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Ultrashort energetic terahertz (THz) pulses have created an exciting new area of research on light interactions with matter. For material studies in small laboratories, widely tunable femtosecond THz pulses with peak field strength close to MV cm-1 are desired. Currently, they can be largely acquired by optical rectification and difference frequency generation in crystals without inversion symmetry. We describe in this paper a novel scheme of THz pulse generation with no frequency tuning gap based on Raman-resonance-enhanced four-wave mixing in centrosymmetric media, particularly diamond. We show that we could generate highly stable, few-cycle pulses with near-Gaussian spatial and temporal profiles and carrier frequency tunable from 5 to >20 THz. They had a stable and controllable carrier-envelop phase and carried ~15 nJ energy per pulse at 10 THz (with a peak field strength of ~1 MV cm-1 at focus) from a 0.5-mm-thick diamond. The measured THz pulse characteristics agreed well with theoretical predictions. Other merits of the scheme are discussed, including the possibility of improving the THz output energy to a much higher level.
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The utility of cancer whole genome and transcriptome sequencing (cWGTS) in oncology is increasingly recognized. However, implementation of cWGTS is challenged by the need to deliver results within clinically relevant timeframes, concerns about assay sensitivity, reporting and prioritization of findings. In a prospective research study we develop a workflow that reports comprehensive cWGTS results in 9 days. Comparison of cWGTS to diagnostic panel assays demonstrates the potential of cWGTS to capture all clinically reported mutations with comparable sensitivity in a single workflow. Benchmarking identifies a minimum of 80× as optimal depth for clinical WGS sequencing. Integration of germline, somatic DNA and RNA-seq data enable data-driven variant prioritization and reporting, with oncogenic findings reported in 54% more patients than standard of care. These results establish key technical considerations for the implementation of cWGTS as an integrated test in clinical oncology.
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Perfilación de la Expresión Génica , Neoplasias , Niño , Estudios de Factibilidad , Perfilación de la Expresión Génica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Estudios Prospectivos , Transcriptoma/genética , Secuenciación Completa del Genoma/métodos , Adulto JovenRESUMEN
Generation of octave-spanning spectrum that spans from 570 nm to 1300 nm utilizing 1030 nm 170 fs pulses from a Yb:KGW laser and a two-stage multiple-plate arrangement is demonstrated. 3.21 fs sub-single-cycle pulses are obtained after dispersion compensation. The high compression ratio of more than 50 times is achieved for two scenarios with widely different parameters including high input peak power at 1 kHz repetition rate and modest peak power at a high repetition rate of 100 kHz. The output pulses have good spatial mode quality and exhibit long-term stability. The achieved compression ratio and flexibility are unprecedented in ultrafast pulse compression to single-cycle regime. The experiments demonstrate that the technique of multiple-plate pulse compression is versatile and applicable for a wide range of laser pulse parameters.
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The generation of high average power, carrier-envelope phase (CEP) stable, near-single-cycle pulses at a repetition rate of 100 kHz is demonstrated using an all solid-state setup. By exploiting self-phase modulation in thin quartz plates and air, the spectrum of intense pulses from a high-power, high repetition rate non-collinear optical parametric chirped pulse amplifier (NOPCPA) is extended to beyond one octave, and pulse compression down to 3.7 fs is achieved. The octave-spanning spectrum furthermore allows performing straightforward f-to-2f interferometry by frequency-doubling the long-wavelength part of the spectrum. Excellent CEP-stability is demonstrated for extended periods of time. A full spatio-spectral characterization of the compressed pulses shows only minor asymmetries between the two perpendicular beam axes. We believe that the completed system represents the first laser system satisfying all requirements for performing high repetition rate attosecond pump-probe experiments with fully correlated detection of all ions and electrons produced in the experiment.
