gebhart/patrepeval huggingface dataset:
Single amino acid changes in DR and antigen define residues critical for peptide-MHC binding and T cell recognition (1991)

Single amino acid substitutions of Ag and MHC were used to analyze the fine structure of the influenza hemagglutinin (HA)-derived epitope (HA 307-319) recognized in the context of DR7 molecules by a T cell clone. Putative T cell (HA 308, 310, 311, 313, and 316) and DR (HA 309, 312, and 317) contact residues of the Ag were identified by the use of single amino acid-substituted analogs that were tested for their T cell-activating and DR-binding capacities. The peptide-DR7-T cell interaction was further characterized by the use of a panel of 13 site-directed DR7 mutant transfectants analyzed for their capacity to present Ag to T cells, and for their purified mutant DR7 molecules to bind HA 307-319 or its single amino acid-substituted analogs. Eight mutants lost their Ag-presenting function, whereas only one had any decrease in peptide binding. Finally, for three of the mutants it was possible to correct the deleterious effects of mutation by using a particular single amino acid-substituted analog of the peptide molecule. The observed pattern of complementation led to a model that predicts that the Ag assumes an extended conformation, with a turn, in the binding groove, such that the following residues are in close proximity: DR 86-HA 309, DR 71-HA 312, DR 30-HA 314, and 315.
Quantitative assessment of the leukocyte infiltrate in ovarian cancer and its relationship to the expression of C-C chemokines. (1997)

We have defined the host leukocyte infiltrate in epithelial ovarian tumors and related this to the expression of C-C chemokines. Immunohistochemical analysis of 20 paraffin-embedded biopsies showed that the infiltrate was primarily composed of CD68+ macrophages and CD8+/CD45RO+ T cells (median values, 3700 cells/mm3 and 2200 cells/mm3, respectively). Natural killer cells, B cells, and mast cells occurred in lower numbers (median values, 0 to 200 cells/mm3). Eosinophils were rarely seen and neutrophils were mainly confined to blood vessels. More infiltrating cells were found in stromal than in tumor areas. Only macrophages occurred in significant numbers in areas of necrosis (P < 0.0005). Using in situ hybridization to mRNA, we examined expression of the chemokines MCP-1, MIP-1 alpha, MIP-1 beta, and RANTES. MCP-1 and MIP-1 alpha were expressed by significantly more cells than MIP-1 beta and RANTES (P < 0.005). In tumor epithelial areas, the predominant chemokine was MCP-1. MCP-1 and MIP-1 alpha were the predominant stromal chemokines. A significant correlation was found between the total number of CD8+ T cells and the number of cells expressing MCP-1 (rs = 0.63 and P < 0.003, respectively) and between the CD8+ population and RANTES-expressing cells (rs = 0.6 and P < 0.003). A correlation was also found between CD68+ macrophages and the number of cells expressing MCP-1 (rs = 0.50 and P = 0.026). We suggest that MCP-1 may be responsible for the leukocyte infiltrate in ovarian carcinomas, but the expression of other chemokines may determine its exact nature.
Identification of naturally processed peptides bound to the class I MHC molecule H‐2Kd of normal and TAP‐deficient cells (2006)

This report details the biochemical features of natural peptides selected by the H-2Kd class I MHC molecule. In normal cell lines, the length of the naturally processed peptides ranged from 8 to 18 amino acids, although the majority were 9-mers (16% were longer than nine residues). The binding motif for the 9-mer peptides was dominated by the presence of a tyrosine at P2 and an isoleucine/leucine at the P9 position. The P2 residue contributed most towards binding; and the short peptides bound better and formed longer-lived cell surface complexes than the long peptides, which bound poorly and dissociated rapidly. The longer peptides did not exhibit this strictly defined motif. Trimming the long peptides to their shorter forms did not enhance binding and conversely, extending the 9-mer peptides did not decrease binding. The long peptides were present on the cell-surface bound to H-2Kd (Kd) and were not intermediate products of the class I MHC processing pathway. Finally, in two different TAP-deficient cells the long peptides were the dominant species, which suggested that TAP-independent pathways selected for long peptides by class I MHC molecules.
Therapy of patients with malignant melanoma using a monoclonal antimelanoma antibody-ricin A chain immunotoxin. (1987)

