gebhart/patrepeval huggingface dataset:
The Synthetic Tie2 Agonist Peptide Vasculotide Protects Renal Vascular Barrier Function In Experimental Acute Kidney Injury (2016)

Microvascular barrier dysfunction plays a major role in the pathophysiology of acute kidney injury (AKI). Angiopoietin-1, the natural agonist ligand for the endothelial-specific Tie2 receptor, is a non-redundant endothelial survival and vascular stabilization factor. Here we evaluate the efficacy of a polyethylene glycol-clustered Tie2 agonist peptide, vasculotide (VT), to protect against endothelial-cell activation with subsequent microvascular dysfunction in a murine model of ischemic AKI. Renal ischemia reperfusion injury (IRI) was induced by clamping of the renal arteries for 35 minutes. Mice were treated with VT or PEGylated cysteine before IRI. Sham-operated animals served as time-matched controls. Treatment with VT significantly reduced transcapillary albumin flux and renal tissue edema after IRI. The protective effects of VT were associated with activation of Tie2 and stabilization of its downstream effector, VE-cadherin in renal vasculature. VT abolished the decline in renal tissue blood flow, attenuated the increase of serum creatinine and blood urea nitrogen after IRI, improved recovery of renal function and markedly reduced mortality compared to PEG [HR 0.14 (95% CI 0.05-0.78) P < 0.05]. VT is inexpensive to produce, chemically stable and unrelated to any Tie2 ligands. Thus, VT may represent a novel therapy to prevent AKI in patients.
Phase 3 study of the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age and older with acute myeloid leukemia: Cancer and Leukemia Group B Study 9720 (2002)

The Cancer and Leukemia Group B conducted a phase 3 trial of the P-glycoprotein modulator PSC-833 in untreated acute myeloid leukemia patients aged 60 years and older. Patients were randomized to 1 of 2 regimens, with doses determined in a prior phase 1 study, consisting of cytarabine 100 mg/m(2)/d by 7-day infusion, with daunorubicin 60 mg/m(2) and etoposide 100 mg/m(2) daily for 3 days (ADE), or daunorubicin 40 mg/m(2) and etoposide 60 mg/m(2) for 3 days with PSC-833, 2.8 mg/kg over 2 hours, and then 10 mg/kg/d by 3-day infusion (ADEP). The ADEP arm was closed after randomization of 120 patients (61 to ADE and 59 to ADEP) because of excessive early mortality. Rates of complete remission, nonresponse, and death were 46%, 34%, and 20% for ADE, versus 39%, 17%, and 44% for ADEP (P =.008). Nevertheless, disease-free survival (median 7 vs 8 months; P =.38) and overall survival (approximately 33% alive at 1 year) did not differ and were similar to historical results. Although the number of patients was limited, ADE patients whose pretreatment cells exhibited PSC-833-modulated dye efflux in vitro (n = 22) had worse outcomes than those without efflux (n = 11) (complete remission, nonresponse, and death rates of 41%, 41%, and 18%, compared with 91%, 9%, and 0%; P =.03), but with ADEP outcomes were nearly identical. Moreover, for patients with PSC-833-modulated efflux, median disease-free survival was 5 months with ADE and 14 months with ADEP (P =.07). Further modulation trials in older patients must await the design of less-toxic regimens.
Genomic Classifier ColoPrint Predicts Recurrence in Stage II Colorectal Cancer Patients More Accurately Than Clinical Factors (2015)

ColoPrint significantly improved prognostic accuracy independent of microsatellite status or clinical variables, facilitating the identification of patients at higher risk who might be considered for additional treatment.
Phosphorylation-induced Conformational Changes in a Mitogen-activated Protein Kinase Substrate (2002)

