gebhart/patrepeval huggingface dataset:
Methotrexate-Conjugated PEGylated Dendrimers Show Differential Patterns of Deposition and Activity in Tumor-Burdened Lymph Nodes after Intravenous and Subcutaneous Administration in Rats (2014)

The current study sought to explore whether the subcutaneous administration of lymph targeted dendrimers, conjugated with a model chemotherapeutic (methotrexate, MTX), was able to enhance anticancer activity against lymph node metastases. The lymphatic pharmacokinetics and antitumor activity of PEGylated polylysine dendrimers conjugated to MTX [D-MTX(OH)] via a tumor-labile hexapeptide linker was examined in rats and compared to a similar system where MTX was α-carboxyl O-tert-butylated [D-MTX(OtBu)]. The latter has previously been shown to exhibit longer plasma circulation times. D-MTX(OtBu) was well absorbed from the subcutaneous injection site via the lymph, and 3 to 4%/g of the dose was retained by sentinel lymph nodes. In contrast, D-MTX(OH) showed limited absorption from the subcutaneous injection site, but absorption was almost exclusively via the lymph. The retention of D-MTX(OH) by sentinel lymph nodes was also significantly elevated (approximately 30% dose/g). MTX alone was not absorbed into the lymph. All dendrimers displayed lower lymph node targeting after intravenous administration. Despite significant differences in the lymph node retention of D-MTX(OH) and D-MTX(OtBu) after subcutaneous and intravenous administration, the growth of lymph node metastases was similarly inhibited. In contrast, the administration of MTX alone did not significantly reduce lymph node tumor growth. Subcutaneous administration of drug-conjugated dendrimers therefore provides an opportunity to improve drug deposition in downstream tumor-burdened lymph nodes. In this case, however, increased lymph node biodistribution did not correlate well with antitumor activity, possibly suggesting constrained drug release at the site of action.
High-dose recombinant tumor necrosis factor alpha in combination with interferon gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma. (1992)

This preliminary analysis of a phase II study suggests that high-dose rTNF alpha can be administered with acceptable toxicity by ILP with dopamine and hyperhydration. Tumor responses can be evidenced in melanoma and sarcoma. Furthermore, combination of rTNF alpha, rIFN-gamma, and melphalan seems to achieve high efficacy with minimal toxicity, even after failure of prior therapy with melphalan alone.
Systems Analysis of ATF3 in Stress Response and Cancer Reveals Opposing Effects on Pro-Apoptotic Genes in p53 Pathway (2011)

Stress-inducible transcription factors play a pivotal role in cellular adaptation to environment to maintain homeostasis and integrity of the genome. Activating transcription factor 3 (ATF3) is induced by a variety of stress and inflammatory conditions and is over-expressed in many kinds of cancer cells. However, molecular mechanisms underlying pleiotropic functions of ATF3 have remained elusive. Here we employed systems analysis to identify genome-wide targets of ATF3 that is either induced by an alkylating agent methyl methanesulfonate (MMS) or over-expressed in a prostate tumour cell line LNCaP. We show that stress-induced and cancer-associated ATF3 is recruited to 5,984 and 1,423 targets, respectively, in the human genome, 89% of which are common. Notably, ATF3 targets are highly enriched for not only ATF/CRE motifs but also binding sites of several other stress-inducible transcription factors indicating an extensive network of stress response factors in transcriptional regulation of target genes. Further analysis of effects of ATF3 knockdown on these targets revealed that stress-induced ATF3 regulates genes in metabolic pathways, cell cycle, apoptosis, cell adhesion, and signalling including insulin, p53, Wnt, and VEGF pathways. Cancer-associated ATF3 is involved in regulation of distinct sets of genes in processes such as calcium signalling, Wnt, p53 and diabetes pathways. Notably, stress-induced ATF3 binds to 40% of p53 targets and activates pro-apoptotic genes such as TNFRSF10B/DR5 and BBC3/PUMA. Cancer-associated ATF3, by contrast, represses these pro-apoptotic genes in addition to CDKN1A/p21. Taken together, our data reveal an extensive network of stress-inducible transcription factors and demonstrate that ATF3 has opposing, cell context-dependent effects on p53 target genes in DNA damage response and cancer development.
Synthesis of 3,4,3 LI 1,2 HOPO labelled with 14C (2001)

