gebhart/patrepeval huggingface dataset:
Linker Technologies for Antibody–Drug Conjugates (2013)

Antibody-drug conjugates (ADCs), which combine the specificity, favorable pharmacokinetics, and biodistribution of a monoclonal antibody (mAb) with the cytotoxic potency of a drug, are promising new therapies for cancer. Along with the development of monoclonal antibodies (mAbs) and cytotoxic drugs, the design of the linker is of essential importance, because it impacts the efficacy and tolerability of ADCs. The linker needs to provide sufficient stability during systemic circulation but allow for the rapid and efficient release of the cytotoxic drug in an active form inside the tumor cells. This review provides an overview of linker technologies currently used for ADCs and advances that have resulted in linkers with improved properties. Also provided is a brief summary of some considerations for the conjugation of antibody and drug linker such as drug-to-antibody ratio and site of conjugation.
Alterations in TGF-β1 expression in lambs with increased pulmonary blood flow and pulmonary hypertension (2003)

The mechanisms responsible for pulmonary vascular remodeling in congenital heart disease with increased pulmonary blood flow remain unclear. We developed a lamb model of congenital heart disease and increased pulmonary blood flow utilizing an in utero placed aortopulmonary vascular graft (shunted lambs). Morphometric analysis of barium-injected pulmonary arteries indicated that by 4 wk of age, shunts had twice the pulmonary arterial density of controls (P < 0.05), and their pulmonary vessels showed increased muscularization and medial thickness at both 4 and 8 wk of age (P < 0.05). To determine the potential role of TGF-beta1 in this vascular remodeling, we investigated vascular changes in expression and localization of TGF-beta1 and its receptors TbetaRI, ALK-1, and TbetaRII in lungs of shunted and control lambs at 1 day and 1, 4, and 8 wk of life. Western blots demonstrated that TGF-beta1 and ALK-1 expression was elevated in shunts compared with control at 1 and 4 wk of age (P < 0.05). In contrast, the antiangiogenic signaling receptor TbetaRI was decreased at 4 wk of age (P < 0.05). Immunohistochemistry demonstrated shunts had increased TGF-beta1 and TbetaRI expression in smooth muscle layer and increased TGF-beta1 and ALK-1 in endothelium of small pulmonary arteries at 1 and 4 wk of age. Moreover, TbetaRI expression was significantly reduced in endothelium of pulmonary arteries in the shunt at 1 and 4 wk. Our data suggest that increased pulmonary blood flow dysregulates TGF-beta1 signaling, producing imbalance between pro- and antiangiogenic signaling that may be important in vascular remodeling in shunted lambs.
Nonspecific cross-reacting antigen-50/90 (NCA-50/90) as a new tumor marker. (2000)

The present study suggests that increases in blood levels of NCA-50/90 occur in a population of cancer patients which is different from those with elevated levels of CEA and that NCA-50/90 might be useful for NCA-50/90-positive, but CEA-negative patients.
2/3-inch format MOS single-chip color imager (1982)

A new 2/3 format MOS single-chip color imager, that includes 384 × 485 elements, has been developed. The device features a low-noise design; high sensitivity (9 nApp/lx for 2855 K W lamp), through employment of a complementary color filter; and wide dynamic range (over 60 dB), through introduction of a p <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">+</sup> -layer in the photodiode and a vertical buffer circuit. The imager also features low aliasing (Moire) and clear color due to the use of a new color filter arrangement and unique multivideo lines. The die measures 10.0mm × 8.5 mm, which is realized using standard 3-µm Si-gate MOSLSI technology. Combining this small size and technological simplicity with on-wafer color filter processing, has made this device suitable for LSI volume production.
Prognostic value of the cysteine proteases cathepsins B and cathepsin L in human breast cancer. (1995)

