gebhart/patrepeval huggingface dataset:
Renal Medullary Infusion of CoPP Prevents Angiotensin‐II Dependent Hypertension in Mice (2007)

Several studies have established systemic induction of Heme Oxygenase‐1 (HO‐1) as a viable means of attenuating the development of hypertension in several experimental models. However, the precise mechanism behind the anti‐hypertensive actions of HO‐1 induction is still unclear. In this study, we tested the hypothesis that kidney specific induction of HO‐1 can prevent the development of Ang‐II dependent hypertension. To test this hypothesis, renal medullary interstitial catheters were implanted into the left kidney of uninephrectomized mice. Infusion of a known inducer of HO‐1, cobalt protoporphyrin (CoPP; 250 μg/ml; at 50 μl/hr for 48hrs), resulted in significant induction of HO‐1 mainly in the renal medulla when examined 2 weeks after the infusion with no induction observed in other organs such as the brain, heart, and liver. Next, we examined the effect of this approach of inducing of HO‐1 on the development of Ang II dependent hypertension. CoPP or Vehicle (0.1 M NaOH, pH 8.3) was infused as indicated above 2 days prior to implantation of an osmotic minipump which delivered Ang II at a rate of 1 μg/kg/min. Mean arterial pressure (MAP) was measured in conscious, unrestrained mice for 3 consecutive days starting 7 days after the implantation of the Ang II minipumps. MAP averaged 112 ± 4, 121 ± 4, 162 ± 2 and 126 ± 6 mmHg in Vehicle + Vehicle, CoPP + Vehicle, Vehicle + Ang II and CoPP + Ang II treated mice respectively (n=6). These results suggest that renal medullary infusion of CoPP to induce HO‐1 specifically in the kidneys can prevent the development of Ang II dependent hypertension in mice. Induction of HO‐1 in the renal medulla may be the mechanism by which systemic delivery of CoPP lowers blood pressure in Ang‐II dependent hypertension.
MEF2C repressor variant deregulation leads to cell cycle re-entry and development of heart failure (2020)

São Paulo Research Foundation (FAPESP); Brazilian National Research Council (CNPq).
Strong Therapeutic Effect Of Anti-IL1RAP Immunotherapy In a Xenograft Model Of Acute Myeloid Leukemia (2013)

Abstract Acute myeloid leukemia is a genetically heterogeneous disease characterized by expansion of immature hematopoietic cells in the bone marrow. The disease is associated with a general poor survival and thus the need for novel treatment strategies is urgent. We have previously shown that the IL1 receptor accessory protein (IL1RAP) is highly expressed on primitive chronic myeloid leukemia (CML) cells and that a polyclonal antibody against IL1RAP can direct natural killer cells to specifically target and destroy CML CD34+CD38- cells in an in vitro-based antibody dependant cell-mediated cytotoxicity (ADCC) assay (Järås et al, PNAS, 2010). We recently also demonstrated that IL1RAP is upregulated in about 80% of AML patients and that primitive AML cells can be targeted by a monoclonal antibody against IL1RAP and selectively killed by ADCC (Askmyr et al, Blood, 2013). In this study, we applied these findings to a human AML xenograft model. NOD/SCID mice were engrafted with lethal doses of MA9Ras cells, previously generated by transformation of human umbilical cord blood CD34+ cells by retroviral integration of cDNAs directing the expression of an MLL/AF9 fusion and an activated NRAS gene. Leukemic mice were treated twice weekly with Mab81.2, a monoclonal antibody targeting IL1RAP, or a corresponding isotype control antibody. Notably, the seven mice treated with Mab81.2 displayed a significant reduction of leukemic cells in the peripheral blood 35 days after transplantation compared to the seven mice in the isotype control treated group (0.10±0.04% vs. 0.69±0.45% CD45+ cells, p=0.0043). This reduction was even more significant at 62 days (3.75±2.50% vs. 46.46±24.92% CD45+ cells, p=0.0007). Treatment with the IL1RAP-targeting antibody also resulted in an increased overall survival compared to the isotype control treated group (median survival 75 days vs 64 days, p=0.0089). Furthermore, at time of sacrifice, the Mab81.2-treated mice were shown to have significantly lower frequency of leukemic cells in the bone marrow (4.99±3.34% vs. 59.51±25.18% CD45+ cells, p=0,0001) and spleen (17.19±10.21% vs. 49.71±23.09% CD45+ cells, p=0,0052). In conclusion, we show that in vivo delivery of the Mab81.2 monoclonal antibody results in significant suppression of human MA9Ras cells and prolongs survival in a xenograft setting, demonstrating that anti-IL1RAP immunotherapy provides a new promising treatment approach for AML. Disclosures: Richter: Cantargia: Consultancy, Equity Ownership. Järås:Cantargia AB: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Fioretos:Cantargia AB: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding.
Supplemental Figure 5 from Tumor-Localized Secretion of Soluble PD1 Enhances Oncolytic Virotherapy (2023)

