gebhart/patrepeval huggingface dataset:
A first-in-human phase 1 study of ACE910, a novel factor VIII–mimetic bispecific antibody, in healthy subjects (2015)

ACE910 is a recombinant humanized bispecific antibody that binds to activated factor IX and factor X and mimics the cofactor function of factor VIII (FVIII). This first-in-human study examined the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ACE910 in healthy male adults. A total of 40 Japanese and 24 white subjects were randomized to receive a single subcutaneous injection of ACE910 (Japanese: 0.001, 0.01, 0.1, 0.3, or 1 mg/kg; white: 0.1, 0.3, or 1 mg/kg; n = 6 per dose group) or placebo (n = 2 per dose group). ACE910 exhibited a linear PK profile and had a half-life of ∼4 to 5 weeks. In FVIII-neutralized plasma, ACE910 shortened activated partial thromboplastin time and increased peak height of thrombin generation in a dose-dependent manner. All adverse events were nonserious and did not lead to any subject's withdrawal. Neither clinical findings nor laboratory abnormalities indicating hypercoagulability were observed. Two of 48 subjects receiving ACE910 (1 Japanese and 1 white) were positive for anti-ACE910 antibodies (anti-drug antibodies [ADAs]). One subject tested positive for ADAs both before and after ACE910 administration, whereas the other became ADA positive after receiving ACE910. The PK and PD profiles of ACE910 were similar in healthy Japanese and white subjects and suggest that ACE910 will be an effective and convenient prophylactic treatment of hemophilia A. This trial was registered at www.clinicaltrials.jp as #JapicCTI-121934.
Carotid Artery Hemodynamics: Observing Patient-specific Changes with Amlodipine and Lisinopril by Using MR Imaging Computation Fluid Dynamics (2010)

Purpose To assess whether using magnetic resonance (MR) imaging combined with computational fluid dynamics (CFD) could reveal changes in common carotid artery (CCA) flow and wall shear stress (WSS) that might contribute to differences in CCA remodeling between amlodipine, a calcium channel blocker, and lisinopril, an angiotensin-converting enzyme inhibitor, despite similar reductions in blood pressure (BP). Materials and Methods Institutional review board approval was obtained, and participants gave informed consent. Nine subjects with hypertension were recruited into a double-blind placebo-controlled randomized three-way crossover study to compare the hemodynamic effects of 7 days of treatment with placebo, amlodipine, or lisinopril. After each treatment period, patients underwent CCA ultrasonography, BP measurement, and MR imaging with CFD. Analyses were performed by using repeated-measures analysis of variance, followed by the Tukey test or the Wilcoxon matched-pairs test. Results Amlodipine and lisinopril lowered BP similarly, but CCA flow rate was significantly higher (P < .01) and distal vascular resistance was lower (P = .016) after amlodipine treatment than after lisinopril treatment. WSS on the inner wall of the CCA was significantly lower after lisinopril treatment than after amlodipine treatment (P = .03). The change in WSS in the CCA correlated with the change in vascular resistance (r = −0.85, P < .001). Conclusion Amlodipine causes increased blood flow and increased time-averaged WSS in the CCA compared with lisinopril, despite similar reductions in BP. Differences in the subacute hemodynamic effects of amlodipine and lisinopril could contribute to the differences in CCA remodeling seen in long-term studies. © RSNA, 2010 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100788/-/DC1
Friction effects in the deflection of atomic force microscope cantilevers (1994)

