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Background Activating mutations [internal tandem duplication (ITD)] or overexpression of the FMS-like tyrosine kinase receptor-3 ( FLT3 ) gene are associated with poor outcome in acute myeloid leukemia (AML) patients, underscoring the need for novel therapeutic approaches. The natural product silvestrol has potent antitumor activity in several malignancies, but its therapeutic impact on distinct molecular high-risk AML subsets remains to be fully investigated. We examined here the preclinical activity of silvestrol in FLT3 -ITD and FLT3 wild-type (wt) AML. Methods Silvestrol in vitro anti-leukemic activity was examined by colorimetric cell viability assay, colony-forming and flow cytometry assays assessing growth inhibition and apoptosis, respectively. Pharmacological activity of silvestrol on FLT3 mRNA translation, mRNA and protein expression was determined by RNA-immunoprecipitation, qRT-PCR and immunoblot analyses, respectively. Silvestrol in vivo efficacy was investigated using MV4-11 leukemia-engrafted mice. Results Silvestrol shows antileukemia activity at nanomolar concentrations both in FLT3 -wt overexpressing (THP-1) and FLT3 -ITD (MV4-11) expressing AML cell lines (IC 50  = 3.8 and 2.7 nM, respectively) and patients’ primary blasts [IC 50  = ~12 nM ( FLT3 -wt) and ~5 nM ( FLT3 -ITD)]. Silvestrol increased apoptosis (~4fold, P = 0.0001), and inhibited colony-formation (100%, P < 0.0001) in primary blasts. Silvestrol efficiently inhibited FLT3 translation reducing FLT3 protein expression by 80–90% and decreased miR-155 levels (~60%), a frequently co-regulated onco-miR in FLT3 -ITD-positive AML. The median survival of silvestrol-treated vs vehicle-treated mice was 63 vs 29 days post-engraftment, respectively (P < 0.0001). Conclusions Silvestrol exhibits significant in vivo and in vitro antileukemic activities in AML through a novel mechanism resulting in inhibition of FLT3 and miR-155 expression. These encouraging results warrant a rapid translation of silvestrol for clinical testing in AML.

Drug-resistance of tumor-initiating cells, impaired NK cell immune-response, PP2A loss-of- function and aberrant miRNA expression are cancer features resulting from microenvironmental- and tumor-specific signals. Here we report that genomic-imprinted MIR300 is a cell context- independent dual function tumor suppressor which is upregulated in quiescent leukemic stem (LSC) and NK cells by microenvironmental signals to induce quiescence and impair immune- response, respectively, but inhibited in CML and AML proliferating blasts to prevent PP2A- induced apoptosis. MIR300 anti-proliferative and PP2A-activating functions are differentially activated through dose-dependent CCND2/CDK6 and SET inhibition, respectively. LSCs escape PP2A-mediated apoptosis through TUG1 lncRNA that uncouples and limits MIR300 functions to cytostasis by regulating unbound-MIR300 levels. Halting MIR300 homeostasis restores NK cell activity and suppresses leukemic but not normal hematopoiesis by eradicating nearly all LSCs. Thus, MIR300 tumor suppressor activity is essential and therapeutically important for LSC-driven leukemias.

The measurement of environmental pollutants is often very difficult because they are typically present at low concentrations in complex matrices. The research described herein details the development and optimization of analytical methods for the chemical and physical speciation of semi-volatile organic and inorganic compounds in solid and aqueous matrices in an effort to better understand the transport and fate of these pollutants in the environment. A novel method for real-time in situ characterization of polycyclic aromatic hydrocarbons (PAHs) in submerged freshwater sediments was developed. Field-testing was conducted at 10 sites in the Milwaukee Harbor (total PAH concentrations ranged from ∼10 to 650 μg g−1); conventional sediment core samples were collected concurrently. The core samples were analyzed by an improved Pressurized Liquid Extraction (PLE) method and EPA Method 8270C (Gas Chromatography-Mass Spectrometry, GC-MS) for PAHs. The optimized method is simple, fast, efficient, and requires small amounts of sample and generates small amounts of secondary waste. The method described requires ∼90% less extraction solvent and yields 45% improvement in precision compared to previously published methods. A Flow Field-Flow Fractionation (FlFFF) method was developed to determine the distribution of “dissolved” colloids (<0.45 μm) in an ultra-filtered concentrated groundwater sample. The FlFFF method was developed using 50, 112, 214, and 402 nm polystyrene sulfonate (PSS) particle standards. Constant, time-delayed exponential, and linear crossflow decay programs were developed with the PSS standards and a high-resolution separation method was created. The FlFFF method was then used to study the efficiency and retention of the PSS standards by 0.45 μm cellulose acetate (CA) and polytetrafluoroethylene (PTFE) syringe filters. A concentrated groundwater sample was then fractionated using the linear crossflow decay method and collected fractions were studied to determine the distribution of inorganic arsenic with different sized colloids. Arsenic and iron were quantified in collected fractions by Inductively Coupled Plasma-Mass Spectrometry. Although recovery of the concentrate during the FlFFF separation was low, a plot of iron concentration and the arsenic associated with it illustrated the absence of size specific adsorption between arsenic and iron oxides in groundwater. (Abstract shortened by UMI.)

ObjectiveTo characterise the long-term outcomes of patients with COVID-19 admitted to a large New York City medical centre at 3 and 6 months after hospitalisation and describe their healthcare usage, symptoms, morbidity and mortality.DesignRetrospective cohort through manual chart review of the electronic medical record.SettingNewYork-Presbyterian/Columbia University Irving Medical Center, a quaternary care academic medical centre in New York City.ParticipantsThe first 1190 consecutive patients with symptoms of COVID-19 who presented to the hospital for care between 1 March and 8 April 2020 and tested positive for SARS-CoV-2 on reverse transcriptase PCR assay.Main outcome measuresType and frequency of follow-up encounters, self-reported symptoms, morbidity and mortality at 3 and 6 months after presentation, respectively; patient disposition information prior to admission, at discharge, and at 3 and 6 months after hospital presentation.ResultsOf the 1190 reviewed patients, 929 survived their initial hospitalisation and 261 died. Among survivors, 570 had follow-up encounters (488 at 3 months and 364 at 6 months). An additional 33 patients died in the follow-up period. In the first 3 months after admission, most encounters were telehealth visits (59%). Cardiopulmonary symptoms (35.7% and 28%), especially dyspnoea (22.1% and 15.9%), were the most common reported symptoms at 3-month and 6-month encounters, respectively. Additionally, a large number of patients reported generalised (26.4%) or neuropsychiatric (24.2%) symptoms 6 months after hospitalisation. Patients with severe COVID-19 were more likely to have reduced mobility, reduced independence or a new dialysis requirement in the 6 months after hospitalisation.ConclusionsPatients hospitalised with SARS-CoV-2 infection reported persistent symptoms up to 6 months after diagnosis. These results highlight the long-term morbidity of COVID-19 and its burden on patients and healthcare resources.