Mitogen-activated protein (MAP) kinase-mediated phosphorylation of specific residues in tyrosine hydroxylase leads to an increase in enzyme activity. However, the mechanism whereby phosphorylation affects enzyme turnover is not well understood. We used a combination of fluorescence resonance energy transfer (FRET) measurements and molecular dynamics simulations to explore the conformational free energy landscape of a 10-residue MAP kinase substrate found near the N terminus of the enzyme. This region is believed to be part of an autoregulatory sequence that overlies the active site of the enzyme. FRET was used to measure the effect of phosphorylation on the ensemble of peptide conformations, and molecular dynamics simulations generated free energy profiles for both the unphosphorylated and phosphorylated peptides. We demonstrate how FRET transfer efficiencies can be calculated from molecular dynamics simulations. For both the unphosphorylated and phosphorylated peptides, the calculated FRET efficiencies are in excellent agreement with the experimentally determined values. Moreover, the FRET measurements and molecular simulations suggest that phosphorylation causes the peptide backbone to change direction and fold into a compact structure relative to the unphosphorylated state. These results are consistent with a model of enzyme activation where phosphorylation of the MAP kinase substrate causes the N-terminal region to adopt a compact structure away from the active site. The methods we employ provide a general framework for analyzing the accessible conformational states of peptides and small molecules. Therefore, they are expected to be applicable to a variety of different systems.
The bovine pericardial xenograft: I. Effect of fixation in aldehydes without constraint on the tensile viscoelastic properties of bovine pericardium (1989)

Tensile testing of tissue strips has been used to examine the effect of simple fixation in glutaraldehyde and formaldehyde on the viscoelastic properties of bovine pericardium. To assess tissue anisotropy, tissue strips were cut at 0 degree, 30 degrees, 60 degrees, and 90 degrees relative to the base-to-apex direction. Fresh anterior pericardium was modestly anisotropic, being least extensible in the base-to-apex direction; however, fixation removed this anisotropy. Fixation also produced a marked change in the response of the material to initial cyclic loading during preconditioning. Overall extensibility of the fixed material was significantly greater than that for the fresh tissue, consistent with a 10.7% shrinkage in aldehydes calculated from strain at fracture data. Reductions in stress relaxation and creep after fixation were noted as well, consistent with intrafibrillar crosslinking. Cyclic hysteresis and ultimate tensile strength were unaffected. Since the observed changes in the stress-strain response were largely attributable to shrinkage, control of shrinkage by physical means would allow for engineering modification of bovine pericardial mechanics for controlled anisotropy.
Isolation and pure culture of a freshwater magnetic spirillum in chemically defined medium (1979)

A bipolarly flagellated magnetotactic spirillum containing intracellular chains of single domain-sized magnetite crystals was isolated by applying a magnetic field to sediments from a freshwater swamp. The organism was cultured in a chemically defined medium containing ferric quinate and succinate as sources of iron and carbon, respectively. Nonmagnetic variants of this isolate were maintained in chemically defined medium lacking ferric quinate. In contrast to magnetic cells, these had less iron and lacked measurable magnetic remanence and the intracytoplasmic crystals. In other respects, including moles percent guanine plus cytosine content, growth characteristics, nutrition, and physiology, the two types were similar. The isolate reduced nitrate without accumulating nitrite and produced ammonia during growth. Nitrate or ammonium ions served as a nitrogen source. The organism was microaerophilic and did not grow anaerobically with nitrate in the medium. In chemically defined medium, cells synthesized magnetite only if the initial O2 concentration in the atmosphere of sealed cultures was 6% (vol/vol) or less.
Direct Carbon−Carbon Bond Formation via Soft Enolization:  A Facile and Efficient Synthesis of 1,3-Diketones (2007)

Ketones undergo soft enolate formation and acylation on treatment with MgBr(2).OEt(2), i-Pr(2)NEt, and various acylating agents to give 1,3-diketones. The process is particularly efficient for N-acylbenzotriazoles and O-Pfp esters, and, in these cases, is conducted with untreated, reagent-grade CH(2)Cl(2) open to the air, thus providing an exceptionally simple approach to the synthesis of this important class of compounds.
FKBP-rapamycin inhibits a cyclin-dependent kinase activity and a cyclin D1-Cdk association in early G1 of an osteosarcoma cell line. (1993)

