gebhart/patrepeval huggingface dataset:
The bispecific immunoligand ULBP2‐aCEA redirects natural killer cells to tumor cells and reveals potent anti‐tumor activity against colon carcinoma (2013)

NKG2D, an activating receptor expressed on NK cells and T cells, is critically involved in tumor immunosurveillance. In this study, we explored the potential therapeutic utility of the NKG2D ligand ULBP2 for the treatment of colon carcinoma. To this end we designed a fusion protein consisting of human ULBP2 and an antibody-derived single chain targeting the tumor carcinoembryonic antigen (CEA). The bispecific recombinant fusion protein re-directed NK cells towards malignant cells by binding to both, tumor cells and NK cells, and triggered NK cell-mediated target cell killing in vitro. Moreover, tumor growth was significantly delayed in a syngeneic colon carcinoma mouse model in response to immunoligand treatment. The anti-tumor activity could be attributed to the stimulation of immune cells with an elevated expression of the activation marker CD69 on NK, T and NKT cells and the infiltration of CD45+ immune cells into the solid tumor. In summary, it was demonstrated that immunoligands provide specific tumor targeting by NK cells and exert anti-tumor activity in vitro and in vivo. This technology represents a novel immunotherapeutic strategy for solid tumors with the potential to be further developed for clinical applications.
A lipidomics analysis of influenza infection and PPARγ activation (53.17) (2012)

Abstract While vaccines are a reliable preventative of influenza infection, useful therapeutics for treatment of the disease would be key to minimizing the impact of a major pandemic. In this study we have focused on the use of the anti-inflammatory compounds Abscisic Acid (ABA) and 61610 in the presence of PPARγ to reduce lung inflammation and damage. The mechanisms by which these therapeutics activate PPARγ have not yet been identified, but a promising avenue is through the modification of known lipid mediators produced during Arachidonic Acid metabolism. In this study, we present a lipidomics analysis of influenza infected C57BL6 Wild Type mice treated with ABA and 61610. Our data demonstrate a rise in lipid mediator levels due to infection as well as in the presence of ABA, and to a lesser extent, 61610. Quantitative Real-Time PCR was performed in order to link the expression of lipid metabolic regulators to observed changes in lipid levels. In addition to this, molecular docking studies of PPARγ were performed to compare predicted binding affinities of previously identified ligands to other eicosanoids. The results of the simulations rank many previously identified PPARγ ligands below other metabolites, indicating that studies analyzing for the presence of previously unexplored eicosanoids may be fruitful in identifying new lipid mediators involved in anti-inflammatory pathways.
Dabrafenib plus trametinib in patients with relapsed/refractoryBRAFV600E mutation–positive hairy cell leukemia (2022)

BRAF V600E is the key oncogenic driver mutation in hairy cell leukemia (HCL). We report the efficacy and safety of dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive HCL. This open-label, phase 2 study enrolled patients with BRAF V600E mutation-positive HCL refractory to first-line treatment with a purine analog or relapsed after ≥2 prior lines of treatment. Patients received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed objective response rate (ORR) per criteria adapted from National Comprehensive Cancer Network-Consensus Resolution guidelines. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients with BRAF V600E mutation-positive HCL were enrolled. The investigator-assessed ORR was 89.0% (95% confidence interval, 77.8%-95.9%); 65.5% of patients had a complete response (without minimal residual disease [MRD]: 9.1% [negative immunohistochemistry of bone marrow {BM} biopsy], 12.7% [negative BM aspirate flow cytometry {FC}], 16.4% [negative immunohistochemistry and/or FC results]; with MRD, 49.1%), and 23.6% had a partial response. The 24-month DOR was 97.7% with 24-month PFS and OS rates of 94.4% and 94.5%, respectively. The most common treatment-related adverse events were pyrexia (58.2%), chills (47.3%), and hyperglycemia (40.0%). Dabrafenib plus trametinib demonstrated durable responses with a manageable safety profile consistent with previous observations in other indications and should be considered as a rituximab-free therapeutic option for patients with relapsed/refractory BRAF V600E mutation-positive HCL. This trial is registered at www.clinicaltrials.gov as #NCT02034110.
A cell-specific enhancer that specifieslin-3expression in theC. elegansanchor cell for vulval development (2003)

