gebhart/patrepeval huggingface dataset:
SUPEROXIDE RADICAL AND SUPEROXIDE DISMUTASES (1995)

O2- oxidizes the [4Fe-4S] clusters of dehydratases, such as aconitase, causing-inactivation and release of Fe(II), which may then reduce H2O2 to OH- +OH.. SODs inhibit such HO. production by scavengingO2-, but Cu, ZnSODs, by virtue of a nonspecific peroxidase activity, may peroxidize spin trapping agents and thus give the appearance of catalyzing OH. production from H2O2. There is a glycosylated, tetrameric Cu, ZnSOD in the extracellular space that binds to acidic glycosamino-glycans. It minimizes the reaction of O2- with NO. E. coli, and other gram negative microorganisms, contain a periplasmic Cu, ZnSOD that may serve to protect against extracellular O2-. Mn(III) complexes of multidentate macrocyclic nitrogenous ligands catalyze the dismutation of O2- and are being explored as potential pharmaceutical agents. SOD-null mutants have been prepared to reveal the biological effects of O2-. SodA, sodB E. coli exhibit dioxygen-dependent auxotrophies and enhanced mutagenesis, reflecting O2(-)-sensitive biosynthetic pathways and DNA damage. Yeast, lacking either Cu, ZnSOD or MnSOD, are oxygen intolerant, and the double mutant was hypermutable and defective in sporulation and exhibited requirements for methionine and lysine. A Cu, ZnSOD-null Drosophila exhibited a shortened lifespan.
Rapid expulsion of Trichinella spiralis in suckling rats: mediation by monoclonal antibodies. (1988)

Pups born to rats immunized with the excretory/secretory antigens (ESA) of Trichinella spiralis L1 larvae expressed rapid expulsion when challenged orally. Rat monoclonal antibodies specific for ESA were produced and tested for their specificity in Western blots, binding to intact larvae and protective capacity in suckling rats. Eight antibodies had apparently identical specificity in Western blots, each recognizing a polypeptide family that included three molecular weight species sized at 41,000-50,000 MW. These polypeptides formed a series of higher molecular weight aggregates that were also bound by the monoclonal antibodies. Four of eight antibodies were protective when serially transferred to suckling pups. Each protective antibody was able to bind to intact larvae. Antibodies of two subclasses, IgG1 and IgG2c, were strongly protective, delivering to pups the capacity to expel as much as 94% of the challenge dose.
A phase I study of two different schedules of nab-paclitaxel (Nab-p) with ascending doses of vandetanib (V) in patients (pts) with advanced solid tumors. (2010)

3059 Background: Nab-p is an albumin bound paclitaxel. V is a potent inhibitor of VEGFR 2 and EGFR. Preclinical data reveal enhanced Nab-p activity with concurrent VEGF inhibition. Primary objective was to determine the maximum tolerated dose (MTD). Methods: Pts were randomized to one of 2 cohorts. Dose of Nab-p was fixed (Cohort A: Nab-p 100 mg/m2 IV weekly for 3 wks q 28 days; Cohort B: Nab-p 260 mg/m2 IV q 3 wks) while 3 doses of V were evaluated in both cohorts (100 mg, 200 mg, 300 mg PO daily). A standard 3+3 design was used. Expansion at the MTD was planned for both cohorts. Results: 46 pts were treated: 21 (cohort A), 13 (cohort B), 12 (cohort B expansion). Median age 56 (range 26-81), Karnofsky PS 100% (6), 90% (21), 80% (17), <70% (2). 17 males, 29 females. Median number of prior treatments 2 (range 1-7). Most common disease sites: pancreatic 15 (33%), ovarian 8 (17%), gastric 7 (15%), endometrial 3 (6%), lung 3 (6%). There was one DLT at each dose level in cohort A (grade 3 rash in 2 pts, grade 4 neutropenia in 1 pt). No DLTs in cohort B. MTD was Nab-p 100 mg/m2 IV weekly for 3/4 wks and V 300 mg daily in cohort A; Nab-p 260 mg/m2 IV q 3 wks and V 300 mg daily in cohort B. No grade 4 toxicities in cycle 1. Toxicities in all cycles were comparable to those in cycle 1 and will be reported at the time of presentation. 4 pts (3 with pancreatic ca and 1 with unknown primary ca) had a PR; 24 pts had SD (pancreatic 8, ovarian 7, prostate 2, lung 2, other 5). The median duration of SD was 5.7 mo (95% CI: 3.9-6.7). Conclusions: Both schedules of Nab-p with V are safe and well tolerated. The MTD for both cohorts was the maximum planned dose. Accrual to the expansion phase at the MTD in cohort A is ongoing and restricted to pts with advanced pancreatic cancer. Exploratory analysis of SPARC genomic polymorphisms as potential markers of efficacy is in progress. Cycle 1 grade 3 toxicities (other than DLT) Cohort A (n= 21) Cohort B dose escalation + expansion (n= 25) Neutropenia 19% 12% Nausea 5% — Vomiting 5% — Mucositis 5% — Hypertension 10% 8% Prolonged QT (asymptomatic) 5% 8% Arthralgia — 4% Diarrhea — 4% Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca Abraxis BioScience, AstraZeneca
The influence of antibody fragment format on phage display based affinity maturation of IgG (2013)

