gebhart/patrepeval huggingface dataset:
Phase I and imaging trial of a monoclonal antibody directed against gastrin-releasing peptide in patients with lung cancer. (1999)

Small cell lung cancer (SCLC) cells express and secrete bombesin-like peptides (BLP) that can activate specific receptors that stimulate the growth of these cells. A murine monoclonal antibody, 2A11, which binds to the BLP, gastrin-releasing peptide with high affinity, has been reported to decrease the growth of SCLC cells in vitro and in athymic nude mice. A Phase I trial in lung cancer patients was performed using multiple doses of 2A11. Thirteen patients with lung cancer received 12 doses of 2A11 antibody three times a week for 4 weeks at one of four dose levels. Serum samples were obtained prior to initiation and before each dose of 2A11 antibody therapy for measurement of 2A11 antibody levels and determination of serum human anti-mouse antibody levels. A pilot imaging evaluation using 111In conjugated 2A11 monoclonal antibody was also performed in the same patients to aid in the study of pharmacokinetics and biodistribution. No toxic reactions were observed, and none of the patients developed detectable human antimouse antibody; however, no objective antitumor responses were observed. The mean trough serum 2A11 levels in patients increased with increasing dose level: 0.26+/-0.2 microg/ml, 6.7+/-6 microg/ml, 71.5+/-60 microg/ml, 248+/-184 microg/ml for dose levels 1 mg/m2, 10 mg/m2, 100 mg/m2, and 250 mg/m2, respectively. At each dose level, sustained detectable serum levels of the monoclonal antibody were achieved. Tumor uptake was noted in 11 of 12 patients who were injected with 111In conjugated 2A11. Because no dose-limiting clinical toxicity was observed, a mathematical model was used to define the recommended Phase II dose of 250 mg/m2. This trial established that repeated doses of monoclonal antibody 2A11 could be given safely to patients, and sustained levels could be achieved for a 4-week schedule. Further evaluation of the antitumor effects of 2A11 is warranted.
Nerve growth factor may stimulate either division or differentiation of cloned C1300 neuroblastoma cells in serum‐free cultures (1980)

Two clones of mouse C1300 neuroblastoma cells (clones NB1R and NB6R) bind mouse 2.5S Nerve Growth Factor (NGF) in vitro. The ligand is then capped and internalized by the cells. This step requires active cell processing. In serum-free or low serum conditions, clear effects of NGF are seen with both clones. Cultured NB1R cells are stimulated, after a lag interval of a few hours, to synthesize DNA and to proliferate, whereas NB6R cells are stimulated to cell differentiation and maintain viability under these conditions much longer than similar cultures in the absence of NGF. Stimulation of clone NB1R occurs within an optimal dose concentration of the same order as that used in the Levi-Montalcini bioassay with 8-day-old chick embryo-sensitive ganglia; the effects on clone NB6R, however, need higher NGF concentrations. Both effects are protein-specific since they are inhibited in the presence of added anti-NGF antibodies. This system could provide a convenient means to study the control of cell division in susceptible malignant neuroblastoma clones and to correlate NGF binding to receptors and biological activity.
The NHE3 Juxtamembrane Cytoplasmic Domain Directly Binds Ezrin: Dual Role in NHE3 Trafficking and Mobility in the Brush Border (2006)

Based on physiological studies, the epithelial brush-border (BB) Na+/H+ antiporter3 (NHE3) seems to associate with the actin cytoskeleton both by binding to and independently of the PDZ domain containing proteins NHERF1 and NHERF2. We now show that NHE3 directly binds ezrin at a site in its C terminus between aa 475-589, which is separate from the PSD95/dlg/zonular occludens-1 (PDZ) interacting domain. This is an area predicted to be alpha-helical, with a positive aa cluster on one side (K516, R520, and R527). Point mutations of these positively charged aa reduced (NHE3 double mutant [R520F, R527F]) or abolished (NHE3 triple mutant [K516Q, R520F, R 527F]) ezrin binding. Functional consequences of these NHE3 point mutants included the following. 1) A marked decrease in surface amount with a greater decrease in NHE3 activity. 2) Decreased surface expression due to decreased rates of exocytosis and plasma membrane delivery of newly synthesized NHE3, with normal total expression levels and slightly reduced endocytosis rates. 3) A longer plasma membrane half-life of mutant NHE3 with normal total half-life. 4) Decreased BB mobile fraction of NHE3 double mutant. These results show that NHE3 binds ezrin directly as well as indirectly and suggest that the former is related to 1) the exocytic trafficking of and plasma membrane delivery of newly synthesized NHE3, which determines the amount of plasma membrane NHE3 and partially determines NHE3 activity, and 2) BB mobility of NHE3, which may increase its delivery from microvilli to the intervillus clefts, perhaps for NHE3-regulated endocytosis.
Map projections: A working manual (1987)