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AIMS: Korea has the highest suicide rate of developed countries, two times higher than the USA. Suicide trends among Koreans Americans living in the USA during the same period have not yet been described. We report suicide mortality rates and trends for four groups: (1) Korean Americans, (2) non-Hispanic White (NHW) Americans, (3) selected Asian American subgroups and (4) Koreans living in the Republic of Korea. METHODS: We used US national (n = 18 113 585) and World Health Organization (WHO) (n = 232 919 253) mortality records for Korea from 2003 to 2012 to calculate suicide rates, all expressed per 100 000 persons. We assessed temporal trends and differences in age, gender and race/ethnicity using binomial regression. RESULTS: Suicide rates are highest in Koreans living in the Republic of Korea (32.4 for men and 14.8 for women). Suicide rates in Korean Americans (13.9 for men and 6.5 for women) have nearly doubled from 2003 to 2012 and exceed rates for all other Asian American subgroups (5.4-10.7 for men and 1.6-4.2 for women). Suicide rates among NHWs (21.0 for men and 5.6 for women) remain high. Among elders, suicide in Korean Americans (32.9 for men and 15.4 for women) is the highest of all examined racial/ethnic groups in the USA. CONCLUSIONS: Suicide in Korean Americans is higher than for other Asian Americans and follows temporal patterns more similar to Korea than the USA. Interventions to prevent suicide in Korean American populations, particularly among the elderly, are needed.
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Asiático/psicología , Suicidio/estadística & datos numéricos , Población Blanca/psicología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Asiático/estadística & datos numéricos , Niño , Preescolar , Comparación Transcultural , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , República de Corea/etnología , Suicidio/tendencias , Estados Unidos/epidemiología , Población Blanca/estadística & datos numéricos , Adulto JovenRESUMEN
This study aimed to investigate the postoperative longitudinal skeletal changes and stability following intraoral vertical ramus osteotomies (IVRO) for orthognathic mandibular setback, and the possible risk factors that might affect the stability. A retrospective cohort study was conducted. Lateral cephalograms were analyzed for the predictor (magnitude of setback and adjunctive procedures) and outcome (stability of vertical and horizontal dimensions) variables at six time points. A total of 152 patients (mean age 24.2 years) were included in the study. Following IVRO, the mandible measured at B-point had moved a mean 0.50mm posteriorly at 1 week after the removal of intermaxillary fixation (7 weeks postoperative); this was followed by progressive small anterior relapse. At 2 years postoperative, the mean relapse of the mandible after IVRO measured at B-point was 0.05mm (standard deviation 1.14mm), representing 0.7% of the mean surgical movement. Large setback (>8mm) showed significantly higher relapse compared to small setback (<4mm) at 2 years after surgery (P=0.021). Patients who underwent adjunctive mandibular surgeries other than IVRO showed no significant differences in relapse compared to those who underwent IVRO alone. In conclusion, IVRO for mandibular setback is a stable procedure in the long term, with small relapse of 0.05mm after 2 years.
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Mentoplastia/métodos , Osteotomía Mandibular/métodos , Osteotomía Le Fort/métodos , Osteotomía Sagital de Rama Mandibular/métodos , Prognatismo/cirugía , Adolescente , Adulto , Cefalometría , Femenino , Hong Kong , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Factores de Riesgo , Resultado del Tratamiento , Dimensión VerticalRESUMEN
The purpose of this review is to assess the most recent evidence in the management of primary hyperparathyroidism (PHPT) and provide updated recommendations for its evaluation, diagnosis and treatment. A Medline search of "Hyperparathyroidism. Primary" was conducted and the literature with the highest levels of evidence were reviewed and used to formulate recommendations. PHPT is a common endocrine disorder usually discovered by routine biochemical screening. PHPT is defined as hypercalcemia with increased or inappropriately normal plasma parathyroid hormone (PTH). It is most commonly seen after the age of 50 years, with women predominating by three to fourfold. In countries with routine multichannel screening, PHPT is identified earlier and may be asymptomatic. Where biochemical testing is not routine, PHPT is more likely to present with skeletal complications, or nephrolithiasis. Parathyroidectomy (PTx) is indicated for those with symptomatic disease. For asymptomatic patients, recent guidelines have recommended criteria for surgery, however PTx can also be considered in those who do not meet criteria, and prefer surgery. Non-surgical therapies are available when surgery is not appropriate. This review presents the current state of the art in the diagnosis and management of PHPT and updates the Canadian Position paper on PHPT. An overview of the impact of PHPT on the skeleton and other target organs is presented with international consensus. Differences in the international presentation of this condition are also summarized.
