gebhart/patrepeval huggingface dataset:
Dose-Related α-Difluoromethylornithine Ototoxicity (1991)

We assessed the ototoxicity associated with oral alpha-difluoromethylornithine (DFMO) administration in 58 patients with metastatic malignant melanoma. One hundred seventy-nine sequential audiograms obtained from patients treated with DFMO alone (16 patients) or in combination with alpha 2b-interferon (42 patients) were evaluated. DFMO doses ranged from 2 to 12 g/m2/d and were given over periods of 2 to 50 weeks. Total doses ranging from 60 g/m2 to 1390 g/m2 were correlated with clinical effects and pure tone audiometric changes. By regression analysis cumulative DFMO dose showed a consistent and statistically significant positive relationship to hearing loss at multiple frequencies (500, 1000, 2000, 4000, and 8000 Hz). Patients with normal (threshold less than 30 db) baseline audiograms demonstrated more hearing loss than those with abnormal (threshold greater than or equal to 30 db) baseline audiograms at the higher frequency levels. Of the patients with normal prestudy hearing thresholds 10% or less developed a demonstrable hearing deficit at cumulative DFMO doses below 150 g/m2. Conversely, up to 75% of the patients who received more than 250 g/m2 developed a clinically demonstrable hearing loss. Other factors which adversely affected hearing included age, male gender, and the concomitant use of alpha 2b-interferon. In summary, the risk of clinically significant hearing loss in patients treated with DFMO was primarily related to dose and the presence of a pre-existing hearing deficit.
Lifestyle Risk and Delaying Factors (2006)

Research findings suggest that dementia risk is lower in individuals with more extensive education, greater engagement in mentally stimulating leisure activities during adulthood, and higher occupational complexity. Other recent findings support the importance of early-life risk factors, such as socioeconomic conditions, early-life development, and exposure to infection, in explaining individual differences in dementia risk. Life-style variables have been conceptualized as delaying factors, postponing onset of dementia and thereby reducing total population burden of dementia. Using a sample of Swedish twins from the HARMONY study, we found that education significantly affects dementia onset, that is, occurrence and timing of dementia symptoms. In the HARMONY data, we also showed that differences in education are reflected in differences in leisure activities and occupation, suggesting that differences in cognitive engagement begin early and persist over the life course. Such findings point to the importance of taking a life-course perspective to designing interventions to delay or to prevent dementia.
Dishevelled C‐terminus: prolyl and histidinyl motifs (2011)

The phosphoprotein scaffold Dishevelled is an essential component of both Wnt signalling and of the signalsome that constitutes the supermolecular 'punctae' of assembled proteins often observed in fluorescence microscopy. The C-terminal region beyond the DEP domain displays unique and interesting character, exploited herein by careful analysis of the primary structure. Human Dishevelled-1, -2, -3 and fly Dishevelled (Dsh) sequences were downloaded and interrogated in silico. The C-terminus of Dishevelled-3 is revealed by FoldIndex(®) to be rich in ordered structure. It displays primary sequence that is unique and divergent in important ways from vertebrate isoforms as well as from the fly Dsh. The region is amphipathic, high in prolyl content, and harbours polyprolines. Dishevelled-3 displays some regions, where the proline content is >40%. Polyprolyl sequences (2-4 residues) likely constitute important sites of interaction with other Dishevelled isoforms. Several histidine-single amino acid repeats are notable. The 637,638/647,648 repeats of Dvl3 are essential for Wnt non-canonical, but not canonical signalling. Mutagenesis reveals that the C-terminal sequence is essential for the formation of punctae, made visible by fluorescence microscopy. These Dvl3-based signalsomes are very large (25-35 MDa-MW), supermolecular complexes that display dynamic reorganization in response to Wnt stimulation. Dishevelled-3 C-terminus is rich in structure and unique motifs, worthy of detailed analysis with modern molecular tools.
Aggregation-resistant VHs selected by in vitro evolution tend to have disulfide-bonded loops and acidic isoelectric points (2008)