We conducted a trial of a murine monoclonal antimelanoma antibody-ricin A chain immunotoxin (XOMAZYME-MEL) in 22 patients with metastatic malignant melanoma. The dose of immunotoxin administered ranged from 0.01 mg/kg daily for 5 days to 1 mg/kg daily for 4 days (total dose: 3.2 to 300 mg). Side effects observed in most patients were a transient fall in serum albumin with an associated fall in serum protein, weight gain, and fluid shifts resulting in edema. In addition, patients experienced mild to moderate malaise, fatigue, myalgia, decrease in appetite, and fevers. There was a transient decrease in voltage on electrocardiograms without clinical symptoms, change in serial echocardiograms or elevation of creatine phosphokinase MB isozyme levels. Symptoms consistent with mild allergic reactions were observed in three patients. The side effects were related to the dose of immunotoxin administered and were generally transient and reversible. Encouraging clinical results were observed, even after a single course of a low dose of immunotoxin. In addition, localization of antibody and A chain to sites of metastatic disease was demonstrated by immunoperoxidase staining of biopsy specimens. Additional studies are being conducted to continue the evaluation of safety and efficacy of immunotoxin therapy for malignancy.
Autocrine Adenosine Regulates Tumor Polyfunctional CD73+CD4+ Effector T Cells Devoid of Immune Checkpoints (2018)

The production of CD73-derived adenosine (Ado) by Tregs has been proposed as a resistance mechanism to anti-PD-1 therapy in murine tumor models. We reported that human Tregs express the ectonucleotidase CD39, which generates AMP from ATP, but do not express the AMPase CD73. In contrast, CD73 defined a subset of effector CD4<sup>+</sup> T cells (Teffs) enriched in polyfunctional Th1.17 cells characterized by expression of CXCR3, CCR6, and MDR1, and production of IL17A/IFNγ/IL22/GM-CSF. CD39<sup>+</sup> Tregs selectively targeted CD73<sup>+</sup> Teffs through cooperative degradation of ATP into Ado inhibiting and restricting the ability of CD73<sup>+</sup> Teffs to secrete IL17A. CD73<sup>+</sup> Teffs infiltrating breast and ovarian tumors were functionally blunted by Tregs expressing upregulated levels of CD39 and ATPase activity. Moreover, tumor-infiltrating CD73<sup>+</sup> Teffs failed to express inhibitory immune checkpoints, suggesting that CD73 might be selected under pressure from immune checkpoint blockade therapy and thus may represent a nonredundant target for restoring antitumor immunity.<b>Significance:</b> Polyfunctional CD73<sup>+</sup> T-cell effectors lacking other immune checkpoints are selectively targeted by CD39 overexpressing Tregs that dominate the breast tumor environment. <i>Cancer Res; 78(13); 3604-18. ©2018 AACR</i>.
Lymphocyte‐Bound Complement Activation Products as Biomarkers for Diagnosis of Systemic Lupus Erythematosus (2009)

Systemic lupus erythematosus (SLE) is frequently misdiagnosed due to the lack of definitive diagnostic tests. The purpose of this study was to determine specifically whether complement activation products (CAP) are deposited on lymphocytes of SLE patients and whether lymphocyte-bound CAP (LB-CAP) may serve as novel biomarkers for the diagnosis of SLE. We conducted a cross-sectional study of 224 patients with SLE, 179 patients with other diseases, and 114 healthy controls. LB-CAP on peripheral blood lymphocytes was measured by flow cytometry. Diagnostic utility of LB-CAP was determined by receiver operating characteristic (ROC) analysis. Significantly elevated levels of C4d and C3d were detected specifically on T and B lymphocytes (designated T-C4d, T-C3d, B-C4d, and B-C3d) of SLE patients. As diagnostic tools, T-C4d and B-C4d, respectively, were 56% sensitive/80% specific and 60% sensitive/82% specific in differentiating SLE from other diseases. Moreover, compared with measurement of anti-dsDNA, serum C3, or serum C4, measurement of T-C4d/B-C4d was significantly more sensitive in identifying SLE patients during a single clinic visit. This is the first investigation of lymphocytes bearing complement activation products in human disease. T-C4d and B-C4d have high diagnostic sensitivity and specificity for SLE and may have added value to current laboratory tests for SLE diagnosis.
Polo-like Kinase 1 Is Involved in Invasion through Extracellular Matrix (2007)

