gebhart/patrepeval huggingface dataset:
Novel Recombinant Human B7-H4 Antibodies Overcome Tumoral Immune Escape to Potentiate T-Cell Antitumor Responses (2013)

B7-H4 (VTCN1, B7x, B7s) is a ligand for inhibitory coreceptors on T cells implicated in antigenic tolerization. B7-H4 is expressed by tumor cells and tumor-associated macrophages (TAM), but its potential contributions to tumoral immune escape and therapeutic targeting have been less studied. To interrogate B7-H4 expression on tumor cells, we analyzed fresh primary ovarian cancer cells collected from patient ascites and solid tumors, and established cell lines before and after in vivo passaging. B7-H4 expression was detected on the surface of all fresh primary human tumors and tumor xenotransplants, but not on most established cell lines, and B7-H4 was lost rapidly by tumor xenograft cells after short-term in vitro culture. These results indicated an in vivo requirement for B7-H4 induction and defined conditions for targeting studies. To generate anti-B7-H4-targeting reagents, we isolated antibodies by differential cell screening of a yeast-display single-chain fragments variable (scFv) library derived from patients with ovarian cancer. We identified anti-B7-H4 scFv that reversed in vitro inhibition of CD3-stimulated T cells by B7-H4 protein. Notably, these reagents rescued tumor antigen-specific T-cell activation, which was otherwise inhibited by coculture with antigen-loaded B7-H4+ APCs, B7-H4+ tumor cells, or B7-H4- tumor cells mixed with B7-H4+ TAMs; peritoneal administration of anti-B7-H4 scFv delayed the growth of established tumors. Together, our findings showed that cell surface expression of B7-H4 occurs only in tumors in vivo and that antibody binding of B7-H4 could restore antitumor T-cell responses. We suggest that blocking of B7-H4/B7-H4 ligand interactions may represent a feasible therapeutic strategy for ovarian cancer.
Soluble gp130 is the natural inhibitor of soluble interleukin‐6 receptor transsignaling responses (2001)

Signal transduction in response to interleukin-6 (IL-6) requires binding of the cytokine to its receptor (IL-6R) and subsequent homodimerization of the signal transducer gp130. The complex of IL-6 and soluble IL-6R (sIL-6R) triggers dimerization of gp130 and induces responses on cells that do not express membrane bound IL-6R. Naturally occurring soluble gp130 (sgp130) can be found in a ternary complex with IL-6 and sIL-6R. We created recombinant sgp130 proteins that showed binding to IL-6 in complex with sIL-6R and inhibited IL-6/sIL-6R induced proliferation of BAF/3 cells expressing gp130. Surprisingly, sgp130 proteins did not affect IL-6 stimulated proliferation of BAF/3 cells expressing gp130 and membrane bound IL-6R, indicating that sgp130 did not interfere with IL-6 bound to IL-6R on the cell surface. Additionally, sgp130 partially inhibited proliferation induced by leukemia inhibitory factor (LIF) and oncostatin M (OSM) albeit at higher concentrations. Recombinant sgp130 protein could be used to block the anti-apoptotic effect of sIL-6R on lamina propria cells from Crohn disease patients. We conclude that sgp130 is the natural inhibitor of IL-6 responses dependent on sIL-6R. Furthermore, recombinant sgp130 is expected to be a valuable therapeutic tool to specifically block disease states in which sIL-6R transsignaling responses exist, e.g. in morbus Crohn disease.
Adjuvant Treatment of Colorectal Cancer (2007)

Colorectal cancer is the fourth most common noncutaneous malignancy in the United States and the second most frequent cause of cancer-related death. Approximately three quarters of patients are diagnosed with disease limited to the bowel wall or surrounding lymph nodes. Over the past decade, significant progress has been made in the treatment of localized colorectal cancer due to advances in surgery, radiotherapy, and chemotherapy. For patients with Stage III colon cancer, an overall survival benefit for fluorouracil-based chemotherapy has been firmly established, and recent data have shown further efficacy through the inclusion of oxaliplatin into adjuvant treatment programs. For patients with Stage II colon cancer, the use of adjuvant chemotherapy remains controversial, but may be appropriate in a subset of individuals at high risk for disease recurrence. In the treatment of patients with rectal cancer, improved outcomes have been noted with the use of total mesorectal excision and preoperative concurrent chemoradiotherapy. Current randomized clinical trials in the adjuvant therapy of colorectal cancer are examining the value of adding agents known to be active in metastatic disease, including those that modify specific molecular targets.
Interfacial Tension Driven Monodispersed Droplet Formation from Microfabricated Channel Array (2001)

