gebhart/patrepeval huggingface dataset:
Characterization of IgG and IgM antibodies induced in melanoma patients by immunization with purified GM2 ganglioside. (1989)

The ganglioside GM2 is a differentiation antigen expressed on the cell surface of human malignant melanomas and other cancers of neuroectodermal origin. We have previously reported that immunization with purified GM2 combined with Bacillus Calmette-Guérin as adjuvant and pretreatment with low-dose cyclophosphamide induced production of antibodies against GM2 in five of six patients. We have now extended our study and analyzed the induced antibodies against GM2 were not detected. After immunization, high-titer IgM antibodies were induced in 17 of 24 patients, and high-titer IgG antibodies in eight cases. Additional treatment of 12 patients with cimetidine, a histamine H2 receptor antagonist reported to have antisuppressor cell activity, had no effect on GM2 antibody titers. Antibodies against asialo-GM2 were present in all patients, and antibodies against GM1 were present in 33% of patients, before and after immunization. Antibodies induced by immunization were specific for GM2, though some reacted predominantly with N-acetylneuraminic acid GM2 (GM2), and some reacted with GM2 and N-glycolylneuraminic acid GM2(NeuGcGM2). The pattern of reactivity with GM2 is consistent with the response to T-cell-independent antigens: both IgM and IgG antibody responses against GM2 were short lived; peak titers seen after initial and secondary vaccinations were similar; and delayed-type hypersensitivity responses to skin test challenges with GM2 were not detected in any patients. However, the IgG response typed as predominantly IgG1 and IgG3, not IgG2 as might be expected for carbohydrate antigens (which are generally T-cell-independent antigens). Because IgG1 and IgG3 antibody responses are usually to T-cell-dependent antigens, the humoral immune response elicited by GM2 vaccination has both T-cell-dependent and T-cell-independent characteristics. These IgM and IgG responses against this neuroectodermal differentiation antigen expressed on melanoma cells have been induced without evidence of neurological or other toxicity.
Combined targeting of Raf and Mek synergistically inhibits tumorigenesis in triple negative breast cancer model systems (2017)

Aberrant Ras-MAPK signaling from receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2), is a hallmark of triple negative breast cancer (TNBC); thus providing rationale for targeting the Ras-MAPK pathway. Components of this EGFR/HER2-Ras-Raf-Mek-Erk pathway were co-targeted in the MDA-MB-231 and MDA-MB-468 human TNBC cell lines, and <i>in vitro</i> effects on signaling and cytotoxicity, as well as <i>in vivo</i> effects on xenograft tumor growth and metastasis were assessed. The dual EGFR/HER2 inhibitor lapatinib (LPN) displayed greater cytotoxic potency and MAPK signaling inhibition than the EGFR inhibitor erlotinib, suggesting both EGFR and HER2 contribute to MAPK signaling in this TNBC model. The Raf inhibitor sorafenib (SFN) or the Mek inhibitor U0126 suppressed MAPK signaling to a greater extent than LPN; which correlated with greater cytotoxic potency of SFN, but not U0126. However, U0126 potentiated the cytotoxic efficacy of LPN and SFN in an additive and synergistic manner, respectively. This in-series Raf-Mek co-targeting synergy was recapitulated in orthotopic mouse xenografts, where SFN and the Mek inhibitor selumitinib (AZD6244) inhibited primary tumor growth and pulmonary metastasis. Raf and Mek co-inhibition exhibits synergy in TNBC models and represent a promising combination therapy for this aggressive breast cancer type.
Impedance Matched Ferrite Layers as Ground Plane Treatments to Improve Antenna Wide-Band Performance (2009)

In low-profile applications, ground plane backing significantly degrades antenna performance when the electrical height is a small fraction of a wavelength. An approach to suppress the destructive interference from the ground plane reflections is to employ absorbing layers of ferrite materials. In this paper, we introduce a means to also control and utilize the mode excited in these finite ferrite layers to recover antenna performance at ultra/very high frequencies. Experimental verification is provided using commercial ferrite materials.
Domain structure of fibronectin and its relation to function. Disulfides and sulfhydryl groups. (1979)

