAV-Go.1 capsid was 94% identical to the human AAV-5, with differences predicted to be largely on the surface and on or under the spike-like protrusions. In an in vitro neutralization assay using human immunoglobulin G (IgG) (intravenous immune globulin [IVIG]), AAV-Go.1 had higher resistance than AAV-5 (100-fold) and resistance similar to that of AAV-4 or AAV-8. In an in vivo model, SCID mice were pretreated with IVIG to generate normal human IgG plasma levels prior to the administration of AAV human factor IX vectors. Protein expression after intramuscular administration of AAV-Go.1 was unaffected in IVIG-pretreated mice, while it was reduced 5- and 10-fold after administration of AAV-1 and AAV-8, respectively. In contrast, protein expression after intravenous administration of AAV-Go.1 was reduced 7.1-fold, similar to the 3.8-fold reduction observed after AAV-8 administration in IVIG-pretreated mice, and protein expression was essentially extinguished after AAV-2 administration in mice pretreated with much less IVIG (15-fold). AAV-Go.1 vectors also demonstrated a marked tropism for lung when administered intravenously in SCID mice. The pulmonary tropism and high neutralization resistance to human preexisting antibodies suggest novel therapeutic uses for AAV-Go.1 vectors, including targeting diseases such as cystic fibrosis. Nonprimate sources of AAVs may be useful to identify additional capsids with distinct tropisms and high resistance to neutralization by human preexisting antibodies.
Comparative tumor localization of whole immunoglobulin g anticarcinoembryonic antigen monoclonal antibodies immu-4 and immu-4 f(ab′)2 in colorectal cancer patients (1994)

In short, the biodistribution and pharmacokinetics of IMMU-4 F(ab')2 were comparable to those of IMMU-4-IgG.
Transglutaminases: Nature’s biological glues (2002)

Transglutaminases (Tgases) are a widely distributed group of enzymes that catalyse the post-translational modification of proteins by the formation of isopeptide bonds. This occurs either through protein cross-linking via epsilon-(gamma-glutamyl)lysine bonds or through incorporation of primary amines at selected peptide-bound glutamine residues. The cross-linked products, often of high molecular mass, are highly resistant to mechanical challenge and proteolytic degradation, and their accumulation is found in a number of tissues and processes where such properties are important, including skin, hair, blood clotting and wound healing. However, deregulation of enzyme activity generally associated with major disruptions in cellular homoeostatic mechanisms has resulted in these enzymes contributing to a number of human diseases, including chronic neurodegeneration, neoplastic diseases, autoimmune diseases, diseases involving progressive tissue fibrosis and diseases related to the epidermis of the skin. In the present review we detail the structural and regulatory features important in mammalian Tgases, with particular focus on the ubiquitous type 2 tissue enzyme. Physiological roles and substrates are discussed with a view to increasing and understanding the pathogenesis of the diseases associated with transglutaminases. Moreover the ability of these enzymes to modify proteins and act as biological glues has not gone unnoticed by the commercial sector. As a consequence, we have included some of the present and future biotechnological applications of this increasingly important group of enzymes.