During C. elegans vulval development, the anchor cell (AC) in the somatic gonad expresses lin-3, activating the EGF receptor signaling pathway in vulval precursor cells (VPCs) and thereby inducing and patterning VPCs. Previous studies with lin-3 mutants and transgene expression have revealed that the level of LIN-3 in the AC must be precisely regulated for proper vulval development. To understand how lin-3 expression is achieved in the AC, we identified a 59 bp lin-3 enhancer sufficient to activate lin-3 transcription solely in the AC. The enhancer contains two E-box elements, and one FTZ-F1 nuclear hormone receptor (NHR) binding site that is mutated in a vulvaless mutant, lin-3(e1417). Mutagenesis studies show that both E-boxes and the NHR binding site are necessary to express lin-3 in the AC. In vitro DNA-binding studies and in vivo functional assays indicate that distinct trans-acting factors, including the E-protein/Daughterless homolog HLH-2 and unidentified nuclear hormone receptor(s), are necessary for lin-3 transcription in the AC and thus are involved in vulval development.
In situ vaccination with local radiation and intratumoral immunocytokine to elicit a tumor-specific memory B-cell response. (2017)

69 Background: In a murine melanoma (MEL) model, we reported an in situ vaccination response to combined radiation (RT) and intra-tumor (IT) injection of anti-GD2 hu14.18-IL2 immunocytokine (IC). This treatment resulted in 71% complete regression of 5-week (~ 200mm 3 ) tumors, a memory T cell response, and augmented response to systemic anti-CTLA-4 antibody (mAb) checkpoint blockade. We hypothesized that mice rendered disease-free (DF) by RT, IT-IC, and anti-CTLA-4 mAb might also exhibit a memory B cell response. Methods: C57BL/6 mice were implanted with 2x10 6 syngeneic, GD2+ B78 MEL cells and tumors developed for 5 weeks. Mice were treated with 12 Gy RT to this tumor followed by 5 daily IT injections of hu14.18-IL2 d6-10 after RT and IP injection of anti-CTLA-4 d3, 6, and 9 after RT. DF mice and naïve controls were challenged by subcutaneous implantation with 2x10 6 B78 MEL cells. Peripheral blood was collected from mice before and after B78 challenge and serum was evaluated for presence of tumor-specific mAbs using flow cytometry and ELISA. Results: Seventy-three percent of mice were rendered DF by treatment with RT, IT-hu14.18-IL2, and anti-CTLA-4. All of these (13/13) rejected a rechallange B78 implantation &gt; 1 year later (range d378 – 511), whereas no naïve mice rejected B78 implantation (0/66). IgG from serum of DF mice bound selectively to B78 and parental GD2- B16 MEL cells and the level of this mAb response appeared to increase modestly d14 after B78 challenge. In naïve mice, a modest increase in tumor-specific mAb was identified between non-tumor implanted mice and d35 post-implantation mice (bearing tumors &gt; 200mm 3 ), however this level remained ~ 5 fold below that observed in DF mice prior to B78 rechallenge. In contrast, no appreciable mAb response was observed for unrelated syngeneic GD2+ Panc02 pancreatic tumor cells in serum of DF or naïve mice. Conclusions: We report an endogenous anti-tumor IgG humoral response in DF mice &gt; 1 year after treatment with RT, IT-IC, and anti-CTLA-4 mAb, concurrent with demonstration of long lasting immune protection from re-challenge. Studies are underway to determine whether this response is involved in the therapeutic efficacy of this in situ vaccination regimen.
Influence of a holey cladding structure on spectral characteristics of side-polished endlessly single-mode photonic crystal fibers (2006)

We experimentally investigate the spectral characteristics of side-polished endlessly single-mode photonic crystal fibers of different polishing depths and radii of curvature that are important to mode field diameter, evanescent coupling, waveguide losses, higher-order mode excitation, and dispersion slopes of photonic crystal fiber components. A polished photonic crystal fiber with a greater polishing depth or a larger radius of curvature shows a more dispersive characteristic. In contrast to conventional single-mode fibers, in photonic crystal fibers the evanescent field is more strongly localized, and the propagating light can be more efficiently guided within the deformed core.
Gabor-domain optical coherence microscopy with integrated dual-axis MEMS scanner for fast 3D imaging and metrology (2015)

