RESUMEN
T-prolymphocytic leukemia (T-PLL) is a mature T-cell neoplasm associated with marked chemotherapy resistance and continued poor clinical outcomes. Current treatments, i.e. the CD52-antibody alemtuzumab, offer transient responses, with relapses being almost inevitable without consolidating allogeneic transplantation. Recent more detailed concepts of T-PLL's pathobiology fostered the identification of actionable vulnerabilities: (i) altered epigenetics, (ii) defective DNA damage responses, (iii) aberrant cell-cycle regulation, and (iv) deregulated pro-survival pathways, including TCR and JAK/STAT signaling. To further develop related pre-clinical therapeutic concepts, we studied inhibitors of (H)DACs, BCL2, CDK, MDM2, and clas-sical cytostatics, utilizing (a) single-agent and combinatorial compound testing in 20 well-characterized and molecularly-profiled primary T-PLL (validated by additional 42 cases), and (b) 2 independent murine models (syngeneic transplants and patient-derived xenografts). Overall, the most efficient/selective single-agents and combinations (in vitro and in mice) in-cluded Cladribine, Romidepsin ((H)DAC), Venetoclax (BCL2), and/or Idasanutlin (MDM2). Cladribine sensitivity correlated with expression of its target RRM2. T-PLL cells revealed low overall apoptotic priming with heterogeneous dependencies on BCL2 proteins. In additional 38 T-cell leukemia/lymphoma lines, TP53 mutations were associated with resistance towards MDM2 inhibitors. P53 of T-PLL cells, predominantly in wild-type configuration, was amenable to MDM2 inhibition, which increased its MDM2-unbound fraction. This facilitated P53 activa-tion and down-stream signals (including enhanced accessibility of target-gene chromatin re-gions), in particular synergy with insults by Cladribine. Our data emphasize the therapeutic potential of pharmacologic strategies to reinstate P53-mediated apoptotic responses. The identified efficacies and their synergies provide an informative background on compound and patient selection for trial designs in T-PLL.
RESUMEN
MicroRNA (miRNA) dysregulation is a hallmark of cutaneous T-cell lymphoma (CTCL), an often-fatal malignancy of skin-homing CD4+ T cells for which there are few effective therapies. The role of microRNAs (miRs) in controlling epigenetic modifier-dependent transcriptional regulation in CTCL is unknown. In this study, we characterize a novel miR dysregulation that contributes to overexpression of the epigenetic reader bromodomain-containing protein 4 (BRD4). We used patient CD4+ T cells to show diminished levels of miR-29b compared with healthy donor cells. Patient cells and miR-29b-/- mouse cells revealed an inverse relationship between miR-29b and BRD4, the latter of which is overexpressed in these cells. Chromatin immunoprecipitation and sequencing analysis revealed increased genome-wide BRD4 occupancy at promoter and enhancer regions in CD4+ T cells from CTCL patients. The cumulative result of BRD4 binding was increased expression of tumor-associated genes such as NOTCH1 and RBPJ, as well as the interleukin-15 (IL-15) receptor complex, the latter enhancing IL-15 autocrine signaling. Furthermore, we confirm the in vivo relevance of this pathway in our IL-15 transgenic mouse model of CTCL by showing that interference with BRD4-mediated pathogenesis, either by restoring miR-29b levels via bortezomib treatment or by directly inhibiting BRD4 binding via JQ1 treatment, prevents progression of CTCL. We describe a novel oncogenic pathway featuring IL-15, miR-29b, and BRD4 in CTCL and suggest targeting of these components as a potentially effective therapy for CTCL patients.