Abstract 3,4,3 LI 1,2 HOPO 1 or LIHOPO (1,5,10,14‐tetra (1‐hydroxy‐2‐pyridone‐6‐oyl)‐1,5,10,14‐tetraazatetradecane.) is a decorporation agent used against actinides. It was synthesised labelled with carbon 14 with a view to metabolism studies. [6,9‐ 14 C]‐LIHOPO 2 was obtained in two radioactive steps through a very convenient synthesis in 50% radioactive yield from commercially available [1,4‐ 14 C]‐spermine, hydrochloride and 1‐benzyloxy‐6‐oxo‐1,6‐dihydropyridine‐2‐carbonyl chloride 7 . The synthesis of 7 is also described. Copyright © 2001 John Wiley &amp; Sons, Ltd.
Antibody-free, targeted mass-spectrometric approach for quantification of proteins at low picogram per milliliter levels in human plasma/serum (2012)

Sensitive detection of low-abundance proteins in complex biological samples has typically been achieved by immunoassays that use antibodies specific to target proteins; however, de novo development of antibodies is associated with high costs, long development lead times, and high failure rates. To address these challenges, we developed an antibody-free strategy that involves PRISM (high-pressure, high-resolution separations coupled with intelligent selection and multiplexing) for sensitive selected reaction monitoring (SRM)-based targeted protein quantification. The strategy capitalizes on high-resolution reversed-phase liquid chromatographic separations for analyte enrichment, intelligent selection of target fractions via on-line SRM monitoring of internal standards, and fraction multiplexing before nano-liquid chromatography-SRM quantification. Application of this strategy to human plasma/serum demonstrated accurate and reproducible quantification of proteins at concentrations in the 50-100 pg/mL range, which represents a major advance in the sensitivity of targeted protein quantification without the need for specific-affinity reagents. Application to a set of clinical serum samples illustrated an excellent correlation between the results obtained from the PRISM-SRM assay and those from clinical immunoassay for the prostate-specific antigen level.
Cloning and functional characterization of Phaeodactylum tricornutum front‐end desaturases involved in eicosapentaenoic acid biosynthesis (2002)

Phaeodactylum tricornutum is an unicellular silica-less diatom in which eicosapentaenoic acid accumulates up to 30% of the total fatty acids. This marine diatom was used for cloning genes encoding fatty acid desaturases involved in eicosapentaenoic acid biosynthesis. Using a combination of PCR, mass sequencing and library screening, the coding sequences of two desaturases were identified. Both protein sequences contained a cytochrome b5 domain fused to the N-terminus and the three histidine clusters common to all front-end fatty acid desaturases. The full length clones were expressed in Saccharomyces cerevisiae and characterized as Delta5- and Delta6-fatty acid desaturases. The substrate specificity of each enzyme was determined and confirmed their involvement in eicosapentaenoic acid biosynthesis. Using both desaturases in combination with the Delta6-specific elongase from Physcomitrella patens, the biosynthetic pathways of arachidonic and eicosapentaenoic acid were reconstituted in yeast. These reconstitutions indicated that these two desaturases functioned in the omega3- and omega6-pathways, in good agreement with both routes coexisting in Phaeodactylum tricornutum. Interestingly, when the substrate selectivity of each enzyme was determined, both desaturases converted the omega3- and omega6-fatty acids with similar efficiencies, indicating that none of them was specific for either the omega3- or the omega6-pathway. To our knowledge, this is the first report describing the isolation and biochemical characterization of fatty acid desaturases from diatoms.
A Large-Scale Preparation and Some Physicochemical Properties of RecA Protein (1981)