After decades of using only one map projection, the Polyconic, for its mapping program, the U.S. Geological Survey (USGS) now uses several of the more common projections for its published maps. For larger scale maps, including topographic quadrangles and the State Base Map Series, conformal projections such as the Transverse Mercator and the Lambert Conformal Conic are used. Equal-area and equidistant projections appear in the National Atlas. Other projections, such as the Miller Cylindrical and the Van der Grinten, are chosen occasionally for convenience, sometimes making use of existing base maps prepared by others. Some projections treat the Earth only as a sphere, others as either ellipsoid or sphere. The USGS has also conceived and designed several new projections, including the Space Oblique Mercator, the first map projection designed to permit mapping of the Earth continuously from a satellite with low distortion. The mapping of extraterrestrial bodies has resulted in the use of standard projections in completely new settings. Several other projections which have not been used by the USGS are frequently of interest to the cartographic public. With increased computerization, it is important to realize that rectangular coordinates for all these projections may be mathematically calculated with formulas which would have seemed too complicated in the past, but which now may be programmed routinely, especially if aided by numerical examples. A discussion of appearance, usage, and history is given together with both forward and inverse equations for each projection involved.
Cyclization of N‐cyanovinyl‐lactam imines to condensed 4‐aminopyridines or substituted aminopyrazole (1992)

Abstract N ‐Cyanovinyl‐lactam imines 2 react with hydrazine giving aminopyrazole 4a while lactam imine 3 is split off. Treatment of 2 with strong bases gives intramolecular cyclization to condensed 4‐aminopyridines 5 . The progress of reaction was observed by polarographic method.
Irreversible Electroporation Ablation: Is All the Damage Nonthermal? (2012)

In some conditions of high intensity, IRE can produce sufficient heating to induce "white zone" thermal coagulation. While this can be useful in some settings to increase tumor destruction, further characterization of the thermal profile created with clinical electrodes and energy parameters is therefore needed to better understand the best ways to avoid unintended damage when ablating near thermally sensitive critical structures.
Post-traumatic stress disorder: the neurobiological impact of psychological trauma (2011)

The classic fight-or-flight response to perceived threat is a reflexive nervous phenomenon thai has obvious survival advantages in evolutionary terms. However, the systems that organize the constellation of reflexive survival behaviors following exposure to perceived threat can under some circumstances become dysregulated in the process. Chronic dysregulation of these systems can lead to functional impairment in certain individuals who become "psychologically traumatized" and suffer from post-traumatic stress disorder (PTSD), A body of data accumulated over several decades has demonstrated neurobiological abnormalities in PTSD patients. Some of these findings offer insight into the pathophysiology of PTSD as well as the biological vulnerability of certain populations to develop PTSD, Several pathological features found in PTSD patients overlap with features found in patients with traumatic brain injury paralleling the shared signs and symptoms of these clinical syndromes.
EPH receptors in cancer. (2008)

EPH receptors and their ephrin ligands constitute the largest sub-family of receptor tyrosine kinases (RTKs) and are components of cell signaling pathways involved in animal development. The ability of the EPH/ephrin guidance system to position cells and modulate cell morphology underlies their various roles in development. In addition, EPH signaling plays an important role in oncogenic processes observed in several organs. These receptors are involved in a wide range of processes directly related with tumorigenesis and metastasis, including cell attachment and shape, migration, and angiogenesis. Accordingly, deregulation of EPH expression and signaling activity could be crucial for the tumorigenic process. This review focuses on EPH receptors' roles in oncogenic transformation and tumor progression.
Pro-1 of Macrophage Migration Inhibitory Factor Functions as a Catalytic Base in the Phenylpyruvate Tautomerase Activity, (1999)