The lysosomal cysteine proteases cathepsin B and cathepsin L have been implicated in tumor spread and metastasis. To evaluate the prognostic impact of these proteases for disease-free survival and overall survival in breast cancer, the antigen content of cathepsin B and cathepsin L was determined using ELISA in tumor cytosol fractions of 167 breast cancer patients and in cytosols of 29 benign breast tissue specimens. Median values of 856 ng versus 76 ng cathepsin B/mg protein and of 428 ng versus 56 ng cathepsin L/mg protein were found in tumor versus benign cytosol fractions. A positive correlation between cathepsin B and cathepsin L (r = 0.32, P = 0.0000, Spearman test) was found. Cathepsin L was inversely correlated to hormone receptor status (P = 0.0014, Mann-Whitney U test) and to the presence of tumor necrosis (P = 0.009, Mann-Whitney U test). There were no correlations of cathepsin B or cathepsin L to tumor size, axillary lymph node status, age, menopausal status, tumor grading, and vessel invasion. To perform univariate analyses of disease-free survival, optimal cutoff points were determined by isotonic regression and classification and regression trees analysis. Patients with a high content of cathepsin B (>1092 ng/mg protein) or cathepsin L (>376 ng/mg protein) in their primary tumors had a statistically significantly higher risk of recurrence than patients with a low content of cathepsin B or cathepsin L (5-year disease-free survival: cathepsin B, 70% versus 52%, P = 0.04; cathepsin L, 83% versus 52%, P = 0.0002). Median follow-up was 39 (range, 6-73) months. Multivariate analysis for disease-free survival showed that cathepsin L is a strong and independent prognostic factor with a prognostic impact comparable to that of axillary lymph node status and grading. We conclude that both cathepsin B and cathepsin L may serve as prognostic factors for tumor recurrence in human breast cancer. These data underline the significance of tumor-associated proteolysis for invasion and metastasis.
Modification at the Lipophilic Domain of RXR Agonists Differentially Influences Activation of RXR Heterodimers (2010)

RXR permissive heterodimers are reported to be activated differently depending upon the chemical structure of RXR agonists, but the relationship of agonist structure to differential heterodimer activation has not been explored in detail. In this study, we performed systematic conversion of the alkoxy side chain of 5a (6-[ethyl-(3-isopropoxy-4-isopropylphenyl)amino]nicotinic acid, NEt-3IP) and evaluated the RXR-, PPAR/RXR-, and LXR/RXR-agonist activities of the products. The cyclopropylmethoxy analogue (5c) showed similar RXR- and LXR/RXR-agonistic activities to the benzyloxy analogue (5i) and n-propoxy analogue (5k) but exhibited more potent PPAR/RXR-agonistic activity than 5i or 5k. Differential modulation of RXR heterodimer-activating ability by conversion of the alkoxy group located in the lipophilic domain of the RXR-agonist common structure is expected be a useful approach in the design of new RXR agonists for the treatment of hyperlipidemia or type 2 diabetes.
First Divergent Strategy Using Two AB2 Unprotected Monomers for the Rapid Synthesis of Dendrimers (2001)

ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTADDITION / CORRECTIONThis article has been corrected. View the notice.First Divergent Strategy Using Two AB2 Unprotected Monomers for the Rapid Synthesis of DendrimersLaurent Brauge, Germinal Magro, Anne-Marie Caminade, and Jean-Pierre MajoralView Author Information Laboratoire de Chimie de Coordination CNRS, 205 route de Narbonne 31077 Toulouse Cedex 4, France Cite this: J. Am. Chem. Soc. 2001, 123, 27, 6698–6699Publication Date (Web):June 19, 2001Publication History Received7 August 2000Published online19 June 2001Published inissue 1 July 2001https://pubs.acs.org/doi/10.1021/ja0029228https://doi.org/10.1021/ja0029228rapid-communicationACS PublicationsCopyright © 2001 American Chemical SocietyRequest reuse permissionsArticle Views735Altmetric-Citations88LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information SUBJECTS:Aldehydes,Chemical synthesis,Condensation,Dendrons,Monomers Get e-Alerts
Selective Inhibition of the Lectin Pathway of Complement with Phage Display Selected Peptides against Mannose-Binding Lectin-Associated Serine Protease (MASP)-1 and -2: Significant Contribution of MASP-1 to Lectin Pathway Activation (2010)