Microspheres (MS), such as emulsion droplets, multiple emulsions, microparticles, microcapsules, and liposomes, have been utilized in various industries. However, size control of MS is not so easy. Recently, we proposed a novel method for preparing monodispersed emulsion droplets with a coefficient of variation less than 5% from a microfabricated channel (MC) array. In this study, we analyzed a droplet-formation mechanism from a MC using a microscope high-speed camera system. During droplet formation, the dispersed phase passed through the channel inflated on the terrace in a disklike shape, and the droplets were formed in 0.01 s. A droplet-formation mechanism was suggested in which the distorted dispersed phase on the terrace is cut off spontaneously into spherical droplets by interfacial tension. The mechanism is shown to be an adequate model from the viewpoint of interfacial free energy. This emulsification technique exploits the interfacial tension, which is the dominating force on a micrometer scale. It is a promising technique for producing MS requiring extreme monodispersity because of its simplicity.
Visual outcomes with the yellow intraocular lens (2006)

Abstract. Purpose: To compare postoperative best distance visual acuity (VA), contrast sensitivity and colour perception with the blue light‐filtering AcrySof ® Natural (SN60AT) and AcrySof ® single‐piece (SA60AT) intraocular lenses (IOLs). Methods: This was a prospective, randomized, comparative, interventional study comparing postoperative performance between the SN60 and SA60 IOLs. There were nine patients (nine eyes) in the SN60 group and 10 patients (10 eyes) in the SA60 group. All patients were operated using phacoemulsification. Postoperative VA (Snellen chart), contrast sensitivity (Pelli−Robson contrast sensitivity chart) and colour perception (Farnsworth−Munsell D‐15 panel test) were measured at 1, 3 and 6 months postoperatively. Results: Postoperative best corrected VA after 6 months was 20/20 or better in 89% of SN60 eyes and 100% of SA60 eyes. Postoperative contrast sensitivity scores improved significantly in both groups under both photopic and mesopic conditions. There were no statistically significant differences in contrast sensitivity scores between the SN60 and SA60 groups at any of the postoperative evaluation time‐points. Postoperative colour perception improved significantly in both the SN60 and SA60 groups, and there were no statistically significant differences in colour perception performance between the two groups. Conclusion: The blue light‐filtering AcrySof ® Natural (SN60) IOL has postoperative visual performance comparable with that of the AcrySof ® single‐piece (SA60) IOL.
Pathogenesis of aneurysms. (1995)

We now know our past concepts of AAA pathogenesis to be oversimplified and inaccurate. In fact, the metabolic activity of the aneurysm wall is markedly increased in comparison with normal aorta. It has become clear that AAAs result not from passive dilatation, but from a complex remodeling process involving both the synthesis and degradation of matrix proteins. Our understanding of this process has been advanced by applying molecular biology techniques. Although elastin fragmentation and medial attenuation remain the most striking histological features of AAA tissue, experimental and clinical evidence suggests that the adventitia, which is predominantly collagen, is capable of maintaining the dimensional stability of the aorta in the absence of the medial elastin network. Thus, although factors that result in fragmentation and attenuation of elastin may be important in the etiology of AAA, factors regulating the balance of collagen synthesis and degradation likely determine the rate of AAA progression. The resident inflammatory cells in AAA undoubtedly play an important pathological role in aortic dilatation. Thus, understanding the interaction between aortic mesenchymal cells (smooth muscle cells and fibroblasts) and inflammatory cells (lymphocytes and macrophages) should allow for the identification of genetic factors that predispose to AAA. In addition to the possibility of early identification of patients at risk for AAA, new insights into AAA pathogenesis might allow for development of pharmacological strategies for inhibiting expansion of small AAA.
β-Cell Deficit and Increased β-Cell Apoptosis in Humans With Type 2 Diabetes (2003)

