KPT-330 inhibitor of CRM1 (XPO1)-mediated nuclear export has selective anti-leukaemic activity in preclinical models of T-cell acute lymphoblastic leukaemia and acute myeloid leukaemia.

This study explored the anti-leukaemic efficacy of novel irreversible inhibitors of the major nuclear export receptor, chromosome region maintenance 1 (CRM1, also termed XPO1). We found that these novel CRM1 antagonists, termed SINE (Selective Inhibitors of Nuclear Export), induced rapid apoptosis at low nanomolar concentrations in a panel of 14 human T-cell acute lymphoblastic leukaemia (T-ALL) cell lines representing different molecular subtypes of the disease. To assess in vivo anti-leukaemia cell activity, we engrafted immunodeficient mice intravenously with the human T-ALL MOLT-4 cells, which harbour activating mutations of NOTCH1 and NRAS as well as loss of function of the CDKN2A, PTEN and TP53 tumour suppressors and express a high level of oncogenic transcription factor TAL1.

Selective inhibitors of nuclear export block pancreatic cancer cell proliferation and reduce tumor growth in mice.

Background & Aims: Tumor-suppressor proteins are inactivated by many different mechanisms, including nuclear exclusion by chromosome region maintenance (CRM)-1. Increased tumor levels of CRM-1 have been correlated with poor prognosis of patients with pancreatic cancer, making it a therapeutic target. Selective inhibitors of nuclear export (SINEs) bind to CRM-1 to irreversibly inhibit its ability to export proteins; we investigated a new class of SINEs in pancreatic cancer cells.

CRM1 blockade by selective inhibitors of nuclear export attenuates kidney cancer growth.

Purpose: Renal cell carcinoma often presents asymptomatically and patients are commonly diagnosed at the metastatic stage, when treatment options are limited and survival is poor. Since progression-free survival using current therapy for metastatic renal cell carcinoma is only 1 to 2 years and existing drugs are associated with a high resistance rate, new pharmacological targets are needed. We identified and evaluated the nuclear exporter protein CRM1 as a novel potential therapy for renal cell carcinoma.

SLC6A4 gene variants and temporal lobe epilepsy susceptibility: a meta-analysis.

There seems to be a role for serotoninergic neuro-transmission in the pathophysiology of the epilepsies. Different groups have studied the role of regulatory variants in the SLC6A4 gene, which code for the central serotonin transporter, in the complex genetics of temporal lobe epilepsy (TLE) obtaining contradictory findings. Therefore, a systematic review and critical analysis of this topic seem to be timely.

Identification and characterization of novel catalytic bioscavengers of organophosphorus nerve agents.

In an effort to discover novel catalytic bioscavengers of organophosphorus (OP) nerve agents, cell lysates from a diverse set of bacterial strains were screened for their capacity to hydrolyze the OP nerve agents VX, VR, and soman (GD). The library of bacterial strains was identified using both random and rational approaches. Specifically, two representative strains from eight categories of extremophiles were chosen at random.

Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia.

The nuclear export protein XPO1 is overexpressed in cancer, leading to the cytoplasmic mislocalization of multiple tumor suppressor proteins. Existing XPO1-targeting agents lack selectivity and have been associated with significant toxicity. Small molecule selective inhibitors of nuclear export (SINEs) were designed that specifically inhibit XPO1.

Novel selective inhibitors of nuclear export CRM1 antagonists for therapy in mantle cell lymphoma.

Overexpression of the cellular nuclear exportin 1, more commonly called chromosomal region maintenance 1 (CRM1), has been associated with malignant progression and mortality. Therefore, activation of nuclear export can play a significant etiologic role in some forms of human neoplasia and serve as a novel target for the treatment of these cancers. Mantle cell lymphoma (MCL) is an aggressive histotype of B-cell non-Hodgkin lymphoma that remains incurable.

Antileukemic activity of nuclear export inhibitors that spare normal hematopoietic cells.

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.

Diastereoselective chelation-controlled additions to β-silyloxy aldehydes.

A general diastereoselective method for the addition of dialkylzincs and (E)-di- and (E)-trisubstituted vinylzinc reagents to β-silyloxy aldehydes is presented. This method employs alkyl zinc triflate and nonaflate Lewis acids and affords chelation-controlled products (6:1 to > 20:1 dr).

Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia.

Chromosome maintenance protein 1 (CRM1) is a nuclear export receptor involved in the active transport of tumor suppressors (e.g., p53 and nucleophosmin) whose function is altered in cancer because of increased expression and overactive transport.

Malformations of cortical development and epilepsy in adult patients.

Objective: To describe clinical features of epilepsy secondary to Malformation of Cortical Development (MCD) in a series of adult patients.

Materials And Methods: We searched our database for all cases with confirmed epilepsy and MCD and included in the study only those with complete data. Mean age, sex, age at seizure onset (ASO), seizure types, abnormal neurological exam (ANE), mental retardation, family history, gestational or perinatal insults (G-PI), interictal EEG and response to treatment were analyzed.

[Contribution of diffusion tensor magnetic resonance imaging to the diagnosis of focal cortical dysplasias].

Introduction: Focal cortical dysplasias (FCD) are cortical malformations and, although they display typical characteristics in conventional magnetic resonance imaging (MRI), the precise determination of the epileptogenic zone remains a controversial issue. The less favourable progress during the post-operative period with respect to other symptomatic epilepsies could be explained by the existence of epileptogenic areas that do not show up in conventional MRI. Diffusion tensor imaging (DTI) is sensitive to subtle microstructural abnormalities, and fractional anisotropy, which is an indirect indicator, shows areas with reductions in the underlying white matter that go beyond the alterations detected with conventional MRI in isolated cases in previous works.

