466 research outputs found
Mortgage indenture
No full textThis document is an indenture between Benjamin N. Ogle of Red Lion Hundred and Clara A., his wife, of the first part, and Adam Prince of Brandywine Hundred of the second part. It was recorded in the office for Recording of Deeds at New Castle in Deed Record G, Volume 2, Page 507 by A.P. Shannon, Recorder, and Deputy B.R. Ustick. The indenture secures the payment of a debt of one thousand dollars owed by Benjamin N. Ogle to Adam Prince. In consideration of this debt, Benjamin N. Ogle and Clara A. Ogle convey a lot of land with buildings in Delaware City, Red Lion Hundred. This parcel is bounded by Ninth Street, Franklin Street, and lands formerly owned by D. Newbold and John Newbold. The document references previous indentures dating back to June 29, 1846, conveying the same property to Benjamin N. Ogle. The document is signed by Benjamin and Clara Ogle, with a green seal from the notary public, Daniel Farra, opposite the signatures. Additionally, the document includes an assignment of mortgage by John M. C. Prince and George S. Cloud, executors of Adam Prince, deceased, to Sallie A. Cloud. This assignment transfers the mortgage and accompanying bond, as well as the described lot, to Sallie A. Cloud. Witnessed by George O'Neill, Notary Public, and Thomas Davis, the assignment is signed and sealed by John M. C. Prince and George L. Cloud, with a red seal from the notary public below the signatures. The last page of the document acknowledges that the mortgage was recorded in the Records Office in Record H, Volume 1, Page 357, on September 16, 1818, by Thomas M. Ogle, Recorder
Mortgage indenture
No full textThis document is an indenture between Benjamin N. Ogle of Red Lion Hundred and Clara A., his wife, of the first part, and Adam Prince of Brandywine Hundred of the second part. It was recorded in the office for Recording of Deeds at New Castle in Deed Record G, Volume 2, Page 507 by A.P. Shannon, Recorder, and Deputy B.R. Ustick. The indenture secures the payment of a debt of one thousand dollars owed by Benjamin N. Ogle to Adam Prince. In consideration of this debt, Benjamin N. Ogle and Clara A. Ogle convey a lot of land with buildings in Delaware City, Red Lion Hundred. This parcel is bounded by Ninth Street, Franklin Street, and lands formerly owned by D. Newbold and John Newbold. The document references previous indentures dating back to June 29, 1846, conveying the same property to Benjamin N. Ogle. The document is signed by Benjamin and Clara Ogle, with a green seal from the notary public, Daniel Farra, opposite the signatures. Additionally, the document includes an assignment of mortgage by John M. C. Prince and George S. Cloud, executors of Adam Prince, deceased, to Sallie A. Cloud. This assignment transfers the mortgage and accompanying bond, as well as the described lot, to Sallie A. Cloud. Witnessed by George O'Neill, Notary Public, and Thomas Davis, the assignment is signed and sealed by John M. C. Prince and George L. Cloud, with a red seal from the notary public below the signatures. The last page of the document acknowledges that the mortgage was recorded in the Records Office in Record H, Volume 1, Page 357, on September 16, 1818, by Thomas M. Ogle, Recorder
Unconventional surface state pairs in a high-symmetry lattice with anti-ferromagnetic band-folding
No full textMany complex magnetic structures in a high-symmetry lattice can arise from a superposition of well-defined magnetic wave vectors. These “multi-q” structures have garnered much attention because of interesting real-space spin textures such as skyrmions. However, the role multi-q structures play in the topology of electronic bands in momentum space has remained rather elusive. Here we show that the type-I anti-ferromagnetic 1q, 2q and 3q structures in an face-centered cubic sublattice with band inversion, such as NdBi, can induce unconventional surface state pairs inside the band-folding hybridization bulk gap. Our density functional theory calculations match well with the recent experimental observation of unconventional surface states with hole Fermi arc-like features and electron pockets below the Neel temperature. We further show that these multi-q structures have Dirac and Weyl nodes. Our work reveals the special role that band-folding from anti-ferromagnetism and multi-q structures can play in developing new types of surface states.This article is published as Wang, Lin-Lin, Junyeong Ahn, Robert-Jan Slager, Yevhen Kushnirenko, Benjamin G. Ueland, Aashish Sapkota, Benjamin Schrunk et al. "Unconventional surface state pairs in a high-symmetry lattice with anti-ferromagnetic band-folding." Communications Physics 6, no. 1 (2023): 78.
