gebhart/patrepeval huggingface dataset:
<i>Smoothened</i> Mutation Confers Resistance to a Hedgehog Pathway Inhibitor in Medulloblastoma (2009)

The Hedgehog (Hh) signaling pathway is inappropriately activated in certain human cancers, including medulloblastoma, an aggressive brain tumor. GDC-0449, a drug that inhibits Hh signaling by targeting the serpentine receptor Smoothened (SMO), has produced promising anti-tumor responses in early clinical studies of cancers driven by mutations in this pathway. To evaluate the mechanism of resistance in a medulloblastoma patient who had relapsed after an initial response to GDC-0449, we determined the mutational status of Hh signaling genes in the tumor after disease progression. We identified an amino acid substitution at a conserved aspartic acid residue of SMO that had no effect on Hh signaling but disrupted the ability of GDC-0449 to bind SMO and suppress this pathway. A mutation altering the same amino acid also arose in a GDC-0449-resistant mouse model of medulloblastoma. These findings show that acquired mutations in a serpentine receptor with features of a G protein-coupled receptor can serve as a mechanism of drug resistance in human cancer.
Anti-Candida albicans biofilm effect of novel heterocyclic compounds (2013)

We developed novel anti-biofilm agents that both inhibited and destroyed C. albicans biofilm. With some further development, these agents might be suitable for therapeutic purposes.
High-pulse-rate 10-W KrF laser (1978)

A discharge-pumped KrF excimer laser, utilizing a rapid recirculation of atmospheric-pressure gas, has generated 10 W of average output power at a pulse repetition rate of 1 kHz. The usual spark gap was replaced with a hydrogen thyratron for the switch in the pulse-forming network, and a corona discharge was used as the source for discharge preionization. Operating at 30 psi (absolute) and at a pulse rate of 2 Hz, a similar device has generated output pulse energies of 100 mJ at 1% efficiency and 80 mJ at 1.6% efficiency.
High-acceleration cable deployment (1980)

Prototype high-acceleration umbilical-cable deployment allows electrical communication between above-ground instrumentation and ballistic projectile below surface. Cable deployment is made up of forebody and afterbody. Foreboy can be separated from afterbody by rocket, or they can be fired as unit at target that stops afterbody on impact (forebody would continue, deploying cable). Similar design could be used in study of sea ice and in other surface-penetration studies.
Hatching the behavioral addiction egg: Reward Deficiency Solution System (RDSS)™ as a function of dopaminergic neurogenetics and brain functional connectivity linking all addictions under a common rubric (2014)

Importantly, the proposal is that the real phenotype is RDS and impairments in the brain's reward cascade, either genetically or environmentally (epigenetically) induced, influence both substance and non-substance, addictive behaviors. Understanding shared common mechanisms will ultimately lead to better diagnosis, treatment and prevention of relapse. While, at this juncture, we cannot as yet state that we have "hatched the behavioral addiction egg", we are beginning to ask the correct questions and through an intense global effort will hopefully find a way of "redeeming joy" and permitting homo sapiens live a life, free of addiction and pain.
Human Beta Defensins and Cancer: Contradictions and Common Ground (2019)

Human beta-defensins (hBDs, -1, 2, 3) are a family of epithelial cell derived antimicrobial peptides (AMPs) that protect mucosal membranes from microbial challenges. In addition to their antimicrobial activities, they possess other functions; e.g., cell activation, proliferation, regulation of cytokine/chemokine production, migration, differentiation, angiogenesis, and wound healing processes. It has also become apparent that defensin levels change with the development of neoplasia. However, inconsistent observations published by various laboratories make it difficult to reach a consensus as to the direction of the dysregulation and role the hBDs may play in various cancers. This is particularly evident in studies focusing on oral squamous cell carcinoma (OSCC). By segregating each hBD by cancer type, interrogating methodologies, and scrutinizing the subject cohorts used in the studies, we have endeavored to identify the "take home message" for each one of the three hBDs. We discovered that (1) consensus-driven findings indicate that hBD-1 and-2 are down- while hBD-3 is up-regulated in OSCC; (2) hBD dysregulation is cancer-type specific; (3) the inhibition/activation effect an hBD has on cancer cell lines is related to the direction of the hBD dysregulation (up or down) in the cancer from which the cell lines derive. Therefore, studies addressing hBD dysregulation in various cancers are not generalizable and comparisons should be avoided. Systematic delineation of the fate and role of the hBDs in a specific cancer type may lead to innovative ways to use defensins as prospective biomarkers for diagnostic/prognostic purposes and/or in novel therapeutic modalities.
Gate-Lifted nMOS ESD Protection Device Triggered by a p-n-p in Series With a Diode (2019)

