gebhart/patrepeval huggingface dataset:
Decay Accelerating Activity of Complement Receptor Type 1 (CD35) (1999)

The goal of this study was to identify the site(s) in CR1 that mediate the dissociation of the C3 and C5 convertases. To that end, truncated derivatives of CR1 whose extracellular part is composed of 30 tandem repeating modules, termed complement control protein repeats (CCPs), were generated. Site 1 (CCPs 1-3) alone mediated the decay acceleration of the classical and alternative pathway C3 convertases. Site 2 (CCPs 8-10 or the nearly identical CCPs 15-17) had one-fifth the activity of site 1. In contrast, for the C5 convertase, site 1 had only 0.5% of the decay accelerating activity, while site 2 had no detectable activity. Efficient C5 decay accelerating activity was detected in recombinants that carried both site 1 and site 2. The activity was reduced if the intervening repeats between site 1 and site 2 were deleted. The results indicate that, for the C5 convertases, decay accelerating activity is mediated primarily by site 1. A properly spaced site 2 has an important auxiliary role, which may involve its C3b binding capacity. Moreover, using homologous substitution mutagenesis, residues important in site 1 for dissociating activity were identified. Based on these results, we generated proteins one-fourth the size of CR1 but with enhanced decay accelerating activity for the C3 convertases.
Induction of an Inner‐ear‐specific Autoreactive T‐Cell Line for the Diagnostic Evaluation of an Autoimmune Disease of the Inner Ear (1997)

Different patterns of sensorineural hearing loss with a potential improvement in auditory function following immunosuppressive therapy might be caused by an isolated autoimmune disease of the inner ear. Because of the lack of well-defined detection methods to identify autoimmune processes within the inner ear and the fact that the human inner ear is one of the few organs of the body not amenable to diagnostic biopsy, there has been great interest in developing animal models. Previous studies found evidence that this entity might be cellular mediated. By heterologeous immunization of inbred Lewis rats with inner-ear tissue, an autoreactive inner-ear-specific T-cell line was established. After passive transfer of these cells, a labyrinthitis was induced in recipient animals. The experimental design can serve as an animal model for a cellular-mediated autoimmune disease of the inner ear. Further studies have to split the cochlear proteins and to identify the protein with the strongest autoimmunological potency. After biotechnical production of this protein, a clinical test to diagnose an autoimmune disease of the inner ear in man should be possible.
Soluble CD4 and CD4-Mimetic Compounds Inhibit HIV-1 Infection by Induction of a Short-Lived Activated State (2009)

Binding to the CD4 receptor induces conformational changes in the human immunodeficiency virus (HIV-1) gp120 exterior envelope glycoprotein. These changes allow gp120 to bind the coreceptor, either CCR5 or CXCR4, and prime the gp41 transmembrane envelope glycoprotein to mediate virus-cell membrane fusion and virus entry. Soluble forms of CD4 (sCD4) and small-molecule CD4 mimics (here exemplified by JRC-II-191) also induce these conformational changes in the HIV-1 envelope glycoproteins, but typically inhibit HIV-1 entry into CD4-expressing cells. To investigate the mechanism of inhibition, we monitored at high temporal resolution inhibitor-induced changes in the conformation and functional competence of the HIV-1 envelope glycoproteins that immediately follow engagement of the soluble CD4 mimics. Both sCD4 and JRC-II-191 efficiently activated the envelope glycoproteins to mediate infection of cells lacking CD4, in a manner dependent on coreceptor affinity and density. This activated state, however, was transient and was followed by spontaneous and apparently irreversible changes of conformation and by loss of functional competence. The longevity of the activated intermediate depended on temperature and the particular HIV-1 strain, but was indistinguishable for sCD4 and JRC-II-191; by contrast, the activated intermediate induced by cell-surface CD4 was relatively long-lived. The inactivating effects of these activation-based inhibitors predominantly affected cell-free virus, whereas virus that was prebound to the target cell surface was mainly activated, infecting the cells even at high concentrations of the CD4 analogue. These results demonstrate the ability of soluble CD4 mimics to inactivate HIV-1 by prematurely triggering active but transient intermediate states of the envelope glycoproteins. This novel strategy for inhibition may be generally applicable to high-potential-energy viral entry machines that are normally activated by receptor binding.
Maintenance Therapy with Certolizumab Pegol for Crohn's Disease (2007)