Today, most approved therapeutic antibodies are provided as immunoglobulin G (IgG), whereas small recombinant antibody formats are required for in vitro antibody generation and engineering during drug development. Particularly,single chain (sc) antibody fragments like scFv or scFab are well suited for phage display and bacterial expression, but some have been found to lose affinity during conversion into IgG.In this study, we compared the influence of the antibody format on affinity maturation of the CD30-specific scFv antibody fragment SH313-F9, with the overall objective being improvement of the IgG. The variable genes of SH313-F9 were randomly mutated and then cloned into libraries encoding different recombinant antibody formats, including scFv, Fab, scFabΔC, and FabΔC. All tested antibody formats except Fab allowed functional phage display of the parental antibody SH313-F9, and the corresponding mutated antibody gene libraries allowed isolation of candidates with enhanced CD30 binding. Moreover, scFv and scFabΔC antibody variants retained improved antigen binding after subcloning into the single gene encoded IgG-like formats scFv-Fc or scIgG, but lost affinity after conversion into IgGs.Only affinity maturation using the Fab-like FabΔC format, which does not contain the carboxy terminal cysteines, allowed successful selection of molecules with improved binding that was retained after conversion to IgG. Thus, affinity maturation of IgGs is dependent on the antibody format employed for selection and screening. In this study, only FabΔC resulted in the efficient selection of IgG candidates with higher affinity by combination of Fab-like conformation and improved phage display compared with Fab.
Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: Contribution of the DHEAge Study to a sociobiomedical issue (2000)

The secretion and the blood levels of the adrenal steroid dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) decrease profoundly with age, and the question is posed whether administration of the steroid to compensate for the decline counteracts defects associated with aging. The commercial availability of DHEA outside the regular pharmaceutical-medical network in the United States creates a real public health problem that may be resolved only by appropriate long-term clinical trials in elderly men and women. Two hundred and eighty healthy individuals (women and men 60-79 years old) were given DHEA, 50 mg, or placebo, orally, daily for a year in a double-blind, placebo-controlled study. No potentially harmful accumulation of DHEAS and active steroids was recorded. Besides the reestablishment of a "young" concentration of DHEAS, a small increase of testosterone and estradiol was noted, particularly in women, and may be involved in the significantly demonstrated physiological-clinical manifestations here reported. Bone turnover improved selectively in women >70 years old, as assessed by the dual-energy x-ray absorptiometry (DEXA) technique and the decrease of osteoclastic activity. A significant increase in most libido parameters was also found in these older women. Improvement of the skin status was observed, particularly in women, in terms of hydration, epidermal thickness, sebum production, and pigmentation. A number of biological indices confirmed the lack of harmful consequences of this 50 mg/day DHEA administration over one year, also indicating that this kind of replacement therapy normalized some effects of aging, but does not create "supermen/women" (doping).
Efficient Storage Synchronization for Live Migration in Cloud Infrastructures (2011)

Live migration of virtual machines is an important issue in Cloud computing environments: when physical hosts are overloaded, some or all virtual machines can be moved to a less loaded host. Live migration poses additional challenges when virtual machines use local persistent storage, since the complete disk state needs to be transferred to the destination host while the virtual machines are running and hence are altering the disk state. In this paper, several approaches for implementing and synchronizing persistent storage during live migration of virtual machines in Cloud infrastructures are presented. Furthermore, the approaches also enable users to migrate swap space, which is currently not possible on most virtual machine hypervisors. Finally, measurements regarding disk synchronization, migration time and possible overheads are presented.
Acceleration of human prostate cancer growth in vivo by factors produced by prostate and bone fibroblasts. (1991)