Type 2 diabetes is characterized by impaired insulin secretion. Some but not all studies suggest that a decrease in beta-cell mass contributes to this. We examined pancreatic tissue from 124 autopsies: 91 obese cases (BMI >27 kg/m(2); 41 with type 2 diabetes, 15 with impaired fasting glucose [IFG], and 35 nondiabetic subjects) and 33 lean cases (BMI <25 kg/m(2); 16 type 2 diabetic and 17 nondiabetic subjects). We measured relative beta-cell volume, frequency of beta-cell apoptosis and replication, and new islet formation from exocrine ducts (neogenesis). Relative beta-cell volume was increased in obese versus lean nondiabetic cases (P = 0.05) through the mechanism of increased neogenesis (P < 0.05). Obese humans with IFG and type 2 diabetes had a 40% (P < 0.05) and 63% (P < 0.01) deficit and lean cases of type 2 diabetes had a 41% deficit (P < 0.05) in relative beta-cell volume compared with nondiabetic obese and lean cases, respectively. The frequency of beta-cell replication was very low in all cases and no different among groups. Neogenesis, while increased with obesity, was comparable in obese type 2 diabetic, IFG, or nondiabetic subjects and in lean type 2 diabetic or nondiabetic subjects. However, the frequency of beta-cell apoptosis was increased 10-fold in lean and 3-fold in obese cases of type 2 diabetes compared with their respective nondiabetic control group (P < 0.05). We conclude that beta-cell mass is decreased in type 2 diabetes and that the mechanism underlying this is increased beta-cell apoptosis. Since the major defect leading to a decrease in beta-cell mass in type 2 diabetes is increased apoptosis, while new islet formation and beta-cell replication are normal, therapeutic approaches designed to arrest apoptosis could be a significant new development in the management of type 2 diabetes, because this approach might actually reverse the disease to a degree rather than just palliate glycemia.
Interaction Between the Respiratory Burst Activity of Neutrophil Leukocytes and Experimentally Induced Escherichia coli Mastitis in Cows (1990)

The respiratory burst activity of neutrophil leukocytes from bovine peripheral blood was studied before and during an experimentally induced Escherichia coli mastitis. The competence of neutrophils to generate reactive oxygen species following stimulation with opsonized particles prior to infection was negatively correlated with severity of subsequently induced E. coli mastitis. In the presence of the soluble activator, phorbol myristate acetate, no such correlation was obtained. However, combination of blood neutrophil numbers with phorbol myristate acetate induced respiratory burst competence, called reactive oxygen species-generating capacity, displayed a negative correlation with the intensity of a subsequent inflammation of the bovine mammary gland. At the onset of mastitis, a concomitant reduction in blood neutrophil numbers, a strong shift in cell types, and a substantial decrease in production of reactive oxygen species occurred. Reestablishment and even enhancement of the respiratory burst activity coincided with the reappearance of mature neutrophils. Possible stimulatory effects on neutrophil superoxide generation are discussed. Data suggest that generation of reactive oxygen species by mature neutrophils may be of primary importance for microbial killing during the onset and recovery from mastitis.
Passive immunizing activity of sera from mice infected with Borrelia burgdorferi (1993)

