gebhart/patrepeval huggingface dataset:
Challenges for Targeting SARS-CoV-2 Proteases as a Therapeutic Strategy for COVID-19 (2021)

Two proteases produced by the SARS-CoV-2 virus, the main protease and papain-like protease, are essential for viral replication and have become the focus of drug development programs for treatment of COVID-19. We screened a highly focused library of compounds containing covalent warheads designed to target cysteine proteases to identify new lead scaffolds for both M(pro) and PL(pro) proteases. These efforts identified a small number of hits for the M(pro) protease and no viable hits for the PL(pro) protease. Of the M(pro) hits identified as inhibitors of the purified recombinant protease, only two compounds inhibited viral infectivity in cellular infection assays. However, we observed a substantial drop in antiviral potency upon expression of TMPRSS2, a transmembrane serine protease that acts in an alternative viral entry pathway to the lysosomal cathepsins. This loss of potency is explained by the fact that our lead M(pro) inhibitors are also potent inhibitors of host cell cysteine cathepsins. To determine if this is a general property of M(pro) inhibitors, we evaluated several recently reported compounds and found that they are also effective inhibitors of purified human cathepsin L and B and showed similar loss in activity in cells expressing TMPRSS2. Our results highlight the challenges of targeting M(pro) and PL(pro) proteases and demonstrate the need to carefully assess selectivity of SARS-CoV-2 protease inhibitors to prevent clinical advancement of compounds that function through inhibition of a redundant viral entry pathway.
Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)–based mutagenesis screen: high efficacy of drug combinations (2006)

BMS-354825 (dasatinib) and AMN107 (nilotinib) are potent alternate Abl inhibitors with activity against many imatinib mesylate-resistant BCR-ABL kinase domain (KD) mutants, except T315I. We used N-ethyl-N-nitrosourea (ENU)-exposed Ba/F3-p210(BCR-ABL) cells to compare incidence and types of KD mutants emerging in the presence of imatinib mesylate, dasatinib, and nilotinib, alone and in dual combinations. Although ENU is expected to induce mutations in multiple proteins, resistant clones were almost exclusively BCR-ABL KD mutant at relevant concentrations of nilotinib and dasatinib, consistent with a central role of KD mutations for resistance to these drugs. Twenty different mutations were identified with imatinib mesylate, 10 with nilotinib (including only 1 novel mutation, E292V) and 9 with dasatinib. At intermediate drug levels the spectrum narrowed to F317V and T315I for dasatinib and Y253H, E255V, and T315I for nilotinib. Thus, cross-resistance is limited to T315I, which is also the only mutant isolated at drug concentrations equivalent to maximal achievable plasma trough levels. With drug combinations maximal suppression of resistant clone outgrowth was achieved at lower concentrations compared with single agents, suggesting that such combinations may be equipotent to higher-dose single agents. However, sequencing uniformly revealed T315I, consistent with the need for a T315I inhibitor, to completely block resistance.
Clinically Approved Nanoparticle Imaging Agents (2016)

Nanoparticles are a new class of imaging agent used for both anatomic and molecular imaging. Nanoparticle-based imaging exploits the signal intensity, stability, and biodistribution behavior of submicron-diameter molecular imaging agents. This review focuses on nanoparticles used in human medical imaging, with an emphasis on radionuclide imaging and MRI. Newer nanoparticle platforms are also discussed in relation to theranostic and multimodal uses.
TSG-6: a pluripotent inflammatory mediator? (2006)