The conventional deflection-mode atomic force microscope operates by optically monitoring the slope near the end of a microcantilever in contact with the sample surface. This signal is usually interpreted as a measure of height change. Lateral forces from friction, surface geometry, or inclination of the cantilever to the surface also affect the slope due to cantilever buckling. We calculate the deflection of a hollow triangular model cantilever subject to both lateral and normal forces. The measured response of the servo circuit to an inclined, loaded cantilever is then determined. This shows (1) errors are always present in height measurements of structures on inhomogeneous surfaces; (2) the sensitivity to buckling can be reduced by repositioning the laser; (3) friction measurements can be accurately made by scanning in two directions and applying the proper calibration.
Quinoline Derivatives from 3-Nitro-4-hydroxyquinoline1 (1947)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTQuinoline Derivatives from 3-Nitro-4-hydroxyquinoline1G. Bryant Bachman, D. E. Welton, Glenn L. Jenkins, and John E. ChristianCite this: J. Am. Chem. Soc. 1947, 69, 2, 365–371Publication Date (Print):February 1, 1947Publication History Published online1 May 2002Published inissue 1 February 1947https://doi.org/10.1021/ja01194a060RIGHTS & PERMISSIONSArticle Views817Altmetric-Citations37LEARN 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 InReddit PDF (908 KB) Get e-Alerts Get e-Alerts
BMP gene delivery for alveolar bone engineering at dental implant defects (2004)

A challenge in the tissue engineering of alveolar bone surrounding oral or dental implants is achieving the targeted and sustained delivery of growth-promoting molecules at the osteotomy site. Bone morphogenetic protein-7 (BMP-7) has demonstrated the ability to stimulate bone regeneration in multiple skeletal sites, including the craniofacial complex. This study evaluates in vivo gene delivery of BMP-7 for bone tissue engineering around titanium dental implants. The maxillary first molar teeth of 44 Sprague-Dawley rats were extracted and allowed to heal for a period of 1 month. Large osteotomy defects were created in the edentulous ridge areas followed by the placement of dental implant fixtures. Recombinant adenoviral vectors encoding either the BMP-7 or the luciferase gene were delivered to the osseous defects using a collagen matrix. The kinetics of the gene expression was measured using in vivo bioluminescence optical imaging, while bone regeneration was evaluated under light and scanning electron microscopy. The results revealed sustained, targeted transgene expression for up to 10 days at the osteotomy sites with nearly undetectable levels by 35 days. Treatment of dental implant fixtures with Ad/BMP-7 resulted in enhancement of alveolar bone defect fill, coronal new bone formation, and new bone-to-implant contact. In vivo gene therapy of BMP-7 offers potential for alveolar bone engineering applications.
User-level internet path diagnosis (2003)

Diagnosing faults in the Internet is arduous and time-consuming, in part because the network is composed of diverse components spread across many administrative domains. We consider an extreme form of this problem: can end users, with no special privileges, identify and pinpoint faults inside the network that degrade the performance of their applications? To answer this question, we present both an architecture for user-level Internet path diagnosis and a practical tool to diagnose paths in the current Internet. Our architecture requires only a small amount of network support, yet it is nearly as complete as analyzing a packet trace collected at all routers along the path. Our tool, tulip, diagnoses reordering, loss and significant queuing events by leveraging well deployed but little exploited router features that approximate our architecture. Tulip can locate points of reordering and loss to within three hops and queuing to within four hops on most paths that we measured. This granularity is comparable to that of a hypothetical network tomography tool that uses 65 diverse hosts to localize faults on a given path. We conclude by proposing several simple changes to the Internet to further improve its diagnostic capabilities.
Structure-based design of 3-carboxy-substituted 1,2,3,4-tetrahydroquinolines as inhibitors of myeloid cell leukemia-1 (Mcl-1) (2015)

Mcl-1 has recently emerged as an attractive target to expand the armamentarium in the war on cancer. Using structure-based design, 3-carboxy-substituted 1,2,3,4-tetrahydroquinolines were developed as a new chemotype to inhibit the Mcl-1 oncoprotein. The most potent compound inhibited Mcl-1 with a Ki of 120 nM, as determined by a fluorescence polarization competition assay. Direct binding was confirmed by 2D (1)H-(15)N HSQC NMR spectroscopy with (15)N-Mcl-1, which indicated that interactions with R263 and T266, and occupation of the p2 pocket are likely responsible for the potent binding affinity. The short and facile synthetic chemistry to access target molecules is expected to mediate lead optimization.
Lymphatic Zip Codes in Premalignant Lesions and Tumors (2006)