Upon entering a cell the natural product rapamycin, like the structurally related immunosuppressant FK506, associates with members of the FKBP family of proteins. One or more of the resulting FKBP-rapamycin complexes blocks signaling pathways emanating from some growth factor receptors. Recently, the addition of rapamycin was shown to inhibit the phosphorylation and activation of a 70-kDa ribosomal S6 protein kinase, which normally occurs minutes after the activation of certain cytokine and growth factor receptors. We now report that rapamycin can be added 4 to 6 h after the addition of serum growth factors to quiescent human osteosarcoma cells and still arrest these cells in G1. This window of action correlates with the inducible appearance of a cyclin-dependent kinase (cdk) activity, and the induction of this activity is inhibited by the addition of rapamycin. Furthermore, p36cyclin D1 associates with this cdk protein complex in lysates of untreated cells, but does not associate with this cdk protein complex in lysates of rapamycin-treated cells. Together, these studies demonstrate that FKBP-rapamycin can modulate a cyclin-dependent kinase activity and a cyclin D1-cdk association during early G1 in MG-63 human osteosarcoma cells.
Enhanced tumor cell killing in the presence of ganciclovir by herpes simplex virus type 1 vector-directed coexpression of human tumor necrosis factor-alpha and herpes simplex virus thymidine kinase. (1998)

Past studies have documented the promise of herpes simplex virus type 1 (HSV-1) thymidine kinase (TK) suicide gene therapy as a potential antitumor treatment. HSV-TK converts the pro-drug ganciclovir (GCV) into a toxic nucleotide analogue, the incorporation of which into cellular DNA blocks cell proliferation. In this report, we have examined the hypothesis that the effectiveness of HSV-TK suicide gene therapy can be enhanced by coexpression of the antitumor cytokine human tumor necrosis factor-alpha (TNF-alpha) from the same replication-defective HSV-1 vector. In vitro testing demonstrated that TNF-alpha expression from this vector potentiated the killing of both TNF-alpha-sensitive L929 tumor cells and TNF-alpha-resistant U-87 MG cells in the presence of GCV. Furthermore, treatment of established intradermal L929 tumors in vivo with the TNF-alpha/TK vector and GCV resulted in prolonged animal survival compared with treatment with parental HSV-TK vector in the presence or absence of GCV. Treatment of intracerebral U-87 MG tumors showed a clear benefit of TK therapy, but a significant further increase in survival using the TNF-alpha vector could not be demonstrated. We found that potentiation of cell killing in vitro required intracellular TNF-alpha because purified protein added to the culture medium of cells infected with HSV-TK vector failed to have the same effect. Accordingly, potentiation in vivo should depend on efficient infection, but immunohistochemical analysis indicated that virus administration by U-87 MG intratumoral injection was inadequate, resulting in an estimated <1% infection of all tumor cells. Moreover, the majority of infected tumor cells were localized at the tumor margin. Together, these results suggest that TNF-enhanced tk gene therapy should provide a useful treatment for TNF-alpha-sensitive tumors and perhaps also for TNT-alpha-resistant tumors if vector delivery can be improved to increase the percentage of transduced tumor cells.
Sources of the neurotoxin quinolinic acid in the brain of HIV-1-infected patients and retrovirus-infected macaques (1998)

This study investigated the sources of quinolinic acid, a neurotoxic tryptophan-kynurenine pathway metabolite, in the brain and blood of HIV-infected patients and retrovirus-infected macaques. In brain, quinolinic acid concentrations in HIV-infected patients were elevated by > 300-fold to concentrations that exceeded cerebrospinal fluid (CSF) by 8.9-fold. There were no significant correlations between elevated serum quinolinic acid levels with those in CSF and brain parenchyma. Because nonretrovirus-induced encephalitis confounds the interpretation of human postmortem data, rhesus macaques infected with retrovirus were used to examine the mechanisms of increased quinolinic acid accumulations and determine the relationships of quinolinic acid to encephalitits and systemic responses. The largest kynurenine pathway responses in brain were associated with encephalitis and were independent of systemic responses. CSF quinolinic acid levels were also elevated in all infected macaques, but particularly those with retrovirus-induced encephalitis. In contrast to the brain changes, there was no difference in any systemic measure between macaques with encephalitis vs. those without. Direct measures of the amount of quinolinic acid in brain derived from blood in a macaque with encephalitis showed that almost all quinolinic acid (>98%) was synthesized locally within the brain. These results demonstrate a role for induction of indoleamine-2,3dioxygenase in accelerating the local formation of quinolinic acid within the brain tissue, particularly in areas of encephalitis, rather than entry of quinolinic acid into the brain from the meninges or blood. Strategies to reduce QUIN production, targeted at intracerebral sites, are potential approaches to therapy.
Functional magnetic resonance imaging of regional brain activity in patients with intracerebral arteriovenous malformations before surgical or endovascular therapy (1996)