Macrophage migration inhibitory factor (MIF) is an important immunoregulatory molecule with a unique ability to suppress the anti-inflammatory effects of glucocorticoids. Although considered a cytokine, MIF possesses a three-dimensional structure and active site similar to those of 4-oxalocrotonate tautomerase and 5-carboxymethyl-2-hydroxymuconate isomerase. Moreover, a number of catalytic activities have been defined for MIF. To gain insight into the role of catalysis in the biological function of MIF, we have begun to characterize the catalytic activities in more detail. Here we report the crystal structure of MIF complexed with p-hydroxyphenylpyruvate, a substrate for the phenylpyruvate tautomerase activity of MIF. The three binding sites for p-hydroxyphenylpyruvate in the MIF trimer lie at the interface between two subunits. The substrate interacts with Pro-1, Lys-32, and Ile-64 from one subunit and Tyr-95 and Asn-97 from an adjacent subunit. Pro-1 is positioned to function as a catalytic base. There is no functional group that polarizes the alpha-carbonyl of the substrate to weaken the adjacent C-H bond. Mutation of Pro-1 to glycine substantially reduces the catalytic activity. The insertion of an alanine between Pro-1 and Met-2 essentially abolishes activity. Structural studies of these mutants define a source of the reduced activity and provide insight into the mechanism of the catalytic reaction.
Spermatogonial Stem Cell Self-Renewal Requires OCT4, a Factor Downregulated During Retinoic Acid-Induced Differentiation (2008)

The long-term production of billions of spermatozoa relies on the regulated proliferation and differentiation of spermatogonial stem cells (SSCs). To date only a few factors are known to function in SSCs to provide this regulation. Octamer-4 (OCT4) plays a critical role in pluripotency and cell survival of embryonic stem cells and primordial germ cells; however, it is not known whether it plays a similar function in SSCs. Here, we show that OCT4 is required for SSC maintenance in culture and for colonization activity following cell transplantation, using lentiviral-mediated short hairpin RNA expression to knock down OCT4 in an in vitro model for SSCs ("germline stem" [GS] cells). Expression of promyelocytic leukemia zinc-finger (PLZF), a factor known to be required for SSC self-renewal, was not affected by OCT4 knockdown, suggesting that OCT4 does not function upstream of PLZF. In addition to developing a method to test specific gene function in GS cells, we demonstrate that retinoic acid (RA) triggers GS cells to shift to a differentiated, premeiotic state lacking OCT4 and PLZF expression and colonization activity. Our data support a model in which OCT4 and PLZF maintain SSCs in an undifferentiated state and RA triggers spermatogonial differentiation through the direct or indirect downregulation of OCT4 and PLZF. The current study has important implications for the future use of GS cells as an in vitro model for spermatogonial stem cell biology or as a source of embryonic stem-like cells. Disclosure of potential conflicts of interest is found at the end of this article.
Characterization of the Tautomycin Biosynthetic Gene Cluster from Streptomyces spiroverticillatus Unveiling New Insights into Dialkylmaleic Anhydride and Polyketide Biosynthesis (2008)

Tautomycin (TTM) is a highly potent and specific protein phosphatase inhibitor isolated from Streptomyces spiroverticillatus. The biological activity of TTM makes it an important lead for drug discovery, whereas its spiroketal-containing polyketide chain and rare dialkylmaleic anhydride moiety draw attention to novel biosynthetic chemistries responsible for its production. To elucidate the biosynthetic machinery associated with these novel molecular features, the ttm biosynthetic gene cluster from S. spiroverticillatus was isolated and characterized, and its involvement in TTM biosynthesis was confirmed by gene inactivation and complementation experiments. The ttm cluster was localized to a 86-kb DNA region, consisting of 20 open reading frames that encode three modular type I polyketide synthases (TtmHIJ), one type II thioesterase (TtmT), five proteins for methoxymalonyl-S-acyl carrier protein biosynthesis (Ttm-ABCDE), eight proteins for dialkylmaleic anhydride biosynthesis and regulation (TtmKLMNOPRS), as well as two additional regulatory proteins (TtmF and TtmQ) and one tailoring enzyme (TtmG). A model for TTM biosynthesis is proposed based on functional assignments from sequence analysis, which agrees well with previous feeding experiments, and has been further supported by in vivo gene inactivation experiments. These findings set the stage to fully investigate TTM biosynthesis and to biosynthetically engineer new TTM analogs.
Sarcospan, the 25-kDa Transmembrane Component of the Dystrophin-Glycoprotein Complex (1997)

