gebhart/patrepeval huggingface dataset:
1079 LAG3-targeted IL15/IL15Rα-Fc (LAG3 x IL15) fusion proteins for preferential TIL expansion via cis delivery of IL15 to LAG3+ cells (2022)

<h3>Background</h3> Therapeutic approaches utilizing IL2 or IL15 have suffered from low tolerability, fast clearance, and limited therapeutic window due to extensive activity on peripheral T and NK cells. Conversely, selective targeting of tumor-reactive lymphocytes (TIL) may improve tolerability and anti-tumor activity while simultaneously improving drug PK. We hypothesized that we could selectively target tumor-reactive TILs by combining a reduced potency IL15/IL15Rα heterocomplex with an immune checkpoint(CP)-targeting arm to bias binding and activation to CP-positive TILs, potentially improving therapeutic index. Lymphocyte activation gene 3 (LAG3) was chosen as the CP targeting-arm due to its frequent co-expression with PD1, bias to CD8+ T cells, ability to easily combine with anti-PD1 agents, and recent promising results with anti-LAG3 agents in the clinic. <h3>Methods</h3> First, potency-reduced IL15/IL15Rα were created by engineering amino acid substitutions in IL15 – at the IL2Rβ/γc interface – that reduced in vitro potency by at least 1000-fold. We then designed LAG3 x IL15 fusion proteins containing single-chain IL15/IL15Rα and LAG3-targeting arms attached to a heterodimeric-Fc region, relying on targeting avidity (in cis) to recover potency on LAG3+ cells. In vitro proliferation of lymphocytes in human PBMCs, stimulated with sub-optimal concentrations of anti-CD3 to induce LAG3 expression, was monitored by CFSE dilution or by counting Ki67+ cells after incubation with LAG3 x IL15. In vivo activity was evaluated using a humanized mouse tumor model. Lead LAG3 x IL15 were evaluated in non-human primates (NHP). <h3>Results</h3> LAG3 x IL15 showed &gt;500-fold selectivity compared to a non-targeted IL15 in an in vitro proliferation assay of lymphocytes stimulated for induced LAG3 expression. In vitro potency was greatest on effector memory CD8 T cells. LAG3 x IL15 were 3-fold more potent on CD8 T cells compared to CD4 T cells and had very weak activity on NK cells, consistent with minimal LAG3 expression on this population. In mouse tumor models, LAG3 x IL15 had single-agent anti-tumor activity and promoted significantly increased numbers of T cells. Moreover, LAG3 x IL15 combined productively with anti-PD1 to promote additional anti-tumor activity and T cell expansion. In NHP, LAG3 x IL15 has superior PK compared to native IL15-Fc and showed selective targeting of LAG3+ peripheral T cells. <h3>Conclusions</h3> LAG3 x IL15 shows a promising profile of selective delivery to LAG3+ cells with minimal peripheral activity and may help to preferentially expand LAG3+ TIL in patients with cancer, while potentially avoiding systemic toxicity due to off-target activation and expansion of peripheral lymphocytes.
Cytokine signatures differentiate systemic sclerosis patients at high versus low risk for pulmonary arterial hypertension (2022)

These data suggest that cytokine profiles can distinguish SSc patients who are at high-risk for or have PAH from SSc patients who may be at lower risk for PAH and HC. However, high-risk and PAH patients had very similar cytokine profiles, suggesting that these patients are on a disease continuum.
Organic Electro‐Optic Modulators with Substantially Enhanced Performance Based on Transparent Electrodes (2010)

This chapter contains sections titled: Introduction TC-Based Low-Voltage, High-Speed Organic EO Modulators Full Design: A Detailed Example of High-Frequency Modulator Design Experimental Realization of a TC-Based Organic EO Modulator and Measurement Result Acknowledgements References
Ability of Pure Resting CD8+ Human T Cells to Respond to Alloantigen (1989)