Functional magnetic resonance (MR) imaging was performed in six patients harboring proven intracerebral arteriovenous malformations (AVMs) using a noninvasive blood oxygen level-dependent technique based on the documented discrepancy between regional increases in blood flow and oxygen utilization in response to regional brain activation. Statistical functional MR maps were generated and overlaid directly onto conventional MR images obtained at the same session. In the six patients studied, a total of 23 separate functional MR imaging activation studies were performed. Of these, two runs were discarded because of motion artifacts. All of the remaining 21 studies demonstrated activation in or near expected regions for the paradigm employed. Qualitatively reproducible regional localizations of functional activity in unexpected sites were also seen. The authors' findings indicating aberrant mapping of cortical function may be explained on the basis of the plasticity of brain function, in that the developing brain can take over function that would normally have been performed by regions of brain encompassed by the lesion. Preliminary results in this study's small number of cases also indicate that activity demonstrated within the confines of the apparent AVM nidus may help predict the development of a posttherapy deficit. The authors demonstrate that functional MR imaging can be successfully and reproducibly performed in patients with intracerebral AVMs. Notwithstanding the paucity of normative data using functional MR imaging, the author' findings support cortical reorganization associated with these congenital lesions. Blood oxygen level-dependent MR imaging is a noninvasive method used to localize areas of eloquent cortex in patients harboring AVMs; it may prove to be of value in treatment planning.
Discovery of Small Molecule Inhibitors of the Interaction of the Thyroid Hormone Receptor with Transcriptional Coregulators (2005)

Thyroid hormone (3,5,3'-triiodo-L-thyronine, T3) is an endocrine hormone that exerts homeostatic regulation of basal metabolic rate, heart rate and contractility, fat deposition, and other phenomena (1, 2). T3 binds to the thyroid hormone receptors (TRs) and controls their regulation of transcription of target genes. The binding of TRs to thyroid hormone induces a conformational change in TRs that regulates the composition of the transcriptional regulatory complex. Recruitment of the correct coregulators (CoR) is important for successful gene regulation. In principle, inhibition of the TR-CoR interaction can have a direct influence on gene transcription in the presence of thyroid hormones. Herein we report a high throughput screen for small molecules capable of inhibiting TR coactivator interactions. One class of inhibitors identified in this screen was aromatic beta-aminoketones, which exhibited IC50 values of approximately 2 microm. These compounds can undergo a deamination, generating unsaturated ketones capable of reacting with nucleophilic amino acids. Several experiments confirm the hypothesis that these inhibitors are covalently bound to TR. Optimization of these compounds produced leads that inhibited the TR-CoR interaction in vitro with potency of approximately 0.6 microm and thyroid signaling in cellular systems. These are the first small molecules irreversibly inhibiting the coactivator binding of a nuclear receptor and suppressing its transcriptional activity.
Physically Uncloneable Functions in the Universal Composition Framework. (2011)

Recently, there have been numerous works about hardware-assisted cryptographic protocols, either improving previous constructions in terms of efficiency, or in terms of security. In particular, many suggestions use Canetti’s universal composition (UC) framework to model hardware tokens and to derive schemes with strong security guarantees in the UC framework. Here, we augment this approach by considering Physically Uncloneable Functions (PUFs) in the UC framework. Interestingly, when doing so, one encounters several peculiarities specific to PUFs, such as the intrinsic non-programmability of such functions. Using our UC notion of PUFs, we then devise efficient UC-secure protocols for basic tasks like oblivious transfer, commitments, and key exchange. It turns out that designing PUF-based protocols is fundamentally different than for other hardware tokens. For one part this is because of the non-programmability. But also, since the functional behavior is unpredictable even for the creator of the PUF, this causes an asymmetric situation in which only the party in possession of the PUF has full access to the secrets.
Proteins of purified Epstein-Barr virus (2004)