Prostate cancer, the most prevalent cancer affecting men, frequently metastasizes to the axial skeleton where it produces osteoblastic lesions with growth rates often exceeding that of the primary tumor. To evaluate the role of tumor cell-host stromal interaction and stromal specific growth factors (GFs) in prostate cancer growth and progression, we coinoculated athymic mice with human prostate cancer cells (LNCaP) and various nontumorigenic fibroblasts s.c. LNCaP tumor formation was most consistently induced by human bone (MS) fibroblasts (62%), followed by embryonic rat urogenital sinus mesenchymal (rUGM) cells (31%) and Noble rat prostatic fibroblasts (17%), but not by NIH-3T3, normal rat kidney, or human lung CCD16 fibroblasts. Carcinomas formed preferentially in male hosts, demonstrating in vivo androgen sensitivity. The human prostate component of these tumors was confirmed with immunohistochemical staining for prostate-specific antigen (PSA), Northern analysis for PSA expression, and Southern analysis for human repetitive Alu sequences. Elevations in serum PSA paralleled the histomorphological and biochemical findings. LNCaP and fibroblast cell-conditioned media (CM) was used to determine whether autocrine and paracrine mitogenic pathways exist between LNCaP and fibroblast cells in vitro, and various defined GFs were tested to identify possible active factors. Mitogenic assays revealed a 200-300% bidirectional stimulation between LNCaP and bone or prostate fibroblast-derived CM. Lung, normal rat kidney, and 3T3 fibroblast CM were not mitogenic for LNCaP cells. Among the purified GFs tested basic fibroblast growth factor (bFGF) was the most potent mitogen, stimulating LNCaP growth 180% in a concentration-dependent manner. Transforming growth factor alpha and epidermal growth factor were both minimally mitogenic. Coinoculation of LNCaP cells with a slowly absorbed matrix (Gelfoam) absorbed with bFGF or dialyzed and concentrated rUGM or MS CM was also capable of inducing LNCaP tumor formation in vivo. These observations illustrate that fibroblasts differentially modulate prostate cancer growth through the release of paracrine-mediated GFs, possibly including bFGF, and that tumor-stromal cell interactions play an important role in prostate cancer growth and progression.
Genomic and Proteomic Analyses of the Agarolytic System Expressed bySaccharophagus degradans2-40 (2006)

Saccharophagus degradans 2-40 (formerly Microbulbifer degradans 2-40) is a marine gamma-subgroup proteobacterium capable of degrading many complex polysaccharides, such as agar. While several agarolytic systems have been characterized biochemically, the genetics of agarolytic systems have been only partially determined. By use of genomic, proteomic, and genetic approaches, the components of the S. degradans 2-40 agarolytic system were identified. Five agarases were identified in the S. degradans 2-40 genome. Aga50A and Aga50D include GH50 domains. Aga86C and Aga86E contain GH86 domains, whereas Aga16B carries a GH16 domain. Novel family 6 carbohydrate binding modules (CBM6) were identified in Aga16B and Aga86E. Aga86C has an amino-terminal acylation site, suggesting that it is surface associated. Aga16B, Aga86C, and Aga86E were detected by mass spectrometry in agarolytic fractions obtained from culture filtrates of agar-grown cells. Deletion analysis revealed that aga50A and aga86E were essential for the metabolism of agarose. Aga16B was shown to endolytically degrade agarose to release neoagarotetraose, similarly to a beta-agarase I, whereas Aga86E was demonstrated to exolytically degrade agarose to form neoagarobiose. The agarolytic system of S. degradans 2-40 is thus predicted to be composed of a secreted endo-acting GH16-dependent depolymerase, a surface-associated GH50-dependent depolymerase, an exo-acting GH86-dependent agarase, and an alpha-neoagarobiose hydrolase to release galactose from agarose.
Male-specific Modification of Human CD52 (1999)