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Hiperparatiroidismo Primario/diagnóstico por imagen , Humanos , Hipercalcemia/etiología , Hiperparatiroidismo Primario/complicaciones , Hiperparatiroidismo Primario/epidemiología , Hiperparatiroidismo Primario/terapia , Incidencia , Imagen por Resonancia Magnética/métodos , Nefrolitiasis/etiología , Paratiroidectomía , Prevalencia , Cintigrafía/métodos , Tomografía Computarizada por Rayos X/métodosRESUMEN
We analyze femtosecond supercontinuum generation in a distribution of thin solid plates to show that the distributed scheme inhibits processes leading to pulse breakup while allowing spectral expansion to proceed as desired. We introduce basic criteria for setting the plate thickness or initial laser intensity and the location of each plate in the laser beam path and confirm that under these conditions a fully-coherent and intense supercontinuum can be generated for input peak power of as much as two thousand times the critical power for self-focusing of the solid medium.
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Currently available combination chemotherapy for acute myeloid leukemia (AML) often fails to result in long-term remissions, emphasizing the need for novel therapeutic strategies. We reasoned that targeted inhibition of a prominent nuclear exporter, XPO1/CRM1, could eradicate self-renewing leukemia-initiating cells (LICs) whose survival depends on timely XPO1-mediated transport of specific protein and RNA cargoes. Using an immunosuppressed mouse model bearing primary patient-derived AML cells, we demonstrate that selinexor (KPT-330), an oral antagonist of XPO1 that is currently in clinical trials, has strong activity against primary AML cells while sparing normal stem and progenitor cells. Importantly, limiting dilution transplantation assays showed that this cytotoxic activity is not limited to the rapidly proliferating bulk population of leukemic cells but extends to the LICs, whose inherent drug resistance and unrestricted self-renewal capacity has been implicated in the difficulty of curing AML patients with conventional chemotherapy alone.
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Hidrazinas/farmacología , Carioferinas/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Triazoles/farmacología , Animales , Humanos , Terapia de Inmunosupresión , Leucemia Mieloide Aguda/patología , Ratones , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína Exportina 1RESUMEN
Thioamides antithyroid-drugs (ATDs) are important in hyperthyroid disease management. Identification of the susceptibility locus of ATD-induced agranulocytosis is important for clinical management. We performed a genome-wide association study (GWAS) involving 20 patients with ATD-induced agranulocytosis and 775 healthy controls. The top finding was further replicated. A single-nucleotide polymorphism (SNP), rs185386680, showed the strongest association with ATD-induced agranulocytosis in GWAS (odds ratio (OR) = 36.4; 95% confidence interval (CI) = 12.8-103.7; P = 1.3 × 10(-24)) and replication (OR = 37; 95% CI = 3.7-367.4; P = 9.6 × 10(-7)). HLA-B*38:02:01 was in complete linkage disequilibrium with rs185386680. High-resolution HLA typing confirmed that HLA-B*38:02:01 was associated with carbimazole (CMZ)/methimazole (MMI)-induced agranulocytosis (OR = 265.5; 95% CI = 27.9-2528.0; P = 2.5 × 10(-14)), but not associated with propylthiouracil (PTU). The positive and negative predictive values of HLA-B*38:02:01 in predicting CMZ/MMI-induced agranulocytosis were 0.07 and 0.999. Approximately 211 cases need to be screened to prevent one case. Screening for the risk allele will be useful in preventing agranulocytosis in populations in which the frequency of the risk allele is high.