A single injection of serum from C3H mice at 90 days after intradermal inoculation with 10(4) Borrelia burgdorferi spirochetes protected naive mice when administered subcutaneously at -18 h relative to intradermal challenge inoculation with 10(4) B. burgdorferi spirochetes. When immune serum was given at intervals (-18, 0, +24, +48, and +96 h) relative to intradermal challenge with 10(4) B. burgdorferi spirochetes, it was protective if given before or at the time of challenge but not at later times. Protection with 90-day serum given at -18 h was effective at dilutions up to 1:32, but not 1:64, on the basis of culture or disease at either 5 or 15 days after challenge. Passive immunizing activity was also present in sera from mice at 21 days after intradermal challenge with 10(4), 10(2), or 10(1) spirochetes, indicating that the immunizing component was not dose dependent and probably not related to antibody to outer surface protein A. Passive immunizing titers of sera from mice at days 1, 15, 30, 90, 180, and 360 after intradermal B. burgdorferi inoculation appeared as early as day 15, were highest on day 30, and then declined progressively on days 90, 180, and 360. Immunizing titers of sera from mice at 360 days after intradermal B. burgdorferi inoculation were identical in passively immunized mice challenged with the original inoculum or with B. burgdorferi isolated at 360 days after inoculation, suggesting that there was no antigenic discrimination between the original inoculum and late isolates. These results suggest that protective antibody is produced early in the course of B. burgdorferi infection and is unrelated to antibody to outer surface protein A. In addition, the decline of protective serum titers over time despite persistent infection suggests that the antigens eliciting the protective response are either modified or suppressed, but antigenic modification could not be demonstrated.
A stable latent reservoir for HIV-1 in resting CD4+ T lymphocytes in infected children (2000)

HIV-1 persists in a latent state in resting CD4(+) T lymphocytes of infected adults despite prolonged highly active antiretroviral therapy (HAART). To determine whether a latent reservoir for HIV-1 exists in infected children, we performed a quantitative viral culture assay on highly purified resting CD4(+) T cells from 21 children with perinatally acquired infection. Replication-competent HIV-1 was recovered from all 18 children from whom sufficient cells were obtained. The frequency of latently infected resting CD4(+) T cells directly correlated with plasma virus levels, suggesting that in children with ongoing viral replication, most latently infected cells are in the labile preintegration state of latency. However, in each of 7 children who had suppression of viral replication to undetectable levels for 1-3 years on HAART, latent replication-competent HIV-1 persisted with little decay, owing to a stable reservoir of infected cells in the postintegration stage of latency. Drug-resistance mutations generated by previous nonsuppressive regimens persisted in this compartment despite more than 1 year of fully suppressive HAART, rendering untenable the idea of recycling drugs that were part of failed regimens. Thus the latent reservoir for HIV-1 in resting CD4(+) T cells will be a major obstacle to HIV-1 eradication in children.
The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease (2004)

The MHC class I family–like Fc receptor, FcRn, is normally responsible for extending the life span of serum IgG Ab’s, but whether this molecule contributes to autoimmune pathogenesis remains speculative. To determine directly whether this function contributes to humoral autoimmune disease, we examined whether a deficiency in the FcRn heavy chain influences autoimmune arthritis in the K/BxN mouse model. FcRn deficiency conferred either partial or complete protection in the arthritogenic serum transfer and the more aggressive genetically determined K/BxN autoimmune arthritis models. The protective effects of an FcRn deficiency could be overridden with excessive amounts of pathogenic IgG Ab’s. The therapeutic saturation of FcRn by high-dose intravenous IgG (IVIg) also ameliorated arthritis, directly implicating FcRn blockade as a significant mechanism of IVIg’s anti-inflammatory action. The results suggest that FcRn is a potential therapeutic target that links the initiation and effector phases of humoral autoimmune disease.
MAGNETISM AND HYPERFINE FIELDS IN YFE10V2 - A COMBINED NUCLEAR-MAGNETIC-RESONANCE AND MOSSBAUER STUDY (1994)

A combined nuclear magnetic resonance (NMR) and Mossbauer effect study of YFe10V2 has been carried out. Based on the Fe-57 hyperfine fields (HFS) obtained from the Mossbauer results, the resonance lines of the NMR spectrum are assigned and the site preference of V atoms is determined. On the other hand, according to the site preference of vanadium atoms determined by NMR, together with neutron diffraction results, the Fe-57 Mossbauer spectrum is fitted. It can be deduced from the NMR results that the existence of one nearest-neighbour Fe atom leads to an increase in the V HF of about 0.35, and the core electron polarization contribution H(cp), the 4s conduction electron polarization contribution H(s) and the effect of the second-nearest-neighbour Fe atoms on the HF Sites cannot be negligible.
Lipoinjection for unilateral vocal cord paralysis (1991)