Pure recA protein was easily obtained from Escherichia coli harboring plasmid pTM-2 which carried the recA gene by two chromatographic steps on phosphocellulose and DEAE-cellulose. RecA protein was stable in the pH range of 6 to 9 at 25 degrees C. RecA protein was found to aggregate highly under these conditions. Lowering of the protein concentration, the presence of glycerol, and lowering of the pH in the pH stability region diminished the extent of aggregation. The spectroscopic properties of recA protein were measured in the presence of 10% (v/v) glycerol. RecA protein had an absorption maximum at 278 nm. The value of a1% 1cm at 278 nm was determined to be 5.7. The tryptophyl fluorescence spectrum excited at 295 nm had an emission maximum at 340 nm and the quantum efficiency of recA protein relative to N-acetyl-L-tryptophanamide was determined to be 0.65. The CD spectrum of recA protein had negative double maxima at 210 and 220 nm. The alpha-helical content was estimated to be about 40% from the CD spectrum in the region of 200 to 250 nm. All three cysteinyl residues of recA protein were reacted with 5,5'-dithiobis(2-nitrobenzoic acid), and recA protein was found to have neither intramolecular nor intermolecular disulfide bond. The reactivities of the SH groups were changed by the presence of ATP or ADP. The denaturation of recA protein by guanidine hydrochloride was studied by measuring CD at 220 nm and tryptophyl fluorescence. The denaturation curve obtained by CD measurement consisted of two stages, one of which lies between 0 and 1.8 M and the other above 1.8 M guanidine hydrochloride. On the other hand, the denaturation curve obtained by fluorescence measurement consisted of a single transition in the concentration range of about 1 to 2.3 M guanidine hydrochloride.
Gelatinase Activities in Wounds of Healing-Impaired Mice Versus Wounds of Non-Healing-Impaired Mice (2000)

The gelatinases, matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9), have been implicated in different aspects of wound repair. However, little is known about MMP-2 and MMP-9 activity in animal models of impaired wound healing. We sought to compare serial gelatinase activities for 25 days after full-thickness excisional wounds in genetically diabetic healing-impaired mice and their nondiabetic non-healing-impaired littermates. Wound samples were frozen, homogenized, clarified by centrifugation, and analyzed on zymography gels, and MMP bands were quantitated relative to a conditioned media standard from HT-1080 cells. Gelatinase activity in both diabetic mice and nondiabetic mice increased after the mice were wounded. However, levels of latent gelatinases peaked earlier in the diabetic wounds, and there was more active MMP-2 and MMP-9 in the wounds of the diabetic mice than in the wounds of the nondiabetic mice. Because the higher gelatinase activity in the wounds of the diabetic mice was similar to the higher levels of gelatinase reported in difficult-to-heal wounds such as ulcers and burns, this diabetic mouse model may be useful for studies of these proteinases and their inhibitors in impaired wound healing.
Vagus Nerve Stimulation Delivered During Motor Rehabilitation Improves Recovery in a Rat Model of Stroke (2014)

Neural plasticity is widely believed to support functional recovery following brain damage. Vagus nerve stimulation paired with different forelimb movements causes long-lasting map plasticity in rat primary motor cortex that is specific to the paired movement. We tested the hypothesis that repeatedly pairing vagus nerve stimulation with upper forelimb movements would improve recovery of motor function in a rat model of stroke. Rats were separated into 3 groups: vagus nerve stimulation during rehabilitation (rehab), vagus nerve stimulation after rehab, and rehab alone. Animals underwent 4 training stages: shaping (motor skill learning), prelesion training, postlesion training, and therapeutic training. Rats were given a unilateral ischemic lesion within motor cortex and implanted with a left vagus nerve cuff. Animals were allowed 1 week of recovery before postlesion baseline training. During the therapeutic training stage, rats received vagus nerve stimulation paired with each successful trial. All 17 trained rats demonstrated significant contralateral forelimb impairment when performing a bradykinesia assessment task. Forelimb function was recovered completely to prelesion levels when vagus nerve stimulation was delivered during rehab training. Alternatively, intensive rehab training alone (without stimulation) failed to restore function to prelesion levels. Delivering the same amount of stimulation after rehab training did not yield improvements compared with rehab alone. These results demonstrate that vagus nerve stimulation repeatedly paired with successful forelimb movements can improve recovery after motor cortex ischemia and may be a viable option for stroke rehabilitation.
Development of an optimization concept for arc-modulated cone beam therapy (2007)

In this paper, we propose an optimization concept for a rotation therapy technique which is referred to as arc-modulated cone beam therapy (AMCBT). The aim is a reduction of the treatment time while achieving a treatment plan quality equal to or better than that of IMRT. Therefore, the complete dose is delivered in one single gantry rotation and the beam is modulated by a multileaf collimator. The degrees of freedom are the field shapes and weights for a predefined number of beam directions. In the new optimization loop, the beam weights are determined by a gradient algorithm and the field shapes by a tabu search algorithm. We present treatment plans for AMCBT for two clinical cases. In comparison to step-and-shoot IMRT treatment plans, it was possible by AMCBT to achieve dose distributions with a better dose conformity to the target and a lower mean dose for the most relevant organ at risk. Furthermore, the number of applied monitor units was reduced for AMCBT in comparison to IMRT treatment plans.
Groups of adenovirus type 2 mRNA's derived from a large primary transcript: probable nuclear origin and possible common 3' ends (1978)