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Agranulocitosis/inducido químicamente , Antitiroideos/efectos adversos , Carbimazol/efectos adversos , Antígenos HLA-B/genética , Metimazol/efectos adversos , Agranulocitosis/genética , Antitiroideos/administración & dosificación , Carbimazol/administración & dosificación , Estudios de Casos y Controles , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Desequilibrio de Ligamiento/genética , Metimazol/administración & dosificación , Polimorfismo de Nucleótido Simple , Valor Predictivo de las Pruebas , Propiltiouracilo/administración & dosificación , Propiltiouracilo/efectos adversosRESUMEN
UNLABELLED: The study aimed to prospectively evaluate if serum calcium is related to diabetes incidence in Hong Kong Chinese. The results showed that serum calcium has a significant association with increased risk of diabetes. The result of meta-analysis reinforced our findings. INTRODUCTION: This study aimed to evaluate the association of serum calcium, including serum total calcium and albumin-corrected calcium, with incident diabetes in Hong Kong Chinese. METHODS: We conducted a retrospective cohort study in 6096 participants aged 20 or above and free of diabetes at baseline. Serum calcium was measured at baseline. Incident diabetes was determined from several electronic databases. We also searched relevant databases for studies on serum calcium and incident diabetes and conducted a meta-analysis using fixed-effect modeling. RESULTS: During 59,130.9 person-years of follow-up, 631 participants developed diabetes. Serum total calcium and albumin-corrected calcium were associated with incident diabetes in the unadjusted model. After adjusting for demographic and clinical variables, the association remained significant only for serum total calcium (hazard ratio (HR), 1.32 (95 % confidence interval (CI), 1.02-1.70), highest vs. lowest quartile). In a meta-analysis of four studies including the current study, both serum total calcium (pooled risk ratio (RR), 1.38 (95 % CI, 1.15-1.65); I (2) = 5 %, comparing extreme quantiles) and albumin-corrected calcium (pooled RR, 1.29 (95 % CI, 1.03-1.61); I (2) = 0 %, comparing extreme quantiles) were associated with incident diabetes. Penalized regression splines showed that the association of incident diabetes with serum total calcium and albumin-correlated calcium was non-linear and linear, respectively. CONCLUSIONS: Elevated serum calcium concentration is associated with incident diabetes. The mechanism underlying this association warrants further investigation.
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Calcio/sangre , Diabetes Mellitus Tipo 2/sangre , Adulto , Anciano , Anciano de 80 o más Años , Diabetes Mellitus Tipo 2/epidemiología , Hong Kong/epidemiología , Humanos , Incidencia , Persona de Mediana Edad , Estudios Observacionales como Asunto , Estudios Retrospectivos , Factores de Riesgo , Albúmina Sérica/análisis , Adulto JovenAsunto(s)
Conservadores de la Densidad Ósea/economía , Análisis Costo-Beneficio/métodos , Costos de la Atención en Salud , Osteoporosis Posmenopáusica/tratamiento farmacológico , Factores de Edad , Anciano , Conservadores de la Densidad Ósea/uso terapéutico , Femenino , Fracturas de Cadera/economía , Fracturas de Cadera/epidemiología , Fracturas de Cadera/etiología , Hong Kong/epidemiología , Humanos , Incidencia , Cadenas de Markov , Persona de Mediana Edad , Osteoporosis Posmenopáusica/economía , Osteoporosis Posmenopáusica/mortalidad , Fracturas Osteoporóticas/economía , Fracturas Osteoporóticas/epidemiología , Años de Vida Ajustados por Calidad de Vida , Fracturas de la Columna Vertebral/economía , Fracturas de la Columna Vertebral/epidemiología , Fracturas de la Columna Vertebral/etiología , Factores de Tiempo , Traumatismos de la Muñeca/economía , Traumatismos de la Muñeca/epidemiología , Traumatismos de la Muñeca/etiologíaRESUMEN
AIM: To study the oral health status of Chinese children and adolescents undergoing chemotherapy in Hong Kong. METHOD: All Chinese children and adolescent oncology patients aged 18 or below attending the Children's Centre for Cancer and Blood Disease at a hospital for chemotherapy were invited and parental consent was sought before they were accepted into the study. The study comprised of 1) a parental questionnaire, 2) the collection of medical history and 3) a clinical examination for tooth decay (caries) and mucosal status. RESULTS: A total of 69 patients were invited, and they all participated in this study. Their mean age was 9.2±5.0 and 44 (64%) were males. Twenty-six patients (38%) had no caries experience (DMFT and/or dmft = 0). Higher caries experience was detected in participants that were not born in Hong Kong, had completed active chemotherapy, participated in school dental care service and whose parents had low educational levels. There were 41 patients with active chemotherapy, 24 of whom were diagnosed with acute leukaemia, 5 with haematological malignancies other than leukaemia and 11 with solid tumours. Antimetabolites, cytotoxic antibiotics, alkylating agents and plant alkaloids were administered in 49%, 32%, 24% and 22% of them, respectively. Twenty-six (63%) patients showed no mucosal complications. The most common oral complication was oral mucositis (24%) followed by petechiae (10%). CONCLUSION: About two-thirds of paediatric and adolescent cancer patients had caries experience, which was more common among those who had completed chemotherapy. Oral mucositis followed by petechiae were the two most common complications of receiving chemotherapy.