The ability of highly purified resting human CD8 cells to respond to alloantigens in vitro was examined. Necessary conditions for induction of interleukin 2 receptors (IL-2R), IL-2 production, proliferative responses, and various effector functions were determined. Allogeneic non-T cells induced IL-2R expression in a high proportion of resting CD4 and CD8 cells, but only CD4 cells produced detectable amounts of IL-2. CD8 cells also became IL-2 responsive upon stimulation with purified resting allogeneic CD4 or CD8 cells, indicating that HLA class I+, II- cells alone may initiate activation of resting CD8 cells. The activated CD8 cells needed the presence of simultaneously activated CD4 cells or exogenous IL-2 to be able to synthesize DNA. Effector functions like cytotoxicity, mixed lymphocyte culture (MLC) suppression, or gamma interferon (IFN-gamma) production were also only detectable when the CD8 cells were activated in the presence of IL-2.
Abstract 992: Patient-derived tumor organoids of neuroendocrine prostate cancer (2017)

Abstract Background: The development of neuroendocrine prostate cancer (NEPC) is one mechanism of treatment resistance to androgen receptor (AR)-targeted therapies for a subset of patients with advanced prostate cancer. This is associated with transition from a prostate adenocarcinoma to small cell/NEPC histology, low AR signaling signaling, and expression of neuroendocrine markers as Chromogranin A (CGHA), Synaphophysin (SYP) and CD56). Patient derived preclinical models recapitulating the NEPC phenotype may be used to address NEPC pathogenesis and test emerging therapeutic targets. Methods: Tumor organoids were developed according to protocols previously described (Gao et al, Cell 2015). Briefly the tissue biopsies (liver and bone biopsy) were washed, enzymatically digested and then seeded in Matrigel (BD) droplets. Organoids were characterized at genomic (WES), RNA and protein level (IHC) to confirm the expression of specific markers. Lentiviral infections were performed using shRNAs against EZH2 to knock down EZH2 in organoids. Organoids were also subcutaneously injected in NSG mice to generate patient derived xenografts (PDXs) for drug treatment in vivo. Results: We developed and characterized two NEPC tumor organoids from tumor biopsies (liver and bone) of two patients both in vitro and in vivo (as PDXs). NEPC tumor organoid models retained the molecular and histological characteristic of their matched patient samples. We successfully manipulated the activity of the histone methyltransferase EZH2 by using a catalytic inhibitor and its expression by infecting organoids with shEZH2. We showed that the absence of EZH2 affects the expression of neuroendocrine-associated programs as stem cell and neuronal pathway. Moreover treatment with EZH2 inhibitor decreased tumor organoids viability and PDXs tumor volume. Drug screening approaches on NEPC organoids were used to discovery novel drug targets and combinations that could potentially benefit NEPC patients. Top single agent hits included previously identified targets such as EZH2, AURKA, as well as novel synergies. Conclusions NEPC patient tumor organoids are clinically relevant tumor models to study the NEPC phenotype in advanced prostate cancer and may be used to elucidate novel drug targets. Citation Format: Loredana Puca, Rohan Bareja, Reid Shaw, Wouter Karthaus, Dong Gao, Chantal Pauli, Juan Miguel Mosquera, Joanna Cyrta, Rachele Rosati, Rema Rao, Andrea Sboner, Carla Grandori, Giorgio Inghirami, Yu Chen, Mark A. Rubin, Himisha Beltran. Patient-derived tumor organoids of neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 992. doi:10.1158/1538-7445.AM2017-992
Localization of missing entities using parked cars (2015)

We introduce a novel application to detect tagged entities using a platform based on parked cars. We show experimental results based on real data from the city of Dublin.
A single epidermal stem cell strategy for safe ex vivo gene therapy (2015)