TSG-6 is a multifunctional protein that is up-regulated in many pathological and physiological contexts, where it plays important roles in inflammation and tissue remodelling. For example, it is a potent inhibitor of neutrophil migration and can modulate the protease network through inhibition of plasmin. TSG-6 binds a wide range of GAGs (glycosaminoglycans) [i.e. HA (hyaluronan), chondroitin 4-sulphate, dermatan sulphate, heparin and heparan sulphate] as well as a variety of protein ligands, where these interactions can influence the activities of TSG-6. For example, through its association with HA, TSG-6 can mediate HA cross-linking via several different mechanisms, some of which promote leucocyte adhesion. Binding to heparin, however, enhances the ability of TSG-6 to potentiate the anti-plasmin activity of inter-alpha-inhibitor, which binds non-covalently to TSG-6 via its bikunin chain. Furthermore, although HA and heparin interact with distinct sites on the Link module, the binding of heparin can inhibit subsequent interaction with HA. In addition, the interactions of TSG-6 with HA, heparin and at least some of its protein ligands are sensitive to pH. Therefore it seems that in different tissue micro-environments (characterized, for example, by pH and GAG content), TSG-6 could be partitioned into functional pools with distinct activities.
CXCR3, Inflammation, and Autoimmune Diseases (2009)

CXCR3 is a G protein-coupled, seven-transmembrane receptor that binds and is activated by the three IFN-gamma-inducible chemokines of the CXC family named CXCL9, CXCL10, and CXCL11. These chemokines are not constitutively expressed but are up-regulated in a proinflammatory cytokine milieu. Consequently, their major function is to selectively recruit immune cells at inflammation sites, but they also play a role in angiogenesis mechanisms. In the last few years, strong experimental and clinical evidence has been obtained supporting the idea that the CXCR3 pathway is involved in the development of autoimmune diseases, especially by creating local amplification loops of inflammation in target organs, thereby inducing worsening of clinical manifestations. This article briefly reviews what we know today about the nature and functions of CXCR3, with special emphasis on its involvement in two main rheumatic systemic autoimmune diseases, namely rheumatoid arthritis and systemic lupus erythematosus.
Microstructure of Yogurt Stabilized with Milk Proteins (1983)

Skim milk yogurts were stabilized with a variety of casein-and whey protein-based ingredients. Experimental yogurts contained 1.5% added protein and were compared to a reference yogurt prepared with .5% gelatin (225 Bloom strength).
New Methods of Drug Delivery (1990)

Conventional forms of drug administration generally rely on pills, eye drops, ointments, and intravenous solutions. Recently, a number of novel drug delivery approaches have been developed. These approaches include drug modification by chemical means, drug entrapment in small vesicles that are injected into the bloodstream, and drug entrapment within pumps or polymeric materials that are placed in desired bodily compartments (for example, the eye or beneath the skin). These techniques have already led to delivery systems that improve human health, and continued research may revolutionize the way many drugs are delivered.
Synthesis and antimicrobial activity of clindamycin analogs: pirlimycin, a potent antibacterial agent (1984)

The preparation of a series of analogues of clindamycin is described in which the naturally occurring five-membered cyclic amino acid amide portion of the molecule is replaced by a four-, six-, or seven-membered cyclic amino acid amide. The most interesting compound is pirlimycin (7e, U-57,930E), in which the (2S-trans)-4-n-propylhygramide portion of clindamycin is replaced by (2S-cis)-4-ethylpipecolamide. This structural modification results in significantly favorable changes in toxicity, metabolism, and antibacterial potency. Although the in vitro antibacterial activity of clindamycin and pirlimycin are nearly identical, the latter compound is 2-20 times more active than clindamycin when administered to mice experimentally infected with strains of Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Bacteroides fragilis, and Plasmodium berghei. Pirlimycin is absorbed in rats and mice following both subcutaneous and oral administration. It readily penetrates B. fragilis induced abscesses in mice and is sequestered within these abscesses. A drug concentration of at least 60 times the required inhibitory concentration is maintained for 6 h following a single subcutaneous dose of 200 mg/kg. Urinary excretion of total bioactivity consists only of intact pirlimycin with no other antibacterially active metabolites being detected. Pirlimycin is tolerated well in rats and mice at the administered levels.
Covalent modification of a metal–organic framework with isocyanates: probing substrate scope and reactivity (2008)

Isoreticular metal-organic framework-3 (IRMOF-3) has been postsynthetically modified with isocyanates to generate unprecedented, microporous urea-functionalized frameworks.
Trafficking and Postsecretory Events Responsible for the Formation of Secreted Human Salivary Peptides (2008)