Patients with moderate-to-severe Crohn's disease who had a response to induction therapy with 400 mg of certolizumab pegol were more likely to have a maintained response and a remission at 26 weeks with continued certolizumab pegol treatment than with a switch to placebo. (ClinicalTrials.gov number, NCT00152425 [ClinicalTrials.gov].).
Outer-Sphere Redox Couples as Shuttles in Dye-Sensitized Solar Cells. Performance Enhancement Based on Photoelectrode Modification via Atomic Layer Deposition (2008)

Atomic layer deposition (ALD) has been used to create conformal TiO2 blocking layers on fluorine-doped tin-oxide substrates in dye-sensitized solar cells (DSSCs), effectively eliminating shunting. ALD has also been used to deposit, in controlled fashion, ultrathin coatings of alumina on nanoparticle-based TiO2 DSSC photoanodes. These modified electrodes enable ferrocenium/ferrocene, an outer-sphere redox couple, to be used as a shuttle. The photovoltaic performance and interfacial charge-transfer dynamics were investigated in DSSCs employing this shuttle. It was found that a single ALD cycle is able to passivate surface states, resulting in a dramatic improvement in photovoltaic performance. Subsequent alumina deposition resulted in exponentially increasing electron lifetimes as a function of alumina layer thickness, indicating that the layers behave as barriers to electron tunneling. The characterization of DSSC photovoltaic performance and interfacial charge-transfer dynamics was extended to cells employing derivatives of ferrocenium and ferrocene featuring more positive redox potentials; these cells yielded larger open-circuit photovoltages.
Clues to understanding cold sensation: Thermodynamics and electrophysiological analysis of the cold receptor TRPM8 (2004)

The cold and menthol receptor, TRPM8, also designated CMR1, is a member of the transient receptor potential (TRP) family of excitatory ion channels. TRPM8 is a channel activated by cold temperatures, voltage, and menthol. In this study, we characterize the cold- and voltage-induced activation of TRPM8 channel in an attempt to identify the temperature- and voltage-dependent components involved in channel activation. Under equilibrium conditions, decreasing temperature has two effects. (i) It shifts the normalized conductance vs. voltage curves toward the left, along the voltage axis. This effect indicates that the degree of order is higher when the channel is in the open configuration. (ii) It increases the maximum channel open probability, suggesting that temperature affects both voltage-dependent and -independent pathways. In the temperature range between 18 degrees C and 25 degrees C, large changes in enthalpy (DeltaH=-112 kcal/mol) and entropy (DeltaS=-384 cal/mol K) accompany the activation process. The Q10 calculated in the same temperature range is 24. This thermodynamic analysis strongly suggests that the process of opening involves large conformational changes of the channel-forming protein. Therefore, the highly temperature-dependent transition between open and closed configurations is possible because enthalpy and entropy are both large and compensate each other. Our data also demonstrate that temperature and voltage interact allosterically to enhance channel opening.
Simple, Sensitive, and Specific Detection of Human Immunodeficiency Virus Type 1 Subtype B DNA in Dried Blood Samples for Diagnosis in Infants in the Field (2001)

The detection of virus is used to diagnose human immunodeficiency virus type 1 (HIV-1) infection in infants due to the persistence of maternal antibodies for a year or more. An HIV-1 DNA PCR assay with simple specimen collection and processing was developed and evaluated. Whole blood was collected on filter paper that lysed cells and bound the DNA, eliminating specimen centrifugation and extraction procedures. The DNA remained bound to the filter paper during PCR amplification. Assays of copy number standards showed reproducible detection of 5 to 10 copies of HIV-1 in 5 microl of whole blood. The sensitivity of the assay did not decrease after storage of the standards on filter paper for 3 months at room temperature or after incubation at 37 or 45 degrees C for 20 h. The primers used for nested PCR of the HIV-1 pol gene amplified templates from a reference panel of multiple HIV-1 subtypes but did not amplify a subtype A or a subtype C virus from children living in Seattle. The assay had a sensitivity of 98.4% and a specificity of 98.3% for testing of 122 specimens from 35 HIV-1-infected and 16 uninfected children and 43 seronegative adults living in Washington. The assay had a sensitivity of 99% and a specificity of 100% for testing of 102 HIV-1-positive (as determined by enzyme immunoassay) Peruvian women and 6 seropositive and 34 seronegative infants. This assay, with adsorption of whole blood to filter paper and no specimen processing, provides a practical, economical, sensitive, and specific method for the diagnosis of HIV-1 subtype B infection in infants.
Cetuximab plus FOLFOX for colorectal cancer (EXPLORE): Preliminary efficacy analysis of a randomized phase III trial (2005)

