gebhart/patrepeval huggingface dataset:
Abstract 962: Novel targeting of tumor-infiltrating TNFR2 Tregs: removing suppression with microenvironment-specific antibodies (2017)

Abstract Background: A recognized and potent subtype of regulatory T cells (Tregs) expresses tumor necrosis factor receptor 2 (TNFR2), a member of the tumor necrosis factor (TNF) superfamily. TNFR2 expressing Tregs are overabundant in human and murine tumors and are the most potent suppressors of host immune responses. In addition, recent data in diverse human tumors show that TNFR2-expressing host T cells are the dominant Tregs in the tumor microenvironment, expressed far in excess of OX40 and GITR. Unlike many tumor markers, TNFR2 has limited expression in the immune system and almost no expression on parenchymal cells. This makes TNFR2 Tregs an attractive target for anticancer therapy. Methods: We produced monoclonal antibodies to human TNFR2 with the goal of inactivating the potent host Tregs that express TNFR2, competing with the agonism of TNF and inactivating infiltating Tregs of human tumors. Tregs from fresh ovarian ascites fluid were compared to Tregs from normal human blood donors for antibody potency. Results: Using a 48-hr cell-based Treg assay, we showed that TNFR2 antagonistic antibodies can inhibit Treg proliferation, suppress soluble TNFR2 secretion on normal cells and allow T effector expansion. The antagonism is dominant, succeeding even in the presence of TNF, which is a TNFR2 agonist. Furthermore, the structural biology of dominant TNFR2 receptor antagonism uncovers a unique conformation that equally inhibits downstream NFkB signaling. We also showed that dominant TNFR2 antibodies in a dose dependent fashion kill Tregs in ovarian cancer infiltrates more strongly than Tregs from healthy donors. Treg killing in the cancer microenvironment was dependent on cell proliferation and turnover the Tregs. Conclusion: In sum, blocking TNFR2 signaling on the most potent Tregs of the tumor microenvironment with a dominant antagonist antibody selectively heightens death of the immunosuppressive Tregs in the tumor microenvironment, at least in ovarian cancer. With the expanding knowledge that TNFR2 Tregs are the most potent host cells of the immune response, their dominance in diverse human tumor infiltrates and the natural low expression of this marker on normal lymphoid cells makes targeting of TNFR2 in the tumor microenvironment attractive. Citation Format: Heather Torrey, John Butterworth, Toshiyuki Mera, Yoshiaki Okubo, Limei Wang, Danielle Baum, Audrey Defusco, Sara Plager, Sarah Warden, Daniel Huang, Eva Vanamee, Rosemary Foster, Denise L. Faustman. Novel targeting of tumor-infiltrating TNFR2 Tregs: removing suppression with microenvironment-specific antibodies [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 962. doi:10.1158/1538-7445.AM2017-962
Temperature-Switchable Agglomeration of Magnetic Particles Designed for Continuous Separation Processes in Biotechnology (2015)

The purpose of this work was the synthesis and characterization of thermally switchable magnetic particles for use in biotechnological applications such as protein purification and enzymatic conversions. Reversible addition-fragmentation chain-transfer polymerization was employed to synthesize poly(N-isopropylacrylamide) brushes via a "graft-from" approach on the surface of magnetic microparticles. The resulting particles were characterized by infrared spectroscopy and thermogravimetric analysis and their temperature-dependent agglomeration behavior was assessed. The influence of several factors on particle agglomeration (pH, temperature, salt type, and particle concentration) was evaluated. The results showed that a low pH value (pH 3-4), a kosmotropic salt (ammonium sulfate), and a high particle concentration (4 g/L) resulted in improved agglomeration at elevated temperature (40 °C). Recycling of particles and reversibility of the temperature-switchable agglomeration were successfully demonstrated for ten heating-cooling cycles. Additionally, enhanced magnetic separation was observed for the modified particles. Ionic monomers were integrated into the polymer chain to create end-group functionalized particles as well as two- and three-block copolymer particles for protein binding. The adsorption of lactoferrin, bovine serum albumin, and lysozyme to these ion exchange particles was evaluated and showed a binding capacity of up to 135 mg/g. The dual-responsive particles combined magnetic and thermoresponsive properties for switchable agglomeration, easy separability, and efficient protein adsorption.
Metabolic and Functional Genomic Studies Identify Deoxythymidylate Kinase as a Target in LKB1-Mutant Lung Cancer (2020)