Hamster cell fibronectin is a glycoprotein consisting of two 230,000-dalton subunits in a disulfide-bonded dimer. The molecule is composed of domains which can be separated by partial proteolytic cleavage. The carbohydrates, disulfide bonds, and a single free sulfhydryl group per chain are distributed nonuniformly among these regions. All the interchain disulfides are within 10,000 daltons of the end of the molecule and are removed by mild proteolysis which also generates 200,000- and 25,000-dalton fragments which do not contain interchain disulfides. The 200,000-dalton fragment contains all or most of the carbohydrate side chains, and the free sulfhydryl group, but is relatively poor in cystine. The 25,000-dalton fragment is carbohydrate-free and cystine-rich but has no free sulfhydryl groups. There is heterogeneity in carbohydrate content among the monomeric chains of intact fibronectin and the 200,000-dalton fragments. The gelatin binding site of fibronectin is in the 200,000 fragment. Intact disulfide bonds are required for binding of fibronectin to cells and to gelatin and blockage of the free sulfhydryl groups prevents binding of fibronectin to cells, suggesting that intermolecular disulfide bonding may be important.
Ceramides in Alzheimer’s Disease: Key Mediators of Neuronal Apoptosis Induced by Oxidative Stress and AβAccumulation (2015)

Alzheimer's disease (AD), the most common chronic and progressive neurodegenerative disorder, is characterized by extracellular deposits of amyloid β-peptides (Aβ) and intracellular deposits of hyperphosphorylated tau (phospho-tau) protein. Ceramides, the major molecules of sphingolipid metabolism and lipid second messengers, have been associated with AD progression and pathology via Aβ generation. Enhanced levels of ceramides directly increase Aβ through stabilization of β-secretase, the key enzyme in the amyloidogenic processing of Aβ precursor protein (APP). As a positive feedback loop, the generated oligomeric and fibrillar Aβ induces a further increase in ceramide levels by activating sphingomyelinases that catalyze the catabolic breakdown of sphingomyelin to ceramide. Evidence also supports important role of ceramides in neuronal apoptosis. Ceramides may initiate a cascade of biochemical alterations, which ultimately leads to neuronal death by diverse mechanisms, including depolarization and permeabilization of mitochondria, increased production of reactive oxygen species (ROS), cytochrome c release, Bcl-2 depletion, and caspase-3 activation, mainly by modulating intracellular signalling, particularly along the pathways related to Akt/PKB kinase and mitogen-activated protein kinases (MAPKs). This review summarizes recent findings related to the role of ceramides in oxidative stress-driven neuronal apoptosis and interplay with Aβ in the cascade of events ending in neuronal degeneration.
Fibroblast growth factor-223 binds directly to the survival of motoneuron protein and is associated with small nuclear RNAs (2004)

The SMN (survival of motoneuron) protein is mutated in patients with the neurodegenerative disease spinal muscular atrophy. We have shown previously that a high-molecular-mass isoform of FGF (fibroblast growth factor) 2 (FGF-2(23)) is in a complex with SMN [Claus, Doring, Gringel, Muller-Ostermeyer, Fuhlrott, Kraft and Grothe (2003) J. Biol. Chem. 278, 479-485]. FGF-2 is a neurotrophic factor for motoneurons, and is known not only as a classical extracellular growth factor, but also as a nuclear protein. In the present study, we demonstrate that SMN binds to the arginine-rich N-terminus of FGF-2(23). In turn, FGF-2(23) interacts with amino acid residues 1-90 of the human SMN protein. This sequence displays nucleic-acid-binding capacity and overlaps partially with known binding sites for Gemin2/SIP1 (SMN-interacting protein 1) and p53. Finally, as a functional consequence of FGF-2(23) binding to SMN, FGF-2(23) is in a complex with the small nuclear RNAs U2 and U4. Since SMN functions as an assembly factor for snRNPs (small nuclear ribonucleoprotein particles), these results suggest binding of FGF-2(23) to snRNPs.
A Human NK Cell Activation/Inhibition Threshold Allows Small Changes in the Target Cell Surface Phenotype To Dramatically Alter Susceptibility to NK Cells (2010)

