Real earnings management activities prior to bondissuance

We examine real activities manipulation by firms prior to their debt issuances andhow such manipulation activities affect bond yield spreads. We find that bond-issuing firmsincrease their real activities manipulation in the five quarters leading to a bond issuance. Wedocument an inverse association between yield spread and pre-issue real activities manipula-tion, i.e., firms engaged in abnormally high levels of real activities manipulation are associatedwith subsequent lower cost of debt

Acute Sensitivity of Ph-like Acute Lymphoblastic Leukemia to the SMAC-Mimetic Birinapant

Abstract Ph-like acute lymphoblastic leukemia (ALL) is a genetically defined high-risk ALL subtype with a generally poor prognosis. In this study, we evaluated the efficacy of birinapant, a small-molecule mimetic of the apoptotic regulator SMAC, against a diverse set of ALL subtypes. Birinapant exhibited potent and selective cytotoxicity against B-cell precursor ALL (BCP-ALL) cells that were cultured ex vivo or in vivo as patient-derived tumor xenografts (PDX). Cytotoxicity was consistently most acute in Ph-like BCP-ALL. Unbiased gene expression analysis of BCP-ALL PDX specimens identified a 68-gene signature associated with birinapant sensitivity, including an enrichment for genes involved in inflammatory response, hematopoiesis, and cell death pathways. All Ph-like PDXs analyzed clustered within this 68-gene classifier. Mechanistically, birinapant sensitivity was associated with expression of TNF receptor TNFR1 and was abrogated by interfering with the TNFα/TNFR1 interaction. In combination therapy, birinapant enhanced the in vivo efficacy of an induction-type regimen of vincristine, dexamethasone, and L-asparaginase against Ph-like ALL xenografts, offering a preclinical rationale to further evaluate this SMAC mimetic for BCP-ALL treatment. Cancer Res; 76(15); 4579–91. ©2016 AACR.</jats:p

Protein-metabolite association studies identify novel proteomic determinants of metabolite levels in human plasma

Although many novel gene-metabolite and gene-protein associations have been identified using high-throughput biochemical profiling, systematic studies that leverage human genetics to illuminate causal relationships between circulating proteins and metabolites are lacking. Here, we performed protein-metabolite association studies in 3,626 plasma samples from three human cohorts. We detected 171,800 significant protein-metabolite pairwise correlations between 1,265 proteins and 365 metabolites, including established relationships in metabolic and signaling pathways such as the protein thyroxine-binding globulin and the metabolite thyroxine, as well as thousands of new findings. In Mendelian randomization (MR) analyses, we identified putative causal protein-to-metabolite associations. We experimentally validated top MR associations in proof-of-concept plasma metabolomics studies in three murine knockout strains of key protein regulators. These analyses identified previously unrecognized associations between bioactive proteins and metabolites in human plasma. We provide publicly available data to be leveraged for studies in human metabolism and disease

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

Cell Death Mechanisms in T cell Differentiation and Homeostasis

© 2021 Alissa Kathryn RobbinsT cells are an essential component of the vertebrate adaptive immune system. In concert with the innate immune system, T cells protect the host from any number of pathogens that could be experienced over an organism’s lifetime. The hallmark of a T cell is its distinctive T cell receptor generated by somatic gene rearrangement. Variability in the T cell receptor repertoire arises during thymic T cell differentiation, which is then subjected to strict selection processes. Mature T cells in the periphery can undergo further differentiation upon the activation of naive cells to mount immune responses to pathogens. These differentiation events are accompanied by significant proliferative bursts, followed by the clearance of defective or superfluous cells. It follows then, that cell death is also an essential component of T cell differentiation and homeostasis. This PhD thesis explores the molecular mechanisms regulating the differentiation, proliferation and death of T cells, and how interplay among these mechanisms gives rise to immune homeostasis. This study examines how distinct cell death pathways, including the intrinsic and extrinsic apoptotic pathways and necroptosis, are differentially regulated through T cell differentiation and in the various subsets of mature T cells. We found that only inhibition of the intrinsic pathway of apoptosis overcomes failure of beta-selection in the absence of preTCR signalling or proliferation, enabling further differentiation. We also discovered that caspase 8 plays an important pro-survival role in inhibiting necroptosis in recent thymic emigrant T cells and regulatory T cells, and that this feature can be exploited in the case of regulatory T cells for therapeutic intervention in infection settings. In summary, this thesis defines context-specific roles of cell death modalities in controlling T cell differentiation and homeostasis, revealing the potential for immune interventions using targeted therapies

Goal alignment and unintended consequences of accountable care: How the structure of Oregon’s Medicaid coordinated care model shapes health plan–clinic partnerships