There is a widespread agreement from patient and professional organisations alike that the safety of stem cell therapeutics is of paramount importance, particularly for ex vivo autologous gene therapy. Yet current technology makes it difficult to thoroughly evaluate the behaviour of genetically corrected stem cells before they are transplanted. To address this, we have developed a strategy that permits transplantation of a clonal population of genetically corrected autologous stem cells that meet stringent selection criteria and the principle of precaution. As a proof of concept, we have stably transduced epidermal stem cells (holoclones) obtained from a patient suffering from recessive dystrophic epidermolysis bullosa. Holoclones were infected with selfinactivating retroviruses bearing a COL7A1 cDNA and cloned before the progeny of individual stem cells were characterised using a number of criteria. Clonal analysis revealed a great deal of heterogeneity among transduced stem cells in their capacity to produce functional type VII collagen (COLVII). Selected transduced stem cells transplanted onto immunodeficient mice regenerated a non-blistering epidermis for months and produced a functional COLVII. Safety was assessed by determining the sites of proviral integration, rearrangements and hit genes and by whole-genome sequencing. The progeny of the selected stem cells also had a diploid karyotype, was not tumorigenic and did not disseminate after long-term transplantation onto immunodeficient mice. In conclusion, a clonal strategy is a powerful and efficient means of by-passing the heterogeneity of a transduced stem cell population. It guarantees a safe and homogenous medicinal product, fulfilling the principle of precaution and the requirements of regulatory affairs. Furthermore, a clonal strategy makes it possible to envision exciting gene-editing technologies like zinc finger nucleases, TALENs and homologous recombination for nextgeneration gene therapy.
Reduction of Hepatotoxicity Induced by Doxorubicin (2017)

Doxorubicin (DOX) has been used in the treatment of variety of cancers but its administration is limited by a dosedependent toxicity. Its cytotoxic effects on malignant cells have shown an increase in the risk of cardiotoxicity, hepatoxicity, renal insufisance. Antioxydants have been explored for both their cancer preventive properties and chemodulatory of DOX toxicity. Resveratrol (RSV) is a polyphenolic constituent of several dietary mainly of grapes and wine origin recently its anticancer potential has been extensively explored, revealing its anti-proliferative effect on different cancer cell lines, both in vitro and in vivo. RSV is also known to have modulatory effects on cell apoptosis, migration and growth via various signaling pathways. Though, RSV possesses great medicinal value, its applications as a therapeutic drug is limited. Problems like low oral bioavailability and poor aqueous solubility make RSV an unreliable candidate for therapeutic purposes. Additionally, the rapid gastrointestinal digestion of RSV is also a major barrier for its clinical translation. Hence, to overcome these disadvantages RSV-based nanodelivery systems have been considered in recent times. Nanodelivery systems of RSV have shown promising results in its uptake by the epithelial system as well as enhanced delivery to the target site. Herein we have tried to bring new new insights into the molecular mechanisms of DOX toxicity with respect to DNA damage, free radicals and whether RSV can be a playmaker as chemodulatory of DOx.
Stabilizing g-States in Centrosymmetric Tetrapyrroles: Two-Photon-Absorbing Porphyrins with Bright Phosphorescence (2017)

Using time-dependent density functional theory (TDDFT) and sum-overstates (SOS) formalism, we predicted significant stabilization of 2P-active g-states in a compact fully symmetric porphyrin, in which all four pyrrolic fragments are fused with phathalimide residues via the β-carbon positions. The synthesis of a soluble, nonaggregating meso-unsubstituted tetraarylphthalimidoporphyrin (TAPIP) was then developed, and the spectroscopic measurements confirmed that a strongly 2P-active state in this porphyrin is stabilized below the B (Soret) state level. Single-crystal X-ray analysis revealed near-ideally planar geometry of the TAPIP macrocycle, while its tetra-meso-arylated analogue (meso-Ar<sub>4</sub>TAPIP) was found to be highly saddled. Consistent with these structural features, Pt meso-Ar<sub>4</sub>TAPIP phosphoresces rather weakly (ϕ<sub>phos</sub> = 0.05 in DMF at 22 °C), while both Pt and Pd complexes of TAPIP are highly phosphorescent (ϕ<sub>phos</sub> = 0.45 and 0.23, respectively). In addition PdTAPIP exhibits non-negligible thermally activated (E-type) delayed fluorescence (ϕ<sub>fl</sub>(d) ∼ 0.012). Taken together, these photophysical properties make metal complexes of meso-unsubstituted tetaarylphthalimidoporphyrins the brightest 2P-absorbing phosphorescent chromophores known to date.
DIAL 2004 working group report on acquisition quality control (2006)