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BACKGROUND: Intrathecal morphine is used for post-cesarean analgesia, but pruritus is a common side effect. Ondansetron would be an attractive treatment because it prevents nausea, is non-sedative or has no anti-analgesic effect. We undertook a study to assess the efficacy of ondansetron for treatment or prophylaxis of intrathecal morphine-induced pruritus. METHODS: Healthy paturients undergoing cesarean delivery with intrathecal morphine 250µg and fentanyl 25µg were randomized to receive: prophylaxis (ondansetron 8mg at cord clamping, normal saline 4mL for treatment of pruritus in the post-anaesthesia care unit); treatment (normal saline 4mL at cord clamping, ondansetron 8mg as required in the post-anesthesia care unit) or control (normal saline 4mL in both). Visual analogue scale scores for pruritus, nausea and pain were recorded preoperatively, on arrival to, at 30, 60, and 120min and on discharge from the post-anesthesia care unit. The primary outcome was the peak pruritus score. ANOVA with Bonferroni correction or Fisher's exact test were used to analyze data; P<0.05 was considered significant. RESULTS: The study was terminated early when interim analysis indicated no effect. Eighty-two of the intended 180 paturients completed the protocol (26 in control group, 32 in treatment group and 24 in prophylaxis). There were no differences in the rate or severity of pruritus at any assessment point, or the request for treatment. Pruritus was reduced after administration of treatment syringe. CONCLUSION: Prophylactic ondansetron did not reduce pruritus when compared with placebo. The use of ondansetron as a treatment did not decrease the severity of pruritus when compared with placebo.
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Analgésicos Opioides/efectos adversos , Anestesia Raquidea/efectos adversos , Antipruriginosos/uso terapéutico , Morfina/efectos adversos , Ondansetrón/uso terapéutico , Prurito/inducido químicamente , Prurito/prevención & control , Adulto , Analgésicos Opioides/administración & dosificación , Cesárea/métodos , Método Doble Ciego , Femenino , Humanos , Inyecciones Espinales , Morfina/administración & dosificación , Dimensión del Dolor , Náusea y Vómito Posoperatorios/prevención & control , EmbarazoRESUMEN
An octave-spanning coherent supercontinuum is generated by non-collinear Raman-assisted four-wave mixing in single-crystal diamond using 7.7 fs laser pulses that have been chirped to about 420 fs in duration. The use of ultrabroad bandwidth pulses as input results in substantial overlap of the generated spectrum of the anti-Stokes sidebands, creating a phase-locked supercontinuum when all the sidebands are combined to overlap in time and space. The overall bandwidth of the generated supercontinuum is sufficient to support its compression to isolated few-to-single cycle attosecond transients. The significant spectral overlap of adjacent anti-Stokes sidebands allows the utilization of straight-forward spectral interferometry to test the relative phase coherence of the anti-Stokes outputs and is demonstrated here for two adjacent pairs of sidebands. The method can subsequently be employed to set the relative phase of the sidebands for pulse compression and for the synthesis of arbitrary field transients.