The complement system, an essential part of the innate immune system, can be activated through three distinct routes: the classical, the alternative, and the lectin pathways. The contribution of individual activation pathways to different biological processes can be assessed by using pathway-selective inhibitors. In this paper, we report lectin pathway-specific short peptide inhibitors developed by phage display against mannose-binding lectin-associated serine proteases (MASPs), MASP-1 and MASP-2. On the basis of the selected peptide sequences, two 14-mer peptides, designated as sunflower MASP inhibitor (SFMI)-1 and SFMI-2, were produced and characterized. SFMI-1 inhibits both MASP-1 and MASP-2 with a K(I) of 65 and 1030 nM, respectively, whereas SFMI-2 inhibits only MASP-2 with a K(I) of 180 nM. Both peptides block the lectin pathway activation completely while leaving the classical and the alternative routes intact and fully functional, demonstrating that of all complement proteases only MASP-1 and/or MASP-2 are inhibited by these peptides. In a C4 deposition inhibitor assay using preactivated MASP-2, SFMI-2 is 10-fold more effective than SFMI-1 in accordance with the fact that SFMI-2 is a more potent inhibitor of MASP-2. Surprisingly, however, out of the two peptides, SFMI-1 is much more effective in preventing C3 and C4 deposition when normal human serum containing zymogen MASPs is used. This suggests that MASP-1 has a crucial role in the initiation steps of lectin pathway activation most probably by activating MASP-2. Because the lectin pathway has been implicated in several life-threatening pathological states, these inhibitors should be considered as lead compounds toward developing lectin pathway blocking therapeutics.
Schizophrenia genesis: the origins of madness (1991)

'The book will appeal to a variety of readers. The history of the illness, its diagnoses, epidemiology, demography, inheritance and environmental stresses would be of general interest. The anguished voices describing personal accounts of the symptoms would probably appeal more to non-professional readers, perhaps patients and their families...To a Psychiatrist, his description of genetic and environmental research is comprehensive...' - Journal of Neurology, Neurosurgery and Psychiatry 'His book is comprehensive, compassionate and easy to read.' - New Scientist
Clinical Identifiers of Complicated Staphylococcus aureus Bacteremia (2003)

Readily available clinical variables can help identify patients at risk for complicated SAB.
Purification of correctly oxidized MHC class I heavy‐chain molecules under denaturing conditions: A novel strategy exploiting disulfide assisted protein folding (2003)

The aim of this study has been to develop a strategy for purifying correctly oxidized denatured major histocompability complex class I (MHC-I) heavy-chain molecules, which on dilution, fold efficiently and become functional. Expression of heavy-chain molecules in bacteria results in the formation of insoluble cellular inclusion bodies, which must be solubilized under denaturing conditions. Their subsequent purification and refolding is complicated by the fact that (1). correct folding can only take place in combined presence of beta(2)-microglobulin and a binding peptide; and (2). optimal in vitro conditions for disulfide bond formation ( approximately pH 8) and peptide binding ( approximately pH 6.6) are far from complementary. Here we present a two-step strategy, which relies on uncoupling the events of disulfide bond formation and peptide binding. In the first phase, heavy-chain molecules with correct disulfide bonding are formed under non-reducing denaturing conditions and separated from scrambled disulfide bond forms by hydrophobic interaction chromatography. In the second step, rapid refolding of the oxidized heavy chains is afforded by disulfide bond-assisted folding in the presence of beta(2)-microglobulin and a specific peptide. Under conditions optimized for peptide binding, refolding and simultaneous peptide binding of the correctly oxidized heavy chain was much more efficient than that of the fully reduced molecule.
Polyhalogenated Methyl Ethyl Ethers (1999)