To elucidate the localization of post-translational modifications of different classes of human salivary proteins and peptides (acidic and basic proline-rich proteins (PRPs), Histatins, Statherin, P-B peptide, and "S type" Cystatins) a comparative reversed phase HPLC-ESI-MS analysis on intact proteins of enriched granule preparations from parotid and submandibular glands as well as parotid, submandibular/sublingual (Sm/Sl), and whole saliva was performed. The main results of this study indicate the following. (i) Phosphorylation of all salivary peptides, sulfation of Histatin 1, proteolytic cleavages of acidic and precursor basic PRPs occur before granule storage. (ii) In agreement with previous studies, basic PRPs are secreted by the parotid gland only, whereas all isoforms of acidic PRPs (aPRPs) are secreted by both parotid and Sm/Sl glands. (iii) Phosphorylation levels of aPRPs, Histatin 1, and Statherin are higher in the parotid gland, whereas the extent of cleavage of aPRP is higher in Sm/Sl glands. (iv) O-Sulfation of tyrosines of Histatin 1 is a post-translational modification specific for the submandibular gland. (v) The concentration of Histatin 3, Histatin 5, and Histatin 6, but not Histatin 1, is higher in parotid saliva. (vi) Histatin 3 is submitted to the first proteolytic cleavage (generating Histatins 6 and 5) during granule maturation, and it occurs to the same relative extent in both glands. (vii) The proteolytic cleavages of Histatin 5 and 6, generating a cascade of Histatin 3 fragments, take place after granule secretion and are more extensive in parotid secretion. (viii) Basic PRPs are cleaved in the oral cavity by unknown peptidases, generating various small proline-rich peptides. (ix) C-terminal removal from Statherin is more extensive in parotid saliva. (x) P-B peptide is secreted by both glands, and its relative quantity is higher in submandibular/sublingual secretion. (xi) In agreement with previous studies, S type Cystatins are mainly the product of Sm/Sl glands.
Risk of pressure ulcer development in surgical patients: a review of the literature. (1999)

There is limited information about pressure ulcer risk in the preoperative, intraoperative, and postoperative periods. Because the surgical period is defined temporally, and more so than pressure ulcers in the chronically ill, this paradigm must be examined using a time-based evaluation. The Agency for Health Care Policy and Research guideline for pressure ulcer prevention needs to be tested in surgical patients.
Flexible, Stretchable, Transparent Conducting Films Made from Superaligned Carbon Nanotubes (2010)

Abstract A straightforward roll‐to‐roll process for fabricating flexible and stretchable superaligned carbon nanotube films as transparent conducting films is demonstrated. Practical touch panels assembled by using these carbon nanotube conducting films are superior in flexibility and wearability—and comparable in linearity—to touch panels based on indium tin oxide (ITO) films. After suitable laser trimming and deposition of Ni and Au metal, the carbon nanotube film possesses excellent performance with two typical values of sheet resistances and transmittances (208 Ω □ −1 , 90% and 24 Ω □ −1 , 83.4%), which are comparable to ITO films and better than the present carbon nanotube conducting films in literature. The results provide a route to produce transparent conducting films more easily, effectively, and cheaply, an important step for realizing industrial‐scale applications of carbon nanotubes for transparent conducting films.
The Effect of Micronized Fenofibrate on Lipid Profiles of Patients Converted from Gemfibrozil (2002)

Although numerous studies have established the efficacy of micronized fenofibrate (MF) and gemfibrozil in improving lipid profiles, there are limited comparative data on the lipid-lowering effects of these two agents. The objective of this study was to evaluate the mean changes in lipid values of hypertriglyceridemic patients crossed over from gemfibrozil to MF. The Medical charts of 21 patients were analyzed retrospectively. Patients were maintained on gemfibrozil 600 mg twice daily for a minimum of 3 months. The patient's last fasting lipid profile on gemfibrozil was compared to the first lipid profile after crossover to MF 200 to 201 mg/day. Patients were excluded if there were alterations in other lipid-lowering therapy during the cross-over or documented non-adherence. The lipid profiles after the crossover showed a significant reduction in triglycerides (56%; P &lt; 0.05) and TC/HDL ratio (38%; P &lt; 0.05) and a significant increase in HDL (22%; P &lt; 0.05). There were nonsignificant changes in other lipid values: TC (-22%; P = 0.058), LDL (+5%; P = 0.866) and LDL/HDL ratio (+6; P = 1.0). The results show that MF had additional favorable effects on triglycerides, HDL, and TC/HDL ratio compared with gemfibrozil. A larger, randomized trial to confirm these effects is warranted.
Proximal Dystrophin Gene Deletions and Protein Alterations in Becker Muscular Dystrophy (2005)