Diagnosis of mitochondrial disorders applying massive pyrosequencing.

Mitochondrial disorders are a frequent cause of neurological disability affecting children and adults. Traditionally, molecular diagnosis of mitochondrial diseases was mostly accomplished by the use of Sanger sequencing and PCR-RFLP. However, there are particular drawbacks associated with the use of these methods.

Cerebrotendinous xanthomatosis revealed in drug-resistant epilepsy diagnostic workup.

Cerebrotendinous xanthomatosis (CTX) is a treatable disorder of bile acid production caused by mutations in the mitochondrial enzyme sterol 27-hydroxilase. This inborn error of bile acid metabolism results in lipid pathologic accumulation in multiple tissues. Progressive neuropsychiatric disturbances are a frequent manifestation of this disease.

European starlings (Sturnus vulgaris) challenged with Escherichia coli O157 can carry and transmit the human pathogen to cattle.

Aims: European starlings (Sturnus vulgaris) are an invasive species in the United States and are considered a nuisance pest to agriculture. The goal of this study was to determine the potential for these birds to be reservoirs and/or vectors for the human pathogen Escherichia coli O157:H7.

Materials And Results: Under biosecurity confinement, starlings were challenged with various doses of E.

Applying lean: implementation of a rapid triage and treatment system.

Objective: Emergency department (ED) crowding creates issues with patient satisfaction, long wait times and leaving the ED without being seen by a doctor (LWBS). Our objective was to evaluate how applying Lean principles to develop a Rapid Triage and Treatment (RTT) system affected ED metrics in our community hospital.

Methods: Using Lean principles, we made ED process improvements that led to the RTT system.

Immunogenicity of an interferon-beta1a product.

In order to determine whether Blastoferon®, a biosimilar interferon (IFN)- beta 1a formulation, shares epitopes with other known IFN-beta products, a series of neutralization bioassays were performed with a set of well-characterized anti-IFN- beta monoclonal antibodies and human sera (World Health Organization Reference Reagents). The bioassay was the interferon-induced inhibition of virus cytopathic effect on human cells in culture (EMC virus and A-549 cells). Computer-calculated results were reported as Tenfold Reduction Units (TRU)/ml.

TNFRSF1A [corrected] R92Q mutation, autoinflammatory symptoms and multiple sclerosis in a cohort from Argentina.

Systemic autoinflammatory diseases are genetic disorders characterized by seemingly unprovoked inflammation, without major involvement of the adaptive immune system. Among them it is recognized the TNF receptor associated periodic syndrome (TRAPS) caused by mutations in the TNFRSF1A gene and characterized by symptoms such as recurrent high fevers, rash, abdominal pain, arthralgia and myalgia. Recent studies have recognized the potential role of TNFRSF1A mutations in Multiple Sclerosis (MS).

Stopover ecology of a migratory ungulate.

1. Birds that migrate long distances use stopover sites to optimize fuel loads and complete migration as quickly as possible. Stopover use has been predicted to facilitate a time-minimization strategy in land migrants as well, but empirical tests have been lacking, and alternative migration strategies have not been considered.

Are wolves saving Yellowstone's aspen? A landscape-level test of a behaviorally mediated trophic cascade.

Behaviorally mediated trophic cascades (BMTCs) occur when the fear of predation among herbivores enhances plant productivity. Based primarily on systems involving small-bodied predators, BMTCs have been proposed as both strong and ubiquitous in natural ecosystems. Recently, however, synthetic work has suggested that the existence of BMTCs may be mediated by predator hunting mode, whereby passive (sit-and-wait) predators have much stronger effects than active (coursing) predators.

ApoE epsilon4 genotype and the age at onset of temporal lobe epilepsy: a case-control study and meta-analysis.

In order to investigate the role of ApoE epsilon4 as a modifier of the age at onset of temporal lobe epilepsy (TLE), we performed a molecular epidemiology study in 78 patients with mesial temporal lobe epilepsy and hippocampal sclerosis. Genotyping was done by a PCR-RFLP assay. In order to better estimate the role of this variant as a modifier of the age at onset, we also performed a systematic review of the literature.

A randomized controlled trial to assess the impact of dietary energy sources, feed supplements, and the presence of super-shedders on the detection of Escherichia coli O157:H7 in feedlot cattle using different diagnostic procedures.

Alteration of the gastro-intestinal tract through manipulation of cattle diets has been proposed as a preharvest control measure to reduce fecal shedding of Escherichia coli O157:H7. The objective of this study was to examine the effects of the energy source's moisture content (high moisture corn and dry whole-shelled corn), two natural feed supplements (Saccaromyces cerevisiae boulardii CNCM 1079-Levucell and Aspergillus oryzae-Amaferm), and two levels of vitamin A (2200 IU/kg and no supplementation) on the fecal excretion of E. coli O157:H7 in naturally infected cattle.

"Chopstick" surgery: a novel technique improves surgeon performance and eliminates arm collision in robotic single-incision laparoscopic surgery.

Introduction: Single-incision laparoscopic surgery (SILS) is limited by the coaxial arrangement of the instruments. A surgical robot with wristed instruments could overcome this limitation, but the arms often collide when working coaxially. This study tests a new technique of "chopstick" surgery to enable use of the robotic arms through a single incision without collision.