&lt;p&gt;Immunological response of mice eradicated of B16/F10 tumors by vPD1&lt;/p&gt;
Understanding and managing sanitary risks due to rodent zoonoses in an African city: beyond the Boston Model (2008)

The Boston Model describes a successful rodent management plan that succeeded in a first-world city in the USA. In third-world cities, which often contain informal shack settlements, it is debatable whether the Boston Model would apply. In Durban, a major harbor city of three million people on the east coast of South Africa, we investigated the sanitary risks due to rodents in both formal (residential and commercial) and informal (shacks) sectors, and we evaluated the relative merits of different management interventions suggested by the Boston Model. Blood and tissue samples of six species (Rattus norvegicus, R. tanezumi, R. rattus, Mus musculus, Mastomys natalensis, Tatera brantsi) from 262 live-trapped rodents from 54 localities were tested for antibodies or DNA for plague (n= 193: antibody test), leptospirosis (n= 221 for antibody test; n= 69 for polymerase chain reaction test for DNA) and toxoplasmosis (n= 217: antibody test). We conducted a socioeconomic survey of 90 household to determine environmental and socioeconomic disease risk factors in the shack settlement of Cato Crest. No rodents were seropositive for plague, but nine Norway rats, R. norvegicus (4.1% of the sample tested) were seropositive for toxoplasmosis, and 22 R. norvegicus (10.0% of sample tested) were seropositive for leptospirosis. Disease endemic areas were concentrated in Cato Crest and the commercial district of Durban. Serology tests of humans living in Cato Crest (n= 219) showed 0% exposure to plague, 23% to leptospirosis and 35% to toxoplasmosis. Compared with shack-dwellers, the residents of brick houses had slightly lower levels of exposure to leptospirosis and toxoplasmosis. Based on our results, environmental hygiene and rodent-trapping campaigns were launched in Cato Crest. The initiative owes much of its current success to implementation of the principles inherent in the Boston Model, even though certain elements were lacking.
Direct Observation of Spin Polarization of Conduction Electrons and Location of Magnetic States in Eu1−xGdxS (1971)

The dependence of photoelectron spin polarization on photon energy was measured for films of Eu1−xGdxS at 4.2 K. The conduction electrons were found to be only 10% polarized for x of the order of 0.07. This indicates, for these states, either a lower 4f-6s exchange interaction or a more important spin-orbit coupling effect than previously assumed. It indicates also that these alloys are not promising for the production of polarized electrons. The states with high polarization (magnetic states) lie in the bandgap between valence and conduction states. A few of these magnetic states are shifted, relative to those for pure EuS, nearer to the bottom of the conduction band.
Cystic Fibrosis Transmembrane Regulator Correctors and Potentiators (2013)

Cystic fibrosis (CF) is caused by loss-of-function mutations in the CF transmembrane conductance regulator (CFTR) protein, a cAMP-regulated anion channel expressed primarily at the apical plasma membrane of secretory epithelia. Nearly 2000 mutations in the CFTR gene have been identified that cause disease by impairing its translation, cellular processing, and/or chloride channel gating. The fundamental premise of CFTR corrector and potentiator therapy for CF is that addressing the underlying defects in the cellular processing and chloride channel function of CF-causing mutant CFTR alleles will result in clinical benefit by addressing the basic defect underlying CF. Correctors are principally targeted at F508del cellular misprocessing, whereas potentiators are intended to restore cAMP-dependent chloride channel activity to mutant CFTRs at the cell surface. This article reviews the discovery of CFTR potentiators and correctors, what is known regarding their mechanistic basis, and encouraging results achieved in clinical testing.
Detection of Lysyl Oxidase-Like 2 (LOXL2), a Biomarker of Metastasis from Breast Cancers Using Human Blood Samples (2015)