We demonstrate a gate-lifted nMOS electrostatic discharge (ESD) protection device triggered by a p-n-p in series with a diode in a 0.18-μm bulk CMOS technologyfor 5-V mobile applications up to 85 °C. This voltage-triggering scheme is suitable for fail-safe, open-drain, supply, and surge protections. In addition, the robust ESD performance is boosted by parasitic embedded-silicon-controlledrectifier action in the high-current regime. No extra masks nor additional RC control circuitry are required for this implementation.
Enhanced ferromagnetic resonance linewidth of the free layer in perpendicular magnetic tunnel junctions (2017)

We report the frequency dependence of the ferromagnetic resonance linewidth of the free layer in magnetic tunnel junctions with all perpendicular-to-the-plane magnetized layers. While the magnetic-field-swept linewidth nominally shows a linear growth with frequency in agreement with Gilbert damping, an additional frequency-dependent linewidth broadening occurs that shows a strong asymmetry between the absorption spectra for increasing- and decreasing external magnetic field. Inhomogeneous magnetic fields produced during reversal of the reference and pinned layer complex is demonstrated to be at the origin of the symmetry breaking and the linewidth enhancement. Consequentially, this linewidth enhancement provides indirect information on the magnetic coercivity of the reference and pinned layers. These results have important implications for the characterization of perpendicular magnetized magnetic random access memory bit cells.
Synthesis of four novel trisaccharides by induction of loose acceptor specificity in Galβ31→4 transferase (EC 2.4.1.22): Gal<sub>p</sub>(β1→4)Glc<sub>p</sub>(X)Glc where X =β1→3: β1→4: β1→6: α1→4 (1992)

Development of tandem mass spectral methods for direct linkage determination in oligosaccharides requires sets of trisaccharides differing only in one structural parameter. In this case, we chose the position of linkage to the reducing-end hexose. These sets of compounds would also be useful for the development of high-resolution separation techniques geared to resolve linkage types. Conventional organic synthesis of such a set could take as long as 2-5 months for each member of the set. Each trisaccharide would require 10-20 steps of synthesis. Instead, we utilized low pH to induce a loose acceptor specificity for bovine milk galactosyltransferase (lactose synthase: EC 2.4.1.22) and by this method, within 2 weeks, generated four novel oligosaccharides for NMR and mass spectral studies. The disaccharides cellobiose (beta 1----4), laminaribiose (beta 1----3), gentiobiose (beta 1----6) and maltose (alpha 1----4) acted as acceptors for EC 2.4.1.22 under these conditions. The beta 1----2-linked disaccharide, sophorose, was not commercially available and is not included in this study. The alpha-linked disaccharides were also examined, but except for the alpha 1----4 disaccharide maltose, were very poor acceptors under a variety of conditions. From these four acceptors, the following four novel trisaccharides were synthesized in micromole amounts, suitable for studies of linkage position using low-energy collision-induced-dissociation tandem mass spectrometry (FAB-MS-CID-MS), and for NMR: Galp(beta 1----4)Glcp(beta 1----3)-Glc, Galp(beta 1----4)Glcp(beta 1----4)Glc, Galp(beta 1----4)Glcp(beta 1----6)-Glc and Galp(beta 1----4)Glcp(alpha 1----4)Glc.
<title>Gray-scale and contrast compensator for LCDs using obliquely oriented anisotropic network</title> (1998)

Birefringent optical compensators containing layers with substantially inclined optic axes can improve not only the contrast but also the gray scale and chromatic stability of 90 degrees twisted nematic LCDs over a large field of view. We present the detailed architecture of such a compensator. It consists of multiple birefringent layers, including one with an in-plane optic axis, one with its optic axis normal to the plane, and two with optic axes inclined at about 40 degrees from the plane. The in-plane and inclined layers are fabricated by photopolymerization of oriented liquid crystal monomers to form anisotropic networks. The precise thicknesses and azimuthal orientations of the various layers are determined by computer optimization. Laboratory measurements of compensated display units show good contrast, gray level, and chromatic stability over a large field of view. The performance is suitable for demanding avionics applications. These compensators are currently being fabricated at the Rockwell Science Center.
Abstract A114: Effect of different standard of care chemotherapeutics on anti-PD-L1 responses in syngeneic mouse tumor models (2016)