Late in adenovirus type 2 infection, a number of mRNA's apparently arise by processing a large nuclear transcript that represents the right-hand 85% of the genome (summarized in Evans et al., Cell 12:733-739, 1977). Hybridization of labeled late mRNA to a series of DNA restriction fragments representing the right-hand 70% of the genome demonstrates at least 12 discrete mRNA's that appear to fall into five groups, each possibly containing a common 3' terminus. The processing necessary to generate these mRNA's apparently occurs in the nucleus. All the mRNA's appear to contain a sequence of approximately 100 nucleotides complementary to a fragment with coordinates 25.5-27.9. This fragment contains one of the regions found by Berget et al. (Proc. Natl. Sci. U.S.A. 74:3171-3175, 1977), Chow et al. (Cell 12:1-18, 1977), and Klessig (Cell 12:9-22, 1977) to the "spliced" onto the 5' end of late adenovirus type 2 mRNA's. Because the sequences to be spliced exist only once per large transcript, any of the mRNA-specific regions might only be preserved from a small fraction of the transcripts. Measurement of the transport efficiency of regions of the large nuclear transcript, if fact, shows that only 15 to 25% of any particular region is transported to the cytoplasm. The overall conclusion of these experiments is that the large late nuclear transcript can be processed in the nucleus to yield any one of many (approximately 12) mRNA's; the unused portions of the primary transcript then accumulate in the nucleus or are destroyed.
Isolation and Characterization of a New Mutant Human Cell Line Unresponsive to Alpha and Beta Interferons (1991)

Previously we described human cell line 2fTGH, in which expression of guanine phosphoribosyltransferase is tightly controlled by the upstream region of interferon (IFN)-stimulated human gene 6-16. After mutagenesis of 2fTGH and selection with 6-thioguanine and IFN-alpha, we isolated 11.1, a recessive mutant that does not respond to IFN-alpha. We now describe U2, a second recessive mutant, selected similarly, that complements 11.1. U2 had no response to IFN-alpha or IFN-beta, and its response to IFN-gamma was partially defective. Although many genes did respond to IFN-gamma in U2, the 9-27 gene did not and the antiviral response of U2 cells to IFN-gamma was greatly reduced. Band shift assays showed that none of the transcription factors normally induced in 2fTGH cells by IFN-alpha (E and M) or IFN-gamma (G) were induced in U2. However, extracts of untreated U2 cells gave rise to a novel band that was increased by treatment with IFN-gamma but not IFN-alpha. Band shift complementation assays revealed that untreated and IFN-gamma-treated U2 cells lack the functional E gamma subunit of transcription factor E and that IFN-alpha-treated U2 cells do contain the functional E alpha subunit.
Release of Propranolol Hydrochloride from Matrix Tablets Containing Sodium Carboxymethylcellulose and Hydroxypropylmethylcellulose (1999)

Hydroxypropylmethylcellulose (HPMC) and three viscosity grades of sodium carboxymethylcellulose (NaCMC), namely NaCMC (Blanose 7H 4XF), NaCMC (Courlose P 800), and NaCMC (Courlose P 350), were investigated for their ability to provide a sustained release of propranolol hydrochloride from matrices. The rank order of release rate, in the absence of HPMC, was NaCMC (Blanose) < NaCMC P 800 < NaCMC P 350 for matrices containing 95-285 mg NaCMC, and was dependent on their viscosity grades. The effects of changing the ratio of HPMC to NaCMC (Blanose) and the drug/total polymer ratio were examined. The release rates decreased as the proportion of NaCMC in the matrices increased. Zero-order release of propranolol hydrochloride was obtained from matrices containing 285 mg 3:1 NaCMC (Blanose)/HPMC. Differential scanning calorimetry was used to quantify the moisture uptake by the polymers at 37 degrees C. Wafers containing NaCMC (Blanose) or 1:1 HPMC/NaCMC (Blanose) absorbed water similarly. A study of the erosion rates of matrices containing polymer only indicated that NaCMC (Blanose) eroded more quickly than HPMC. When propranolol hydrochloride was included in matrices containing NaCMC (Blanose), the erosion was reduced as a result of the insolubility of a complex formed between NaCMC and propranolol hydrochloride. The interaction between propranolol hydrochloride and NaCMC (Blanose) was confirmed by both dialysis and by monitoring the release of sodium ions from the matrices.
Quantitative Analysis of Localized Sources Identified by Focal Impulse and Rotor Modulation Mapping in Atrial Fibrillation (2015)