Metastasis accounts for 90% of the mortality associated with breast cancer. Upregulated expression of members of the lysyl oxidase (LOX) family of secreted copper amine oxidases catalyzes the crosslinking of collagens and elastin in the extracellular matrix. LOXs are linked to the development and metastatic progression of breast cancers. Accordingly, aberrant expression of LOX-like 2 (LOXL2) is observed in poorly differentiated, high-grade tumors and is predictive of diseases recurrence, and for decreased overall patient survival. Therefore, LOXL2 expression may serve as a biomarker for breast cancer. Mechanistically, hydrogen peroxide is produced as a byproduct of LOXL2 when using an appropriate substrate, lysine. We exploited this chemistry to generate a revolutionary gold-based electrochemical biosensor capable of accurately detecting nanomolar quantities of LOXL2 in mouse blood, and in human blood samples. Two different sources of the blood samples obtained from breast cancer patients were used in this study indicating the applicability of detecting LOXL2 in breast cancers patients. Limited numbers of urine specimens from breast cancer patients were also tested. Collectively, all of these tests show the promise and potential of this biosensor for detecting LOXL2 as a surrogate biomarker of breast cancer. This work is described in WO 052962 A1 (2014).
Plasticity of Cells andEx VivoProduction of Red Blood Cells (2011)

The supply of transfusable red blood cells (RBCs) is not sufficient in many countries. If transfusable RBCs could be produced abundantly from certain resources, it would be very useful. Our group has developed a method to produce enucleated RBCs efficiently from hematopoietic stem/progenitor cells present in umbilical cord blood. More recently, it was reported that enucleated RBCs could be abundantly produced from human embryonic stem (ES) cells. The common obstacle for application of these methods is that they require very high cost to produce sufficient number of RBCs that are applicable in the clinic. If erythroid cell lines (immortalized cell lines) able to produce transfusable RBCs ex vivo were established, they would be valuable resources. Our group developed a robust method to obtain immortalized erythroid cell lines able to produce mature RBCs. To the best of our knowledge, this was the first paper to show the feasibility of establishing immortalized erythroid progenitor cell lines able to produce enucleated RBCs ex vivo. This result strongly suggests that immortalized human erythroid progenitor cell lines able to produce mature RBCs ex vivo can also be established.
Supplementary Figures from Analysis of Liver Tumor-Prone Mouse Models of the Hippo Kinase Scaffold Proteins RASSF1A and SAV1 (2023)

&lt;p&gt;Supplementary Figures: Figure S1: Genotyping of Rassf1a and Sav1 mutant mice. Figure S2: Liver from a Sav1+/+ Rassf1a-/- mouse. Figure S3: Liver from a Sav1+/- Rassf1a-/- mouse. Figure S4: Liver size and weight of gene-targeted mice. Figure S5: Gene ontology analysis of differentially expressed genes using the DAVID tool. Figure S6: DNA methylation analysis of the RASSF1A and SAV1 genes in human liver cancer specimens. Figure S7: DNA methylation analysis of the Mst1 and Mst2 genes in human liver cancer specimens. Figure S8: Methylation and expression of MST1 and MST2 in human HCC.&lt;/p&gt;
The US/UK World Magnetic Model for 2010-2015 (2010)

This report contains a complete description of the World Magnetic Model (WMM) 2010. Section 1 contains information that users of WMM2010 require in order to implement the model and software in navigation and heading systems, and to understand magnetic charts, poles and geomagnetic coordinate systems. Section 2 contains a detailed summary of the data used and the modeling techniques employed. Section 3 contains an assessment of model accuracy and applicability. Section 4 contains charts of all the magnetic elements at 2010.0 and their expected annual rates of change between 2010.0 and 2015.0.&#13;\nSponsored by the U.S. National Geospatial-Intelligence Agency (NGA) and the U.K. Defence Geographic Centre (DGC), the World Magnetic Model (WMM) is produced by the U.S. National Oceanographic and Atmospheric Administration’s National Geophysical Data Center (NOAA/NGDC) and the British Geological Survey (BGS). It is the standard model used by the U.S. Department of Defense (DoD), the U.K. Ministry of Defence, the North Atlantic Treaty Organization (NATO) and the International Hydrographic Organization (IHO), for navigation, attitude and heading referencing systems using the geomagnetic field. It is also used widely in civilian navigation and heading systems.
Percutaneous pulmonary artery denervation completely abolishes experimental pulmonary arterial hypertension in vivo (2013)

