Imipramine blue sensitively and selectively targets FLT3-ITD positive acute myeloid leukemia cells.

Aberrant cytokine signaling initiated from mutant receptor tyrosine kinases (RTKs) provides critical growth and survival signals in high risk acute myeloid leukemia (AML). Inhibitors to FLT3 have already been tested in clinical trials, however, drug resistance limits clinical efficacy. Mutant receptor tyrosine kinases are mislocalized in the endoplasmic reticulum (ER) of AML and play an important role in the non-canonical activation of signal transducer and activator of transcription 5 (STAT5). Here, we have tested a potent new drug called imipramine blue (IB), which is a chimeric molecule with a dual mechanism of action. At 200-300 nM concentrations, IB is a potent inhibitor of STAT5 through liberation of endogenous phosphatase activity following NADPH oxidase (NOX) inhibition. However, at 75-150 nM concentrations, IB was highly effective at killing mutant FLT3-driven AML cells through a similar mechanism as thapsigargin (TG), involving increased cytosolic calcium. IB also potently inhibited survival of primary human FLT3/ITD+ AML cells compared to FLT3/ITDneg cells and spared normal umbilical cord blood cells. Therefore, IB functions through a mechanism involving vulnerability to dysregulated calcium metabolism and the combination of fusing a lipophilic amine to a NOX inhibiting dye shows promise for further pre-clinical development for targeting high risk AML

Cooperation of imipramine blue and tyrosine kinase blockade demonstrates activity against chronic myeloid leukemia

The use of tyrosine kinase inhibitors (TKI), including nilotinib, has revolutionized the treatment of chronic myeloid leukemia (CML). However current unmet clinical needs include combating activation of additional survival signaling pathways in persistent leukemia stem cells after long-term TKI therapy. A ubiquitous signaling alteration in cancer, including CML, is activation of reactive oxygen species (ROS) signaling, which may potentiate stem cell activity and mediate resistance to both conventional chemotherapy and targeted inhibitors. We have developed a novel nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, imipramine blue (IB) that targets ROS generation. ROS levels are known to be elevated in CML with respect to normal hematopoietic stem/progenitor cells and not corrected by TKI. We demonstrate that IB has additive benefit with nilotinib in inhibiting proliferation, viability, and clonogenic function of TKI-insensitive quiescent CD34+ CML chronic phase (CP) cells while normal CD34+ cells retained their clonogenic capacity in response to this combination therapy in vitro. Mechanistically, the pro-apoptotic activity of IB likely resides in part through its dual ability to block NF-κB and re-activate the tumor suppressor protein phosphatase 2A (PP2A). Combining BCR-ABL1 kinase inhibition with NADPH oxidase blockade may be beneficial in eradication of CML and worthy of further investigation

Expression of the neural stem cell markers NG2 and L1 in human angiomyolipoma: are angiomyolipomas neoplasms of stem cells?

Angiomyolipomas are benign tumors of the kidney which express phenotypes of smooth muscle, fat, and melanocytes. These tumors appear with increased frequency in the autosomal dominant disorder tuberous sclerosis and are the leading cause of morbidity in adults with tuberous sclerosis. While benign, these tumors are capable of provoking life threatening hemorrhage and replacement of the kidney parenchyma, resulting in renal failure. The histogenesis of these tumors is currently unclear, although currently, we believe these tumors arise from perivascular epithelioid cells of which no normal counterpart has been convincingly demonstrated. Recently, stem cell precursors have been recognized that can give rise to smooth muscle and melanocytes. These precursors have been shown to express the neural stem cell marker NG2 and L1. In order to determine whether angiomyolipomas, which exhibit smooth muscle and melanocytic phenotypes, express NG2 and L1, we performed immunocytochemistry on a cell line derived from a human angiomyolipoma, and found that these cells are uniformly positive. Immunohistochemistry of human angiomyolipoma specimens revealed uniform staining of tumor cells, while renal cell carcinomas revealed positivity only of angiogenic vessels. These results support a novel histogenesis of angiomyolipoma as a defect in differentiation of stem cell precursors

A System F accounting for scalars

The Algebraic lambda-calculus and the Linear-Algebraic lambda-calculus extend the lambda-calculus with the possibility of making arbitrary linear combinations of terms. In this paper we provide a fine-grained, System F-like type system for the linear-algebraic lambda-calculus. We show that this "scalar" type system enjoys both the subject-reduction property and the strong-normalisation property, our main technical results. The latter yields a significant simplification of the linear-algebraic lambda-calculus itself, by removing the need for some restrictions in its reduction rules. But the more important, original feature of this scalar type system is that it keeps track of 'the amount of a type' that is present in each term. As an example of its use, we shown that it can serve as a guarantee that the normal form of a term is barycentric, i.e that its scalars are summing to one