Abstract Immunotherapy with checkpoint inhibitors has proven to be highly effective, with durable responses in a subset of patients. In an effort to broaden the number of responding individuals, overcome resistance to single-agent therapy and extend the duration of responses, combination of immunotherapy with other treatments such as chemotherapy is currently being tested in multiple clinical trials. Importantly, combination of immunotherapy with standard of care chemotherapy could bring the benefits of immunotherapy into earlier lines of treatment. Here, we have evaluated the effects of different classes of chemotherapeutic agents alone or in combination with anti-PD-L1 treatment in syngeneic murine tumor models. We have found that combination of anti-PD-L1 with various alkylating agents, taxanes and platins caused differential changes on the frequency and number of intratumoral immune cell subsets, but did not antagonize the functional changes mediated by anti-PD-L1 treatment. Importantly, by comparing the effects of these chemotherapies in different tumor models, we have observed that their effects are model-specific. These differences may be due to tumor-specific immune composition and tumor intrinsic responses to different chemotherapies. Our results demonstrate that in the models we have tested, chemotherapeutic agents do not appear to directly antagonize the activity of anti-PD-L1 as measured by pharmacodynamic changes in immune cell activation although some differences can be observed in the frequency and number of certain intratumoral immune cell subsets. Additionally, our findings also reveal that tumor models might respond differently to the same chemotherapeutic treatment adding complexity to how we evaluate the effect of combination treatments with chemotherapy. Nonetheless, our results suggest a rationale for combining immunotherapy with chemotherapy in the clinic, although consideration should be taken when generalizing results from mouse tumor models. Citation Format: Rafael Cubas, Marina Moskalenko, Jeanne Cheung, Shiuh-Ming Luoh, Erin McNamara, Marcia Belvin, Jeong Kim, Stephen Gould. Effect of different standard of care chemotherapeutics on anti-PD-L1 responses in syngeneic mouse tumor models [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A114.
High-Throughput Screening for Small-Molecule Inhibitors of Staphylococcus epidermidis RP62a Biofilms (2013)

High-throughput screening (HTS) of 42 865 compounds was performed to identify compounds that inhibit formation of or kill Staphylococcus epidermidis RP62a biofilms. Three biological processes were assayed, including (1) growth of planktonic/biofilm bacteria, (2) assessment of metabolically active biofilm bacteria using a resazurin assay, and (3) assessment of biofilm biomass by crystal violet staining. After completing the three tiers (primary screening, hit confirmation, and dose-response curves), 352 compounds (representing ~0.8%) were selected as confirmed hit compounds from the HTS assay. The compounds were divided into groups based on their effectiveness on S. epidermidis biofilm properties. The majority of these affected both inhibition and killing of bacterial biofilm cultures. Only 16 of the confirmed hit compounds that have either an AC50 lower than 10 µM and/or Sconst ≥70 from those processed were selected for further study by confocal laser scanning microscopy (CLSM). The CLSM was used to evaluate the confirmed hit compounds on (1) inhibition of biofilm formation and (2) killing of preexisting S. epidermidis biofilms. Taken together, with further testing (e.g., disease-related conditions), such compounds may have applications as broad antimicrobial/antibiofilm use for prophylactic or therapeutic intervention to combat infections in surgical and intensive care clinics and battlefield settings.
Humanization of high-affinity antibodies targeting glypican-3 in hepatocellular carcinoma (2016)