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The key nuclear export protein CRM1/XPO1 may represent a promising novel therapeutic target in human multiple myeloma (MM). Here we showed that chromosome region maintenance 1 (CRM1) is highly expressed in patients with MM, plasma cell leukemia cells and increased in patient cells resistant to bortezomib treatment. CRM1 expression also correlates with increased lytic bone and shorter survival. Importantly, CRM1 knockdown inhibits MM cell viability. Novel, oral, irreversible selective inhibitors of nuclear export (SINEs) targeting CRM1 (KPT-185, KPT-330) induce cytotoxicity against MM cells (ED50<200 nM), alone and cocultured with bone marrow stromal cells (BMSCs) or osteoclasts (OC). SINEs trigger nuclear accumulation of multiple CRM1 cargo tumor suppressor proteins followed by growth arrest and apoptosis in MM cells. They further block c-myc, Mcl-1, and nuclear factor κB (NF-κB) activity. SINEs induce proteasome-dependent CRM1 protein degradation; concurrently, they upregulate CRM1, p53-targeted, apoptosis-related, anti-inflammatory and stress-related gene transcripts in MM cells. In SCID mice with diffuse human MM bone lesions, SINEs show strong anti-MM activity, inhibit MM-induced bone lysis and prolong survival. Moreover, SINEs directly impair osteoclastogenesis and bone resorption via blockade of RANKL-induced NF-κB and NFATc1, with minimal impact on osteoblasts and BMSCs. These results support clinical development of SINE CRM1 antagonists to improve patient outcome in MM.
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Carioferinas/antagonistas & inhibidores , Mieloma Múltiple/terapia , Osteoclastos/patología , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Humanos , Mieloma Múltiple/patología , Proteína Exportina 1RESUMEN
SUMMARY: A total of 2,266 postmenopausal Chinese women were followed for 4.5 years to determine the incidence of new fractures. The positive predictive value, negative predictive value, sensitivity and specificity of different treatment strategies were compared. Using a fixed optimal threshold calculated from receiver operating characteristics (ROC) curve had the highest sensitivity but lowest specificity. INTRODUCTION: There is no specific intervention threshold based on FRAX to guide treatment for Asian populations. This prospective study sought to determine the impact of applying different intervention thresholds to a cohort of Chinese postmenopausal women. METHODS: This study was part of the Hong Kong Osteoporosis Study. A total of 2,266 treatment-naïve postmenopausal women underwent clinical risk factor and BMD assessments. The subjects were followed to assess fractures. We calculated the FRAX probability of major osteoporotic fractures corresponding to women with prior fractures but no other clinical risk factors. Different treatment strategies which include treating women with prior fractures, women with age-specific FRAX probability corresponding to those with prior fractures, women with osteoporosis as well as women with FRAX probability above a fixed cut-off based on optimizing sensitivity and specificity on the ROC curve were compared. RESULTS: The mean age at baseline was 62.1 ± 8.5 years, and the mean follow-up time was 4.5 ± 2.8 years. One hundred six new major osteoporotic fractures were reported. An optimal (FRAX, with BMD) cut-off point of 9.95 % was identified. All strategies had negative predictive value of >90 %. Using a fixed cut-off had the highest sensitivity (62.3 %) but lowest specificity (73.5 %) and positive predictive value (10.3 %). Using a fixed cut-off would direct treatment from younger women with lower absolute risk to elderly women with higher absolute risk. CONCLUSION: Targeting only women with prior fractures is unlikely to reduce fracture burden. Other treatment strategies with higher sensitivity need to be considered but they have different shortcomings.