Asunto(s)
Linfoma Cutáneo de Células T/genética , MicroARNs/genética , Proteínas Nucleares/fisiología , Oncogenes/genética , Neoplasias Cutáneas/genética , Factores de Transcripción/fisiología , Animales , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Proteínas de Ciclo Celular , Células Cultivadas , Regulación hacia Abajo/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Linfoma Cutáneo de Células T/inmunología , Linfoma Cutáneo de Células T/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Activación TranscripcionalRESUMEN
Acute myeloid leukemia (AML) can evade the mouse and human innate immune system by suppressing natural killer (NK) cell development and NK cell function. This is driven in part by the overexpression of microRNA (miR)-29b in the NK cells of AML patients, but how this occurs is unknown. In the current study, we demonstrate that the transcription factor aryl hydrocarbon receptor (AHR) directly regulates miR-29b expression. We show that human AML blasts activate the AHR pathway and induce miR-29b expression in NK cells, thereby impairing NK cell maturation and NK cell function, which can be reversed by treating NK cells with an AHR antagonist. Finally, we show that inhibition of constitutive AHR activation in AML blasts lowers their threshold for apoptosis and decreases their resistance to NK cell cytotoxicity. Together, these results identify the AHR pathway as a molecular mechanism by which AML impairs NK cell development and function. The results lay the groundwork in establishing AHR antagonists as potential therapeutic agents for clinical development in the treatment of AML.
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Regulación Leucémica de la Expresión Génica/genética , Células Asesinas Naturales/inmunología , Leucemia Mieloide Aguda/inmunología , MicroARNs/biosíntesis , Receptores de Hidrocarburo de Aril/metabolismo , Animales , Humanos , Células Asesinas Naturales/citología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Ratones , Transducción de Señal/fisiologíaRESUMEN
It is known that microRNAs (miRs) are involved in lymphocyte development, homeostasis, activation, and occasionally malignant transformation. In this study, a miR-155 transgene (tg) was driven to be overexpressed off of the lck promoter in order to assess its effects on natural killer (NK) cell biology in vivo. miR-155 tg mice have an increase in NK-cell number with an excess of the CD11b(low)CD27(high) NK subset, indicative of a halt in terminal NK-cell differentiation that proved to be intrinsic to the cell itself. The increase in NK cells results, in part, from improved survival in medium alone and enhanced expansion with endogenous or exogenous interleukin 15. Phenotypic and functional data from miR-155 tg NK cells showed constitutive activation and enhanced target cell conjugation, resulting in more potent antitumor activity in vitro and improved survival of lymphoma-bearing mice in vivo when compared with wild type NK cells. The enhanced NK-cell survival, expansion, activation, and tumor control that result from overexpression of miR-155 in NK cells could be explained, in part, via diminished expression of the inositol phosphatase SHIP1 and increased activation of ERK and AKT kinases. Thus, the regulation of miR-155 is important for NK-cell development, homeostasis, and activation.
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Células Asesinas Naturales/inmunología , Linfoma/inmunología , MicroARNs/genética , Regulación hacia Arriba , Animales , Recuento de Células , Diferenciación Celular , Línea Celular Tumoral , Supervivencia Celular , Células Cultivadas , Regulación hacia Abajo , Inositol Polifosfato 5-Fosfatasas , Interferón gamma/inmunología , Interleucina-15/inmunología , Células Asesinas Naturales/citología , Células Asesinas Naturales/metabolismo , Linfoma/genética , Linfoma/patología , Sistema de Señalización de MAP Quinasas , Ratones , Ratones Endogámicos C57BL , MicroARNs/inmunología , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas , Monoéster Fosfórico Hidrolasas/genética , Proteínas Proto-Oncogénicas c-akt/inmunología , TransgenesRESUMEN
The coexpression of the MLL partial tandem duplication (PTD) and the FLT3 internal tandem duplication (ITD) mutations associate with a poor outcome in cytogenetically normal acute myeloid leukemia (AML). In mice, a double knock-in (dKI) of Mll(PTD/wt) and Flt3(ITD/wt) mutations induces spontaneous AML with an increase in DNA methyltransferases (Dnmt1, 3a, and 3b) and global DNA methylation index, thereby recapitulating its human AML counterpart. We determined that a regulator of Dnmts, miR-29b, is downregulated in bone marrow of dKI AML mice. Bortezomib exerted a dose-dependent increase in miR-29b expression in AML blasts ex vivo, followed by decreased Dnmts, reduced proliferation, and increased apoptosis. In vivo, bortezomib was not active against dKI AML, yet liposomal-encapsulated bortezomib, as a single agent, reversed downregulation of miR-29b in vivo and induced a long-term (90-day) disease-free remission in 80% of dKI AML mice that exhibited high leukemic burden at the start of therapy, yet showed no signs of relapse at autopsy. Taken together, these data support that liposomal bortezomib, as a single agent, eradicates Mll(PTD/wt):Flt3(ITD/wt) AML in mouse and may represent a powerful and potentially curative approach to high-risk human disease.