NK cell activation is negatively regulated by the expression of target cell MHC class I molecules. We show that this relationship is nonlinear due to an NK cell activation/inhibition threshold. Ewing's sarcoma family tumor cell monolayers, which were highly susceptible to NK cells in vitro, developed a highly resistant phenotype when cultured as three-dimensional multicellular tumor spheroid structures. This suggested that tumor architecture is likely to influence the susceptibility to NK cells in vivo. Resistance of the multicellular tumor spheroid was associated with the increased expression of MHC class I molecules and greatly reduced NK cell activation, implying that a threshold of NK cell activation/inhibition had been crossed. Reducing MHC class I expression on Ewing's sarcoma family tumor monolayers did not alter their susceptibility to NK cells, whereas increased expression of MHC class I rendered them resistant and allowed the threshold point to be identified. This threshold, as defined by MHC class I expression, was predictive of the number of NK-resistant target cells within a population. A threshold permits modest changes in the target cell surface phenotype to profoundly alter the susceptibility to NK cells. Whereas this allows for the efficient detection of target cells, it also provides a route for pathogens and tumors to evade NK cell attack.
Listeriolysin O is essential for virulence of Listeria monocytogenes: direct evidence obtained by gene complementation (1989)

The role of listeriolysin O in the intracellular multiplication of Listeria monocytogenes and, therefore, its pathogenicity was questioned through a genetic complementation study. A nonhemolytic mutant was generated by inserting a single copy of transposon Tn917 in the bacterial chromosome. This insertion was localized by DNA sequence analysis in hlyA, the gene coding for listeriolysin O. As was another mutant that we previously characterized, this mutant was avirulent in the mouse. It was transformed with a plasmid carrying only hlyA, able to replicate in L. monocytogenes, and stably maintained in vitro and in vivo. The complemented strain displayed a hemolytic phenotype identical to that of the wild-type strain and was fully virulent, therefore attributing a crucial role to listeriolysin O in virulence and excluding the hypothesis of a polar effect of the transposon insertion on genes adjacent to hlyA and possibly involved in virulence.
Induction of therapeutic T-cell immunity by tumor targeting with soluble recombinant B7-immunoglobulin costimulatory molecules. (1999)

Tumor targeting with immunomodulatory molecules is an attractive strategy to enhance the host's antitumor response. Expression of CD80 (B7-1) and CD86 (B7-2) costimulatory molecules in tumor cells has proven to be an efficient way to enhance their immunogenicity. Here, we studied the effects of tumor targeting with biotinylated recombinant soluble B7-1- and B7-2 immunoglobulin G molecules (bio-B7-IgG) using a pretargeting approach based on the sequential use of a biotinylated antitumor monoclonal antibody and avidin. Mouse RMA T-lymphoma cells bearing either bio-B7-1-IgG or bio-B7-2-IgG on their surface prime in vitro naive CD8+ CTLs, which are highly effective in adoptive immunotherapy, and induce therapeutic immunity when injected in tumor-bearing animals. In vivo targeting of established RMA tumors with bio-B7-IgG either cures tumor-bearing mice or significantly prolongs their survival. The antitumor response induced by targeted bio-B7-IgG depends on both CD4+ and CD8+ T cells. Moreover, tumor targeting with bio-B7-IgG in vivo is critical for both expansion in lymphoid organs and mobilization into the tumor of tumor-specific CD8+ CTLs. When targeting is performed on poorly immunogenic TS/A mammary adenocarcinoma, only bio-B7-1-IgG primes naive CTLs in vitro and cures or significantly prolongs the survival of tumor-bearing mice in vivo, confirming that the two costimulatory molecules are not redundant with this tumor. Altogether, these data suggest that tumor avidination and targeting with soluble bio-B7-IgG may represent a promising strategy to enhance the antitumor response in the host.
Epidemic Modelling: An Introduction (2000)

Preface 1. Some history 2. Deterministic models 3. Stochastic models in continuous time 4. Stochastic models in discrete time 5. Rumours: modelling spread and its cessation 6. Fitting epidemic data 7. The control of epidemics References and author index Subject index.
A new model of resonance in the winter stratosphere (1985)