Injection of Teflon paste is a commonly accepted procedure to improve the caliber of voice in unilateral vocal cord paralysis. There are several drawbacks to Teflon injection, among them respiratory obstruction (from overinjected Teflon) and unsatisfactory voice quality (Teflon causes stiffness of the vocal folds). This paper is a preliminary report on lipoinjection instead of Teflon injection into a paralyzed vocal fold. Fat appears to impart a soft bulkiness to the injected cord, while allowing it to retain its vibratory qualities. It is autologous material and can be retrieved if excessively overinjected. The fate of autologous fat injected into a paralyzed vocal cord remains unknown. Most of the literature on lipoinjection concerns repairs of depressed scars or breast augmentation. Our longest follow-up has been 12 months. Three patients have had this procedure, and the results appear to be very encouraging.
Effective Gene Silencing by Multilayered siRNA‐Coated Gold Nanoparticles (2010)

Small interfering RNA (siRNA) has been widely proposed to treat various diseases by silencing genes, but its delivery remains a challenge. A well controlled assembly approach is applied to prepare a protease-assisted nanodelivery system. Protease-degradable poly-L-lysine (PLL) and siRNA are fabricated onto gold nanoparticles (AuNPs), by alternating the charged polyelectrolytes. In this study, up to 4 layers of PLL and 3 layers of siRNA (sR3P) are coated. Due to the slow degradation of PLL, the incorporated siRNA is released gradually and shows extended gene-silencing effects. Importantly, the inhibition effect in cells is found to correlate with the number of siRNA layers.
Non-nucleoside inhibitors of the HCV NS5B polymerase: progress in the discovery and development of novel agents for the treatment of HCV infections. (2007)

The severe health conditions associated with chronic HCV infection remain a global concern. Small-molecule drugs that specifically target essential virally encoded enzymes have not yet progressed to market, and the current standard of care continues to rely on a combination of pegylated IFN with ribavirin. This therapy has serious side effects and a significant proportion of patients infected with HCV genotype 1 (the major genotype in industrialized countries) have an unsatisfactory outcome with this therapy. Major advances have been realized in the development of specific non-nucleoside inhibitors of the viral NS5B RNA-dependent RNA polymerase. This well-characterized replicative enzyme is a highly drugable target that, in addition to its active site, features at least three known allosteric binding pockets that regulate RNA synthesis and are suitable for inhibitor design. Clinical proof-of-concept for allosteric non-nucleoside HCV polymerase inhibitors has been reported and several compounds have progressed into preclinical studies. It is likely that in the future NS5B inhibitors will form an integral part of more effective anti-HCV therapies, combining the use of small-molecule antiviral drugs with or without the assistance of immune modulators such as IFNs in order to minimize the emergence of resistance.
Interaction of antibodies with Fc receptors in substrate-supported planar membranes measured by total internal reflection fluorescence microscopy (1990)

A procedure for constructing substrate-supported planar membranes using membrane fragments isolated from the macrophage-related cell line J774A.1 is described. Total internal reflection (TIR) fluorescence microscopy is employed to demonstrate that fluorescently labeled Fab fragments of a monoclonal antibody (2.4G2) with specificity for a murine macrophage cell-surface receptor for IgG (moFc gamma RII) bind to the planar model membranes. These measurements show that the planar membranes contain moFc gamma RII and yield a value for the association constant of 2.4G2 Fab fragments with moFc gamma RII equal to (9.6 +/- 0.4) x 10(8) M-1 and indicate that the surface density of reconstituted moFc gamma RII is approximately 50 molecules/microns 2. In addition, TIR fluorescence microscopy is used to investigate the Fc-mediated competition of unlabeled, polyclonal murine IgG with labeled 2.4G2 Fab fragments for moFc gamma RII in the planar membranes. These measurements indicate that the reconstituted moFc gamma RII recognized by 2.4G2 Fab fragments also retains the ability to bind murine IgG Fc regions and yield a value for the association constant of polyclonal murine IgG with moFc gamma RII equal to (1-5) x 10(5) M-1. This work represents one of the first applications of TIR fluorescence microscopy to specific ligand-receptor interactions.