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N-Metiltransferasa de Histona-Lisina/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Proteína de la Leucemia Mieloide-Linfoide/genética , Tirosina Quinasa 3 Similar a fms/genética , Animales , Antineoplásicos/administración & dosificación , Ácidos Borónicos/administración & dosificación , Bortezomib , Metilación de ADN , Portadores de Fármacos , Humanos , Leucemia Experimental/genética , Leucemia Experimental/metabolismo , Leucemia Experimental/terapia , Leucemia Mieloide Aguda/metabolismo , Liposomas , Ratones , Ratones Mutantes , MicroARNs/genética , MicroARNs/metabolismo , Mutación , Inhibidores de Proteasoma/administración & dosificación , Pirazinas/administración & dosificación , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , Secuencias Repetidas en TándemRESUMEN
The MLL-partial tandem duplication (PTD) associates with high-risk cytogenetically normal acute myeloid leukemia (AML). Concurrent presence of FLT3-internal tandem duplication (ITD) is observed in 25% of patients with MLL-PTD AML. However, mice expressing either Mll-PTD or Flt3-ITD do not develop AML, suggesting that 2 mutations are necessary for the AML phenotype. Thus, we generated a mouse expressing both Mll-PTD and Flt3-ITD. Mll(PTD/WT):Flt3(ITD/WT) mice developed acute leukemia with 100% penetrance, at a median of 49 weeks. As in human MLL-PTD and/or the FLT3-ITD AML, mouse blasts exhibited normal cytogenetics, decreased Mll-WT-to-Mll-PTD ratio, loss of the Flt3-WT allele, and increased total Flt3. Highlighting the adverse impact of FLT3-ITD dosage on patient survival, mice with homozygous Flt3-ITD alleles, Mll(PTD/WT):Flt3(ITD/ITD), demonstrated a nearly 30-week reduction in latency to overt AML. Here we demonstrate, for the first time, that Mll-PTD contributes to leukemogenesis as a gain-of-function mutation and describe a novel murine model closely recapitulating human AML.
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Duplicación de Gen/fisiología , Técnicas de Sustitución del Gen , Leucemia Mieloide Aguda/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Tirosina Quinasa 3 Similar a fms/genética , Animales , Transformación Celular Neoplásica/genética , Modelos Animales de Enfermedad , N-Metiltransferasa de Histona-Lisina , Humanos , Leucemia Mieloide Aguda/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Secuencias Repetidas en Tándem/genéticaRESUMEN
Dysregulated nuclear-cytoplasmic trafficking has been shown to play a role in oncogenesis in several types of solid tumors and hematological malignancies. Exportin 1 (XPO1) is responsible for the nuclear export of several proteins and RNA species, mainly tumor suppressors. KPT-330, a small molecule inhibitor of XPO1, is approved for treating relapsed multiple myeloma and diffuse large B-cell lymphoma. Cutaneous T-cell lymphoma (CTCL) is an extranodal non-Hodgkin lymphoma with an adverse prognosis and limited treatment options in advanced stages. The effect of therapeutically targeting XPO1 with KPT-330 in CTCL has not been established. We report that XPO1 expression is upregulated in CTCL cells. KPT-330 reduces cell proliferation, induces G1 cell cycle arrest and apoptosis. RNA-sequencing was used to explore the underlying mechanisms. Genes associated with the cell cycle and the p53 pathway were significantly enriched with KPT-330 treatment. KPT-330 suppressed XPO1 expression, upregulated p53, p21WAF1/Cip1, and p27Kip1 and their nuclear localization, and downregulated anti-apoptotic protein (Survivin). The in vivo efficacy of KPT-330 was investigated using a bioluminescent xenograft mouse model of CTCL. KPT-330 blocked tumor growth and prolonged survival (p < 0.0002) compared to controls. These findings support investigating the use of KPT-330 and next-generation XPO1 inhibitors in CTCL.