It is generally accepted that the planetary waves observed in the winter stratosphere are primarily a response to dynamical forcing from the troposphere. Nevertheless, the mechanism by which wave amplitudes sometimes become larger remains uncertain. It is possible that anomalously large waves in the stratosphere might simply be the result of anomalously large tropospheric forcing. However, it has also been suggested that they are a response to a stratospheric-tropospheric cavity being in a near-resonant configuration. It has been suggested that nonlinear self-tuning effects could play an important role in the behavior of such a cavity. Self-tuning may occur when a system starts to one side of resonance, such that the mean-state change induced by growing waves brings the system closer to resonance. A new model of the stratospheric cavity is introduced and is then used to re-examine the possibility of wave growth in the real atmosphere and in atmospheric models due to self-tuning effects. The new model is based on the picture of the winter-time stratosphere which has been revealed by the observations of Ertel's potential vorticity, Q. Isentropic maps of Q show two rather distinct regions, the first containing the circumpolar vortex, where gradients of Q are large and Rossby waves may propagate easily. Surrounding this is a second, low-latitude region where the gradients are generally weak and where, because the Eulerian-mean flow is comparable with their phase speed, Rossby waves must be continually breaking. As the waves are observed to grow the relative sizes of these two regions change in time. This leads to the interesting possibility that self-tuning, mainly due to irreversible changes in the size of the polar vortex, is taking place.
Quiescence, cycling, and turnover in the primitive hematopoietic stem cell compartment. (1997)

Continuous oral bromodeoxyuridine (BrdU) administration was used for the non-invasive measurement of the in vivo cell cycling characteristics of hematopoietic stem and progenitor cell populations of increasing maturity, isolated on the basis of their relative levels of Rhodamine 123 (Rh) and Hoechst 33342 (Ho) fluorescence. The results showed that whereas primitive hematopoietic stem cells (PHSCs) are hierarchically ordered on the basis of quiescence, the most primitive of these, characterized by their Rh/Ho(dull) phenotype and their capacity for long-term hematopoietic reconstitution, are not dormant, but cycle slowly in normal steady-state bone marrow (BM). Cell cycle analysis showed that 30 +/- 7% of Rh/Ho(dull) PHSCs had cycled and incorporated BrdU following continuous administration over 1 week, whereas 60 +/- 14% and 89 +/- 3% of these cells were BrdU positive at 4 and 12 weeks, respectively. Linear regression analysis of these data showed that Rh/Ho(dull) PHSCs cycle with an average turnover time of 4.3 weeks (30 days), and a t1/2 (time to 50% cycled) of 2.75 weeks (19 days).
Determining Protein Size Using an Electrochemically Machined Pore Gradient in Silicon (2002)

Porous silicon films displaying a distribution of pore dimensions can be generated by electrochemically etching silicon in aqueous ethanolic HF using an asymmetric electrode configuration. The median pore size and breadth of the size-distribution in the film can be set by adjusting the HF concentration, current density, and position of the counter electrode relative to the silicon electrode. Films with pore sizes in the range of a few nanometers are used as size-exclusion matrices to perform an on-chip determination of macromolecule dimensions. The test molecule used in this study is bovine serum albumin (BSA). Optical reflectivity spectra of the thin porous Si films display distinctive shifts in the Fabry–Perot fringes in regions of the film where the pore dimensions are larger than a critical size, interpreted to be the characteristic dimensions of the protein. Gating of the protein in and out of the porous films is demonstrated by adjustment of the solution pH below and above the pI (isoelectric point) value, respectively.
Accumulation of hyaluronan (hyaluronic acid) in myocardial interstitial tissue parallels development of transplantation edema in heart allografts in rats. (1990)