Alterations in production of cytoskeletal protein dystrophin caused by in-frame gene mutations lead to the Becker muscular dystrophy. In this study we analyzed genotype-phenotype correlation in a group of Becker muscular dystrophy patients with deletions affecting the proximal part of dystrophin gene, encompassing exons 3-13. Four patients with deletions affecting N terminal dystrophin domain had early onset and faster progression of the disease, while three patients with deletions in the proximal part of dystrophin's rod domain had a more benign disease course. Our study suggests that proximal gene deletions in Becker muscular dystrophy have various phenotypic effects depending on the affected domain of protein dystrophin.
A Nanoparticle Cocktail: Temporal Release of Predefined Drug Combinations (2015)

A single magic bullet is not enough for treatment of metastatic cancers. However, administration of a combination of free drugs can be extremely challenging because of the inability to control the correct choice of dosages and definitive delivery of the effective drug ratio at the target tissue due to the differences in pharmacokinetics and biodistribution of individual drugs. Here we report an engineered biodegradable polymer containing combination therapeutics that can be self-assembled into a controlled release nanoparticle with abilities to deliver multiple therapeutics in a predefined ratio following temporal release patterns. This platform technology can lead to a rationally designed combination therapy.
Multilateralism, Regionalism, Bilateral and Crossregional Free Trade Arrangements: All Paved with Good Intentions for ASEAN? (2003)

Current initiatives in Asia and Asia Pacific regionalism are responses to regionalism happening elsewhere in the context of globalization, information communication technology and knowledge‐based economy. The conclusion is that many economies are ‘having it both ways’ in multilateralism under World Trade Organization (WTO) and new regionalism. The argument is that the ‘first best’ theory of free trade under multilateralism and WTO have fallen short. A ‘second best’ theory of new regionalism has been acknowledged by the Doha ministerial declaration to complement and supplement WTO. Both Asia challenged Asia‐Pacific Economic Cooperation (APEC) and the Association of South‐East Asian Nations (ASEAN) are challenged by ASEAN Plus Three (APT), which originated from the Asian crisis in the failed Asian Monetary Fund (AMF). Singapore has responded to these challenges in bilateral trading agreements, driven by its idiosyncratic features of a small, city–state economy and frustrated by laggard ASEAN. Increasingly, there is a divergence in macroeconomic policy between Singapore and ASEAN in terms of openness and competition. The dilemma in Singapore's strategy of bilateral trading agreements and foreign economic trade policy is precisely this divergence in macroeconomic philosophy and policy. The pressure on ASEAN is no less from APT, China and regionalism elsewhere than from Singapore. However, the present paper concedes that bilateral and crossregional trading arrangements are still second best, and that broader regionalism and multilateralism are still superior. With so many regional trading arrangements and emerging competition policy there may be rules of origin or ‘spaghetti bowl’ effects for Singapore. In ‘realpolitiks’ and real political economy, the balancing of gains and benefits is not easy.
Characterization of a human ovarian carcinoma cell line (NIH:OVCAR-3) with androgen and estrogen receptors. (1983)