Abstract Introduction: Accountable care models for Medicaid reimbursement aim to improve care quality and reduce costs by linking payments to performance. Oregon’s coordinated care organizations (CCOs) assume financial responsibility for their members and are incentivized to help clinics improve performance on specific quality metrics. This study explores how Oregon’s CCO model influences partnerships between payers and primary care clinics, focusing on strategies used to enhance screening and treatment for unhealthy alcohol use (UAU). Methods: In this qualitative study, we conducted semi-structured interviews with informants from 12 of 13 Oregon CCOs active in 2019 and 2020. The interviews focused on payer–provider partnerships, specifically around UAU screening and treatment, which is a long-standing CCO metric. We used thematic analysis to identify key themes and causal-loop diagramming to uncover feedback dynamics and communicate key findings. Meadows’ leverage point framework was applied to categorize findings based on their potential to drive change. Results: CCO strategies to support clinics included building relationships, reporting on metric progress, providing EHR technical assistance, offering training, and implementing alternative payment methods. CCOs prioritized clinics with more members and those highly motivated. Our analysis showed that while the CCO model aligned goals between payers and clinics, it may perpetuate rural disparities by prioritizing larger, better-resourced clinics. Conclusions: Oregon’s CCO model fosters partnerships centered on quality metrics but may unintentionally reinforce rural disparities by incentivizing support for larger clinics. Applying the Meadows framework highlighted leverage points within these partnerships

PD-1 cooperates with AIRE-mediated tolerance to prevent lethal autoimmune disease

Significance A variety of mechanisms safeguard the body from autoimmune reactions, yet how these processes cooperate is largely unclear. Using a range of mouse genetic models, we uncover a critical tolerogenic axis between the autoimmune regulator, AIRE, and the immune checkpoint molecule, PD-1. Their combined loss induced an early-onset lethal autoimmune syndrome driven by autoreactive CD4 + T cells that could not be restrained by regulatory T cells. These data shed light on how central and peripheral tolerance mechanisms work together, and highlight thymic function as a potentially key modifier of responses to anti–PD-1 therapies. </jats:p

The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified &gt;300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection

Abstract 1620: In vivo and in vitro efficacy of birinapant in preclinical models of Ph-like pediatric acute lymphoblastic leukemia

Abstract Despite the success of current therapies for pediatric acute lymphoblastic leukemia (ALL) more effective treatments are required for the management of high-risk subtypes. Ph-like ALL is a high-risk subtype defined by a gene expression signature similar to that of BCR-ABL1-positive ALL despite the absence of the BCR-ABL1 translocation. Approximately 50% of Ph-like pediatric ALLs harbor mutations in Janus kinases (JAKs). Birinapant is a small molecule SMAC (second mitochondria-derived activator of caspase) mimetic that potently and specifically antagonizes inhibitors of apoptosis proteins (IAPs), resulting in IAP degradation, inactivation of NF-κB survival signaling and tumor necrosis factor (TNF)-dependent apoptosis. The combination of birinapant plus azacitidine is being evaluated in a Phase 2 clinical trial for the treatment of high-risk myeloid dysplastic syndrome. The aim of this study was to evaluate the efficacy of birinapant against patient-derived xenografts (PDXs) of pediatric ALL subtypes. Birinapant (30 mg/kg IP Q3 days × 5) significantly delayed the progression of 17/19 PDXs derived from Ph-like ALL (n = 7), B-cell precursor ALL (BCP-ALL, n = 8), and infant MLL¬-rearranged ALL (MLL-ALL, n = 4) by between 2 and 80 days compared with vehicle-treated controls. Using stringent objective response criteria modeled after the clinical setting, birinapant induced objective responses in 12/19 PDXs, including 7/7 Ph-like ALL (5 complete responses, CRs; 2 maintained CRs, MCRs), which was significantly better than BCP-ALL (4/8; 2 partial responses, PRs; 1 CR; 1 MCR) or infant MLL-ALL (1/4; 1 CR) PDXs (P&amp;lt;0.05). Birinapant induced a CR in a Ph-like PDX at a dose 1/8th (3.8 mg/kg) of its maximum tolerated dose (30 mg/kg). Analysis at 14 days following treatment initiation revealed &amp;gt;98% clearance of human leukemia cells from the bone marrow, spleen and peripheral blood of mice treated with birinapant doses that achieve drug levels attainable in humans. In vitro apoptosis assays confirmed the greater sensitivity of the Ph-like ALL PDX panel. Moreover, the cIAP1 protein was rapidly degraded in PDXs upon birinapant treatment both in vitro and in vivo, regardless of their relative sensitivity. Microarray analysis of gene expression revealed a significant correlation between baseline TNFα expression and in vivo birinapant sensitivity across 19 PDXs (P = 0.002; R2 = 0.46). While exogenously-added TNFα did not potentiate apoptosis induced by birinapant, a TNFα blocking antibody partially reversed apoptosis in 3/4 Ph-like PDXs. These results show that birinapant exerts profound single-agent in vivo efficacy against Ph-like pediatric ALL PDXs, indicate a role for endogenous TNFα in the birinapant mechanism of action against this high-risk pediatric ALL subtype, and support further evaluation of birinapant in the treatment of Ph-like ALL. Supported by NCI NO1CM42216. Citation Format: Jennifer Richmond, Kathryn Evans, Alissa Robbins, Raushan T. Kurmasheva, Peter J. Houghton, Malcolm A. Smith, Richard B. Lock. In vivo and in vitro efficacy of birinapant in preclinical models of Ph-like pediatric acute lymphoblastic leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1620. doi:10.1158/1538-7445.AM2015-1620</jats:p