Blood vessels in tumors are morphologically and functionally distinct from normal resting blood vessels. We probed lymphatic vessels in premalignant lesions and tumors by in vivo screening of phage-displayed peptide libraries, asking whether they too have distinctive signatures. The resulting peptides begin to define such signatures. One peptide identified the lymphatics in a human melanoma xenograft. Another recognized the lymphatics in prostate cancers but not in premalignant prostate lesions; this peptide similarly identifies human prostate cancer lymphatics. A third was selective for the lymphatics in the premalignant prostate lesions. A fourth identified the lymphatics in dysplasias and squamous carcinomas of the cervix and skin. None recognize lymphatics in normal tissues. Thus, tumor development is associated with organ- and stage-specific changes in lymphatics. Systemic treatment of mice with fusions of a lymphatic homing peptide and a proapoptotic motif reduced the number of tumor lymphatics in prostate tumor and melanoma, forecasting future lymphatic targeting agents for detection and therapeutic intervention.
Harnessing the Effect of Adoptively Transferred Tumor‐Reactive T Cells on Endogenous (Host‐Derived) Antitumor Immunity (2010)

Adoptive T cell transfer therapy, the ex vivo activation, expansion, and subsequent administration of tumor-reactive T cells, is already the most effective therapy against certain types of cancer. However, recent evidence in animal models and clinical trials suggests that host conditioning interventions tailored for some of the most aggressive and frequent epithelial cancers will be needed to maximize the benefit of this approach. Similarly, the subsets, stage of differentiation, and ex vivo expansion procedure of tumor-reactive T cells to be adoptively transferred influence their in vivo effectiveness and may need to be adapted for different types of cancer and host conditioning interventions. The effects of adoptively transferred tumor-reactive T cells on the mechanisms of endogenous (host-derived) antitumor immunity, and how to maximize their combined effects, are further discussed.
Yeast Catalysed Reduction of β-Keto Esters (2): Optimisation of the Stereospecific Reduction by Zygosaccharomyces Rouxii (1995)

Zygosaccharomyces rouxii catalysed the reduction of ethyl 4-chloroacetoacetate (ethyl 4-chloro-3-oxobutanoate) to the corresponding (S)-hydroxy ester (ethyl (S)-4-chloro-3-hydroxybutanoate) in high enantiomeric excess. The productivity of non-immobilised cells was compared to cells immobilised on a range of organic and inorganic supports. Cells immobilised in calcium alginate displayed a catalytic activity significantly higher than that of non-immobilised cells. A time dependent fall in the enantiomeric purity of the product was observed with the use of this matrix. This phenomenon was not seen in the reduction catalysed by non-immobilised cells.
Fluorescence lifetime imaging using a confocal laser scanning microscope (1992)

Abstract The implementation of a fast fluorescence life‐time imaging method in a confocal laser scanning microscope is described. The set up utilizes a low‐power continuous wave (CW) argon ion laser equipped with an electro‐optic chopper producing nanosecond pulses with a repetition rate up to 25 MHz. A time‐gated detection technique enables the measurement of the lifetime of a pixel in 40 μs. The first confocal fluorescence lifetime contrast images are presented. Application of fluorescence lifetime imaging in multilabelling experiments for discrimination between different labels with overlapping emission bands, for probing the local environment of a fluorescent molecule, and for quantitative fluorescence are discussed.
Vaccine-Induced Antibody Isotypes Are Skewed by Impaired CD4 T Cell and Invariant NKT Cell Effector Responses in MyD88-Deficient Mice (2009)