A cell line, NIH:OVCAR-3, has been established from the malignant ascites of a patient with progressive adenocarcinoma of the ovary after combination chemotherapy with cyclophosphamide, Adriamycin, and cisplatin. OVCAR-3 grows as a cobblestone-like monolayer with foci of multilayering, is tumorigenic in athymic mice, clones in agarose, and has an abnormal karyotype which includes a homogeneous staining region and a double minute chromosome. The cultured cells and xenografts contain cytoplasmic androgen- and estrogen-binding macromolecules with the specificity of the respective steroid hormone receptors. These components have sedimentation coefficients of 7 to 9S in low-salt sucrose-density gradients, have dissociation constants of 250 and 9.6 pM, and are present at concentrations of 30 and 28 fmol/mg cytosol protein characteristic of androgen and estrogen receptors, respectively. OVCAR-3 is resistant in vitro to clinically relevant concentrations of Adriamycin (5 X 10(-8) M), melphalan (5 X 10(-6) M), and cisplatin (5 X 10(-7) M) with survival compared to untreated controls of 43, 45, and 77%, respectively. Furthermore, there are multiple histological similarities between the patient's original tumor, the cell line, and the transplantable tumor. These data indicate that OVCAR-3 may be of use for investigations as to the significance of androgens and estrogens and the mechanisms of cytotoxic drug resistance in ovarian cancer.
Spectrum Scanning and Reserve Channel Methods for Link Maintenance in Cognitive Radio Systems (2008)

Underutilization of the limited spectrum sparked the need for dynamic spectrum access and flexible spectrum policies. Accurate estimation of spectrum occupancy is an essential step for spectrum access in distributed networks. This paper analyzes a bidirectional and dual scanning method that scans multiple spectrum bands to find a suitable free-channel. Moreover, secondary users' access to available spectrum could be interrupted by the arrival of primary spectrum users, forcing the well-behaved secondary users to switch to another free-channel. A pointer and adaptive reserve channel mechanism is proposed in this paper to facilitate quicker and smoother channel switching. Simulation results for both techniques show improved overall connectivity is maintained for varying primary users' arrival rates.
cDNA recombinant plasmid complementary to mRNAs for light chains 1 and 3 of mouse skeletal muscle myosin. (1982)

A recombinant plasmid with a cDNA sequence transcribed from mouse skeletal muscle RNA is shown to hybridize with mRNAs for myosin light chains LC1F and LC3F. The inserted fragment corresponds exclusively to the 3'-noncoding region of the mRNA. It hybridizes almost exclusively with the two light chain messengers from fast skeletal muscle RNA of adult mouse. Slight hybridization is seen with RNA from heart muscle and embryonic skeletal muscle. The implications of the conservation of the 3'-noncoding regions between the two mRNAs are discussed.
Redirected Activity of Human Antitumor Chimeric Immune Receptors is Governed by Antigen and Receptor Expression Levels and Affinity of Interaction (2007)

Novel Ab-based immunotherapeutic strategies have exploited T-cell receptor-like chimeric immune receptors (CIR) expressed on the surface of transduced human peripheral blood mononuclear cell (PBMC) to redirect potent non-major histocompatibility complex-dependent cytotoxicity to tumor cells expressing a tumor-associated antigens. We transduced human PBMC with 2 fully human CIRs that trigger through the zeta-chain of CD3 and contain either one of two human scFv specific for the same epitope on the extracellular domain of HER2 but with distinctly different affinities (KD 1616 and 1 nM) for this antigen. Potent direct CIR-mediated killing and in vitro tumor growth inhibition mediated by transduced PBMC were observed against targets expressing different levels of HER2. High-affinity CIR showed stronger ability to bind Ag and retain binding than low-affinity CIR. When lytic potential of the 2 CIRs was evaluated, their efficiency was comparable under conditions of high CIR and Ag expression, whereas low-affinity CIR was more efficient than high-affinity CIR in conditions of limiting Ag and CIR expression levels. When tumor growth inhibition was evaluated, Ag and CIR levels, rather than CIR affinity appeared relevant. Ag-driven CIR activation resulted in the production of soluble factors mediating efficient bystander effect. By carefully defining CIR surface expression and increasing affinity for a specific target antigen, it may be possible to selectively exclude CIR-mediated activity against targets expressing low levels of antigen, as normal cells. On the contrary, low antigen-expressing tumor variants could be eliminated by decreasing CIR affinity. Tuning CIR expression and affinity might help in discriminating different biologic contexts.