Glypican-3 (GPC3) is a cell-surface heparan sulfate proteoglycan highly expressed in hepatocellular carcinoma (HCC). We have generated a group of high-affinity mouse monoclonal antibodies targeting GPC3. Here, we report the humanization and testing of these antibodies for clinical development. We compared the affinity and cytotoxicity of recombinant immunotoxins containing mouse single-chain variable regions fused with a Pseudomonas toxin. To humanize the mouse Fvs, we grafted the combined KABAT/IMGT complementarity determining regions (CDR) into a human IgG germline framework. Interestingly, we found that the proline at position 41, a non-CDR residue in heavy chain variable regions (VH), is important for humanization of mouse antibodies. We also showed that two humanized anti-GPC3 antibodies (hYP7 and hYP9.1b) in the IgG format induced antibody-dependent cell-mediated cytotoxicity and complement-dependent-cytotoxicity in GPC3-positive cancer cells. The hYP7 antibody was tested and showed inhibition of HCC xenograft tumor growth in nude mice. This study successfully humanizes and validates high affinity anti-GPC3 antibodies and sets a foundation for future development of these antibodies in various clinical formats in the treatment of liver cancer.
Direct SIRPa Blockade Augments Macrophage Responses to Therapeutic Anticancer Antibodies (2014)

Abstract Antibody-dependent phagocytosis is a crucial mechanism underlying the efficacy of therapeutic antibodies for cancer. However, a major barrier to phagocytosis exists in the CD47-SIRPa interaction. CD47, a molecular “don’t eat me” signal, is highly expressed on many types of cancer and acts as a myeloid-specific immune checkpoint. By engaging SIRPa, an inhibitory receptor on macrophages, CD47 limits the ability of macrophages to respond to therapeutic antibodies. In this study, we developed anti-human SIRPa antibodies that block the interaction between CD47 and SIRPa. By themselves, these antibodies were not sufficient to induce human macrophage phagocytosis. However, when combined with a variety of tumor-specific antibodies, the anti-SIRPa antibodies exhibited remarkable synergy and augmented antibody-dependent phagocytosis of human cancer cells. Addition of anti-SIRPa antibodies improved phagocytosis of cancer in response to rituximab, cetuximab, and trastuzumab, among other therapeutic antibodies. Moreover, anti-SIRPa antibodies enhanced macrophage phagocytosis of lymphoma cells in response to anti-CD20 variants produced with each subclass of human IgG or glycoengineered anti-CD20 antibodies, indicating they could be effective for the majority of therapeutic antibodies that are clinically approved or under development. Importantly, both polarized macrophages and primary tumor-associated macrophages exhibited increased responses to therapeutic antibodies when SIRPa was blocked. In contrast to therapies targeting CD47 directly, anti-SIRPa antibodies benefit from more restricted expression of SIRPa and could have more favorable pharmacokinetic and toxicity profiles. They are an important addition to the growing arsenal of therapeutics targeting the CD47-SIRPa axis for cancer and could act as universal adjuvants to therapeutic antibodies. Disclosures Weiskopf: Stanford University: CD47/SIRPa blocking therapies Patents & Royalties. Ring:Stanford University: CD47/SIRPa blocking therapies Patents & Royalties. Guo:Stanford University: CD47/SIRPa blocking therapies Patents & Royalties. Volkmer:Stanford University: CD47/SIRPa blocking therapies Patents & Royalties. Weissman:Stanford University: CD47/SIRPa blocking therapies Patents & Royalties.
4-Aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high throughput screening assay, structure-activity relationships of the 7, 8-positions (2006)

1129 We have recently reported the discovery of 2-amino-3-cyano-7-dimethylamino-4- (3-methoxy-4,5-methylenedioxyphenyl)-4H-chromene (1a) as potent apoptosis inducers using a novel cell- and caspase-based HTS assay and the SAR of the 4-position with a dimethylamino group in the 7-position (Kemnitzer, W. et al. J. Med. Chem. 2004, 47, 6299). These chromenes were found to be active in the HUVEC tube formation assay, suggesting that this series of compounds may have antivascular activity, and several compounds were also found to be highly active in anti-cancer in vivo tumor models. (Kasibhatla, S. et al. Mol. Cancer Ther. 2004, 3, 1365, and Gourdeau, H. et al. Mol. Cancer Ther. 2004, 3, 1375). In this presentation, we will describe the SAR of the 7-and 8-positions of 4-aryl-4H-chromenes as inducers of apoptosis, including 7,8-disubstituted analogs (Kemnitzer, W. et al. Bioorg. Med. Chem. Lett. 2005, 15, 4745), as well as analogs with a fused ring at the 7, 8-positions. We will report in detail the chemistry, in vitro and in vivo characterization of these compounds.
Developments in the Material Fabrication and Performance of LiMn2O4 dCld Cathode Material (2016)