When panned with a transient heat denaturation approach against target enzymes, a human V(H) (antibody heavy chain variable domain) phage display library yielded V(H)s with composite characteristics of binding, non-aggregation and reversible thermal unfolding. Moreover, selection was characterized by enrichment for V(H)s with (i) an even number of disulfide forming Cys residues in complementarity-determining region (CDR) 1 and CDR3 and (ii) acidic isoelectric points. This parallels naturally occurring camelid and shark single-domain antibodies (sdAbs) which are also characterized by (i) solubility and reversible unfolding, (ii) a high occurrence of disulfide forming Cys in their CDRs, particularly, in CDR1 and CDR3 and (iii) acidic V(H)s as inferred here by a pI distribution analysis, reported here, of pools of human and camelid V(H) and V(H)H (camelid heavy chain antibody V(H)) sequences. Our results, reinforced by previous observations by others, suggest that protein acidification may yet be another mechanism nature has devised to create functional sdAbs and that this concept along with the inclusion of inter-CDR disulfide linkages may be applied to human V(H) domains/libraries for non-aggregation optimization. In addition, calculation of theoretical pIs of V(H)s selected by panning may be used for rapid and precise identification of non-aggregating V(H)s.
Lenalidomide as a novel treatment of acute myeloid leukemia (2013)

Lenalidomide has clinical activity in AML with manageable toxicity. The population that would benefit from lenalidomide and optimal dose needs to be better defined. Recent trials have focused on combining lenalidomide with other agents active in MDS and AML and promising data are emerging.
Organization of the Drosophila melanogaster hsp70 heat shock regulation unit. (1987)

Expression from the Drosophila melanogaster hsp70 promoter was controlled by a regulatory unit that was composed of two sequence elements that resembled the heat shock consensus sequence. The unit functioned in both orientations and at different distances from downstream promoter sequences. Each element of the unit alone was essentially inactive. Association of two elements resulted in a dramatic increase of transcription from the hsp70 promoter. This synergistic effect was independent of the relative orientation of the elements and, to a large extent, of the distance between them. Duplication of a region containing only one element also yielded a highly active, heat-regulated promoter. Genes with three to five elements were three to four times more active than those with a single regulatory unit.
Unique α,β‐ and α,α,β,β‐Peptide Foldamers Based on cis‐β‐Aminocyclopentanecarboxylic Acid (2012)

Waterproof: cis-β-Aminocylopentanecarboxylic acid is a highly suitable building block for the synthesis of α,β- and α,α,β,β-peptides that have unique helical structures with high stability in methanol and aqueous media. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Validation of UBE2C protein as a prognostic marker in node-positive breast cancer (2009)

We confirmed that UBE2C protein measured by IHC could be used as a prognostic marker in N+ breast cancer. The potential predictive interest of UBE2C as a marker of proteasome activity needs further investigations.
Novel Process For A Monolithic Integrated Accelerometer (2005)

A monolithic sensor, fabricated using a technology that combines surface micromachining with a BiCMOS process, is described. The capacitive sensing element consists of a 10/spl mu/m thick layer of polysilicon that is deposited in an early stage of the IC fabrication sequence. A high degree of synergy is achieved and conflicting issues regarding the merging of the processes are avoided by us ing IC processing steps for manufacturing of the sensor element. Adhesion between parts of the sensor structure, during their release, is eliminated by using an HF vapor phase etching process for the sacrificial layer. The completed sensor has been characterized successfully.
Increased expression of a 58-kDa protein kinase leads to changes in the CHO cell cycle. (1990)

We have isolated and characterized cDNA encoding a human 58-kDa protein kinase that is homologous to the cell division control (CDC) protein kinases. This protein kinase also contains a unique N-terminal domain that may potentially regulate its function. Due to its relatedness to p34CDC2, the human p58 cDNA was overexpressed in CHO cells to determine the effect on the cell cycle. Elevated expression of p58 in these cells resulted in prolonged late telophase and early G1 phase of the cell cycle. These p58 overexpressors showed a significantly increased frequency of tubulin midbodies as well as significant increases in mitotic abnormalities. Thus, proper regulation of p58 protein kinase is essential for normal cell cycle progression in these cells.
Pharmacological actions and therapeutic uses of cannabis and cannabinoids (2001)