CD52 is an unusually short, bipolar glycopeptide bearing a highly charged <i>N</i>-linked carbohydrate moiety and a glycosylphosphatidylinositol membrane anchor. It is exclusively expressed on lymphocytes and in the male genital tract where it is shed into the seminal plasma and inserts into the sperm membrane. The sperm surface molecule has potential significance as a target for antibodies that inhibit sperm function and gamete interaction. Western blot analyses suggested cell type-specific modifications of the antigen. It was purified from seminal plasma and a detailed structural analysis performed. The majority of anchor structures in male genital tract CD52 showed 2-inositol palmitoylation, rendering molecules insensitive toward phospholipase C, and a<i>sn</i>-1-alkyl-2-<i>lyso</i>-glycerol structure in place of the diacylated anchor described by Treumann <i>et al.</i>(Treumann, A., Lifely, M. R., Schneider, P., and Ferguson, M. A. (1995) <i>J. Biol. Chem</i>. 270, 6088–6099).<i>N</i>-Glycans of the male genital tract product were based on bi-, tri-, and tetraantennary structures of highly charged (up to -7), terminally sialylated complex-type sugars. A substantial proportion carried varying numbers of lactosamine repeats of which nearly 30% were branched. Different from lymphocytes, 10–15% of all<i>N</i>-glycans of the male genital tract antigen also contained peripheral fucose. These data confirm that male genital tract CD52 is distinct from the lymphocyte form by both <i>N</i>-linked glycans and COOH-terminal attached lipid anchor.
A New Agenda (1996)

Recorded in Alumni Memorial Chapel, at the Southern Baptist Theological Seminary, on December 3, 1996.
A Phase I, Open-Label Study of Siltuximab, an Anti–IL-6 Monoclonal Antibody, in Patients with B-cell Non-Hodgkin Lymphoma, Multiple Myeloma, or Castleman Disease (2013)

No dose-related or cumulative toxicity was apparent across all disease indications. A dose of 12 mg/kg every 3 weeks was recommended on the basis of the high response rates in Castleman disease and the sustained CRP suppression. Randomized studies are ongoing in Castleman disease and multiple myeloma.
The S100P/RAGE signaling pathway regulates expression of microRNA‐21 in colon cancer cells (2015)

S100P signaling through the receptor for advanced glycation end-products (RAGE) contributes to colon cancer invasion and metastasis, but the mechanistic features of this process are obscure. Here, we investigate whether activation of S100P/RAGE signaling regulates oncogenic microRNA-21 (miR-21). We show that exogenous S100P up-regulates miR-21 levels in human colon cancer cells, whereas knockdown of S100P results in a decrease of miR-21. Furthermore, blockage of RAGE with anti-RAGE antibody suppresses S100P induction of miR-21. In addition, we found that S100P induction of miR-21 expression involves ERK and is suppressed by the MEK inhibitor U0126. Also, S100P treatment stimulates the enrichment of c-Fos, and AP-1 family members, at the miR-21 gene promoter.
Identification of Common Transcriptional Regulatory Elements in Interleukin-17 Target Genes (2006)

Interleukin (IL)-17 is the founding member of a novel family of inflammatory cytokines. Although produced by T cells, IL-17 activates genes and signals typical of innate immune mediators such as tumor necrosis factor (TNF)-alpha and IL-1beta. Most IL-17 target genes characterized to date are cytokines or neutrophil-attractive chemokines. Our recent microarray studies identified an acute phase response gene, 24p3/lipocalin 2, as a novel IL-17-induced gene. Here we describe a detailed analysis of the 24p3 promoter. We find that, unlike cytokine or chemokine gene target genes, 24p3 is regulated primarily at the level of transcription rather than mRNA stability and that synergy between IL-17 and TNFalpha occurs at the level of the 24p3 promoter. Two key transcription factor binding sites (TFBS) were identified, corresponding to NF-kappaB and CCAAT/enhancer-binding protein (C/EBP). Deletion of either site eliminated 24p3 promoter activity in response to IL-17. These findings were strikingly similar to the IL-6 promoter, where IL-17-mediated regulation of both NF-kappaB and C/EBP is essential. To determine whether joint use of NF-kappaB and C/EBP is common to all IL-17 target genes, we performed a computational analysis on 18 well documented IL-17 target promoters to assess statistical enrichment of specific TFBSs. Indeed, NF-kappaB and C/EBP sites were over-represented in these genes, as were AP1 and OCT1 sites. Moreover, these promoters fell into three definable subcategories based on TFBS location and usage. Analysis of IL-17 target gene regulation is key for understanding this important host-defense molecule and also contributes to an understanding of upstream signaling mechanisms used by IL-17, either alone or in concert with TNFalpha.
A One-Step Conversion of Benzene to Phenol with a Palladium Membrane (2002)