The dystrophin-glycoprotein complex is a multisubunit protein complex that spans the sarcolemma and forms a link between the subsarcolemmal cytoskeleton and the extracellular matrix. Primary mutations in the genes encoding the proteins of this complex are associated with several forms of muscular dystrophy. Here we report the cloning and characterization of sarcospan, a unique 25-kDa member of this complex. Topology algorithms predict that sarcospan contains four transmembrane spanning helices with both N- and C-terminal domains located intracellularly. Phylogenetic analysis reveals that sarcospan's arrangement in the membrane as well as its primary sequence are similar to that of the tetraspan superfamily of proteins. Sarcospan co-localizes and co-purifies with the dystrophin-glycoprotein complex, demonstrating that it is an integral component of the complex. We also show that sarcospan expression is dramatically reduced in muscle from patients with Duchenne muscular dystrophy. This suggests that localization of sarcospan to the membrane is dependent on proper dystrophin expression. The gene encoding sarcospan maps to human chromosome 12p11.2, which falls within the genetic locus for congenital fibrosis of the extraocular muscle, an autosomal dominant muscular dystrophy.
Synthesis, Aggregation, and Biological Properties of a New Class of Gemini Cationic Amphiphilic Compounds from Arginine, bis(Args) (1996)

In this work the synthesis and evaluation of a novel class of gemini biocompatible surfactants from arginine with chemical, biological, and fundamental research applications are presented for the first time. In this strategy the environmental acceptability of the already biocompatible single chain Nα-acyl arginine surfactants was reinforced by chemical dimerization in order to obtain a gemini surfactant with a high physicochemical efficiency and a low toxicity. The application of these molecules (with a very low intrinsic toxicity) in industrial processess could lead to a dramatic reduction in the concentration of surface active material for the same level of performance.
Lysosomal enzyme targeting. N-Acetylglucosaminylphosphotransferase selectively phosphorylates native lysosomal enzymes. (1981)

Lysosomal enzymes contain 6-phosphomannosyl moieties which mediate their translocation to lysosomes. This recognition marker is synthesized by the sequential action of UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase and alpha-N-acetylglucosaminyl phosphodiesterase. A new assay for the N-acetylglucosaminylphosphotransferase, using alpha-methylmannoside as acceptor, is presented. Using this assay, we partially purified the transferase and examined its substrate specificity. The transferase exhibited a very high affinity toward lysosomal enzymes (apparent Km values of less than 20 microM) and was greater than 100-fold more efficient (Vmax/Km) when using lysosomal enzymes as acceptors as compared to nonlysosomal glycoproteins that contain high mannose oligosaccharide units. Heat denaturation of the lysosomal enzymes resulted in the loss of acceptor activity. The model compounds alpha-methylmannoside and Man5--8GlcNAc were poor acceptors. We propose that this enzyme catalyzes the initial, determining step by which synthesized acid hydrolases are distinguished from other newly synthesized glycoproteins and thus are eventually targeted to lysosomes.
Osteocyte regulation of orthodontic force-mediated tooth movement via RANKL expression (2017)

Orthodontic tooth movement is achieved by the remodeling of the alveolar bone surrounding roots of teeth. Upon the application of orthodontic force, osteoclastic bone resorption occurs on the compression side of alveolar bone, towards which the teeth are driven. However, the molecular basis for the regulatory mechanisms underlying alveolar bone remodeling has not been sufficiently elucidated. Osteoclastogenesis is regulated by receptor activator of nuclear factor-κB ligand (RANKL), which is postulated to be expressed by the cells surrounding the tooth roots. Here, we show that osteocytes are the critical source of RANKL in alveolar bone remodeling during orthodontic tooth movement. Using a newly established method for the isolation of periodontal tissue component cells from alveolar bone, we found that osteocytes expressed a much higher amount of RANKL than other cells did in periodontal tissue. The critical role of osteocyte-derived RANKL was confirmed by the reduction of orthodontic tooth movement in mice specifically lacking RANKL in osteocytes. Thus, we provide in vivo evidence for the key role of osteocyte-derived RANKL in alveolar bone remodeling, establishing a molecular basis for orthodontic force-mediated bone resorption.
Antibody‐dependent cellular cytotoxicity of cetuximab against tumor cells with wild‐type or mutant epidermal growth factor receptor (2007)