This review highlights the pharmacology, pharmacokinetics, pharmacological actions, therapeutic uses and adverse effects of cannabinoids. The effect of cannabinoids on anaesthesia is mentioned briefly. Important advances have taken place in cannabinoid research over the last few years and have led to the discovery of novel ligands. The possible clinical applications of these ligands and the direction of future research are discussed.
Anti-Renal-Cell Carcinoma Chimeric Antibody G250 Facilitates Antibody-Dependent Cellular Cytotoxicity with In Vitro and In Vivo Interleukin-2-Activated Effectors (1996)

Renal cell carcinoma (RCC) is relatively resistant to chemotherapy and radiotherapy, whereas treatment with biologics has achieved limited success. Although monoclonal antibodies able to recognize human RCC have been identified, most induce little complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity (ADCC), and thus are of limited potential as therapeutic modalities in their natural conformation. We evaluated a human/ mouse chimeric derivative of the previously described G250 murine monoclonal antibody (mAb), reactive with RCC, to identify a reagent for potential immunotherapy. This chimeric antibody (ch-G250) is composed of the murine variable region from the G250 mAb, which recognizes a tumor-associated antigen expressed on 95% of primary and 86% of metastatic renal cell carcinomas. The constant region of the ch-G250 is comprised of the human IgG1 isotype domains. This chimeric antibody does not bind to normal renal tissue or other normal human tissues, with the exception of gastric mucosal cells and large bile-duct epithelium. Clinical radiolocalization studies have demonstrated the relative tumor-targeting potential of this radiolabeled antibody. This ch-G250 antibody facilitated potent ADCC against several RCC lines when using in vitro and in vivo interleukin-2 (IL-2)-activated peripheral blood mononuclear cells obtained from healthy control donors and patients with cancer, respectively. This lymphocyte-mediated ADCC was specific for RCC cells recognized by the ch-G250 antibody. Using flow cytometry, we found that the level of ADCC was directly related to the degree of binding of ch-G250 to the renal cell target. These in vitro data suggest that this antibody may improve efficacy of IL-2 therapy by targeting cytokine-activated effector cells directly to the tumor and facilitating in vivo ADCC. Clinical studies combining this chimeric antibody with IL-2 treatment will be needed to test the antitumor effects of this ADCC effect in vivo.
MSCRAMM-MEDIATED ADHERENCE OF MICROORGANISMS TO HOST TISSUES (1994)

Microbial adhesion to host tissue is the initial critical event in the pathogenesis of most infections and, as such, is an attractive target for the development of new antimicrobial therapeutics. Specific microbial components (adhesins) mediate adherence to host tissues by participating in amazingly sophisticated interactions with host molecules. This review focuses on a class of cell surface adhesins that specifically interact with extracellular matrix components and which we have designated MSCRAMMs (microbial surface components recognizing adhesive matrix molecules). MSCRAMMs recognizing fibronectin-, fibrinogen-, collagen-, and heparin-related polysaccharides are discussed in terms of structural organization, ligand-binding structures, importance in host tissue colonization and invasion, and role as virulence factors.
Inhibition of platelet function by organic nitrate vasodilators (1980)

There is evidence that platelet activation in the coronary circulation may be important in the pathogenesis of myocardial ischemia. Since organic nitrate vasodilators are commonly used in coronary artery disease, we have studied the in vitro effects of these drugs on platelet function. Nitroglycerin, isosorbide dinitrate, and their biotransformation product, inorganic nitrite, inhibited platelet aggregation with collagen, epinephrine, arachidonate, and ionophore, and blocked both primary and secondary aggregation in response to ADP. Nitroglycerin was studied in more detail. Its inhibitory effect was reversible and not dependent on external calcium concentration. It inhibited arachidonic acid oxygenation as measured by the arachidonate-induced oxygen burst and malonaldehyde production. These effects were not due to an increase in intracellular cyclic AMP. This unusual generalized inhibition of platelet function by nitroglycerin possibly contributes to its beneficial effect in myocardial ischemia in part by attenuating platelet reactivity in the coronary circulation.
Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage (2004)