Balloon occlusion of the left pulmonary interlobar artery led to a significant increase of haemodynamic parameters of the pulmonary artery. The pressure responses were completely abolished by the PADN treatment at the main bifurcation area of the left pulmonary artery.
Curves on normal rational cubic surfaces (2007)

Let k be an algebraically closed field, let X 0 be a rational normal cubic surface in ‫ސ‬ 3 = ‫ސ‬ 3 k , and let C 0 ⊂ X 0 be a locally Cohen-Macaulay curve, which is therefore an effective Weil divisor on X 0 .I show that C 0 can be expressed as the limit of a family of curves whose general member lies on a smooth surface, in the following sense: There exists a flat family X t of cubic surfaces specializing to X 0 and a flat family C t of curves specializing to C 0 , parametrized by a smooth (noncomplete) curve T , such that the general member of X t is a smooth cubic surface and C t ⊂ X t is an effective (Cartier) divisor for all t ∈ T \ {0}.
Lack of Pain Associated with Microfabricated Microneedles (2001)

Microscopic needles previously shown capable of transdermal delivery of drugs and proteins are demonstrated to be painless when pressed into the skin of human subjects.
Development of a DNA damage response (DDR) therapeutics platform for oncology. (2021)

e15036 Background: Cancer cells respond to increases in DNA damage by deploying their DNA damage response (DDR) pathways. We are building a platform for the discovery and development of target-specific DDR therapeutics, including small molecule inhibitors and targeted protein degradation warheads, founded on fragment- and structure-based drug discovery. Methods: Our DDR platform, which includes hit-to-lead, lead optimization and candidate selection, starts with hit generation from a new technology that uses high-throughput protein X-ray crystallography to directly screen compound libraries. Our hit generation process produces empirical evidence of direct target engagement. The elucidation of high-quality ligand-bound 3D structures reveals the location and pose of the ligand and details of the protein-ligand interactions. Thus we can predict the structure-function consequences of the hit molecule engagement, which sets the stage for rapid assessment of synthetic tractability and intellectual property. After hit identification, we apply a multi-pronged approach in hit-to-lead conversion and lead optimization using iterative biophysical and biochemical assays, coupled with crystallography. We are applying our approach to several new targets in DDR and will present some early progress in this space. Results: Apurinic/apyrimidinic endonuclease 1 (APE1) is the major repair enzyme for abasic sites in DNA and contributes to DNA strand break processing. Many studies have associated increased APE1 levels with enhanced growth, migration, and drug resistance in human tumor cells, and with decreased patient survival. APE1 has been implicated in over 20 human cancers, including glioblastoma, making the protein an attractive target for the development of anticancer therapeutics. Despite intensive effort, there are no clinical endonuclease inhibitors of APE1. We have identified 25 diverse small molecule fragments that bind to APE1 at two distinct sites, including the endonuclease site. Pol eta (or PolH) is a DNA polymerase implicated, among other things, in the development of cisplatin resistance in a subset of ovarian cancers. In our quest to develop PolH inhibitors, we have identified 5 diverse fragments that bind to two distinct sites in the polymerase including a new potential allosteric site. Our results on APE1 and PolH represent the first known cases of crystal structures of small molecules bound to these proteins. Flap endonuclease (FEN1) is implicated in several cancers including for example ER/tamoxifen-resistant breast cancer. We are developing a targeted protein degradation approach using PROTACs (Proteolysis-Targeting Chimeras) toward the development of novel therapeutics against FEN1. Conclusions: Our results will help us develop small molecule inhibitors and targeted protein degradation against DDR targets that may be effective as single therapies or be used to make existing therapies more effective.
Redirecting Immune Activation in the Tumor Microenvironment of Estrogen Receptor Negative Breast Cancer (2020)