The requirement for TLR signaling in the initiation of an Ag-specific Ab response is controversial. In this report we show that a novel OVA-expressing recombinant Salmonella vaccine (Salmonella-OVA) elicits a Th1-biased cell-mediated and serum Ab response upon oral or i.p. immunization of C57BL/6 mice. In MyD88(-/-) mice, Th1-dependent Ab responses are greatly reduced while Th2-dependent Ab isotypes are elevated in response to oral and i.p., but not s.c. footpad, immunization. When the T effector response to oral vaccination is examined we find that activated, adoptively transferred Ag-specific CD4(+) T cells accumulate in the draining lymph nodes, but fail to produce IFN-gamma, in MyD88(-/-) mice. Moreover, CD1d tetramer staining shows that invariant NKT cells are activated in response to oral Salmonella-OVA vaccination in wild-type, but not MyD88(-/-), mice. Treatment with neutralizing Ab to CD1d reduces the OVA-specific Ab response only in MyD88-sufficient wild-type mice, suggesting that both Ag-specific CD4 T cell and invariant NKT cell effector responses to Salmonella-OVA vaccination are MyD88 dependent. Taken together, our data indicate that the type of adaptive immune response generated to this live attenuated vaccine is regulated by both the presence of MyD88-mediated signals and vaccination route, which may have important implications for future vaccine design.
Molecular Profiling of Human Hepatocellular Carcinoma Defines Mutually Exclusive Interferon Regulation and Insulin-Like Growth Factor II Overexpression (2004)

Molecular subtyping of human hepatocellular carcinoma (HCC) with potential mechanistic and therapeutic impact has not been achieved thus far. We have analyzed the mRNA expression patterns of 43 different human HCC samples and 3 HCC cell lines in comparison with normal adult liver using high-density cDNA microarrays. Two main groups of HCC, designated group A (65%) and group B (35%), were distinguished based on clustering of the most highly varying genes. Group A HCCs were characterized by induction of a number of interferon (IFN)-regulated genes, whereas group B was characterized mainly by down-regulation of several apoptosis-relevant and IFN-regulated genes. The number of apoptotic tumor cells and tumor-infiltrating lymphocytes was significantly higher in tumors of group A as compared with those of group B. Based on the expression pattern, group B was further subdivided into two subgroups, designated subgroup B1 (6 of 43 tumors, 14%) and subgroup B2 (9 of 43 tumors, 21%). A prominent characteristic of subgroup B1 was high overexpression of insulin-like growth factor (IGF)-II. All tested HCC cell lines expressed equally high concentrations of IGF-II transcripts and co-segregated with group B1 in clustering. IGF-II overexpression and induction of IFN-related genes were mutually exclusive, even when analysis was extended to other cancer expression profile studies. Moreover, IFN-gamma treatment substantially reduced IGF-II expression in HCC cells. In conclusion, cDNA microarray analyses provided subtyping of HCCs that is related to intratumor inflammation and tumor cell apoptosis. This profiling may be of mechanistic and therapeutic impact because IGF-II overexpression has been linked to reduced apoptosis and increased proliferation and may be accessible to therapeutic intervention.
Simulation and Testing of Deployable CFRP Booms for Large Space Structures (2011)

Since about 15 years DLR has been investigating the use of deployable masts for large deployable space structures. Applications include antennas, solar arrays, solar sails, de-orbiting devices and many more. Currently, a project each on solar sails (GOSSAMER-1) and de-orbiting structures are in progress. Both use the rollable lightweight CFRP masts (booms) of DLR for the provision of structural stiffness. The deployable booms are hollow, thin walled structures. Thus, the behaviour under bending or compression load is dominated by stability effects, or more specifically, buckling. In the present work a FE model is developed and verified for the prediction of limit buckling loads of the booms. Patran/Nastran 2010.1 has been used for the simulations and a bending test rack has been designed to carry out practical experiments. The simulation results and experimental results are compared and the differences are discussed. In the present work the manufacturing process of the deployable booms is also discussed and improvements are suggested to improve the quality of the booms.
Characterization and Modeling of Dye-Sensitized Solar Cells (2007)