BRCA1 (BReast-CAncer susceptibility gene 1) and BRCA2 are tumor suppressor genes, the mutant phenotypes of which predispose to breast and ovarian cancers. Intensive research has shown that BRCA proteins are involved in a multitude of pivotal cellular processes. In particular, both genes contribute to DNA repair and transcriptional regulation in response to DNA damage. Recent studies suggest that BRCA proteins are required for maintenance of chromosomal stability, thereby protecting the genome from damage. New data also show that BRCAs transcriptionally regulate some genes involved in DNA repair, the cell cycle, and apoptosis. Many of these functions are mediated by a large number of cellular proteins that interact with BRCAs. The functions of BRCA proteins are also linked to distinct and specific phosphorylation events; however, the extent to which phosphorylation-activated molecular pathways contribute to tumor suppressor activity remains unclear. Finally, the reasons why mutations in BRCA genes lead to the development of breast and ovarian cancers are not clearly understood. Elucidation of the precise molecular functions of BRCAs is expected to improve our understanding of hereditary as well as sporadic mammary carcinogenesis.
Dynamic Enolate Recognition in Aqueous Solution by Zinc(II) in a Phenacyl-Pendant Cyclen Complex:  Implications for the Role of Zinc(II) in Class II Aldolases (1999)

A zinc(II) complex of 1-(4-bromophenacyl)-1,4,7,10-tetraazacyclododecane, ZnL, has been synthesized to mimic the active center of class II aldolases. Its X-ray crystal structure showed that zinc(II) remains atop the four nitrogen atoms of cyclen (average Zn−N distance 2.170 Å) to bind with the carbonyl oxygen (Zn−O distance of 2.159(3) Å) and one H2O (Zn−O distance of 2.130(3) Å). Crystal data: monoclinic, space group P21/n (No. 14), with a = 12.221(8) Å, b = 11.052(7) Å, c = 18.194(9) Å, β = 97.12(3)°, V = 2438(5) Å3, Z = 4, R = 0.041, and Rw = 0.046. The potentiometric pH titration of ZnL in aqueous solution disclosed dissociation of one proton with pKa = 8.41 at 25 °C and I = 0.1 (NaClO4), which yields a mixture of a hydroxide-bound complex (ZnL−OH-) and an enolate-bound complex (ZnH-1L) in a 3:1 ratio, as determined by UV spectrophotometric and 13C and 1H NMR titrations. This is the first quantitative assessment of enolate formation promoted by a proximate zinc(II) ion near neutral pH in aqueous solution. The enolate-bound complex ZnH-1L independently isolated by treatment of ZnL with an equivalent amount NaOMe in acetonitrile was fully characterized to compare with ZnL. The equilibrium between the ZnL−OH- and ZnH-1L varied with temperature (15, 25, and 35 °C), from which thermodynamic parameters of ΔG = 3.0 kJ mol-1, ΔH = 8.7 kJ mol-1, and ΔS = 19 J mol-1 K-1 at 25 °C were determined. Because of the facile enolization by zinc(II), the methylene hydrogen atoms (adjacent to the carbonyl) of ZnL were readily exchanged by deuterium under physiological conditions. The half-life at 25 °C for this H−D exchange at pD 7 (20 mM MOPS buffer) was determined to be 25 min by 1H NMR measurements. Implications of the present results for the role of zinc(II) in the active center of class II aldolases are discussed.
Regulation of c-Src tyrosine kinase activity by the Src SH2 domain. (1993)

The protein-tyrosine kinase activity of pp60c-src (c-Src) is inhibited by phosphorylation of tyr527, within the c-Src c-terminal tail. Genetic and biochemical data have suggested that this negative regulation requires an intact Src homology 2 (SH2) domain. Since SH2 domains recognize phosphotyrosine, it is possible that these two non-catalytic domains associate, and thereby repress c-Src kinase activity. Consistent with this model, an isolated Src SH2 domain expressed in bacteria as a GST fusion protein bound in vitro to a synthetic phosphotyrosine-containing peptide modeled on the C-terminal 13 residues of the c-Src tail. Binding was absolutely dependent on phosphorylation of tyr527 in the tail peptide, and was modified by both the length and sequence of the peptide. Competition experiments indicated only a moderate binding affinity between the Src SH2 domain and the phosphorylated tail. A distinct phosphotyrosine-containing peptide previously identified as binding the Src SH2 domain with high affinity stimulated c-Src tyrosine kinase activity in vitro, possibly by competing with the endogenous tail phosphorylation site for binding to the SH2 domain. Indeed, this activation was competitively inhibited by purified bacterial Src SH2 domain. These data provide direct evidence that the c-Src tail has an intrinsic affinity for the Src SH2 domain, and suggest that such an interaction in the intact molecule contributes to maintaining c-Src in an inactive form.
Thermo Sequenase™ DNA Polymerase and T. acidophilum Pyrophosphatase: New Thermostable Enzymes for DNA Sequencing (1997)