Cetuximab (Erbitux, IMC-C225) is a monoclonal antibody targeted to the epidermal growth factor receptor (EGFR). To clarify the mode of antitumor action of cetuximab, we examined antibody-dependent cellular cytotoxicity (ADCC) activity against several tumor cell lines expressing wild-type or mutant EGFR. ADCC activity and complement-dependent cytolysis activity were analyzed using the CytoTox 96 assay. ADCC activities correlated with the EGFR expression value (R = 0.924). ADCC activities were detected against all tumor cell lines, except K562 cells in a manner dependent on the cellular EGFR expression level, whereas complement-dependent cytolysis activity was not detected in any of the cell lines. The ADCC activity mediated by cetuximab was examined in HEK293 cells transfected with wild-type EGFR (293W) and a deletional mutant of EGFR (293D) in comparison with the mock transfectant (293M). ADCC activity was detected in 293W and 293D cells, in a cetuximab dose-dependent manner, but not in 293M cells (<10%). These results indicate that ADCC-dependent antitumor activity results from the degree of affinity of cetuximab for the extracellular domain of EGFR, independent of EGFR mutation status. These results suggest ADCC activity to be one of the modes of therapeutic action of cetuximab and to depend on EGFR expression on the tumor cell surface.
Measurements of classical deceleration of beam ions in the DIII-D tokamak (1990)

Studies of the slowing down of short pulses of deuterium beam ions in the DIII-D tokamak [Nucl. Fusion 28, 1897 (1988)] are extended to the regime where ion drag dominates electron drag. The deceleration of the beam ions is consistent with Sivukhin’s classical theory [Reviews of Plasma Physics (Consultants Bureau, New York, 1966), Vol. 4, p. 93] to within 25%.
First-in-human, Pharmacokinetic and Pharmacodynamic Phase I Study of Resminostat, an Oral Histone Deacetylase Inhibitor, in Patients with Advanced Solid Tumors (2013)

Resminostat was safely administered with a dose-proportional pharmacokinetic profile, optimal on-target pharmacodynamic activity at dose levels ≥400 mg and signs of antitumor efficacy. The recommended phase II dose is 600 mg once-daily on days 1 to 5 every 14 days.
Protection against yellow fever in monkeys by immunization with yellow fever virus nonstructural protein NS1 (1986)

Immunization of monkeys with yellow fever virus-specified nonstructural protein NS1 resulted in protection against fatal hepatitis as well as marked reduction in the magnitude of viremia after subcutaneous challenge with yellow fever virus. The results may be relevant to the design of possible subunit or recombinant flavivirus vaccines.
Virtual full-duplex wireless communication via rapid on-off-division duplex (2010)

This paper introduces a novel paradigm for designing the physical and medium access control (MAC) layers of mobile ad hoc or peer-to-peer networks formed by half-duplex radios. A node equipped with such a radio cannot simultaneously transmit and receive useful signals at the same frequency. Unlike in conventional designs, where a node's transmission frames are scheduled away from its reception, each node transmits its signal through a randomly generated on-off duplex mask (or signature) over every frame interval, and receive a signal through each of its own off-slots. This is called rapid on-off-division duplex (RODD). Over the period of a single frame, every node can transmit a message to some or all of its peers, and may simultaneously receive a message from each peer. Thus RODD achieves virtual full-duplex communication using half-duplex radios and can simplify the design of higher layers of a network protocol stack significantly. The throughput of RODD is evaluated under some general settings, which is significantly larger than that of ALOHA. RODD is especially efficient in case the dominant traffic is simultaneous broadcast from nodes to their one-hop peers, such as in spontaneous wireless social networks, emergency situations or on battlefield. Important design issues of peer discovery, distribution of on-off signatures, synchronization and error-control coding are also addressed.
Intestinal colonization with phylogenetic group B2 Escherichia coli related to inflammatory bowel disease: a systematic review and meta-analysis (2015)

Our study reveals that intestinal colonization with phylogenetic group B2 E. coli is associated with UC. Due to the design, we are unable to determine if the colonization with B2 E. coli leads to the development of the disease or the disease increases the risk of colonization with B2 E. coli.