Las teorías en la práctica psicoanalítica

This paper is a reflection on the diverse theoretical corpus of psychoanalysis, on the way of conceiving its practice, and on the relationship between one and the other. I favor a pluralistic stance as regards the theories; a pluralism that I prefer to call "agreedupon". I see psychoanalytic practice as a "therapeutic interaction", following the teachings of David Liberman. I understand that, in contrast with traditional medicine, in such practice, the personality of the operator, by means of his "operating psychoanalytic self",is the defining factor of the therapeutic action. As a result, the idea of the practice as a communicative interaction is inextricably and necessarily linked to the already mentioned agreed-upon pluralism and to the notion of the ECRO. In the second part of the paper I enumerate and loosely discuss a limited and arbitrary series of controversial theoretical-technical items which I faced and still face in my professional practice as a psychoanalyst; and which have decanted in my ECRO. I end by suggesting a general shift of our perspective on the theoretical field: instead of wearing out our desires in the search of the "true" psychoanalysis, I propose "in exchange" to distill a "lowest common denominator" which embraces the majority of the current theoretical paradigms. In my opinion, the most embracing characteristic of psychoanalysis would be to define it as an "inquiring" method.Este trabajo es una reflexión en torno al diverso corpus teórico del psicoanálisis y a la forma de concebir su práctica, y la relación entre uno y otra. Me alineo en una postura pluralista en cuanto a las teorías; pluralismo que prefiero llamar "concertado". Y adhiero a concebir la práctica psicoanalítica como una "interacción terapéutica", siguiendo las enseñanzas de David Liberman. Entiendo que, en contraste con la medicina tradicional, en dicha práctica, la personalidad del operador, a través de su "self psicoanalítico operativo", es el factor decisivo de la acción terapéutica. En consecuencia la concepción de la práctica como interacción comunicativa es inextricable y necesariamente solidaria con el mencionado pluralismo concertado y con la noción de ECRO. En la segunda parte enumero y discuto laxamente una serie acotada y arbitraria de ítems teórico-técnicos controversiales con los que me enfrenté y enfrento en el ejercicio de mi profesión de psicoanalista; y que fueron decantado en mi ECRO. Y finalizo sugiriendo un cambio general de la óptica acerca del campo teórico: en vez de fatigar nuestros anhelos en la búsqueda del "verdadero" psicoanálisis, propongo -a cambio- destilar un "mínimo común denominador" que abarque a la mayoría de los paradigmas teóricos vigentes. A mi juicio, la característica más abarcativa de psicoanálisis sería catalogarlo como un método "indagatorio"

Cooperative benefit for the combination of rapamycin and imatinib in tuberous sclerosis complex neoplasia

Tuberous sclerosis (TS) is a common autosomal-dominant disorder characterized by tumors of the skin, lung, brain, and kidneys. Monotherapy with rapamycin however resulted in partial regression of tumors, implying the involvement of additional pathways. We have previously implicated platelet-derived growth factor-BB in TS-related tumorigenesis, thus providing a rationale for a combination of mTOR/PDGF blockade using rapamycin and imatinib. Here, we test this combination using a well-established preclinical model of cutaneous tumorigenesis in TS, tsc2ang1 cells derived from a skin tumor from a mouse heterozygous for tsc2. Treatment of tsc2ang1 cells with a combination of rapamycin and imatinib led to an inhibition of proliferation compared with either vehicle treatment or treatment with rapamycin or imatinib monotherapy. Combination therapy also led to a decrease in Akt activation. Potent in vivo activity in animal experiments by combination therapy was noted, without toxicity to the animals. Our findings provide a rationale for the combined use of rapamycin and imatinib, both FDA approved drugs, for the treatment of TS

El costo de eliminación de equilibrios en juegos de suma cero

Estudiamos el problema de la eliminación de equilibrios de Nash en juegos de suma cero para dos jugadores usando mínimos cambios. Damos algoritmos lineales que, dado un juego, calculan otro sin equilibrios a distancia óptima o sub óptima, de acuerdo a distintas métricas, preservando los dominios de valores así como otras propiedades del juego. Exhibimos para esto distintos sistemas de reglas que, en base a patrones dados por formas ordinales, guían en el proceso de cambio sobre la matriz de pagos.Sociedad Argentina de Informática e Investigación Operativ

Valor mixto en distintas formas de la paradoja del examen sorpresa

Se formula y estudia la paradoja del examen sorpresa para n días como juego de suma cero entre dos jugadores, el docente y el alumno, considerando los costos de estudio por día y el costo que representa el ser examinado en forma imprevista, permitiendo que el docente pueda tomar el examen cualquiera de los n días o incluso ninguno de ellos, y que el alumno pueda elegir para estudio cualquier subconjunto de esos n días (desde ninguno hasta todos). Calculamos el valor mixto de este juego en función del número de días y del costo de la posible sorpresa, y analizamos el rol de esta sorpresa como determinante para la eliminación de estrategias.Sociedad Argentina de Informática e Investigación Operativ

Valor mixto en distintas formas de la paradoja del examen sorpresa

Se formula y estudia la paradoja del examen sorpresa para n días como juego de suma cero entre dos jugadores, el docente y el alumno, considerando los costos de estudio por día y el costo que representa el ser examinado en forma imprevista, permitiendo que el docente pueda tomar el examen cualquiera de los n días o incluso ninguno de ellos, y que el alumno pueda elegir para estudio cualquier subconjunto de esos n días (desde ninguno hasta todos). Calculamos el valor mixto de este juego en función del número de días y del costo de la posible sorpresa, y analizamos el rol de esta sorpresa como determinante para la eliminación de estrategias.Sociedad Argentina de Informática e Investigación Operativ

El costo de eliminación de equilibrios en juegos de suma cero

Estudiamos el problema de la eliminación de equilibrios de Nash en juegos de suma cero para dos jugadores usando mínimos cambios. Damos algoritmos lineales que, dado un juego, calculan otro sin equilibrios a distancia óptima o sub óptima, de acuerdo a distintas métricas, preservando los dominios de valores así como otras propiedades del juego. Exhibimos para esto distintos sistemas de reglas que, en base a patrones dados por formas ordinales, guían en el proceso de cambio sobre la matriz de pagos.Sociedad Argentina de Informática e Investigación Operativ