The several potent inhaled anesthetics released for clinical use in the past four decades have been halogenated ethers, and, with one exception, methyl ethyl ethers.In the present report, we detail some structural and physical properties associated with anesthetic potency in 27 polyhalogenated methyl ethyl ethers. We obtained new data for 22 compounds. We used response/nonresponse of rats to electrical stimulation of the tail as the anesthetic end point (i.e., we measured the minimum alveolar anesthetic concentration [MAC]). For compounds that did not produce anesthesia when given alone (they only produced excitation/convulsions), we studied MAC by additivity studies with desflurane. We obtained MAC values for 20 of 22 of the studied ethers, which gave products of MAC x oil/gas partition coefficient ranging from 1.27 to 18.8 atm, compared with a product of 1.82 +/- 0.56 atm for conventional inhaled anesthetics. Despite solubilities in olive oil and application of partial pressures predicted by the Meyer-Overton hypothesis to provide anesthesia, 2 of 22 ethers (CCIF2 OCCIFCF3 and CCIF2 OCF2 CClF2) had no anesthetic (immobilizing) effect when given alone, did not decrease the anesthetic requirement for desflurane, and had excitatory properties when administered alone. As with other inhaled anesthetics, anesthetic potency seemed to correlate with both polar and nonpolar properties. These ethers, representing structural analogs of currently used clinical volatile anesthetics, may be useful in identifying and understanding the mechanisms by which inhaled anesthetics act. Implications: The several potent, inhaled, polyhalogenated methyl ethyl ether anesthetics released for clinical use in the past four decades seem to have specific useful characteristics that set them apart from other methyl ethyl ethers. Properties of this class of compounds have implications for the future development of anesthetics and the mechanisms by which they act. (Anesth Analg 1999;88:1161-7)
That zincing feeling: the effects of EDTA on the behaviour of zinc-binding transcriptional regulators (2004)

Zinc-binding proteins account for nearly half of the transcription regulatory proteins in the human genome and are the most abundant class of proteins in the human proteome. The zinc-binding transcriptional regulatory proteins utilize Zn2+ to fold structural domains that participate in intermolecular interactions. A study by Matt et al. in this issue of the Biochemical Journal has examined the transcription factor binding properties of the zinc-binding module C/H1 (cysteine/histidine-rich region 1) found in the transcriptional co-activator proteins CBP (CREB-binding protein) and p300. Their studies revealed that EDTA treatment of native C/H1 leads to irreversible denaturation and aggregation. Of particular concern is their finding that unfolded C/H1 participates in non-specific protein-protein interactions. The implications of these results are significant. EDTA is a very potent zinc-chelating agent that is used ubiquitously in protein interaction studies and in molecular biology in general. The potentially detrimental effects of EDTA on the structure and interactions of zinc-binding proteins should be taken into account in the interpretation of a sizeable number of published studies and must be considered in future experiments.
The role of high rates of glycolysis and glutamine utilization in rapidly dividing cells (1985)

The rates of utilization of both glucose and glutamine are high in rapidly dividing ceils such as enterocytes, lymphocytes, thymocytes, tumour cells; the oxidation of both glucose and glutamine is only partial, glucose to lactate and glutamine to glutamate, alanine or aspartate; and these partial processes are termed glycolysis and glutaminolysis respectively. Both processes generate energy and also provide precursors for important biosynthetic processes in such cells. However, the rates of utilization of precursors for macromolecular biosynthesis are very low in comparison to the rates oi partial oxidation, and energy generation per se may not be the correct explanation for high rates of glycolysis and glutaminolysis in these cells since oxidation is only partial and other fuels can be used to generate energy. Both the high fluxes and the metabolic characteristics of these two processes can be explained by application of quantitative principles of control as applied to branched metabolic pathway s (Crabtree &amp; Newsholme, 1985). If the flux through one branch is greatly in excess of the other, then the sensitivity of the flux of the low-flux pathway to regulators is very high. Hence, it is suggested that, in rapidly dividing ceils, high rates of glycolysis and gtutaminolysis are required not for energy or precursor provision per se but for high sensitivity of the pathways involved in the use of precursors for macromolecular synthesis to specific regulators to permithigh rates of proliferation when required for example, in lymphocytes in response to a massive infection.
Clostridium difficile: its disease and toxins (1988)