Abstract 3276: Evaluation of the Bcl-2 inhibitor ABT-199 in xenograft models of acute lymphoblastic leukemia by the pediatric preclinical testing program

Abstract Targeting the apoptosis pathway with BH3 mimetics such as ABT-263 (navitoclax) and ABT-199 is an appealing strategy for cancer therapy. While the Bcl-2/Bcl-w/Bcl-xL inhibitor navitoclax has shown promising activity in adults with lymphoid malignancies and in preclinical models of pediatric acute lymphoblastic leukemia (ALL), its application in pediatric patients has been limited by Bcl-xL-mediated thrombocytopenia. The specific Bcl-2 inhibitor ABT-199 has shown remarkable efficacy against adult chronic lymphocytic leukemia in recent clinical trials, although its activity against pediatric ALL is yet to be tested. The aim of this study was to evaluate the in vivo efficacy of ABT-199 against a large panel of pediatric ALL patient-derived xenografts (PDXs), and to identify biomarkers predictive of ABT-199 response. Immune-deficient (NOD/SCID or NSG) mice inoculated with PDXs derived from patients with infant ALL harboring rearrangement of the Mixed Lineage Leukemia (MLL) oncogene (infant MLL-ALL, n = 4), B-cell precursor ALL (BCP-ALL, n = 6), BCP-ALL categorized as Ph-like (n = 4), T-cell ALL (T-ALL, n = 4) or early T-cell precursor ALL (ETP-ALL, n = 2) were treated with ABT-199 (100 mg/kg x 21 days, p.o.) or vehicle control. Responses were assessed by time to event measurements or stringent objective response criteria modeled after the clinical setting. ABT-199 significantly delayed the progression of 12/20 PDXs by between 0.4 and 28 days, and elicited objective responses in 6/20 (30%) of PDXs (4 complete responses and 2 partial responses). No objective responses were observed in the T-ALL or ETP-ALL PDXs. By comparison, navitoclax administered on the same dose and schedule as ABT-199 elicited objective responses in 19/31 (61%) of PDXs derived from the same pediatric ALL subtypes. Analysis of basal gene and protein expression revealed that high Bcl-xL and low Bcl-2 expression were significantly associated with in vivo ABT-199 resistance. Moreover, the Bcl-2/Bcl-xL gene (P = 0.03) and protein (P = 0.002) expression ratios were significantly elevated in PDXs that responded to ABT-199 in vivo compared with non-responders. Notably, Mcl-1 expression at the gene or protein level showed no significant correlation with in vivo ABT-199 sensitivity. In conclusion, the inferior objective response rate observed for ABT-199 (30%) compared with navitoclax (61%) indicates that pediatric ALL PDXs are less dependent on Bcl-2 for cell survival compared with adult chronic lymphocytic leukemia. Moreover, Bcl-xL appears to be a more significant ABT-199 resistance factor than Mcl-1 in pediatric ALL. While ABT-199 has the potential to exert significant efficacy in the treatment of aggressive and chemoresistant pediatric ALL, the prospective identification of patients who might benefit from such treatment is of paramount importance. Supported by NCI NO1CM42216. Citation Format: Santi Suryani, Kathryn Evans, Jennifer Richmond, Alissa Robbins, Lauryn Bracken, Raushan Kurmasheva, Peter J. Houghton, Malcolm A. Smith, Richard B. Lock. Evaluation of the Bcl-2 inhibitor ABT-199 in xenograft models of acute lymphoblastic leukemia by the pediatric preclinical testing program. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3276. doi:10.1158/1538-7445.AM2015-3276</jats:p