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Apoptosis , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Proteína Exportina 1 , Carioferinas , Linfoma Cutáneo de Células T , Receptores Citoplasmáticos y Nucleares , Triazoles , Proteína p53 Supresora de Tumor , Humanos , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Linfoma Cutáneo de Células T/tratamiento farmacológico , Linfoma Cutáneo de Células T/patología , Linfoma Cutáneo de Células T/metabolismo , Linfoma Cutáneo de Células T/genética , Apoptosis/efectos de los fármacos , Animales , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Carioferinas/metabolismo , Carioferinas/antagonistas & inhibidores , Ratones , Línea Celular Tumoral , Triazoles/farmacología , Proliferación Celular/efectos de los fármacos , Hidrazinas/farmacología , Hidrazinas/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Transducción de Señal/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacosRESUMEN
CONTEXT: There have been many cases of medication-induced tremors. We report a patient who developed significant chin tremors after the administration of paroxetine. CASE REPORT: A 68-year-old Vietnamese female with a past medical history including GIST and pancreatic cancer status post Whipple procedure and six months of adjuvant chemotherapy with gemcitabine presented with symptoms of anxiety for which she was treated with paroxetine. Within 2 weeks she developed chin tremors which resolved after paroxetine was discontinued. CONCLUSIONS: To our knowledge, this is the first case report of a temporary chin tremor associated with paroxetine. The exact mechanism of this phenomenon is unclear. However, it has been suggested that movement disorders such as chin tremors may be related to elevated serotonin levels causing an inhibition of central dopamine.
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Adenocarcinoma/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Paroxetina/efectos adversos , Temblor/inducido químicamente , Anciano , Antimetabolitos Antineoplásicos/efectos adversos , Ansiedad/inducido químicamente , Ansiedad/tratamiento farmacológico , Quimioterapia Adyuvante , Mentón , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Femenino , Humanos , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Privación de Tratamiento , Gemcitabina , Neoplasias PancreáticasRESUMEN
Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive, rare lymphoma of natural killer (NK) cell origin with poor clinical outcomes. Here we used phenotypic and molecular profiling, including epigenetic analyses, to investigate how ENKTL ontogeny relates to normal NK-cell development. We demonstrate that neoplastic NK cells are stably, but reversibly, arrested at earlier stages of NK-cell maturation. Genes downregulated in the most epigenetic immature tumors were associated with polycomb silencing along with genomic gain and overexpression of EZH2. ENKTL cells exhibited genome-wide DNA hypermethylation. Tumor-specific DNA methylation gains were associated with polycomb-marked regions, involving extensive gene silencing and loss of transcription factor binding. To investigate therapeutic targeting, we treated novel patient-derived xenograft (PDX) models of ENKTL with the DNA hypomethylating agent, 5-azacytidine. Treatment led to reexpression of NK-cell developmental genes, phenotypic NK-cell differentiation, and prolongation of survival. These studies lay the foundation for epigenetic-directed therapy in ENKTL. SIGNIFICANCE: Through epigenetic and transcriptomic analyses of ENKTL, a rare, aggressive malignancy, along with normal NK-cell developmental intermediates, we identified that extreme DNA hypermethylation targets genes required for NK-cell development. Disrupting this epigenetic blockade in novel PDX models led to ENKTL differentiation and improved survival. This article is highlighted in the In This Issue feature, p. 85.