Existing phenol production processes tend to be energy-consuming and produce unwanted by-products. We report an efficient process using a shell-and-tube reactor, in which a gaseous mixture of benzene and oxygen is fed into a porous alumina tube coated with a palladium thin layer and hydrogen is fed into the shell. Hydrogen dissociated on the palladium layer surface permeates onto the back and reacts with oxygen to give active oxygen species, which attack benzene to produce phenol. This one-step process attained phenol formation selectivities of 80 to 97% at benzene conversions of 2 to 16% below 250 degrees C (phenol yield: 1.5 kilograms per kilogram of catalyst per hour at 150 degrees C).
Dynamic Optimization of Human Walking (2001)

A three-dimensional, neuromusculoskeletal model of the body was combined with dynamic optimization theory to simulate normal walking on level ground. The body was modeled as a 23 degree-of-freedom mechanical linkage, actuated by 54 muscles. The dynamic optimization problem was to calculate the muscle excitation histories, muscle forces, and limb motions subject to minimum metabolic energy expenditure per unit distance traveled. Muscle metabolic energy was calculated by slimming five terms: the basal or resting heat, activation heat, maintenance heat, shortening heat, and the mechanical work done by all the muscles in the model. The gait cycle was assumed to be symmetric; that is, the muscle excitations for the right and left legs and the initial and terminal states in the model were assumed to be equal. Importantly, a tracking problem was not solved. Rather only a set of terminal constraints was placed on the states of the model to enforce repeatability of the gait cycle. Quantitative comparisons of the model predictions with patterns of body-segmental displacements, ground-reaction forces, and muscle activations obtained from experiment show that the simulation reproduces the salient features of normal gait. The simulation results suggest that minimum metabolic energy per unit distance traveled is a valid measure of walking performance.
Novel Bioactive and Stable Neurotensin Peptide Analogues Capable of Delivering Radiopharmaceuticals and Molecular Beacons to Tumors (2003)

The prevalence of neurotensin receptor (NTR) in several human tumors makes it an attractive target for the delivery of cytotoxic drugs and imaging agents. Native neurotensin (NT) is a tridecapeptide that binds to NTR and induces tumor growth. Unfortunately, NT has a short plasma half-life, which hinders its use for in vivo biomedical applications. Numerous reports suggest that Arg(8)-Arg(9) and Tyr(11)-Ile(12) amide bonds are particularly susceptible to degradation by proteolytic enzymes. Predicated on this observation, we substituted Arg(8), Arg(9), and Ile(12) amino acids with the corresponding commercially available mimics. These surrogate amino acids are amenable to standard Fmoc peptide synthesis strategy, and the resulting compounds are stable in biological media for >4 h and bind to NTR with high affinity. Furthermore, conjugating DTPA to the new peptides and subsequent labeling with (111)In-DTPA for nuclear imaging or fluorescein for optical imaging did not diminish the NTR binding affinities of the peptides. In vivo biodistribution of a representative (111)In-DTPA-NT peptide analogue in SCID mice bearing NTR-positive human adenocarcinoma (HT29) xenograft shows that the compound was primarily retained in tumor tissue (2.2% ID/g) and the kidneys (4.8% ID/g) at 4 h postinjection. Coinjection of cold NT and the radiolabeled NT peptide analogue inhibited the tumor but not the kidney uptake, demonstrating that retention of the radiolabeled compound in tumor tissue was mediated by NTR specific uptake while it accumulates in the kidneys by a nonspecific mechanism. These findings show that the new NT peptide analogues are robust and can deliver imaging agents to NTR-positive tumors such as pancreatic cancer.
Intratympanic immunosuppressives for prevention of immune-mediated sensorineural hearing loss. (2000)

Local application of immunosuppressives did not suppress inner ear inflammatory infiltrates and hearing loss in KLH-induced labyrinthitis in a guinea pig model.
Radioimmunotherapy with Alpha-Particle-Emitting Immunoconjugates (1988)

Alpha particles are energetic short-range ions whose higher linear energy transfer produces extreme cytotoxicity. An alpha-particle-emitting radioimmunoconjugate consisting of a bismuth-212-labeled monoclonal immunoglobulin M specific for the murine T cell/neuroectodermal surface antigen Thy 1.2 was prepared. Analysis in vitro showed that the radioimmunoconjugate was selectively cytotoxic to a Thy 1.2+ EL-4 murine tumor cell line. Approximately three bismuth-212-labeled immunoconjugates per target cell reduced the uptake of [3H]thymidine by the EL-4 target cells to background levels. Mice inoculated intraperitoneally with EL-4 cells were cured of their ascites after intraperitoneal injection of 150 microcuries of the antigen-specific radioimmunoconjugate, suggesting a possible role for such conjugates in intracavitary cancer therapy.