FIRM-identified rotor sites did not exhibit quantitative atrial electrogram characteristics expected from rotors and did not differ quantitatively from surrounding tissue. Catheter ablation at these sites, in conjunction with pulmonary vein isolation, resulted in AF termination or organization in a minority of patients (4/24; 17%). Further validation of this approach is necessary.
Congruence Between Specializations in Graduate School and Post-Graduate Employment Patterns for Social Workers (1990)

At the graduate level, the design of the social work curriculum on the basis of specializations and concentrations is now well established even though there is much variance from one school to another. A question that has received little attention in research, however, is wheter graduates of school sof social work are typically employed in jobs which are congruent with their graduate school preparation. The present study explores the question through a survey conducted in one state. The reuslts revealed that approximately one-half of all respondents were employed in fields congruent with their graduate school specializations. Implications for social work education are discussed.
A simple assay to determine the functionality of Cre or FLP recombination targets in genomic manipulation constructs (1996)

We report the construction of two Escherichia coli strains (294-Cre and 294-FLP) which express either Cre- or FLP-recombinase. Plasmids containing authentic recognition targets for either recombinase (loxPs or FRTs) are recombined when propagated in the appropriate strain. 294-Cre and 294-FLP thus provide a simple test for the recombination competence of constructs that are designed for use in Cre- or FLP-mediated genomic manipulations.
Surgical Technique For The Nucleus?? Contour??? Cochlear Implant (2002)

This paper deals with the Nucleus C124R (CS) (Contour) cochlear Implant: its characteristics, differences compared with the previous generation of devices, the perimodiolar electrode, and the surgical technique used for safe insertion. We also discuss the rationale behind perimodiolar electrodes in general, as well as the results of laboratory studies validating the design and safety of this particular electrode array. The differences in surgical technique between this device and prior Nucleus cochlear implants are as follows: the incision and the size of the well, or recess, for the electronics are smaller; the cochleostomy is larger; the posterior portion is placed in a subpericranial pocket, not tied down, before electrode insertion; and the insertion process itself is quite different, due to the nature of the electrode, its size, shape, and stylet. The technique described is that used by one experienced cochlear implant center, and reflect the authors' practice. Clearly, there are other possible variations on this theme, which may be equally satisfactory in other hands. Most surgeons find this device to be easier to place than previous generations: complications to date have been uncommon.
Glucose-regulated stresses induce resistance to camptothecin in human cancer cells (1996)

The glucose-regulated stress response in mammalian cells is characterized by the increased synthesis of glucose-regulated proteins (GRPs). In this study, we found that GRP-inducing conditions in culture led to induction of resistance to the topoisomerase I-targeted drug camptothecin in human colon cancer HT-29 and ovarian cancer A2780 cells. The induction of camptothecin resistance was accompanied by decreased levels of camptothecin-induced cleavable complexes, as measured by a topoisomerase I band depletion assay. However, topoisomerase I protein levels were the same in both stressed and non-stressed cells. Furthermore, when isolated nuclei from stressed and non-stressed cells were treated with camptothecin, similar levels of cleavable complexes were obtained, suggesting that the activity of topoisomerase I did not change in stressed cells. In contrast, intracellular accumulation of camptothecin decreased in stressed cells. Our results indicate that stress-induced camptothecin resistance could be explained by reduced camptothecin accumulation, leading to decreased numbers of cleavable complexes, without quantitative or qualitative changes in topoisomerase I levels. In addition, cell cycle analysis revealed that the GRP-inducing treatments resulted in an accumulation of G1/G0-phase cells. As camptothecin shows an S-phase-specific cytotoxicity, the G1/G0-phase accumulation is another mechanism for camptothecin resistance. Since a glucose-regulated response is produced by hypoxia and nutrient deprivation that occur naturally in solid tumors, the resistance observed here can occur in some solid tumors and can be an obstacle to chemotherapy.