Fast, robust, nondestructive 3D imaging is needed for characterization of microscopic structures in industrial and clinical applications. A custom micro-electromechanical system (MEMS)-based 2D scanner system was developed to achieve 55 kHz A-scan acquisition in a Gabor-domain optical coherence microscopy (GD-OCM) instrument with a novel multilevel GPU architecture for high-speed imaging. GD-OCM yields high-definition volumetric imaging with dynamic depth of focusing through a bio-inspired liquid lens-based microscope design, which has no moving parts and is suitable for use in a manufacturing setting or in a medical environment. A dual-axis MEMS mirror was chosen to replace two single-axis galvanometer mirrors; as a result, the astigmatism caused by the mismatch between the optical pupil and the scanning location was eliminated and a 12x reduction in volume of the scanning system was achieved. Imaging at an invariant resolution of 2 μm was demonstrated throughout a volume of 1 × 1 × 0.6 mm3, acquired in less than 2 minutes. The MEMS-based scanner resulted in improved image quality, increased robustness and lighter weight of the system – all factors that are critical for on-field deployment. A custom integrated feedback system consisting of a laser diode and a position-sensing detector was developed to investigate the impact of the resonant frequency of the MEMS and the driving signal of the scanner on the movement of the mirror. Results on the metrology of manufactured materials and characterization of tissue samples with GD-OCM are presented.
Early Lung Disease in Infants and Preschool Children with Cystic Fibrosis. What Have We Learned and What Should We Do about It? (2017)

The past decade has seen significant advances in understanding of the pathogenesis and progression of lung disease in cystic fibrosis (CF). Pulmonary inflammation, infection, and structural lung damage manifest very early in life and are prevalent among preschool children and infants, often in the absence of symptoms or signs. Early childhood represents a pivotal period amenable to intervention strategies that could delay or prevent the onset of lung damage and alter the longer-term clinical trajectory for individuals with CF. This review summarizes what we have learned about early lung disease in children with CF and discusses the implications for future clinical practice and research.
Acute myeloid leukemia is characterized by Wnt pathway inhibitor promoter hypermethylation (2010)

Nuclear localization of non-phosphorylated, active beta-catenin is a measure of Wnt pathway activation and is associated with adverse outcome in patients with acute myeloid leukemia (AML). While genetic alterations of the Wnt pathway are infrequent in AML, inhibitors of this pathway are silenced by promoter methylation in other malignanices. Leukemia cell lines were examined for Wnt pathway inhibitor methylation and total beta-catenin levels, and had frequent methylation of Wnt inhibitors and upregulated beta-catenin by Western blot and immunofluorescence. One hundred sixty-nine AML samples were examined for methylation of Wnt inhibitor genes. Diagnostic samples from 72 patients with normal cytogenetics who received standard high-dose induction chemotherapy were evaluated for associations between methylation and event-free or overall survival. Extensive methylation of Wnt pathway inhibitor genes was observed in cell lines, and 89% of primary AML samples had at least one methylated gene: DKK1 (16%), DKK3 (8%), RUNX3 (27%), sFRP1 (34%), sFRP2 (66%), sFRP4 (9%), sFRP5 (54%), SOX17 (29%), and WIF1 (32%). In contrast to epithelial tumors, methylation of APC (2%) and RASSF1A (0%) was rare. In patients with AML with normal cytogenetics, sFRP2 and sFRP5 methylation at the time of diagnosis was associated with an increased risk of relapse, and sFRP2 methylation was associated with an increased risk for death. In patients with AML: (a) there is a high frequency of Wnt pathway inhibitor methylation; (b) Wnt pathway inhibitor methylation is distinct from that observed in epithelial malignancies; and (c) methylation of sFRP2 and sFRP5 may predict adverse clinical outcome in patients with normal karyotype AML.
P1‐098: Aβ Oligomer Eliminating Compounds Impede Neurodegeneration in Vivo (2016)