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Linfoma Extranodal de Células NK-T , Células T Asesinas Naturales , Epigenómica , Perfilación de la Expresión Génica , Humanos , Células Asesinas Naturales/patología , Linfoma Extranodal de Células NK-T/tratamiento farmacológico , Células T Asesinas Naturales/patologíaRESUMEN
Cutaneous T-cell lymphomas (CTCLs) are a family of primary extranodal lymphomas of mature CD4+, skin-homing or skin-resident T cells. In a significant fraction of patients with CTCL, the neoplastic CD4+ lymphocytes acquire extracutaneous tropism, and with disease progression, they disseminate to the lymph nodes, peripheral blood, and visceral organs. MicroRNA (miR)-based therapies are a newly emerging strategy for many types of diseases, including cancers. CTCL represents one of the disease indications for a clinical trial of miR inhibitor therapy, supporting further investigation of epigenetic dysregulation and miR-driven oncogenesis in this disease. In this study, we interrogated an aberrant miR-based regulatory network that operates in malignant CD4+ T cells and identified potential targets of therapy. We show that miR-214 levels are significantly higher in purified CD4+ neoplastic T cells from patients with CTCL than from healthy donors. We then show that antagomiR-214 treatment of IL-15 transgenic mice with spontaneous, miR-214-overexpressing CTCL leads to significant decrease in disease severity using multiple validated clinical and histological endpoints, compared with scrambled control-treated IL-15 transgenic CTCL mice. Mechanistically, we show that aberrantly expressed TWIST1 and BET protein BRD4 cooperate to drive miR-214 expression in CTCL cell lines and in samples from patients with CTCL and that treatment with BRD4 inhibitor JQ1 leads to down-regulation of miR-214. Based on both in vitro and in vivo data, we propose that the TWIST1/BRD4/miR-214 regulatory loop is an important, targetable, oncogenic pathway in CTCL.
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Antagomirs/administración & dosificación , Linfoma Cutáneo de Células T/tratamiento farmacológico , MicroARNs/antagonistas & inhibidores , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Ensayos de Selección de Medicamentos Antitumorales , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inyecciones Subcutáneas , Interleucina-15/genética , Linfoma Cutáneo de Células T/sangre , Linfoma Cutáneo de Células T/genética , Ratones , Ratones Transgénicos , MicroARNs/metabolismo , Cultivo Primario de Células , Piel/patología , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/genética , Linfocitos TRESUMEN
The resource fairs were well received and provided a good opportunity to improve education for patients, their families, and health care providers.
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Natural killer (NK) cells can have potent antileukemic activity following haplo-mismatched, T cell-depleted stem cell transplantations for the treatment of acute myeloid leukemia (AML), but they are not successful in eradicating de novo AML. Here, we have used a mouse model of de novo AML to elucidate the mechanisms by which AML evades NK cell surveillance. NK cells in leukemic mice displayed a marked reduction in the cytolytic granules perforin and granzyme B. Further, as AML progressed, we noted the selective loss of an immature subset of NK cells in leukemic mice and in AML patients. This absence was not due to elimination by cell death or selective reduction in proliferation, but rather to the result of a block in NK cell differentiation. Indeed, NK cells from leukemic mice and humans with AML showed lower levels of TBET and EOMES, transcription factors that are critical for terminal NK cell differentiation. Further, the microRNA miR-29b, a regulator of T-bet and EOMES, was elevated in leukemic NK cells. Finally, deletion of miR-29b in NK cells reversed the depletion of this NK cell subset in leukemic mice. These results indicate that leukemic evasion of NK cell surveillance occurs through miR-mediated dysregulation of lymphocyte development, representing an additional mechanism of immune escape in cancer.
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Inmunidad Innata , Células Asesinas Naturales/inmunología , Leucemia Mieloide Aguda/inmunología , MicroARNs/inmunología , ARN Neoplásico/inmunología , Escape del Tumor , Animales , Línea Celular Tumoral , Granzimas/genética , Granzimas/inmunología , Humanos , Células Asesinas Naturales/patología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Ratones , Ratones Transgénicos , MicroARNs/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Perforina/genética , Perforina/inmunología , ARN Neoplásico/genética , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/inmunologíaRESUMEN
UNLABELLED: Cutaneous T-cell lymphoma (CTCL) is the most common type of primary cutaneous lymphoma. Here, we report that patients with CTCL show increased IL15 in a clinical stage-dependent manner. Mechanistically, we show that ZEB1 is a transcriptional repressor of IL15 in T cells and that hypermethylation of the ZEB1 binding region within the IL15 promoter, as seen in patients with CTCL, prevents ZEB1 binding and causes increased transcription of IL15 Using a transgenic mouse model of IL15, we provide evidence that overexpression of IL15 induces a spontaneous CTCL that mimics the human neoplasm. Excessive autocrine production of IL15 in T cells inhibits an HDAC1-mediated negative autoregulatory loop, resulting in the upregulation of HDAC1 and HDAC6 and transcriptional induction of the onco-miR-21. Interruption of IL15 downstream signaling with isotype-specific HDAC inhibitors halts (HDAC1) or significantly delays (HDAC6) the progression of CTCL in vivo and provides preclinical evidence supporting a hierarchical model of oncogenic signaling in CTCL. SIGNIFICANCE: To date, CTCL pathogenesis remains unknown, and there are no curative therapies. Our findings not only demonstrate a critical role for IL15-mediated inflammation in cutaneous T-cell lymphomagenesis, but also uncover a new oncogenic regulatory loop in CTCL involving IL15, HDAC1, HDAC6, and miR-21 that shows differential sensitivity to isotype-specific HDAC inhibitors. Cancer Discov; 6(9); 986-1005. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.