The LKB1/STK11 tumor suppressor encodes a serine/threonine kinase which coordinates cell growth, polarity, motility, and metabolism. In non-small cell lung cancer, LKB1 is somatically inactivated in 25-30% of cases, often concurrently with activating KRAS mutation. Here, we employed an integrative approach to define novel therapeutic targets in KRAS-driven LKB1 mutant lung cancers. High-throughput RNAi screens in lung cancer cell lines from genetically engineered mouse models driven by activated KRAS with or without coincident Lkb1 deletion led to the identification of Dtymk, encoding deoxythymidylate kinase which catalyzes dTTP biosynthesis, as synthetically lethal with Lkb1 deficiency in mouse and human lung cancer lines. Global metabolite profiling demonstrated that Lkb1-null cells had striking decreases in multiple nucleotide metabolites as compared to the Lkb1-wt cells. Thus, LKB1 mutant lung cancers have deficits in nucleotide metabolism conferring hypersensitivity to DTYMK inhibition, suggesting that DTYMK is a potential therapeutic target in this aggressive subset of tumors.
The Diversity Order of the Semidefinite Relaxation Detector (2008)

<para xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> In this paper, we consider the detection of binary (antipodal) signals transmitted in a spatially multiplexed fashion over a fading multiple-input–multiple-output (MIMO) channel and where the detection is done by means of semidefinite relaxation (SDR). The SDR detector is an attractive alternative to maximum-likelihood (ML) detection since the complexity is polynomial rather than exponential. Assuming that the channel matrix is drawn with independent identically distributed (i.i.d.) real-valued Gaussian entries, we study the receiver diversity and prove that the SDR detector achieves the maximum possible diversity. Thus, the error probability of the receiver tends to zero at the same rate as the optimal ML receiver in the high signal-to-noise ratio (SNR) limit. This significantly strengthens previous performance guarantees available for the semidefinite relaxation detector. Additionally, it proves that full diversity detection is also possible in certain scenarios when using a noncombinatorial receiver structure. </para>
Uplink D-MIMO Processing Using Kalman Filter Combining (2022)

We propose a decentralized subset method for optimal processing and combining of uplink signals in a distributed MIMO (D-MIMO) network. We further propose the use of Kalman filters with the square-root implementation to estimate the received uplink signals. This square-root implementation is shown to be numerically stable when inverting the covariance matrix, as it always assures the covariance matrix to be symmetric and positive semi-definite. In the paper we also analyze the computational complexity and cost with different combining methods. We show that the Kalman filter implementation provides the same result as the MMSE method in terms of the spectral efficiencies and equivalent SINR. However, the Kalman filter implementation is shown to be very efficient as it provides the possibility to fully utilize parallel computing of distributed hardware processors. Moreover, the processing can be decentralized and the estimates can be aggregated from local estimates to as many access points (APs) as needed to reach the desired performance target. A Kalman filter implementation has the flexibility to aggregate signals in different ways, allowing the fronthaul architecture to support connectivity of individual APs in any combination of parallel or serial manners.
Influence of Gastric Acid on Susceptibility to Infection with Ingested Bacterial Pathogens (2007)

Despite the widely held belief that gastric acid serves as a barrier to bacterial pathogens, there are almost no experimental data to support this hypothesis. We have developed a mouse model to quantify the effectiveness of gastric acid in mediating resistance to infection with ingested bacteria. Mice that were constitutively hypochlorhydric due to a mutation in a gastric H(+)/K(+)-ATPase (proton pump) gene were infected with Yersinia enterocolitica, Salmonella enterica serovar Typhimurium, Citrobacter rodentium, or Clostridium perfringens cells or spores. Significantly greater numbers of Yersinia, Salmonella, and Citrobacter cells (P < OR = 0.006) and Clostridium spores (P = 0.02) survived in hypochlorhydric mice, resulting in reduced median infectious doses. Experiments involving intraperitoneal infection or infection of mice treated with antacids indicated that the increased sensitivity of hypochlorhydric mice to infection was entirely due to the absence of stomach acid. Apart from establishing the role of gastric acid in nonspecific immunity to ingested bacterial pathogens, our model provides an excellent system with which to investigate the effects of hypochlorhydria on susceptibility to infection and to evaluate the in vivo susceptibility to gastric acid of orally administered therapies, such as vaccines and probiotics.
MMP-13 is induced during chondrocyte hypertrophy (2000)