DOI: 10.1038/s42005-023-01180-6.
Copyright 2023 The Author(s).
Attribution 4.0 International (CC BY 4.0).
Posted with permission.
DOE Contract Number(s): AC02-07CH11358; 842901
Creating MHC-Restricted Neoantigens with Covalent Inhibitors That Can Be Targeted by Immune Therapy
No full textIntracellular oncoproteins can be inhibited with targeted therapy, but responses are not durable. Immune therapies can be curative, but most oncogene-driven tumors are unresponsive to these agents. Fragments of intracellular oncoproteins can act as neoantigens presented by the major histocompatibility complex (MHC), but recognizing minimal differences between oncoproteins and their normal counterparts is challenging. We have established a platform technology that exploits hapten–peptide conjugates generated by covalent inhibitors to create distinct neoantigens that selectively mark cancer cells. Using the FDA-approved covalent inhibitors sotorasib and osimertinib, we developed “HapImmune” antibodies that bind to drug–peptide conjugate/MHC complexes but not to the free drugs. A HapImmune-based bispecific T-cell engager selectively and potently kills sotorasib-resistant lung cancer cells upon sotorasib treatment. Notably, it is effective against KRASG12C-mutant cells with different HLA supertypes, HLA-A*02 and A*03/11, suggesting loosening of MHC restriction. Our strategy creates targetable neoantigens by design, unifying targeted and immune therapies. SIGNIFICANCE: Targeted therapies against oncoproteins often have dramatic initial efficacy but lack durability. Immunotherapies can be curative, yet most tumors fail to respond. We developed a generalizable technology platform that exploits hapten–peptides generated by covalent inhibitors as neoantigens presented on MHC to enable engineered antibodies to selectively kill drug-resistant cancer cells
Surmonter la résistance thérapeutique pour vaincre le cancer / Overcoming therapeutic resistance to defeat cancer
No full textSéminaire FSER organisé par David Tuveson (Cold Spring Harbor Laboratory, USA) et Neal Rosen (Memorial Sloan-Kettering Cancer Center, New York, USA) du 27 juin au 2 juillet 2014 Participants Julien Ablain, Laura Attardi, Alberto Bardelli, Glenn Dranoff, Mikala Egeblad, Jeffrey A. Engelman, Gerard Evan, Shridar Ganesan, Joseph Jonkers, Anthony Letai, Richard Marais, Frank McCormick, Benjamin Neel, Scott Powers, Neal Rosen, Louis M. Staudt, Hugues de Thé, David Tuveson, Matthew G. Vander Heiden..
Cardiofaciocutaneous Syndrome-Associated BRAF Mutants in Development and Cancer
No full textCardiofaciocutaneous syndrome (CFCS) is an autosomal-dominant disorder caused by germ-line mutations in members of the RAS/ERK signaling pathway, most commonly in BRAF. Selected mutations that either activate or impair BRAF kinase activity and that are known to cause CFCS have also been identified in melanoma. I found that knock-in mouse mutants expressing BrafK499E (kinase-activating) and BrafG469E (kinase-impaired) alleles have many features of CFCS, including short stature, craniofacial dysmorphia, and an increased heart weight to body weight ratio. Studies of the phenotype of BrafK499E mice show that the effects of this mutation might be affected by genetic modifiers on the 129/B6 mouse background. Endogenous expression of BrafG469E in mouse embryonic fibroblasts (MEFs) caused increased MEK and ERK activation compared to wild-type MEFs . These effects correlated with increased heterodimerization of mutant BRAF with RAF1, as assessed by co-immunoprecipitation. Finally, I found that BrafK499E expression induced post-natally in vivo in melanocytes is not sufficient to cause hyperpigmentation or nevus formation, unlike the highly activated melanoma-associated allele BrafV600E .M.Sc
Novel Metabolic Dependencies in Cancer and Moyamoya Disease
No full textIt is becoming increasingly clear that deregulation of the cellular environment has crucial roles in disease pathogenesis. The tumour microenvironment, which includes the surrounding vasculature, stromal and/or immune cells, can influence the availability of nutrients, oxygen and extracellular signaling factors. Secondary environmental influences, such as diet or infection, also are required for the progression of certain genetic risk alleles, such as stroke. In this doctoral thesis, I present three independent projects related to the effects of the cellular environment on disease outcomes.