Abstract The tumor microenvironment (TME) is an essential contributor to the development and progression of malignancy. Within the TME, tumor associated macrophages (TAMs) mediate angiogenesis, metastasis, and immune suppression, which inhibits infiltration of tumor-specific cytotoxic CD8+ T cells. In previous work, we demonstrated that the synthetic triterpenoid CDDO-methyl ester (CDDO-Me) converts breast TAMs from tumor-promoting to tumor-inhibiting in vitro. We show now for the first time that CDDO-Me remodels the breast TME, redirecting TAM activation and T cell tumor infiltration in vivo. We demonstrate that CDDO-Me significantly attenuates IL-10 and VEGF expression but stimulates TNF production, and reduces surface expression of CD206 and CD115, markers of immunosuppressive TAMs. CDDO-Me treatment redirects the TAM transcriptional profile, inducing signaling pathways associated with immune stimulation, and inhibits TAM tumor infiltration, consistent with decreased expression of CCL2. In CDDO-Me-treated mice, both the absolute number and proportion of CD4+ T cells were reduced, while the proportion of CD8+ T cells was significantly increased in tumors and spleen. Moreover, mice fed CDDO-Me demonstrated significant reductions in numbers of tumor CD4+Foxp3+ regulatory T cells. These results demonstrate for the first time that CDDO-Me relieves immunosuppression in the breast TME and unleashes host adaptive anti-tumor immunity.
Neuroimmunologic Mechanisms in the Etiology of Multiple Sclerosis (2003)

Multiple sclerosis (MS) is a common chronic inflammatory demyelinating disorder of the central nervous system (CNS) (1,2) that is heterogeneous with respect to its clinical course, response to therapy, radiology, structural pathology, and immunopathogenesis. The factors that contribute to this heterogeneity are largely unknown, although it is likely a complex trait with genetic and environmental components. MS is a disease of young people with a median age of onset of 28 yr, and affects approx 0.1% of the population in temperate climates. The disorder is the most common cause of nontraumatic disability in young adults, with 50% of patients requiring a cane to walk 15 yr after disease onset (3).
CHEMICAL CHARACTERIZATION AND TOXICOLOGICAL TESTING OF WINDROW COMPOSTS FROM EXPLOSIVES-CONTAMINATED SEDIMENTS (1995)

Aerated and nonaerated windrow composts of explosives-contaminated sediments at the Umatilla Army Depot Activity (UMDA, Hermiston, OR) were characterized chemically and toxicologically as a function of composting time. The concentrations of explosives in organic solvent extracts of the composts and in the aqueous leachates of the composts, the bacterial mutagenicity of organic solvent extracts from the composts, and the toxicity of aqueous leachates from the composts to Ceriodaphnia dubia all declined rapidly (<15 d) with composting. The nonaerated windrow method of composting was slightly more efficient than was the aerated windrow method for reducing explosives concentrations in the composts (TNT, 99.9%; RDX, >99.7%; HMX, 98.5%) and in their leachates (>99.6%, >98.8%, and >97.5%, respectively). Extractable mutagenicity declined 99.7 and 97.9%, respectively, for strains TA-98 and TA-100 (without S-9 metabolic activation) in the nonaerated compost. The two types (aerated and nonaerated) of windrow composts had about the same level of efficiency in lowering leachable toxicity (by 92% and 87%, based on reductions in C. dubia survival and fecundity, respectively). Thus, windrow composting appeared to be at least as effective as static-pile and mechanically stirred composting evaluated previously. Windrow composting also appeared to be somewhat more effective for HMX transformation.
Intelligent Management of Remote Facilities through a Ubiquitous Cloud Middleware (2009)

This paper introduces a tele-management system as a part of SmartUM which is a ubiquitous cloud middleware for ubiquitous city (u-city). The cloud computing platform allows users to control remote devices. The users get data from a various kinds of remote sensors and scene images about the place of sensors from remote video cameras and control remote devices seeing the scene images of the remote place. Our cloud computing platform has context-awareness and can intelligently control the remote devices according to the circumstance scenario. We used ontology for the context aware intelligence processing.
A Fluoroacetamidine-Based Inactivator of Protein Arginine Deiminase 4:  Design, Synthesis, and in Vitro and in Vivo Evaluation (2006)

Protein arginine deiminase 4 (PAD4) is a calcium-dependent transcriptional corepressor that has been implicated in the onset and progression of rheumatoid arthritis. Herein we describe the synthesis and in vitro evaluation of a fluoroacetamidine-containing compound, N-alpha-benzoyl-N5-(2-fluoro-1-iminoethyl)-l-ornithine amide, 1, hereafter referred to as F-amidine, that is the most potent PAD4 inhibitor ever described. Additional studies described herein indicate that F-amidine can also inhibit PAD4 activity in vivo. The bioavailability of this compound suggests that F-amidine will be a powerful chemical probe of PAD4 function that can be used to dissect the roles of this enzyme in both rheumatoid arthritis and transcriptional control. The fact that inhibition is of an irreversible nature suggests that, with appropriate functionalization, F-amidine analogues will be robust activity-based protein-profiling and proteomic capture reagents.