During development, mRNA for matrix metalloproteinase-13 (MMP-13) is found associated with cartilage undergoing hypertrophy, suggesting that this collagenase plays a role in cell enlargement and/or cartilage calcification. Using chondrocytes from prehypertrophic cartilage of chick embryo sternae, we have examined the relationship between MMP-13 expression and the transition to hypertrophy. When hypertrophy was induced by serum-free culture with ascorbate and bone morphogenetic protein-2 (BMP-2), MMP-13 mRNA levels paralleled those for type X collagen. Chondrocytes from the caudal, nonhypertrophying portion of chick sternae expressed neither type X collagen nor MMP-13, confirming that MMP-13 mRNA is a marker for hypertrophy. Zymography with conditioned medium yielded a proteinase band at 59 kDa, which was absent in nonhypertrophic chondrocytes. A polyclonal antibody raised against chick MMP-13 reacted with the 59-kDa protein, confirming that it is MMP-13. Although mRNA for MMP-13 peaked at days 4-5 of culture, only low levels of MMP-13 activity were present, and the activity increased gradually in parallel with later increases in MMP-2. These results suggest that MMP-13 is activated by MMP-2 during chondrocyte maturation, and that the combination of both proteinases is required to prepare cartilage matrix for subsequent calcification, before endochondral ossification.
Prediction of motor and somatosensory function from human ECoG (2018)

One of the most challenging issues in recent BCI research is not only achieving high performance, but also creating a sense of ownership of artificial devices. To investigate this issue, sensory-motor integrated BMI system should be considered. In this study, we attempted to predict the somatosensory property of tactile stimulus as well as the movement trajectory and type using elctrocorticography (ECoG) signals. We showed that 1) single-trial 3-D movement trajectory can be estimated from low-frequency ECoG signals with relatively high performance, 2) high-gamma activity can be a robust feature for movement type classification, and 3) the location of pressure stimulation can be classified by macro ECoG signals from sensory-related cortical areas. These results might be applied to the closed-loop BMBI systems which simultaneously encode sensory information during movement decoding.
Inclusive jet differential cross sections in photoproduction at HERA (1995)

Inclusive jet differential cross sections for the reaction ep --&gt; jet + X at Q(2) below 4 GeV2 have been measured with the ZEUS detector at HERA using an integrated luminosity of 0.55 pb(-1). These cross sections are given in the kinematic region 0.2 &lt; y &lt; 0.85, for jet pseudorapidities in the ep-laboratory range -1 &lt; eta(jet) &lt; 2 and refer to jets at the hadron level with a cone radius of one unit in the eta - phi plane. These results correspond to quasi-real photoproduction at centre-of-mass energies in the range 130-270 GeV and, approximately, for jet pseudorapidities in the interval -3 &lt; eta(jet)(gamma p CMS) &lt; 0. These measurements cover a new kinematic regime of the partonic structure of the photon, at typical scales up to similar to 300 GeV2 and photon fractional momenta down to x(y) similar to 10(-2). Leading logarithm parton shower Monte Carlo calculations, which include both resolved and direct processes and use the predictions of currently available parametrisations of the photon parton distributions, describe in general the shape and magnitude of the measured eta(jet) and E(T)(jet) distributions.
High concordance of 70-gene recurrence risk signature and 80-gene molecular subtyping signature between core needle biopsy and surgical resection specimens in early-stage breast cancer (2021)