By using biotin-labeled proteoglycan core protein, hyaluronan (hyaluronic acid; HA) was visualized in rat heart grafts at different times (2, 4, and 6 d) after transplantation. In normal, nontransplanted hearts HA was present in the adventitia of arteries and veins and in the myocardial interstitial tissue. An increased accumulation of HA was evident in the edematous interstitial tissue, infiltrated with lymphocytes, on day 4 after allogeneic transplantation, and was even more pronounced by day 6. No apparent increase in HA was seen in syngeneic grafts. Biochemical assay of HA in heart tissue demonstrated that the myocardial content of HA had increased 60% by day 2 after transplantation in allogeneic as well as syngeneic grafts, indicating that surgical trauma may induce some HA accumulation in heart grafts. The extractable amount of HA declined during the following days in the syngeneic grafts, but increased progressively during the development of rejection in the allogeneic grafts, and increased on average three times by day 6. The relative water content also increased progressively during rejection of allogeneic grafts and correlated with the HA accumulation. The interstitial accumulation of HA, a glycosaminoglycan with unique water-binding qualities, is presumably implicated in the development of interstitial edema during rejection of heart grafts.
β‐Amyloid protein converting enzyme 1 and brain‐specific type II membrane protein BRI3: binding partners processed by furin (2004)

Using a yeast two-hybrid system, we screened a human brain cDNA library for possible interacting proteins with the C-terminal cytosolic tail of the beta-secretase beta-amyloid protein converting enzyme (BACE)1. This identified seven potential candidates, including the brain-specific type II membrane protein BRI3. Co-localization and co-immunoprecipitation experiments confirmed that BACE1 and BRI3 co-localize and interact with each other via the cytosolic tail of BACE1. Furthermore, pulse and pulse-chase analyses revealed that the pro-protein convertases furin, and to a lesser extent PC7 and PC5A, process BRI3 into a C-terminal secreted approximately 4-kDa product. Thus, furin efficiently processes both pro-BACE1 and its novel interacting protein pro-BRI3.
Control of the expression of the manXYZ operon in Escherichia coli: Mlc is a negative regulator of the mannose PTS (1998)

The manXYZ operon of Escherichia coli encodes a sugar transporter of the phosphoenol pyruvate (PEP)-dependent phosphotransferase system, which is capable of transporting many sugars, including glucose, mannose and the aminosugars, glucosamine and N-acetylglucosamine. Transcription of manX is strongly dependent on cyclic AMP (cAMP)/cAMP receptor protein (CAP). A cAMP/CAP binding site is located at -40.5, and activation by cAMP/CAP is shown to be typical of a class II promoter. The 5' end of a transcript, potentially encoding two proteins, is expressed divergently from the manXYZ operon. Previously, two binding sites for the NagC repressor were detected upstream of manX, but a mutation in nagC has very little effect on manX expression. However, a mutation in the mlc gene, encoding a homologue of nagC, results in a threefold derepression of manX expression, suggesting that this protein is a more important regulator of manX expression than NagC. The Mlc protein binds to the NagC operators, binding preferentially to the promoter-proximal operator. Plasmids overproducing either the NagC protein or the Mlc protein repress the expression of manX, but the effect of the Mlc protein is stronger. The mlc gene is shown to be allelic with the previously characterized dgsA mutation affecting the mannose phosphoenolpyruvate-dependent phosphotransferase system (PTS).
Characterization of a xenograft model of human ovarian carcinoma which produces ascites and intraabdominal carcinomatosis in mice. (1984)

We have used in vivo and in vitro procedures to select a subpopulation of cells from the human ovarian carcinoma cell line, NIH:OVCAR-3, with the capacity to grow i.p. in female nude athymic mice. After i.p. injection of these cells, animals develop metastatic spread similar to that of clinical ovarian cancer. Disease progression is characterized by the development of massive ascites, extensive invasive i.p. tumors, and pulmonary metastases. The malignant ascites cells are transplantable, manifest cytoplasmic androgen and estrogen receptors, and express the ovarian cancer associated antigen CA125 (116,000 units/ml of ascites supernatant). The cells also have the same chromosome markers which were present in the original cell line, NIH:OVCAR-3. Survival following i.p. passage of ascites is dependent on tumor cell inoculum ranging from a median survival of 39 days with 40 million cells to 84 days for 11.5 million transplanted cells. The characteristics of this unique in vivo model make it well suited for the evaluation of new drugs and novel experimental therapies in ovarian cancer. In addition, this in vivo model, together with ovarian cancer cell lines, may prove particularly useful for the study of pharmacological ways to specifically increase the cytotoxicity of anticancer agents in tumor cells while not increasing toxicity in normal tissues. The presence of hormone receptors should facilitate the experimental evaluation of hormonal therapy in ovarian cancer.