This report summarizes the discussions of the Working Group on Acquisition Quality at the International Workshop on Document Image Analysis for Libraries, Palo Alto, CA, 23-24 January 2004. Acquisition of the image is one of the most time intensive components of forming a digital library, and the quality of the acquisition will affect all later stages of the digital library project. The current state of the art in acquisition is analyzed. Problems and suggested improvements for image acquisition and storage formats and the special problems associated with acquisition from microfilm follows. A list of general suggestions was developed which was complemented by a wish list of things the Working Group would like to see followed in acquisition discussions in the future.
Design and analysis of discontinuous mode series resonant converter (2002)

This paper aims at designing a low power, off-line, high efficiency, complex in size, twin-capacitors half-bridge series resonant converter. It gives steps by steps design procedures of the discontinuous mode series resonant converter starting from power stage circuit design to feedback loop control design. The small signal analysis is based on the injected-absorbed current method.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Ultrasonic tissue characterization with integrated backscatter. Acute myocardial ischemia, reperfusion, and stunned myocardium in patients. (1989)

We have previously shown in studies of experimental animals that myocardium exhibits a cardiac cycle-dependent variation of integrated backscatter that reflects regional myocardial contractile performance and that is blunted promptly after arterial occlusion and recovers after reperfusion. To define the clinical utility of ultrasonic tissue characterization with integrated backscatter for detection of acute myocardial infarction and reperfusion, 21 patients (14 men and seven women) were studied in the cardiac care unit within the first 24 hours (mean time, 11.3 hours; range, 3.5-23.8 hours) after the onset of symptoms indicative of acute myocardial infarction with conventional two-dimensional and M-mode echocardiography and with analysis of integrated backscatter. The magnitude of cyclic variation of integrated backscatter was measured from several sites within acute infarct regions and normal regions remote from the infarct zone for each patient. The average magnitude of cyclic variation among all patients (n = 21) was 4.8 +/- 0.5 dB in normal regions compared with 0.8 +/- 0.3 dB in infarct regions (p less than 0.05) within the first 24 hours after the onset of symptoms. Among the patients who had two studies, 15 (mean, 7.1 days; range, 2-31 days for second study) underwent coronary arteriography to define vessel patency. In patients with vessels with documented patency (n = 10), the magnitude of cyclic variation in infarct regions increased over time from 1.3 +/- 0.6 to 2.5 +/- 0.5 dB from the initial to final study (p less than 0.05). Patients with occluded infarct-related arteries (n = 5) exhibited no significant recovery of cyclic variation (0.3 +/- 0.3-0.6 +/- 0.3 dB). A blinded analysis of standard two-dimensional echocardiographic images revealed no significant recovery of wall thickening in either group over the same time intervals. Ultrasonic tissue characterization promptly detects acute myocardial infarction and may delineate potential beneficial effects of coronary artery reperfusion manifest by restoration of cyclic variation of integrated backscatter in the presence of severe wall motion abnormalities.
Elucidating the Synergetic Mechanism of Ni-Mo Electrocatalysts for the Hydrogen Evolution Reaction (2016)

Hydrogen is a potential future energy vector and a current industrial feedstock. Currently, most hydrogen is produced through the fossil fuel dependent steam reforming reaction. Water electrolysis is a promising alternative, but is currently limited by the availability of non noble metal catalysts that are stable in acid and by the lack of highly active non-noble metal catalysts in base. Nickel based electrcatalysts are a promising option for active catalysts in base. While it is well known that molybdenum enhances the activity of nickel catalysts, the heterogeneous nature of electrode surfaces complicates efforts to gain a fundamental understanding of this enhancement. In our work, we create a series of electrodes by depositing three different sizes of nickel nanoparticles onto molybdenum substrates. This allows us to investigate the effect that distinct domains of molybdenum, rather than an alloy or co-deposited material, has on nickel. We find that the activity is highest for the largest particles, a result that suggests that the enhancement is not occurring solely at the interface. As it is been demonstrated that the coexistence of multiple nickel oxidation states in pure nickel systems increases activity, we posit that the molybdenum acts to maintain the requisite plurality of oxidations states on the nickel nanoparticles.
Discovery of Critical Thresholds in Mixed Exposures and Estimation of Policy Intervention Effects using Targeted Learning (2023)