Recent progress toward understanding the processes taking place in dye-sensitized nanocrystalline solar cells (DSC) is reviewed, and some areas characterized by controversy or poor understanding are highlighted. The thermodynamic and kinetic criteria for successful cell design are outlined, and experimental results obtained by a range of methods for characterizing the stationary and dynamic properties of DCS are discussed. These methods include direct measurement of the quasi-Fermi level using an indicator electrode and charge extraction measurements to determine the energetic distribution of electron traps in the nanocrystalline oxide. The influence of electron trapping on dynamic measurements of electron transfer and transport is discussed within the framework of the quasistatic assumption, and a new assessment of the electron diffusion length in the DSC is given, which suggests that collection of photoinjected electrons should be considerably more efficient than previously assumed.
Height Independent Compressive Modulus of Vertically Aligned Carbon Nanotube Arrays (2008)

The compressive modulus of dense vertically aligned multiwalled carbon nanotube (CNT) arrays synthesized by chemical vapor deposition was investigated using an optically probed precision-loading platform. For CNT arrays with heights ranging from 15 to 500 microm, the moduli were measured to be about 0.25 MPa and were found to be independent of array height. A continuum mechanics model based on multimode buckling guided by the wavy features of CNT arrays is derived and explains well the measured compressive properties. The measured compressive modulus of the CNT arrays also satisfies the "Dahlquist tack criterion" for pressure sensitive adhesives, which was previously observed for these vertically aligned CNT arrays (Zhao, Y., et al. J. Vac. Sci. Technol., B 2006, 24, 331-335).
Identification of genes required for alpha 2 repression in Saccharomyces cerevisiae. (1995)

Transcriptional repression of the a-specific genes in Saccharomyces cerevisiae alpha cells involves the concerted action of several proteins. The homeodomian protein alpha 2, together with MCM1, recruits two general transcriptional repressors, SSN6 and TUP1, to the promoters of a-specific genes. SSN6 and TUP1 then mediate repression of the a-specific genes. SIN4, another general negative regulator, is required for this repression, but unlike tup1 or ssn6 deletions, sin4 deletions cause only partial loss of repression. We have screened for other genes required for a-specific gene repression in alpha cells. In addition to recovering multiple alleles of previously identified genes required for this process (referred to as alpha 2 repression), we have identified four other genes, designated ARE1, ARE2, ARE3, and ARE4 (for alpha 2 repression). Recessive mutations in the ARE genes cause partial loss of a-specific gene repression and cause pleiotropic phenotypes similar to those resulting from mutations in SSN6, TUP1, or SIN4, suggesting that the ARE genes are general negative regulators. Based on our initial analysis, we propose that two distinct classes of general negative regulators cooperate to bring about full levels of alpha 2 repression. The sequence of ARE1 revealed that it encodes a CDC28-related protein kinase, identical to UME5, and thus suggests that protein phosphorylation plays a role in alpha 2 repression.
A Gompertzian model of human breast cancer growth. (1988)

The pattern of growth of human breast cancer is important theoretically and clinically. Speer et al. (Cancer Res., 44: 4124-4130, 1984) have recently proposed that all individual tumors initially grow with identical Gompertzian parameters, but subsequently develop kinetic heterogeneity by a random time-dependent process. This concept has elicited interest because it fits clinical data for the survival of untreated patients, for the progression of shadows on serial paired mammograms, and for time-to-relapse following mastectomy. The success of these curve-fits is compelling, and the model has been applied to clinical trials. However, the assumption of uniform nascent growth is not supported by theory or data, and individual cancers have not been shown to follow the complex growth curves predicted by the Speer model. As an alternative, if kinetic heterogeneity is understood to be an intrinsic property of neoplasia, the same three historical data sets are fit well by an unadorned Gompertzian model which is parsimonious and has many other intuitive and empirical advantages. The two models differ significantly in such clinical projections as the estimated duration of silent growth prior to diagnosis and the anticipated optimal chemotherapy schedule postsurgery.