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Fracturas Osteoporóticas/prevención & control , Absorciometría de Fotón/métodos , Adulto , Anciano , Anciano de 80 o más Años , Densidad Ósea/fisiología , Estudios de Cohortes , Técnicas de Apoyo para la Decisión , Femenino , Hong Kong/epidemiología , Humanos , Persona de Mediana Edad , Osteoporosis Posmenopáusica/diagnóstico , Osteoporosis Posmenopáusica/epidemiología , Osteoporosis Posmenopáusica/fisiopatología , Osteoporosis Posmenopáusica/terapia , Fracturas Osteoporóticas/epidemiología , Fracturas Osteoporóticas/etiología , Fracturas Osteoporóticas/fisiopatología , Valor Predictivo de las Pruebas , Medición de Riesgo/métodos , Factores de RiesgoRESUMEN
Drugs that target the chief mediator of nuclear export, chromosome region maintenance 1 protein (CRM1) have potential as therapeutics for leukemia, but existing CRM1 inhibitors show variable potencies and a broad range of cytotoxic effects. Here, we report the structural analysis and antileukemic activity of a new generation of small-molecule inhibitors of CRM1. Designated selective inhibitors of nuclear export (SINE), these compounds were developed using molecular modeling to screen a small virtual library of compounds against the nuclear export signal (NES) groove of CRM1. The 2.2-Å crystal structure of the CRM1-Ran-RanBP1 complex bound to KPT-251, a representative molecule of this class of inhibitors, shows that the drug occupies part of the groove in CRM1 that is usually occupied by the NES, but penetrates much deeper into the groove and blocks CRM1-directed protein export. SINE inhibitors exhibit potent antileukemic activity, inducing apoptosis at nanomolar concentrations in a panel of 14 human acute myeloid leukemia (AML) cell lines representing different molecular subtypes of the disease. When administered orally to immunodeficient mice engrafted with human AML cells, KPT-251 had potent antileukemic activity with negligible toxicity to normal hematopoietic cells. Thus, KPT-SINE CRM1 antagonists represent a novel class of drugs that warrant further testing in AML patients.
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Transporte Activo de Núcleo Celular/efectos de los fármacos , Antineoplásicos/farmacología , Carioferinas/química , Leucemia Mieloide Aguda/tratamiento farmacológico , Señales de Exportación Nuclear , Proteínas Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/química , Proteína de Unión al GTP ran/metabolismo , Animales , Antineoplásicos/química , Apoptosis , Western Blotting , Ciclo Celular , Núcleo Celular/metabolismo , Proliferación Celular , Células Cultivadas , Cristalización , Cristalografía por Rayos X , Femenino , Células Madre Hematopoyéticas , Humanos , Subunidad gamma Común de Receptores de Interleucina/fisiología , Carioferinas/metabolismo , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Proteínas Nucleares/química , Unión Proteica , Receptores Citoplasmáticos y Nucleares/metabolismo , Bibliotecas de Moléculas Pequeñas , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína de Unión al GTP ran/química , Proteína Exportina 1RESUMEN
Mixed lineage leukemia (MLL)-fusion proteins can induce acute myeloid leukemias (AMLs) from either hematopoietic stem cells (HSCs) or granulocyte-macrophage progenitors (GMPs), but it remains unclear whether the cell of origin influences the biology of the resultant leukemia. MLL-AF9-transduced single HSCs or GMPs could be continuously replated, but HSC-derived clones were more likely than GMP-derived clones to initiate AML in mice. Leukemia stem cells derived from either HSCs or GMPs had a similar immunophenotype consistent with a maturing myeloid cell (LGMP). Gene expression analyses demonstrated that LGMP inherited gene expression programs from the cell of origin including high-level Evi-1 expression in HSC-derived LGMP. The gene expression signature of LGMP derived from HSCs was enriched in poor prognosis human MLL-rearranged AML in three independent data sets. Moreover, global 5'-mC levels were elevated in HSC-derived leukemias as compared with GMP-derived leukemias. This mirrored a difference seen in 5'-mC between MLL-rearranged human leukemias that are either EVI1 positive or EVI1 negative. Finally, HSC-derived leukemias were more resistant to chemotherapy than GMP-derived leukemias. These data demonstrate that the cell of origin influences the gene expression profile, the epigenetic state and the drug response in AML, and that these differences can account for clinical heterogeneity within a molecularly defined group of leukemias.