Parameter Identifiability and Redundancy in a General Class of Stochastic Carcinogenesis Models

Background Heidenreich et al. (Risk Anal 1997 17 391–399) considered parameter identifiability in the context of the two-mutation cancer model and demonstrated that combinations of all but two of the model parameters are identifiable. We consider the problem of identifiability in the recently developed carcinogenesis models of Little and Wright (Math Biosci 2003 183 111–134) and Little et al. (J Theoret Biol 2008 254 229–238). These models, which incorporate genomic instability, generalize a large number of other quasi-biological cancer models, in particular those of Armitage and Doll (Br J Cancer 1954 8 1–12), the two-mutation model (Moolgavkar et al. Math Biosci 1979 47 55–77), the generalized multistage model of Little (Biometrics 1995 51 1278–1291), and a recently developed cancer model of Nowak et al. (PNAS 2002 99 16226–16231). Methodology/Principal Findings We show that in the simpler model proposed by Little and Wright (Math Biosci 2003 183 111–134) the number of identifiable combinations of parameters is at most two less than the number of biological parameters, thereby generalizing previous results of Heidenreich et al. (Risk Anal 1997 17 391–399) for the two-mutation model. For the more general model of Little et al. (J Theoret Biol 2008 254 229–238) the number of identifiable combinations of parameters is at most less than the number of biological parameters, where is the number of destabilization types, thereby also generalizing all these results. Numerical evaluations suggest that these bounds are sharp. We also identify particular combinations of identifiable parameters. Conclusions/Significance We have shown that the previous results on parameter identifiability can be generalized to much larger classes of quasi-biological carcinogenesis model, and also identify particular combinations of identifiable parameters. These results are of theoretical interest, but also of practical significance to anyone attempting to estimate parameters for this large class of cancer models

The MLL-Menin Interaction is a Therapeutic Vulnerability in <em>NUP98</em>-rearranged AML

\ua9 2023 Wolters Kluwer Health. All rights reserved. Chromosomal translocations involving the NUP98 locus are among the most prevalent rearrangements in pediatric acute myeloid leukemia (AML). AML with NUP98 fusions is characterized by high expression of HOXA and MEIS1 genes and is associated with poor clinical outcome. NUP98 fusion proteins are recruited to their target genes by the mixed lineage leukemia (MLL) complex, which involves a direct interaction between MLL and Menin. Here, we show that therapeutic targeting of the Menin-MLL interaction inhibits the propagation of NUP98-rearrranged AML both ex vivo and in vivo. Treatment of primary AML cells with the Menin inhibitor revumenib (SNDX-5613) impairs proliferation and clonogenicity ex vivo in long-term coculture and drives myeloid differentiation. These phenotypic effects are associated with global gene expression changes in primary AML samples that involve the downregulation of many critical NUP98 fusion protein-target genes, such as MEIS1 and CDK6. In addition, Menin inhibition reduces the expression of both wild-type FLT3 and mutated FLT3-ITD, and in combination with FLT3 inhibitor, suppresses patient-derived NUP98-r AML cells in a synergistic manner. Revumenib treatment blocks leukemic engraftment and prevents leukemia-associated death of immunodeficient mice transplanted with NUP98::NSD1 FLT3-ITD-positive patient-derived AML cells. These results demonstrate that NUP98-rearranged AMLs are highly susceptible to inhibition of the MLL-Menin interaction and suggest the inclusion of AML patients harboring NUP98 fusions into the clinical evaluation of Menin inhibitors

Systems biological and mechanistic modelling of radiation-induced cancer

This paper summarises the five presentations at the First International Workshop on Systems Radiation Biology that were concerned with mechanistic models for carcinogenesis. The mathematical description of various hypotheses about the carcinogenic process, and its comparison with available data is an example of systems biology. It promises better understanding of effects at the whole body level based on properties of cells and signalling mechanisms between them. Of these five presentations, three dealt with multistage carcinogenesis within the framework of stochastic multistage clonal expansion models, another presented a deterministic multistage model incorporating chromosomal aberrations and neoplastic transformation, and the last presented a model of DNA double-strand break repair pathways for second breast cancers following radiation therapy