Polo-like kinase 1 (PLK1) has important functions in maintaining genome stability via its role in mitosis. Because PLK1 is up-regulated in many invasive carcinomas, we asked whether it may also play a role in acquisition of invasiveness, a crucial step in transition to malignancy. In a model of metaplastic basal-like breast carcinoma progression, we found that PLK1 expression is necessary but not sufficient to induce invasiveness through laminin-rich extracellular matrix. PLK1 mediates invasion via vimentin and beta1 integrin, both of which are necessary. We observed that PLK1 phosphorylates vimentin on Ser82, which in turn regulates cell surface levels of beta1 integrin. We found PLK1 to be also highly expressed in preinvasive in situ carcinomas of the breast. These results support a role for the involvement of PLK1 in the invasion process and point to this pathway as a potential therapeutic target for preinvasive and invasive breast carcinoma treatment.
Development of Controlled Heterogeneity on a Polymer-Ceramic Hydrogel Scaffold for Osteochondral Repair (2005)

Due to its intrinsically poor repair potential, injuries to articular cartilage do not heal and clinical intervention is required. Osteochondral grafts may improve healing while promoting integration with host tissue. We report here the development of an osteochondral graft based on a hybrid of a hyrogel and a polymer-bioactive glass composite (PLAGA-BG) microsphere scaffold. This novel osteochondral construct consists of three regions: gel-only, gel/composite interface, and a composite-only-region. The three phases differ in calcium phospate (Ca-P) or BG content. The objective of the current study is to investigate the effects of scaffold composition on chondrocyte response, and to evaluate the effects of co-culture on osteoblasts and chondrocyte growh and differentiation on the hybrid scaffold. The PLAGA-BG microsphere scaffold supported the growth of chondrocytes and initial results indicate that in the presence of BG, chondrocyte-mediated mineralization may be stimulated. Co-culture of osteoblasts and chondrocytes on the multi-phased scaffold with varied Ca-P content facilitated the formation of multiple matrix zones: a GAGrich chondrocyte region, an interfacial matrix rich in GAG+collagen, and a mineralized collagen matrix with osteoblasts. In summary, chondrocyte response has been optimized as a function of scaffold composition and the novel osteochondral graft has the potential to support the simultaneous formation of multiple types of tissue in vitro.
Human CD8+ T lymphocyte subsets that express HLA class I-specific inhibitory receptors represent oligoclonally or monoclonally expanded cell populations. (1996)

A small percentage of human T lymphocytes, predominantly CD8+ T cells, express receptors for HLA class 1 molecules of natural killer type (NK-R) that are inhibitory for T-cell antigen receptor (TCR)-mediated functions. In the present study, it is demonstrated that the various NK-R molecules typically expressed by NK cells are also expressed on periheral blood T lymphocytes. These CD3+ NK-R+ cells have a cell surface phenotype typical of memory cells as indicated by the expression of CD45RO and CD29 and by the lack of CD28 and CD45RA. Furthermore, by the combined use of anti-TCR V beta-specific antibodies and a semiquantitative polymerase chain reaction assay, the TCR repertoire in this CD3+ NK-R+ cell subset was found to be skewed; in fact, one or two V beta families were largely represented, and most of the other V beta s were barely detected. In addition, analysis of recombinant clones of the largely represented V beta families demonstrated that these V beta s were oligoclonally or monoclonally expanded.
TCFH–NMI: Direct Access to N-Acyl Imidazoliums for Challenging Amide Bond Formations (2018)