Clostridium difficile is the etiologic agent of pseudomembranous colitis, a severe, sometimes fatal disease that occurs in adults undergoing antimicrobial therapy. The disease, ironically, has been most effectively treated with antibiotics, although some of the newer methods of treatment such as the replacement of the bowel flora may prove more beneficial for patients who continue to relapse with pseudomembranous colitis. The organism produces two potent exotoxins designated toxin A and toxin B. Toxin A is an enterotoxin believed to be responsible for the diarrhea and mucosal tissue damage which occur during the disease. Toxin B is an extremely potent cytotoxin, but its role in the disease has not been as well studied. There appears to be a cascade of events which result in the expression of the activity of these toxins, and these events, ranging from the recognition of a trisaccharide receptor by toxin A to the synergistic action of the toxins and their possible dissemination in the body, are discussed in this review. The advantages and disadvantages of the various assays, including tissue culture assay, enzyme immunoassay, and latex agglutination, currently used in the clinical diagnosis of the disease also are discussed.
Usefulness of procalcitonin for diagnosis of infection in cardiac surgical patients (2000)

Cardiac surgery with cardiopulmonary bypass influences serum PCT concentration with a peak on POD 1. In the presence of fever, PCT is a reliable marker for diagnosis of infection after cardiac surgery, except in patients who previously received antibiotics. PCT was more relevant than CRP for diagnosis of postoperative infection. During a postoperative circulatory failure, a serum PCT concentration >10 ng/mL is highly indicative of a septic shock.
Contribution to catalysis and stability of the five cysteines in Escherichia coli aspartate aminotransferase. Preparation and properties of a cysteine-free enzyme (1992)

The five cysteines, at positions 82, 191, 192, 270, and 401, of Escherichia coli aspartate aminotransferase (AATase) were, individually and in some combinations, converted to alanine by site-directed mutagenesis (C82A, C191A, C192A, C270A, C401A). Cys-191, which is conserved in all AATase isozymes, was mutated to serine as well (C191S). A quintuple mutant, with all cysteines converted to alanines (Quint), was also constructed. The effects of these single and multiple mutations were examined by steady-state kinetics and urea denaturation. The thermal stabilities of Quint and of the wild-type enzyme (WT) were determined by differential scanning calorimetry. The mutants had kcat values up to 50% greater than that of WT and KMAsp and KM alpha-KG values up to 1.5- and 3.3-fold higher than that of WT. The mutants C82A and C191A exhibit nearly the same CM in urea denaturation experiments as WT, while the other single mutants and Quint are less stable, with CM differences of up to 0.7 M urea. Quint is also less thermostable than WT, with a delta TM of 3.3-4.4 degrees C. Thus the five cysteine replacements yield small, but significant, changes in catalytic and denaturation parameters, but none of the cysteines was found to be essential. The changes manifested in the mutation of the conserved Cys-191 to alanine are no greater than those observed with the four nonconserved cysteines. We consider the evolutionary implications of these findings.
A new genus of Ceratopogonini (Diptera : Ceratopogonidae) from Brazil (1992)

(Uploaded by Plazi from the Biodiversity Heritage Library) No abstract provided.
A New Software Tool to Optimize Frequency Table Selection for Cochlear Implants (2010)

A software tool allowing CI users to self-select frequency-to-electrode tables may help in fitting postlingually deaf users. This novel approach may transform current methods of CI fitting.