Several lines of evidence suggest a central role of amyloid-β-peptide (Aβ) in the pathogenesis of Alzheimer’s disease (AD). More than Aβ fibrils, small soluble and prion-like Aβ oligomers are suspected to be the major toxic species responsible for disease development and progression. Therefore, eradication of these Aβ oligomers is our principal objective for therapy of AD. Previously, we have identified the fully D-enantiomeric peptide D3 by mirror image phage display selection [1] and showed that it was able to specifically eliminate Aβ oligomers and convert them into non-toxic species. D3 was able to reduce plaque load in transgenic AD mouse models, and improved cognition even after oral application [2]. More recently, we developed derivatives of D3 with improved properties. Using our newly developed Aβ-QIAD (quantitative determination of interference with Aβ aggregate size distribution) assay we showed that increased Aβ oligomer elimination efficiency correlates with increased activity to slow down neurodegeneration in the TBA2.1 mouse model [3]. Moreover, these compounds were also able to improve cognition in the Tg-SwDI mouse model. As expected from D-peptides, D3 and its derivatives showed superior pharmacokinetic properties, such as long half-lives and high oral bioavailability [4, 5]. I will summarize our newest data on highly efficient D3 derivatives on their way towards the first in man, first in class, clinical phase I study. This will include unpublished data. Compounds that specifically and efficiently eliminate Aβ oligomers are able to enhance cognition and impede neurodegeneration in vivo. [1] vanGroen et al., ChemMedChem 3, 1848-1852 (2008). [2] Funke et al., ACS Chem. Neurosci. 1, 639-648 (2010). [3] Brener et al., Sci. Rep. 5, 13222 (2015). [4] Jiang et al., PLoS One 10, e0128553 (2015). [5] Leithold et al., Pharm Res. 33, 33(2):328-336 (2015).
A Sex Pheromone Receptor in the Hessian Fly Mayetiola destructor (Diptera, Cecidomyiidae) (2016)

The Hessian fly, Mayetiola destructor Say (Diptera, Cecidomyiidae), is a pest of wheat and belongs to a group of gall-inducing herbivores. This species has a unique life history and several ecological features that differentiate it from other Diptera such as Drosophila melanogaster and blood-feeding mosquitoes. These features include a short, non-feeding adult life stage (1-2 days) and the use of a long-range sex pheromone produced and released by adult females. Sex pheromones are detected by members of the odorant receptor (OR) family within the Lepidoptera, but no receptors for similar long-range sex pheromones have been characterized from the Diptera. Previously, 122 OR genes have been annotated from the Hessian fly genome, with many of them showing sex-biased expression in the antennae. Here we have expressed, in HEK293 cells, five MdesORs that display male-biased expression in antennae, and we have identified MdesOR115 as a Hessian fly sex pheromone receptor. MdesOR115 responds primarily to the sex pheromone component (2S,8E,10E)-8,10-tridecadien-2-yl acetate, and secondarily to the corresponding Z,E-isomer. Certain sensory neuron membrane proteins (i.e., SNMP1) are important for responses of pheromone receptors in flies and moths. The Hessian fly genome is unusual in that it encodes six SNMP1 paralogs, of which five are expressed in antennae. We co-expressed each of the five antennal SNMP1 paralogs together with each of the five candidate sex pheromone receptors from the Hessian fly and found that they do not influence the response of MdesOR115, nor do they confer responsiveness in any of the non-responsive ORs to any of the sex pheromone components identified to date in the Hessian fly. Using Western blots, we detected protein expression of MdesOrco, all MdesSNMPs, and all MdesORs except for MdesOR113, potentially explaining the lack of response from this OR. In conclusion, we report the first functional characterization of an OR from the Cecidomyiidae, extending the role of ORs as long-range sex pheromone detectors from the Lepidoptera into the Diptera.
Reacting to Contact: Transparency and Collision Reflex in Actuation (2022)

In unstructured environments, robots run the risk of unexpected collisions. How well they react to these events is determined by how transparent they are to collisions. Transparency is affected by structural properties as well as sensing and control architectures. In this paper, we propose the collision reflex metric as a way to formally quantify transparency. It is defined as the total impulse transferred in collision, which determines the collision mitigation capabilities of a closed-loop robotic system taking into account structure, sensing, and control. We analyze the effect of motor scaling, stiffness, and configuration on the collision reflex of a system using an analytical model. Physical experiments using the move-until-touch behavior are conducted to compare the collision reflex of direct-drive and quasi-direct-drive actuators and robotic hands (Schunk WSG-50 and Dexterous DDHand.) For transparent systems, we see a counter-intuitive trend: the impulse may be lower at higher pre-impact velocities.
Identification and functional study of an alternatively spliced variant of rat TRPV1 receptor mRNA (2006)