Challenging couplings of hindered carboxylic acids with non-nucleophilic amines to form amide bonds can be accomplished in high yields, and in many cases, with complete retention of the adjacent stereogenic centers using the combination of N, N, N', N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) and N-methylimidazole (NMI). This method allows for in situ generation of highly reactive acyl imidazolium ions, which have been demonstrated to be intermediates in the reaction. The reagent delivers high reactivity similar to acid chlorides with the ease of use of modern uronium reagents.
Downregulation of ovule-specific MADS box genes from petunia results in maternally controlled defects in seed development. (1997)

A maternally determined seed defect has been obtained by downregulation of the petunia MADS box genes Floral Binding Protein 7 (FBP7) and FBP11. These genes have been previously shown to play central roles in the determination of ovule identity. Aberrant development of the seed coat and consequent degeneration of the endosperm have been observed in transgenic plants in which these two genes are downregulated by cosuppression. Analysis of the expression pattern of FBP7 and FBP11 and genetic analysis confirmed the maternal inheritance of the phenotype. The FBP7 promoter was cloned and fused to reporter genes. One of these reporter genes was the BARNASE gene for targeted cell ablation. Our results indicate that FBP7 promoter activity is restricted to the seed coat of developing seeds and that it is completely silent in the gametophytically derived tissues. The mutants used in this study provided a unique opportunity to investigate one of the poorly understood aspects of seed development: the interaction of embryo, endosperm, and maternal tissues.
Proof of principle for transfusion of in vitro–generated red blood cells (2011)

In vitro RBC production from stem cells could represent an alternative to classic transfusion products. Until now the clinical feasibility of this concept has not been demonstrated. We addressed the question of the capacity of cultured RBCs (cRBCs) to survive in humans. By using a culture protocol permitting erythroid differentiation from peripheral CD34(+) HSC, we generated a homogeneous population of cRBC functional in terms of their deformability, enzyme content, capacity of their hemoglobin to fix/release oxygen, and expression of blood group antigens. We then demonstrated in the nonobese diabetes/severe combined immunodeficiency mouse that cRBC encountered in vivo the conditions necessary for their complete maturation. These data provided the rationale for injecting into one human a homogeneous sample of 10(10) cRBCs generated under good manufacturing practice conditions and labeled with (51)Cr. The level of these cells in the circulation 26 days after injection was between 41% and 63%, which compares favorably with the reported half-life of 28 ± 2 days for native RBCs. Their survival in vivo testifies globally to their quality and functionality. These data establish the proof of principle for transfusion of in vitro-generated RBCs and path the way toward new developments in transfusion medicine. This study is registered at http://www.clinicaltrials.gov as NCT0929266.
Glutamatergic hippocampal formation projections to prefrontal cortex in the rat are regulated by GABAergic inhibition and show convergence with glutamatergic projections from the limbic thalamus (1994)

Anatomic and physiologic studies in the rat have shown projections from the hippocampal formation (HF) and mediodorsal (MD) thalamic nucleus to the medial prefrontal cortex (mPFC). The authors used multi-barrel iontophoresis to: confirm the neurotransmitter used in the projection from HF to mPFC; investigate the role of GABAergic inhibition in the regulation of this projection; and examine the functional convergence of projections from HF and MD onto single mPFC neurons. During HF stimulation, nine cells (6%) showed excitation followed by prolonged inhibition, 39 cells (26%) showed prolonged inhibition alone and 100 cells (68%) showed no clear response. In a further 12 cells that showed no predrug excitation to HF stimulation (representing 16% of the cells in this category), iontophoresis of the GABAA antagonist bicuculline methiodide (BMI) revealed excitatory responses. A total of six mPFC cells (38% of the cells showing excitatory responses to HF stimulation) showed convergent excitation to HF and MD thalamic (or adjacent paratenial nucleus) stimulation. Five out of eight (63%) of the predrug or BMI-revealed excitatory responses of mPFC neurons to HF stimulation were selectively decreased after AMPA antagonist iontophoresis (either CNQX or DNQX). These data confirm that the HF projection to prefrontal cortex is, at least in part, glutamatergic; suggest that the responses of mPFC neurons to activity in this HF pathway are regulated by GABAergic inhibition; and indicate that projections from HF and MD converge onto single mPFC neurons.
Virulence of newcastle disease virus: what is known so far? (2011)