Traditional regulations of chemical exposure tend to focus on single exposures, overlooking the potential amplified toxicity due to multiple concurrent exposures. We are interested in understanding the average outcome if exposures were limited to fall under a multivariate threshold. Because threshold levels are often unknown a priori, we provide an algorithm that finds exposure threshold levels where the expected outcome is maximized or minimized. Because both identifying thresholds and estimating policy effects on the same data would lead to overfitting bias, we also provide a data-adaptive estimation framework, which allows for both threshold discovery and policy estimation. Simulation studies show asymptotic convergence to the optimal exposure region and to the true effect of an intervention. We demonstrate how our method identifies true interactions in a public synthetic mixture data set. Finally, we applied our method to NHANES data to discover metal exposures that have the most harmful effects on telomere length. We provide an implementation in the CVtreeMLE R package.
Characterization of Self-Similar Multifractals with Wavelet Maxima (1994)

Self-similar multifractals have a wavelet transform whose maxima define self-similar curves in the scale-space plane. We introduce an algorithm that recovers the affine self-similarity parameters through a voting procedure in the corresponding parameter space. The voting approach is robust with respect to renormalization noises and can recover the value of parameters having random fluctuations. We describe numerical applications to Cantor measures, dyadic multifractals, and the study of diffusion limited aggregates.
Cu bonding to co lowK wafers: a systematic study of the mechanical bonding process (2005)

Wire bonding is a widely used interconnection technique. Traditional processes use Au bond wire and Al metal layers. Nowadays there is a trend to go over to Cu bond wire to benefit from its better electrical performance characteristics. However during the bonding process, high pressure is put on the bond pad structure. These bond pad structures can contain low K dielectric materials, which have a low dielectric constant, but also a very low stiffness (standard range varies from 1-10 GPa, depending on the porosity in the dielectric). In this study, we investigate the deformations and stresses in wire bond and bond pad structure during the bonding process. The yield stress of the bond determines the pressure on the bond pad structure. In a first part, a comparison between simulations and experiments gives estimates for the yield stress of Cu bond wire and Au bond wire. A second part of the study investigates the stresses and deformations in the bond pad structure. Several parameters such as thickness of the low K dielectric layer and capping are investigated. Mainly a thicker and stiffer capping is showed to lower local stresses under the edge of the bond.
Tuning the Memory Window of TaOx ReRAM Using the RF Sputtering Power (2021)

In this work, TaOx based ReRAM devices were fabricated by reactive sputtering. The impact of RF power on the device characteristics was investigated using five different RF powers ranging from 116 W (RF 20%) to 356 W (RF 60%), resulting in different film deposition rates. Depending on RF power, both the initial device resistance (R <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">initial</sub> ) and forming voltage (V <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">form</sub> ) were found to be changed. The switching layer sputtered at 116 W shows the highest R <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">initial</sub> (80 GΩ), whereas the lowest resistance (50 kΩ) is obtained at 236 W. The device RESET level (R <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">off</sub> ) is a function of R <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">initial</sub> and V <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">form</sub> . The largest memory window (R <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">off</sub> / R <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">on</sub> ~ 105) and 2-bit MLC operation are achieved at 236 W deposition power. These devices show excellent retention at 125 °C for 10 <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">4</sup> seconds and good endurance up to 10 <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">6</sup> cycles. These results reflect the impact of the sputtering deposition power on the electrical performance of the ReRAM devices. It is due to the fact that the structural defects and oxygen content in the deposited film are modulated by the sputtering power.