Mature Epstein-Barr virus (EBV) was purified from the culture medium of infected lymphocytes made functionally conditional for Zta activation of lytic replication by an in-frame fusion with a mutant estrogen receptor. Proteins in purified virus preparations were separated by gradient gel electrophoresis and trypsin-digested; peptides were then analyzed by tandem hydrophobic chromatography, tandem MS sequencing, and MS scans. Potential peptides were matched with EBV and human gene ORFs. Mature EBV was mostly composed of homologues of proteins previously found in a herpes virion. However, EBV homologues to herpes simplex virus capsid-associated or tegument components UL7 (BBRF2), UL14 (BGLF3), and EBV BFRF1 were not significantly detected. Instead, probable tegument components included the EBV and gamma-herpesvirus-encoded BLRF2, BRRF2, BDLF2 and BKRF4 proteins. Actin was also a major tegument protein, and cofilin, tubulin, heat shock protein 90, and heat shock protein 70 were substantial components. EBV envelope glycoprotein gp350 was highly abundant, followed by glycoprotein gH, intact and furin-cleaved gB, gM, gp42, gL, gp78, gp150, and gN. BILF1 (gp64) and proteins associated with latent EBV infection were not detected in virions.
Evaluation of the L-CLONE Legionella pneumophila Serogroup 1 Urine Antigen Latex Test (1991)

The purpose of this study was to evaluate the L-CLONE Legionella pneumophila Serogroup 1 Urine Antigen Latex Test (Access Medical Systems, Inc., Branford, Conn.) for detection of Legionella antigen in urine. A total of 481 frozen urine samples previously tested by an in-house solid-phase radioimmunoassay (RIA) was thawed and retested by using L-CLONE. Included in this sample were 140 RIA-positive samples from culture-positive or serologically confirmed cases of legionellosis and 341 RIA-negative samples from patients with non-Legionella respiratory disease or bacteriuria. The original RIA test result was accepted as the true value. L-CLONE correctly identified 76 of 140 (54%) known positive samples. False-negative results could not be attributed to a low Legionella antigen concentration or to a Legionella antigen subgroup. L-CLONE correctly identified 252 of 341 (74%) known negative samples. False-positive results were experienced in all groups of negative samples, regardless of the patients' underlying diseases. A total of 141 fresh urine samples was tested; all were Legionella antigen negative by RIA. L-CLONE provided 86% specificity. The sensitivity of the L-CLONE in testing fresh urine samples could not be evaluated because of the lack of Legionella antigen RIA-positive samples.
Delay to institution of therapy and induction of remission using single‐drug or combination–disease‐modifying antirheumatic drug therapy in early rheumatoid arthritis (2002)

Abstract Objective To study the impacts of 1) the delay from the onset of symptoms to the institution of disease‐modifying antirheumatic drug (DMARD) therapy, 2) two treatment strategies (treatment with a combination of DMARDs or with a single drug), and 3) the presence of HLA–DRB1 alleles (shared epitope) on the prediction of disease remission after 2 years in patients with early rheumatoid arthritis (RA). Methods In the FIN‐RACo (FINnish Rheumatoid Arthritis Combination therapy) trial, 195 patients with recent‐onset RA (median duration 6 months) were randomly assigned to receive either 1) a combination of DMARDs (sulfasalazine, methotrexate, hydroxychloroquine, and prednisolone) or 2) a single DMARD with or without prednisolone. The presence of a shared epitope was tested for in 165 of the 178 patients completing the study. The additional variables of age, sex, presence of rheumatoid factor, number of fulfilled American College of Rheumatology criteria for the classification of RA, and length of delay from onset of symptoms to institution of therapy were entered into a logistic regression model to determine the significant predictors for remission at 2 years. Results The delay to therapy (cut point of 4 months) was the only significant predictor for remission in patients treated using the single‐DMARD strategy, while no variable was a significant predictor for remission in those treated using the combination‐DMARD strategy. The frequency of achieving remission in the combination‐DMARD group after 2 years was similar in patients with short (0–4 months) and long (&gt;4 months) delay periods (11 of 26 patients and 22 of 53 patients, respectively [∼42% in each group]), while the corresponding frequencies in the single‐DMARD group were 8 of 23 patients (35%) and 7 of 63 patients (11%) ( P = 0.021). The presence of a shared epitope was not related to the induction of remission. Conclusion The delay of a few months from the onset of symptoms to institution of therapy decreases the ability of the traditional single‐drug strategy to induce remission in early RA.