In the last decade many studies have been performed on the virulence of Newcastle disease virus (NDV). This is mainly due to the development of reverse genetics systems which made it possible to genetically modify NDV and to investigate the contribution of individual genes and genome regions to its virulence. However, the available information is scattered and a comprehensive overview of the factors and conditions determining NDV virulence is lacking. This review summarises, compares and discusses the available literature and shows that virulence of NDV is a complex trait determined by multiple genetic factors.
Dust-Free Bedrooms in the Treatment of Asthmatic Children with House Dust or House Dust Mite Allergy: A Controlled Trial (1983)

Twenty asthmatic children with prick tests positive for house dust or house dust mites were allocated to two groups that were matched for severity. One group was provided with zippered vinyl covers for pillows, mattresses, and box springs, and instructions for making the bedroom as easy to keep clean as a hospital ward; the other group was not. At the end of a 1-month study period, there was a marked and statistically significant difference in symptoms and signs of asthma between the two groups. Those with a dust-free bedroom had fewer days on which wheezing was observed, medication was given, or an abnormally low peak expiratory flow rate was recorded. Bronchial tolerance to aerosolized histamine significantly improved in the group whose bedrooms had been modified. A dust-free bedroom diminishes bronchial irritability and is a practical and effective method for decreasing asthma in children with house dust or house dust mite allergy.
Synthesis and Structure−Activity Relationships of Potent Thrombin Inhibitors:  Piperazides of 3-Amidinophenylalanine (1997)

Thrombin is the key enzyme in the blood coagulation system, and inhibitors of its proteolytic activity are of therapeutic interest since they are potential anticoagulants. The most potent inhibitor of the benzamidine type is N alpha-[(2-naphthylsulfonyl)glycyl]-4-amidinophenylalanylpiperid ide (NAPAP). However, NAPAP and other benzamidine derivatives do not show favorable pharmacological properties; above all, they have very low systemic bioavailability after oral administration. The goal of designing new compounds was to obtain potent inhibitors with improved pharmacokinetic properties. Piperazide derivatives of 3-amidinophenylalanine as the key building block were synthesized. The piperazine moiety opened the possibility to introduce quite different substituents on the second nitrogen using common synthetic procedures. Some of the newly synthesized compounds are potent inhibitors of thrombin and offer an approach to study structure-function relationships for inhibition of thrombin and related enzymes and for the improvement of their pharmacokinetic properties.
Acoustics: An Introduction (2006)

This definitive textbook provides students with a comprehensive introduction to acoustics. Beginning with the basic physical ideas, Acoustics balances the fundamentals with engineering aspects, applications and electroacoustics, also covering music, speech and the properties of human hearing. The concepts of acoustics are exposed and applied in:room acousticssound insulation in buildingsnoise controlunderwater sound and ultrasoundScientifically thorough, but with mathematics kept to a minimum, Acoustics is the perfect introduction to acoustics for students at any level of mechanical, electrical or civil engineering courses and an accessible resource for architects, musicians or sound engineers requiring a technical understanding of acoustics and their applications.
Chronic Angina Pectoris: Inadequacies of Current Therapy (2004)

Chronic angina is a major medical problem in the United States with more than 6 million patients affected, a number that will increase substantially because of the progressive aging of the population. The annual mortality rate for patients with chronic angina is approximately 2%, but is much higher in certain subsets of patients, particularly the elderly. Angina is also associated with major social and economic burdens. Because of poor symptom control and hemodynamic, as well as other drug side effects, angina is commonly associated with a poor quality of life. No new class of drug has been available for angina treatment in more than two decades, and current medications frequently fail to provide adequate symptom control. Thus, the majority of patients are taking two or three antianginal medications. New agents that modulate myocardial metabolism have shown antianginal efficacy, a favorable side-effect profile, and an absence of hemodynamic effects.
Intraperitoneal delivery of liposomal siRNA for therapy of advanced ovarian cancer (2006)

IP injection of siRNA incorporated in DOPC allows intra-tumoral delivery and has therapeutic efficacy in orthotopic ovarian tumors. These findings may have therapeutic implications for siRNA-based strategies.