3574 Background: The EXPLORE study was designed as a randomized phase III study in patients (pts) with metastatic EGFR-positive colorectal cancer (CRC) who had received irinotecan in 1st-line. Pts were to receive either cetuximab (Erbitux) plus FOLFOX4 (5-FU, leucovorin, oxaliplatin), or FOLFOX4. The primary endpoint of the study was to be survival with secondary endpoints including response rate and time-to-progression. Although the study was designed to accrue 1100 pts, due to recent changes in clinical practice resulting in the replacement of irinotecan with oxaliplatin in the 1st-line setting, accrual to the current trial was stopped. An analysis of safety on the first 40 pts randomized to the study was reported at ASCO 2004 (Abstr# 3531). Methods: Pts with metastatic EGFR-positive CRC who had progressed on prior 1st-line irinotecan therapy with an ECOG performance status ≤ 2 received either Cetuximab 400 mg/m2 initial dose followed by 250 mg/m2 weekly dose and FOLFOX4 d1,d2 q 2 weeks (Arm A) or FOLFOX4 q 2 weeks (Arm B). Results: 102 pts were randomized from March 2003 through October 2004. Dosing information is available on 90 pts: 41 women and 49 men with a median age of 59 years (range 29–08). Forty-three pts treated on Arm A received a total of 407 cycles with a median of 8 cycles per patient (range 1–36). Forty-seven pts on Arm B received a total of 304 cycles with a median of 6 cycles per patient (range 1–20). Tumor measurements are available for 43 pts on Arm A and for 42 pts on Arm B pts. In Arm A, 9 pts had partial responses (PR), 20 pts had stable disease (SD) (including 2 unconfirmed PRs (uPR)), and 6 pts had progressive disease (PD). It was too early to report a response in an additional 8 pts. In Arm B, 4 pts had PRs, 26 had SDs (including 2 uPRs), and 9 had PDs. It was too early to determine a response in an additional 3 pts. Of the pts assessed for efficacy, 7 pts on Arm A and 5 pts on Arm B remain on study. The study is closed to accrual and final data on all pts will be presented at the meeting. Conclusions: The combination of FOLFOX4 and Cetuximab is active in pts with metastatic CRC previously treated with irinotecan. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb
Current Trends in the Pharmacotherapy for Gastroesophageal Reflux Disease (1992)

Medical therapy for gastroesophageal reflux disease should entail a multistep approach. After life-style changes, many patients will require histamine2 receptor antagonists in conventional doses with repeated therapeutic courses, if not continuous maintenance. Prokinetic agents are potentially useful in those patients with impaired motor function of the esophageal or gastric smooth muscle. Combination therapy with histamine2 receptor antagonists and prokinetic agents or sucralfate provides modest healing benefit, if any, over that by histamine2 receptor antagonists alone. For patients with more severe refractory disease, omeprazole has provided unequaled healing rates and accelerated symptomatic relief. High-dose (twofold or more standard dose) histamine2 receptor antagonist therapy may also heal high-grade esophagitis, but the reported experience is small. After healing is achieved, an attempt should generally be made to "step down" therapy to standard-dose histamine2 receptor antagonist as maintenance. Finding the least amount of drug to control symptoms and maintain the integrity of the esophageal mucosa would minimize cost and potential long-term risk.
Enhanced Levels of the Aroma and Flavor CompoundS-Linalool by Metabolic Engineering of the Terpenoid Pathway in Tomato Fruits (2001)

The aromas of fruits, vegetables, and flowers are mixtures of volatile metabolites, often present in parts per billion levels or less. We show here that tomato (Lycopersicon esculentum Mill.) plants transgenic for a heterologous Clarkia breweri S-linalool synthase (LIS) gene, under the control of the tomato late-ripening-specific E8 promoter, synthesize and accumulate S-linalool and 8-hydroxylinalool in ripening fruits. Apart from the difference in volatiles, no other phenotypic alterations were noted, including the levels of other terpenoids such as gamma- and alpha-tocopherols, lycopene, beta-carotene, and lutein. Our studies indicate that it is possible to enhance the levels of monoterpenes in ripening fruits by metabolic engineering.
Catalytic Asymmetric Intermolecular Stetter Reaction of Heterocyclic Aldehydes with Nitroalkenes: Backbone Fluorination Improves Selectivity (2009)