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Histona Desacetilasa 1/genética , Histona Desacetilasas/genética , Interleucina-15/genética , Linfoma Cutáneo de Células T/genética , MicroARNs/genética , Animales , Línea Celular Tumoral , Metilación de ADN/genética , Regulación Neoplásica de la Expresión Génica , Histona Desacetilasa 1/biosíntesis , Histona Desacetilasa 6 , Inhibidores de Histona Desacetilasas/uso terapéutico , Histona Desacetilasas/biosíntesis , Humanos , Inflamación/genética , Inflamación/patología , Inflamación/terapia , Linfoma Cutáneo de Células T/patología , Linfoma Cutáneo de Células T/terapia , Ratones , MicroARNs/biosíntesis , Factor de Transcripción STAT3/genética , Transducción de Señal , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genéticaRESUMEN
OBJECTIVE: This retrospective study examined whether changes in ventricular volume correspond with changes in adjustable valve pressure settings in a cohort of patients who received shunts to treat idiopathic normal pressure hydrocephalus. We also examined whether these pressure-volume curves and other patient variables would co-occur with a positive clinical response to shunting. METHODS: We selected 51 patients diagnosed with idiopathic normal pressure hydrocephalus who had undergone implantation of a Codman Hakim programmable valve (Medos S.A., Le Locle, Switzerland). Clinical data were gathered from the patients' records and clinical notes by an investigator blinded to patients' ventricular volumes. Ventricular volume was measured using 3D Slicer, an image analysis and interactive visualization software package developed and maintained at the Surgical Planning Laboratory at Brigham and Women's Hospital. RESULTS: Eighty-six percent of patients with gait disturbance at presentation showed improvement of this symptom, 70% experienced improvement in incontinence, and 69% experienced improvement in dementia. For the group showing 100% clinical improvement, the correlation coefficient of average changes in valve pressure over time (delta P/delta T) and average changes in ventricular volume over time (delta V/delta T) were high at 0.843 (P < 0.05). For the group experiencing no or only partial improvement, the correlation coefficient was 0.257 (P = 0.32), indicating no correlation between average delta V/delta T and average delta P/delta T for each patient. CONCLUSION: This was a carefully analyzed modeling study of idiopathic normal pressure hydrocephalus treatment made possible only by adjustable valve technology. With careful volumetric analysis, we found that changes in ventricular volume correlated with adjustments in valve pressure settings for those patients who improved clinically after shunting. This suggests that positive clinical responders retained parenchymal elasticity, emphasizing the importance of dynamic changes in this cohort.