Transient receptor potential vanilloid 1(TRPV1), or Vanilloid receptor 1(VR1), is a member of the TRP superfamily of nonselective cation channels. TRPV1 consists of a six transmembrane‐spanning domain, a pore region between S5 and S6, and the cytoplasmically oriented C‐ and N‐terminal regions. This receptor is activated by several endogenous ligands and noxious heat, acid as well as inflammatory factors, and has been proposed as a potential target for the treatment of pain and inflammation. Although numerous studies have reported the characterization of the splicing variants of rat, mouse and human TPRV1, these mRNA variants encoded N‐terminal deletion forms of TRPV1 receptors that are inactiveisoforms of TRPV1 receptors. Here, we report the identification and molecular cloning of a C‐terminal truncated form of rat TRPV1 receptor isolated from rat stomach and small intestines cDNA libraries. The deduced protein is designated as TRPV1c and contains 760 amino acids. When TRPV1c was expressed in HEK 293 cells, the TRPV1c acted as a ligand‐gated, Ca2+ permeable channel with similar agonist and antagonist pharmacology to wild type rat TRPV1 in FLIPR‐based Ca2+ assays. The ligands‐ stimulated TRPV1c activation was also shown to be dependent on the assay pH. Higher (pH 9) or lower (pH 5.5) assay pH will dramatically reduce ligands‐stimulated TRPV1c activity.
CD8+ Foxp3+ Regulatory T Cells Mediate Immunosuppression in Prostate Cancer (2007)

Our study shows that like CD4(+)CD25(+) Treg cells, CD8(+) Foxp3(+) Treg cells present in prostate tumor-derived TILs suppress immune responses and that their suppressive function can be regulated by TLR8 ligands, raising the possibility that the manipulation of Treg cell function by TLR8 ligands could improve the efficacy of immunotherapy for prostate cancer patients.
A Novel Anti-CD24 Monoclonal Antibody: Unarmed, Conjugated and Bi-specific, for Targeting Human Malignancies (2017)

Introduction: CD24 is a cell surface heavily glycosylated GPI-anchored protein. We have shown it to be an important oncogene in many tumors a poorer prognosis. It is highly expressed in HMs and in a large variety of solid tumors. The creation of chimeric humanized and bi-specific antibodies was a major breakthrough. Aim: To characterize and improve the efficacy of humanized mAb anti-CD24 Results and Methods:In vivo antibody targeting and accumulation within a CD24 positive tumor and its excess clearance was demonstrated using live imaging and assessment of CD24 levels in the tumors before and after treatment. High affinity antibodies were selected and created from combinatorial phage displayed antibody libraries with varying diversity at randomized positions. A chosen matured clone was isolated and showed higher binding strength and selective recognition and binding to the CD24 antigen. Its stability and pharmacokinetics parameters were enhanced. The matured antibody mediates ADCC in vivo, using a PDX model of CRC, the mAb was more effective than KEYTRUDA. Recombinant bispecific antibodies, targeting CD24 and CD30, were established and their specific binding was verified and compared to that of each monospecific antibody. Based on a glycan microarray, the binding of the different antibody derivatives was proved to be specific to the core protein and not to its sugar residues. Conclusion: CD24 is a promising target for many solid and hematological malignancies. The matured humanized anti-CD24 mAb is more effective than the parental Ab. The susceptibility of tumor cells to bispecific antibodies will be more effective and less toxic.
ChemInform Abstract: Al(OTf)3: An Efficient Recyclable Catalyst for Direct Nucleophilic Substitution of the Hydroxy Group of Propargylic Alcohols with Carbon‐ and Heteroatom‐Centered Nucleophiles to Construct C—C, C—O, C—N and C—S Bonds. (2012)

Abstract Independent of the nucleophile used, the reactions are finished within a few hours.
<title>Kilometric baseline space interferometry</title> (1996)

Two versions of a kilometric interferometer with equivalent science capabilities have been studied, one located on the Moon and the other operating as a free-flyer. It has been found that the Moon is not the ideal site for interferometry because of tidal and micro-meteorite induced disturbances, the need for long delay lines and the large temperature swings from day to night. Automatic deployment of the Moon- based interferometer would be difficult and site preparation and assistance by man appear to be essential. The free-flyer would be implemented as a very accurately controlled cluster of independent satellites placed in a halo orbit around the 2nd Lagrange point of the Sun-Earth system. Both versions could attain the required scientific performances and each one needs the same type of metrology control. The free-flyer is intrinsically advantageous because of its reconfiguration flexibility, quasi-unlimited baseline length and observation efficiency (the Moon-based interferometer cannot be operated during the lunar day because of stray light). The free-flyer is better suited for implementation in the near or mid-term future, but the Moon-based version could be considered in the long term when a human presence would permit maintenance and upgrading leading to a longer lifetime with continuous performance enhancement.