First, I identified a critical role for protein-tyrosine phosphatase 1B (PTP1B) in a novel pathway required for the survival of HER2+ breast cancer cells in hypoxia. In this pathway, PTP1B, via RNF213, most likely increase intracellular vitamin C, Îą-ketoglutarate-dependent dioxygenase(s) activity and non-mitochondrial oxygen consumption. Suppression of PTP1B enhanced non-mitochondrial oxygen consumption, tumour hypoxia and hypoxic cell death.
In a collaborative effort, I also partially characterized the biochemical properties of the RNF213 RING domain, and found that the moyamoya disease-associated single nucleotide polymorphism (SNP), RNF213R4810K, is loss-of-function mutant with impaired E3-ligase activity and acts as a dominant-negative allele to globally decrease ubiquitylation, similar to the effects of RNF213 knockdown. Therefore, the lack of observable moyamoya phenotypes in Rnf213 knockout and predisposing allele knock-in mice suggests that secondary genetic and/or environmental influences are required for disease progression and outcome.
Third, I assessed the biochemical effects of lung adenocarcinoma (LAC)-associated PIK3C3 mutations and the role of such mutations and Pik3c3 hemi- and homozygous deletion on KrasG12D- and BrafV600E-mediated lung tumourigenesis in mice. LAC-associated PIK3C3 mutants have decreased lipid kinase activity and/or impair its ability to form functional complexes, attenuate autophagy, and cooperate with RAS pathway drivers to enhance transformation. Heterozygous LAC-associated Pik3c3 mutation or deletion in KrasG12D-expressing lung epithelial cells alters the proportion of activated tumour-associated macrophages to accelerate tumourigenesis.
Finally, I discuss some remaining questions and provide potential insight of these findings to disease pathogenesis. Taken together, my studies provide additional examples of the importance of the tumour microenvironment and/or secondary environmental influences for the progression and/or maintenance of cancers and diseases.Ph.D.2018-06-19 00:00:0
The Development and Application of Global Proteomic Approaches to Quantify Protein Oxidation
No full textROS and ROS-induced protein oxidation are involved in a variety of physiological and pathological conditions. Methods that can globally detect and quantify protein oxidation are important for studying redox signaling pathways. I developed/optimized two MS-based approaches to detect protein oxidation, one is specialized to monitor classical PTP oxidation and the other detect oxidation of reactive cysteines more generally. Using these two approaches, I identified PTPN12 and PKM2 oxidation in FH-deficient hereditary leiomyomatosis and renal cell carcinoma (HLRCC) cells. PTPN12 oxidation leads to ABL1 activation, which is important for HLRCC cell proliferation and survival, whereas PKM2 is likely to be a redox sensor and its oxidation lowers oxidative stress in HLRCC cells. Overall, globally detecting and characterizing protein oxidation help us to understand the pathobiology of HLRCC and to identify potential therapeutic interventions to treat this cancer.Ph.D
The GAB2/SHP2 Pathway in BCR-ABL1-Induced Hematopoietic Neoplasia
No full textBCR-ABL1 is a gene product of the t(9, 22) chromosomal translocation. It encodes a fusion protein with constitutively activated tyrosine kinase activity and is the direct cause of chronic myeloid leukemia (CML) and a subset of B-lymphoid acute lymphoblastic leukemia (B-ALL). ABL1-targeting tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of BCR- ABL1+ hematopoietic neoplasia, but CML patients suffer from persistence of leukemic stem cells (LSCs), and B-ALL patients exhibit poorer response at diagnosis compared with CML patients. Over time, such patients succumb to TKI-resistant leukemic clones. Therefore, additional