Abstract Introduction With an increase in neoadjuvant therapy recommendations for most early-stage breast cancer patients due to the COVID-19 pandemic, it has become increasingly imperative to ensure that molecular diagnostic assays provide reliable results from preoperative core needle biopsies. Therefore, the objective of this study was to determine the concordance of MammaPrint results (70-gene signature) and BluePrint results (80-gene signature) between core needle biopsies (CNB) and surgical resection (SR) specimens using prospectively collected matched tissues from patients enrolled in the FLEX trial ( NCT03053193 ). Methods We analyzed 113 matched CNB and SR tumor specimens from women with early-stage breast cancer enrolled in the FLEX trial. Each patient enrolled in the trial receives a MammaPrint recurrence risk classification test with or without BluePrint molecular subtyping. Concordance of MammaPrint is reported using overall percentage agreement, positive predictive value (PPV, High Risk), negative predictive value (NPV, Low Risk), and Cohen’s kappa coefficient. Additionally, correlations between sample types are reported using Pearson correlation coefficient. Results We found good concordance for MammaPrint results between CNB and SR tumor samples (90.3%, κ = 0.803), with a 95.1% NPV and 84.6% PPV. There was also a strong correlation of MammaPrint indices between CNB and SR specimens (r = 0.94). In addition to our primary objective, we determined the concordance of BluePrint subtyping in the matched tumor samples, and found excellent concordance (98.2%) and strong correlation of BluePrint scores within each subtype. Conclusion CNB samples demonstrated overall high concordance with paired SR samples for MammaPrint risk classification, ensuring that physicians are provided with accurate prognostic information for therapy decisions based on testing of core biopsy tissue. Further, BluePrint molecular subtyping also had good concordance between the sample types, outperforming concordance rates based on traditional IHC based classification. Overall, with an increase in neoadjuvant therapy, physicans and patients can be assured that MammaPrint and BluePrint provide reliable results that guide timely and appropriate therapies using preoperative CNB specimens.
Optimization of single reflectors for extended sources (2008)

Reflectors for prescribed intensity or illuminance distributions are commonly used in luminaires and automotive headlights. However, their design has remained a challenge. Although reflector shapes are well known for a point source, the point source approximation leads to significant errors in the output distribution with extended and nonuniform source distributions. In practice, source non-idealities usually require the use of automated and manual optimization in the design process. We propose a hybrid optimization scheme that generates reflector shapes for rotationally symmetric systems and an arbitrary source luminance distribution. This method is based on an extension of the traditional algorithm for a point source, and uses a combination of an iterative algorithm and an optimization algorithm. Several case studies are presented.
Hormonal Regulation of Epithelial Organization in a Three-Dimensional Breast Tissue Culture Model (2013)

The establishment of hormone target breast cells in the 1970's resulted in suitable models for the study of hormone control of cell proliferation and gene expression using two-dimensional (2D) cultures. However, to study mammogenesis and breast tumor development in vitro, cells must be able to organize in three-dimensional (3D) structures like in the tissue. We now report the development of a hormone-sensitive 3D culture model for the study of mammogenesis and neoplastic development. Hormone-sensitive T47D breast cancer cells respond to estradiol in a dose-dependent manner by forming complex epithelial structures. Treatment with the synthetic progestagen promegestone, in the presence of estradiol, results in flat epithelial structures that display cytoplasmic projections, a phenomenon reported to precede side-branching. Additionally, as in the mammary gland, treatment with prolactin in the presence of estradiol induces budding structures. These changes in epithelial organization are accompanied by collagen remodeling. Collagen is the major acellular component of the breast stroma and an important player in tumor development and progression. Quantitative analysis of second harmonic generation of collagen fibers revealed that collagen density was more variable surrounding budding and irregularly shaped structures when compared to more regular structures; suggesting that fiber organization in the former is more anisotropic than in the latter. In sum, this new 3D model recapitulates morphogenetic events modulated by mammogenic hormones in the breast, and is suitable for the evaluation of therapeutic agents.
Unraveling the In Vivo Protein Corona (2021)