A combination of thermostable enzymes has been developed that produces higher quality cycle sequences. Thermo Sequenase DNA polymerase is a thermostable enzyme engineered to catalyze the incorporation of ddNTPs with an efficiency several thousandfold better than other thermostable DNA polymerases. Since the enzyme also catalyzes pyrophosphorolysis at dideoxy termini, a thermostable inorganic pyrophosphatase is needed to remove the pyrophosphate produced during sequencing reactions. Thermoplasma acidophilum inorganic pyrophosphatase (TAP) is thermostable and effective for converting pyrophosphate to orthophosphate. The use of the combination of Thermo Sequenase polymerase and TAP for cycle sequencing yields sequence data with uniform band intensities, allowing the determination of longer, more accurate sequence reads. Uniform band intensities also facilitate interpretation of sequence anomalies and the presence of mixed templates. Sequencing PCR products of DNA amplified from heterozygous diploid individuals results in signals of equal intensity from each allele.
Activation of the aryl hydrocarbon receptor promotes allograft-specific tolerance through direct and dendritic cell–mediated effects on regulatory T cells (2008)

VAF347 is a low-molecular-weight compound, which activates the aryl hydrocarbon receptor (AhR). Herein, we report that oral administration of a water-soluble derivative of VAF347 (VAG539) promotes long-term graft acceptance and active tolerance in Balb/c mice that receive a transplant of MHC-mismatched pancreatic islet allografts. In vivo VAG539 treatment results in increased frequency of splenic CD4(+) T cells expressing CD25 and Foxp3, markers associated with regulatory T (Tr) cells, and in vitro VAF347 treatment of splenic CD4(+) T cells improved CD4(+)CD25(+)Foxp3(+) T-cell survival. Interestingly, transfer of CD11c(+) dendritic cells (DCs), but not of CD4(+) T or CD19(+) B cells, from VAG539-treated long-term tolerant hosts into mice that recently underwent transplantation resulted in donor (C57Bl/6)-specific graft acceptance and in a significantly higher frequency of splenic CD4(+)CD25(+)Foxp3(+) Tr cells. Furthermore, the transfer of CD4(+)CD25(+) T cells from these mice into mice that recently underwent transplantation promoted graft acceptance. Similarly, cell therapy with in vitro VAF347-treated bone marrow-derived mature DCs prevented islet graft rejection, and reduced OVA-specific T-cell responses in OVA-immunized mice. Collectively, our data indicate that AhR activation induces islet allograft-specific tolerance through direct as well as DC-mediated effects on Tr-cell survival and function.
Among 17 inducers of differentiation only sodium butyrate causes a permanent down‐regulation of c‐myc in Burkitt's lymphoma (1995)

De-regulation of c-myc by chromosomal translocation is one crucial step for the development of Burkitt's lymphoma. The de-regulation is caused through juxtaposition of c-myc with one of the 3 immunoglobulin loci. We have reported earlier that treatment of Burkitt's lymphoma cells with n-butyrate causes transcriptional down-regulation of c-myc expression. Because of the possible therapeutic implication of this result, we looked for other compounds which, on the one hand, might be applicable in vivo and, on the other hand, might cause down-regulation of c-myc expression in Burkitt's lymphoma cells. Since n-butyrate is known to induce differentiation, we have examined other differentiation inducers of different chemical nature for their ability to reduce c-myc expression in Burkitt's lymphoma cells. Many of the substances tested caused down-regulation of c-myc expression, which, however, was transient except for n-butyrate. Three types of compounds proved to be particularly active: polar planar compounds (e.g., dimethylsulfoxide), heterocyclic compounds (e.g., hypoxanthine), and short-chain fatty acids (e.g., n-butyric acid). The action of n-butyrate on c-myc suppression was exceptional not only in not being transient, but also in being allele-specific: it down-regulated the translocated allele without affecting the normal one. Medium transfer experiments revealed that neither degradation of the active compound nor an intracellular resistance mechanism can fully account for the reversibility of c-myc down-regulation after treatment with the transiently acting polar planar compounds.