Abstract : Lithium manganese oxide spinel materials exhibit promising electrochemical performance and good thermodynamic and kinetic stability when used as a cathode in lithium and lithium-ion electrochemical systems. An inherent disadvantage is their limited cyclability as a result of the energy barriers for removing lithium from the octahedral sites. This work incorporates chlorine into the lattice of the AB2O4 to help assist in lithium deinsertion from the octahedral sites. By introducing this chlorine into the starting material and the subsequent final product, the overall electrochemical performance is enhanced, which will be extremely useful in versatile applications. AB2O4-dCld materials were synthesized using both a solid state reaction method and a common ceramic glycine nitrate combustion process and were evaluated as a cathode for lithium and lithium-ion electrochemical systems. The data presented in this paper is the result of continuing fabrication efforts that allow for an even distribution of chlorine in the AB2O4-dCld material lattice. The material properties were verified using X-ray diffraction and X-ray fluorescence to determine the extent of chlorination into the lithium manganese spinel mixture. Electrochemical coin cells were fabricated and cycled between 4.75 V and 3.5 V at 1-2 mA/cm2 to determine cycle life capability and degradation processes.
General Purpose Parallel Architectures. (1990)

Publisher Summary This chapter focuses on general purpose parallel architectures. Multiprocessor parallel computation has been considered in the context of problems with large inherent parallelism. The results suggest that the XPRAM might turn out to be an appropriate aspiration for the parallel computer architect much as the von Neumann model is in the sequential case. It is conceptually simple, capturing as it does the idea of message passing synchronized in bulk. It is a suitable host on to which higher-level communication and storage management functions can be efficiently compiled. Furthermore, it is a promising candidate for efficient implementation in foreseeable technologies. An XPRAM with ρ processors executes operations in supersteps. In each superstep, each processor executes a number of local instructions and sends or receives some messages that implement global read or write instructions. XPRAM embodies the principle of bulk-synchrony, that is, the processors should be barrier synchronized at regular time intervals long enough for several packets to be transmitted between a pair of nodes.
Practical Performance of Analog Attack Techniques (2022)

The increasing number of vulnerabilities in analog circuits has motivated the development of novel security techniques that protect the analog supply chain. A variety of attacks including ones based on satisfiability modulo theory (SMT) and genetic algorithms (GA) have been executed on different analog circuits to evaluate the vulnerabilities of the added protection. However, the current attack techniques assume ideal conditions, where the attacker has complete knowledge of the IC except for the key used to obfuscate the circuit. In this paper, four different threat models are examined, where an adversary is assumed to have different levels of access to circuit and security information. The analysis of the attack performance on key-based parameter obfuscation is performed premised upon the level of information possessed by the adversary. The analog attack techniques are evaluated on five distinct circuit topologies, each implemented with different key sizes and obfuscated parameters. Through analysis of the results, a characterization of the advantages and disadvantages of the analog attack algorithms is provided.
Purification, crystallization and characterization of <i>N</i>-acetylneuraminate lyase from <i>Escherichia coli</i> (1991)

N-Acetylneuraminate lyase produced by Escherichia coli was purified and crystallized from a genetically engineered strain (E. coli SF8/pNAL1). The enzyme showed apparent molecular masses of 105,000 Da on gel filtration and 35,000 Da on SDS/PAGE, suggesting that the enzyme is a trimer. The apparent optimum pH and temperature were found to be 6.5-7.0 and 80 degrees C respectively. The Km values for N-acetylneuraminate and N-glycollylneuraminate were 3.3 and 3.3 mM respectively. The enzyme was inhibited by reduction with NaBH4 in the presence of the substrate, indicating that the enzyme belongs to the Schiff-base-forming Class I aldolases. The enzyme was strongly inhibited by Cu2+ ions, p-chloromercuribenzoate and N-bromosuccinimide, and also inhibited competitively by the reaction product, pyruvate, and its structurally related compounds, dihydroxyacetone and DL-glyceraldehyde.
Bespoke Processors for Applications with Ultra-Low Area and Power Constraints (2018)

This article makes the case for bespoke processor design, an automated approach that tailors a general-purpose processor IP to a target application by removing all gates from the design that can never be used by the application. The resulting processors are more area- and energy-efficient without sacrificing performance.