EAU guidelines on prostate cancer

Objetivos: Presentar un resumen de la versión del 2007 de la guía de la Asociación Europea de Urología (EAU) para el cáncer de próstata (CaP). Métodos: Se realizó por un grupo de trabajo una revisión de los nuevos datos presentes desde 2004 hasta 2007 en la literatura. Las guías han sido actualizadas y el nivel de evidencia/grado de recomendación ha sido añadido al texto basándose en una revisión sistemática de la literatura, que incluía una búsqueda de las bases de datos online y revisiones bibliográficas. Resultados: Una versión completa está disponible en la EAU Office o en www.uroweb.org. El método diagnóstico de elección es la biopsia sistematizada de la próstata bajo control ecográfico. El tratamiento activo es el recomendado en la mayoría de los pacientes con enfermedad localizada y una larga esperanza de vida, siendo la prostatectomía radical superior a la vigilancia ("watchful waiting") en un ensayo randomizado prospectivo. La prostatectomía radical con preservación de bandeletas es la técnica de elección en la enfermedad órgano-confinada; el bloqueo androgénico neoadyuvante no ha demostrado una mejoría en las variables de resultados. La radioterapia debe realizarse con al menos 72 Gy en el CaP de bajo riesgo y con 78 Gy en el de intermedio - alto riesgo. El bloqueo androgénico en monoterapia es el estándar del tratamiento en el CaP metastásico; el bloqueo androgénico intermitente podría ser un tratamiento alternativo en pacientes seleccionados. El seguimiento se basa principalmente en los niveles de PSA y en la anamnesis específica de la enfermedad, estando las pruebas de imagen sólo indicadas cuando aparecen los síntomas. La quimioterapia con docetaxel ha surgido como el tratamiento de referencia para el CaP metastásico hormonorefractario. Conclusiones: El conocimiento en el campo del CaP está rápidamente cambiando. Estas guías de la EAU resumen los hallazgos más recientes y los aplican a la práctica clínica

Equivalent bosonic theory for the massive Thirring model with non-local interaction

We study, through path-integral methods, an extension of the massive Thirring model in which the interaction between currents is non-local. By examining the mass-expansion of the partition function we show that this non-local massive Thirring model is equivalent to a certain non-local extension of the sine-Gordon theory. Thus, we establish a non-local generalization of the famous Coleman's equivalence. We also discuss some possible applications of this result in the context of one-dimensional strongly correlated systems and finite-size Quantum Field Theories.Comment: 15 pages, latex, no figure

Structure and Strength of Dislocation Junctions: An Atomic Level Analysis

The quasicontinuum method is used to simulate three-dimensional Lomer-Cottrell junctions both in the absence and in the presence of an applied stress. The simulations show that this type of junction is destroyed by an unzipping mechanism in which the dislocations that form the junction are gradually pulled apart along the junction segment. The calculated critical stress needed for breaking the junction is comparable to that predicted by line tension models. The simulations also demonstrate a strong influence of the initial dislocation line directions on the breaking mechanism, an effect that is neglected in the macroscopic treatment of the hardening effect of junctions.Comment: 4 pages, 3 figure

An Interdisciplinary Diagnostic Approach to Guide Therapy in C3 Glomerulopathy

Since the re-classification of membranoproliferative glomerulonephritis the new disease entity C3 glomerulopathy is diagnosed if C3 deposition is clearly dominant over immunoglobulins in immunohistochemistry or immunofluorescence. Although this new definition is more orientated at the pathophysiology as mediated by activity of the alternative complement pathway C3 glomerulopathy remains a heterogenous group of disorders. Genetic or autoimmune causes are associated in several but not in all patients with this disease. However, prognosis is poorly predictable, and clinicians cannot directly identify patients that might benefit from therapy. Moreover, therapy may range from supportive care alone, unspecific immune suppression, plasma treatment, or plasma exchange to complement inhibition. The current biopsy based diagnostic approaches sometimes combined with complement profiling are not sufficient to guide clinicians neither (i) whether to treat an individual patient, nor (ii) to choose the best therapy. With this perspective, we propose an interdisciplinary diagnostic approach, including detailed analysis of the kidney biopsy for morphological alterations and immunohistochemical staining, for genetic analyses of complement genes, complement activation patterning in plasma, and furthermore for applying novel approaches for convertase typing and complement profiling directly in renal tissue. Such a combined diagnostic approach was used here for a 42-year-old female patient with a novel mutation in the Factor H gene, C3 glomerulopathy and signs of chronic endothelial damage. We present here an approach that might in future help to guide therapy of renal diseases with relevant complement activation, especially since diverse new anti-complement agents are under clinical investigation