Understanding the behavior of nanoparticles upon contact with a physiological environment is of urgent need in order to improve their properties for a successful therapeutic application. Most commonly, the interaction of nanoparticles with plasma proteins are studied under in vitro conditions. However, this has been shown to not reflect the complex situation after in vivo administration. Therefore, here we focused on the investigation of magnetic nanoparticles with blood proteins under in vivo conditions. Importantly, we observed a radically different proteome in vivo in comparison to the in vitro situation underlining the significance of in vivo protein corona studies. Next to this, we found that the in vivo corona profile does not significantly change over time. To mimic the in vivo situation, we established an approach, which we termed "ex vivo" as it uses whole blood freshly prepared from an animal. Overall, we present a comprehensive analysis focusing on the interaction between nanoparticles and blood proteins under in vivo conditions and how to mimic this situation with our ex vivo approach. This knowledge is needed to characterize the true biological identity of nanoparticles.
Neural Retinal Disorganization as a Robust Marker of Visual Acuity in Current and Resolved Diabetic Macular Edema (2015)

Despite treatment advances, diabetic eye disease remains a leading cause of visual acuity (VA) loss worldwide. No methods to prospectively determine which patients will gain or lose vision exist, limiting individualized risk assessment and management. We investigated whether noninvasive, readily obtainable spectral domain optical coherence tomography parameters were correlated with VA in eyes with current or resolved center-involved diabetic macular edema (DME). Images were evaluated for disorganization of the retinal inner layers (DRIL), cysts, epiretinal membranes, microaneurysms, subretinal fluid, and outer layer disruption/reflectivity. DRIL affecting ≥50% of the 1-mm central retinal zone was associated with worse VA in all eyes, eyes with current edema, and eyes with resolved edema. Furthermore, early 4-month change in DRIL extent predicted VA change from baseline to 1 year. These data suggest that DRIL is a robust predictor of VA in eyes with present or previous DME and more highly correlated with VA than other widely used measures, such as retinal thickness. If further studies confirm DRIL as a predictive biomarker of future VA, physicians would gain a new tool of substantial clinical and investigative importance that could significantly change the approach to ophthalmic counseling and therapeutic management in patients with diabetes.
Focused ultrasound-mediated brain genome editing (2022)

Gene editing in the mammalian brain has been challenging because of the restricted transport imposed by the blood-brain barrier (BBB). Current approaches rely on local injection to bypass the BBB. However, such administration is highly invasive and not amenable to treating certain delicate regions of the brain. We demonstrate a safe and effective gene editing technique by using focused ultrasound (FUS) to transiently open the BBB for the transport of intravenously delivered CRISPR/Cas9 machinery to the brain.
A new class of nitrosoureas. II. Synthesis and antitumor activity of 1-(2-chloroethyl)-3,3-disubstituted-1-nitrosoureas having a glucopyranosyl, mannopyranosyl or galactopyranosyl moiety. (1981)

Many kinds of 1-(2-chloroethyl)-3-substituted-3-β-D-glycopyranosyl-1-nitrosoureas (V) were synthesized and tested for antitumor activities against leukemia L1210 and Ehrlich ascites carcinoma. The reaction of aldohexoses such as D-glucose, D-mannose, and D-galactose with primary amines followed by treatment with 2-chloroethyl isocyanate usually gave a mixture of structural isomers of glycosylureas (III'). Complete isomerization into thermodynamically stable β-D-glycopyranosylureas (III) was observed when the mixture of isomers was dissolved in formic acid. Glycopyranosylureas (III) were nitrosated with 5 equivalents of dinitrogen tetroxide followed by treatment with methanol to give the corresponding nitrosoureas (V) in good yields. Many of the nitrosoureas (V) were remarkably active against both leukemia L1210 and Ehrlich ascites carcinoma and showed greater therapeutic ratios than those of the positive controls, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, 3 [(4-amino-2-methyl-5-pyrimidinyl) methyl]-1-(2-chloroethyl)-1-nitrosourea, and 1-(2-chloroethyl)-3-(β-D-glucopyranosyl)-1-nitrosourea. In particular, some of the galactopyranosylnitrosoureas showed excellent antitumor activities and sixtyday survivors against leukemia L1210 were observed at dose levels of 25, 50 and 100 mg/kg of the compounds. These nitrosoureas (V) appear to be activated nonenzymatically by attack of the hydroxyl group of the sugar moiety on the carbonyl group to give the cyclic carbamate (VI) without generation of the isocyanate (XI).