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Ventrículos Cerebrales/patología , Presión del Líquido Cefalorraquídeo/fisiología , Derivaciones del Líquido Cefalorraquídeo/instrumentación , Hidrocéfalo Normotenso/diagnóstico , Hidrocéfalo Normotenso/cirugía , Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional , Imagen por Resonancia Magnética , Tomografía Computarizada por Rayos X , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Estudios de Cohortes , Femenino , Humanos , Hipertrofia/diagnóstico , Masculino , Cómputos Matemáticos , Microcomputadores , Persona de Mediana Edad , Estudios Retrospectivos , Diseño de Software , Estadística como AsuntoRESUMEN
5-Fluorouracil (5-FU) is commonly administered as a therapeutic agent for the treatment of various aggressive cancers. Severe toxic reactions to 5-FU have been associated with decreased levels of dihydropyrimidine dehydrogenase (DPD) enzyme activity. Manifestations of 5-FU toxicity typically include cytopenia, diarrhea, stomatitis, mucositis, neurotoxicity, and, in extreme cases, death. A variety of genetic variations in DPYD, the gene encoding DPD, are known to result in decreased DPD enzyme activity and to contribute to 5-FU toxic effects. Recently, it was reported that healthy African American individuals carrying the Y186C DPYD variant (rs115232898) had significantly reduced DPD enzyme activity compared with noncarriers of Y186C. Herein, we describe for the first time, to our knowledge, an African American patient with cancer with the Y186C variant who had severe toxic effects after administration of the standard dose of 5-FU chemotherapy. The patient lacked any additional toxic effect-associated variations in the DPYD gene or the thymidylate synthase (TYMS) promoter. This case suggests that Y186C may have contributed to 5-FU toxicity in this patient and supports the use of Y186C as a predictive marker for 5-FU toxic effects in individuals of African ancestry.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Negro o Afroamericano/genética , Neoplasias del Colon/tratamiento farmacológico , Dihidrouracilo Deshidrogenasa (NADP)/genética , Marcadores Genéticos , Adenocarcinoma/enzimología , Adenocarcinoma/patología , Adenocarcinoma/secundario , Neoplasias del Colon/enzimología , Neoplasias del Colon/patología , Diarrea/inducido químicamente , Dihidrouracilo Deshidrogenasa (NADP)/efectos de los fármacos , Resultado Fatal , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Proteínas de Choque Térmico , Humanos , Leucovorina/efectos adversos , Leucovorina/uso terapéutico , Persona de Mediana Edad , Mucositis/inducido químicamente , Estadificación de Neoplasias , Compuestos Organoplatinos/efectos adversos , Compuestos Organoplatinos/uso terapéutico , Fragmentos de Péptidos , Polimorfismo Genético , Medicina de Precisión , Estomatitis/inducido químicamenteRESUMEN
The rationale for our study was to determine the pattern of ethanol drinking by the high alcohol-drinking (HAD) replicate lines of rats during adolescence and adulthood in both male and female rats. Rats were given 30 days of 24 h free-choice access to ethanol (15%, v/v) and water, with ad lib access to food, starting at the beginning of adolescence (PND 30) or adulthood (PND 90). Water and alcohol drinking patterns were monitored 22 h/day with a "lickometer" set-up. The results indicated that adolescent HAD-1 and HAD-2 males consumed the greatest levels of ethanol and had the most well defined ethanol licking binges among the age and sex groups with increasing levels of ethanol consumption throughout adolescence. In addition, following the first week of adolescence, male and female HAD-1 and HAD-2 rats differed in both ethanol consumption levels and ethanol licking behavior. Adult HAD-1 male and female rats did not differ from one another and their ethanol intake or licking behaviors did not change significantly over weeks. Adult HAD-2 male rats maintained a relatively constant level of ethanol consumption across weeks, whereas adult HAD-2 female rats increased ethanol consumption levels over weeks, peaking during the third week when they consumed more than their adult male counterparts. The results indicate that the HAD rat lines could be used as an effective animal model to examine the development of ethanol consumption and binge drinking in adolescent male and female rats providing information on the long-range consequences of adolescent alcohol drinking.
Asunto(s)
Consumo de Bebidas Alcohólicas , Factores de Edad , Animales , Femenino , Masculino , Ratas , Reproducibilidad de los ResultadosRESUMEN
Dural arteriovenous fistulas are characterized by abnormal arteriovenous shunting localized to the pachymeninges. Fistulae venous drainage is essential to their classification, symptomatology, and treatment. Endovascular therapy is rapidly progressing to an adjunct or even alternative treatment to microsurgical resection. Several techniques, such as transarterial or transvenous embolization with metallic coils, NBCA, or Onyx, have been used successfully in several studies. The long-term clinical and radiographic outcomes of endovascular therapy for the treatment of dural arteriovenous fistulas are satisfactory, and future studies are underway for the refinement of these techniques.