therapeutic targets are needed to cure these malignancies. I assessed the role of the protein-tyrosine phosphatase (PTP) SHP2 in the initiation and/or maintenance of CML and BCR- ABL1+ B-ALL. I found that SHP2 is required for initiation and maintenance of CML, consistent with its essentiality in normal hematopoietic stem cells (HSCs). In BCR-ABL1+ B-ALL, SHP2 is specifically required for the proliferation of BCR-ABL1+, but not WT, B lymphoid progenitors. The SFK and MEK-ERK pathways downstream of SHP2 independently contribute to this differential requirement. I also assessed the role of GAB2 in downstream signaling from BCR- ABL1, and found that its interaction with SHP2 or PI3K activates different signaling pathways, potentially underlying the differential requirement of these interactions for BCR-ABL1-evoked myeloid and lymphoid malignancies.
Furthermore, in a parallel set of studies, I developed a mathematical model to simulate the clinical course of high-grade serous ovarian carcinoma, with potential implications for treatment and screening of this disease. This work is described in the Appendix.Ph.D
Novel Metabolic Dependencies in Cancer and Moyamoya Disease
No full textIt is becoming increasingly clear that deregulation of the cellular environment has crucial roles in disease pathogenesis. The tumour microenvironment, which includes the surrounding vasculature, stromal and/or immune cells, can influence the availability of nutrients, oxygen and extracellular signaling factors. Secondary environmental influences, such as diet or infection, also are required for the progression of certain genetic risk alleles, such as stroke. In this doctoral thesis, I present three independent projects related to the effects of the cellular environment on disease outcomes.
First, I identified a critical role for protein-tyrosine phosphatase 1B (PTP1B) in a novel pathway required for the survival of HER2+ breast cancer cells in hypoxia. In this pathway, PTP1B, via RNF213, most likely increase intracellular vitamin C, Îą-ketoglutarate-dependent dioxygenase(s) activity and non-mitochondrial oxygen consumption. Suppression of PTP1B enhanced non-mitochondrial oxygen consumption, tumour hypoxia and hypoxic cell death.
In a collaborative effort, I also partially characterized the biochemical properties of the RNF213 RING domain, and found that the moyamoya disease-associated single nucleotide polymorphism (SNP), RNF213R4810K, is loss-of-function mutant with impaired E3-ligase activity and acts as a dominant-negative allele to globally decrease ubiquitylation, similar to the effects of RNF213 knockdown. Therefore, the lack of observable moyamoya phenotypes in Rnf213 knockout and predisposing allele knock-in mice suggests that secondary genetic and/or environmental influences are required for disease progression and outcome.
Third, I assessed the biochemical effects of lung adenocarcinoma (LAC)-associated PIK3C3 mutations and the role of such mutations and Pik3c3 hemi- and homozygous deletion on KrasG12D- and BrafV600E-mediated lung tumourigenesis in mice. LAC-associated PIK3C3 mutants have decreased lipid kinase activity and/or impair its ability to form functional complexes, attenuate autophagy, and cooperate with RAS pathway drivers to enhance transformation. Heterozygous LAC-associated Pik3c3 mutation or deletion in KrasG12D-expressing lung epithelial cells alters the proportion of activated tumour-associated macrophages to accelerate tumourigenesis.
Finally, I discuss some remaining questions and provide potential insight of these findings to disease pathogenesis. Taken together, my studies provide additional examples of the importance of the tumour microenvironment and/or secondary environmental influences for the progression and/or maintenance of cancers and diseases.Ph.D.2018-06-19 00:00:0
- …