The catalytic asymmetric intermolecular Stetter reaction of heterocyclic aldehydes and nitroalkenes has been developed. We have identified a strong stereoelectronic effect on catalyst structure when a fluorine substituent is placed in the backbone. X-ray structure analysis provides evidence that hyperconjugative effects are responsible for a change in conformation in the azolium precatalyst. This new N-heterocyclic carbene precursor bearing fluorine substitution in the backbone results in significantly improved enantioselectivities across a range of substrates.
Effects of antiinflammatory drugs on the progression of osteoarthritis of the knee. LINK Study Group. Longitudinal Investigation of Nonsteroidal Antiinflammatory Drugs in Knee Osteoarthritis. (1995)

Indomethacin increased the rate of radiological deterioration of joint space in patients with OA of the knee; tiaprofenic acid did not.
Interferon receptors. Cross-linking of human leukocyte interferon alpha-2 to its receptor on human cells. (1982)

Experiments were carried out to identify the receptor for human interferon (HuIFN)-a on human cells.Binding of '2aI-labeled HuIFN-aa was tested with four human cell lines, Daudi, WISH, and two human osteogenic sarcoma cell lines, SAOS-2 and U20S.The latter cell line is rather insensitive to HuIFN-u and HuIFN-p.Daudi, WISH, and SAOS-2 cells showed specific binding of 'asI-HuIFN-az which was displaced by unlabeled HuIFN-aa, HuIFN-a(Le), and HuIFN-/3 but not by HuIF'N-y.The IFN-insensitive U20S cells showed no detectable displaceable binding of 'Z61-IFN-aa, indicating either a lack of IFN receptors or a much lower aflnity for IFN.Two croos-linking reagents (dithiobis(succinimidy1)propionate) and disuccinimidyl suberate) were used to test whether the cell-bound IFN could be cross-linked to its receptor.The cell-bound IFN-aa was cross-linked and yielded a complex with an apparent M, -160,000.Experiments indicate that this cross-linked complex represents IFN-UZ bound to its receptor or a component of it: (i) this complex formation was not detected on IFN-insensitive U20S cells; (ii) the cross-linked complex could be immunoprecipitated with anti-HuIFN-a antibodies but not with anti-HuIFN-/3 antibodies; (iii) the complex formation with "'11-IFNa 2 was displaced by unlabeled HuIFN-a~, HuIFN-a(Le), and HuIFN-/3 but not by H u m -y and very poorly by mouse IFN-a,P; the latter result suggests that the species specificity of IF'N may reside at the receptor level:(iv) the complex formation was abolished by pretreatment of cells with trypsin but not with neuraminidase, indicating that the receptor is at least in part protein.The complex obtained from neuraminidase-treated cells migrated slightly faster in polyacrylamide gels, suggesting that this IFN-binding component may be a glycoprotein."
Genetics, molecular mechanisms and management of long QT syndrome (1998)

Cardiac arrhythmias cause more than 300,000 sudden deaths each year in the USA alone. Long QT syndrome (LQT) is a cardiac disorder that causes sudden death from ventricular tachyarrhythmias, specifically torsade de pointes. Four LQT genes have been identified: KVLQT1 (LQT1) on chromosome 11p15.5, HERG (LQT2) on chromosome 7q35-36, SCN5A (LQT3) on chromosome 3p21-24, and MinK (LQT5) on chromosome 21q22. SCN5A encodes the cardiac sodium channel, and LQT-causing mutations in SCN5A lead to the generation of a late phase of inactivation-resistant whole-cell inward currents. Mexiletine, a sodium channel blocker, is effective in shortening the QT interval corrected for heart rate (QTc) of patients with SCN5A mutations. HERG encodes the cardiac I(Kr) potassium channel. Mutations in HERG act by a dominant-negative mechanism or by a loss-of-function mechanism. Raising the serum potassium concentration can increase outward HERG potassium current and is effective in shortening the QTc of patients with HERG mutations. KVLQT1 is a cardiac potassium channel protein that interacts with another small potassium channel MinK to form the cardiac I(Ks) potassium channel. Like HERG mutations, mutations in KVLQT1 and MinK can act by a dominant-negative mechanism or a loss-of-function mechanism. An effective treatment for LQT patients with KVLQT1 or MinK mutations is expected to be developed based on the functional characterization of the I(Ks) potassium channel. Genetic testing is now available for some patients with LQT.
Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder (2002)

PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne, OMIM #604416) and familial recurrent arthritis (FRA) are rare inherited disorders of early onset, primarily affecting skin and joint tissues. Recurring inflammatory episodes lead to accumulation of sterile, pyogenic, neutrophil-rich material within the affected joints, ultimately resulting in significant destruction. We recently localized the genes for PAPA syndrome and FRA to chromosome 15q and suggested that they are the same disorder. We have now established this by the identification of co-segregating disease-causing mutations in the CD2-binding protein 1 (CD2BP1; GenBank accession no XM 044569) gene in the two reported families with this disorder. E250Q or A230T amino acid substitutions occur within a domain highly homologous to yeast cleavage furrow-associated protein CDC15. CD2BP1 and its murine ortholog, proline-serine-threonine phosphatase interacting protein (PSTPIP1), are adaptor proteins known to interact with PEST-type protein tyrosine phosphatases (PTP). Yeast two-hybrid assays demonstrate severely reduced binding between PTP PEST and both the E250Q and A230T mutant proteins. Previous evidence supports the integral role of CD2BP1 and its interacting proteins in actin reorganization during cytoskeletal-mediated events. We hypothesize that the disease-causing mutations that we have identified compromise physiologic signaling necessary for the maintenance of proper inflammatory response. Accordingly we suggest classification of PAPA syndrome as an autoinflammatory disease. This CD2BP1-mediated biochemical pathway(s) may function in common inflammatory disorders with apparent etiological overlap, such as rheumatoid arthritis and inflammatory bowel disease.
Array‐based proteomics: mapping of protein circuitries for diagnostics, prognostics, and therapy guidance in cancer (2006)

The human proteome, due to the enormity of post-translational permutations that result in large numbers of isoforms, is much more complex than the genome and alterations in cancer can occur in ways that are not predictable by translational analysis alone. Proteomic analysis therefore represents a more direct way of investigating disease at the individual patient level. Furthermore, since most novel therapeutic targets are proteins, proteomic analysis potentially has a central role in patient care. At the same time, it is becoming clear that mapping entire networks rather than individual markers may be necessary for robust diagnostics as well as tailoring of therapy. Consequently, there is a need for high-throughput multiplexed proteomic techniques, with the capability of scanning multiple cases and analysing large numbers of endpoints. New types of protein arrays combined with advanced bioinformatics are currently being used to identify molecular signatures of individual tumours based on protein pathways and signalling cascades. It is envisaged that analysing the cellular 'circuitry' of ongoing molecular networks will become a powerful clinical tool in patient management.
Inflammation and Structural Changes in the Airways of Patients with Atopic and Nonatopic Asthma (2000)

The aim of the present study was to compare the cellular pattern and structural changes in the airway walls of atopic and nonatopic patients with asthma. Bronchial biopsy specimens were obtained from 13 atopic subjects with asthma, nine nonatopic patients with asthma, and seven healthy control subjects and investigated using immunohistochemical methods. The number of eosinophils increased in both asthma groups, but significantly more in the atopic group. The number of mast cells increased similarly in the two asthma groups, whereas the number of neutrophils increased only in the nonatopic asthma group. The number of T-lymphocytes (CD3-, CD4-, CD8-, CD-25-positive cells) was higher in patients with atopic asthma compared with nonatopic asthma. Interleukin-4 (IL-4) and IL-5-positive cells were more frequently found in the atopic asthma group, whereas cells staining for IL-8 were more frequent in the nonatopic group. The degree of epithelial damage was significantly higher in the atopic asthma group compared with the control subjects and the nonatopic asthmatics. The tenascin and laminin layer was significantly thicker in the atopic group compared with the group of nonatopic asthmatics. In the atopic group, there was a significant negative correlation between epithelial integrity (defined as the relative length of intact epithelium) and the eosinophil count and also between the number of CD25-positive cells and epithelial integrity. The number of mast cells correlated positively with the thickness of tenascin- and laminin-positive layers. In conclusion, we provide evidence of different patterns of involvement of inflammatory cells in atopic and nonatopic patients with asthma. There were also structural differences in the bronchial mucous membrane between atopic asthma and nonatopic asthma. This suggests that there are differences in the extent of the immunopathologic response of these clinically distinct forms of asthma.