NPM1 is the most frequently mutated gene in cytogenetically normal acute myeloid leukemia (AML). In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein ...(NPM1c); however, it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in immediate downregulation of homeobox (HOX) genes followed by differentiation. Finally, we show that XPO1 inhibition relocalizes NPM1c to the nucleus, promotes differentiation of AML cells, and prolongs survival of Npm1-mutated leukemic mice. We describe an exquisite dependency of NPM1-mutant AML cells on NPM1c, providing the rationale for the use of nuclear export inhibitors in AML with mutated NPM1.
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•Relocalization or degradation of mutant NPM1 induces differentiation of AML cells•High HOX expression maintains the leukemic state in NPM1-mutant AML•HOX overexpression is directly dependent on mutant NPM1•AML dependency on mutant NPM1 can be exploited therapeutically
Brunetti et al. show that specific loss of NPM1c from the cytoplasm leads to downregulation of HOX genes and differentiation in NPM1 mutant AML. Blocking NPM1c nuclear export by XPO1 inhibition reduces cytoplasmic NPM1c, promotes AML differentiation, and prolongs the survival of a mouse model of NPM1c+ AML.
Abstract Docosahexaenoic acid (DHA), a polyunsaturated fatty acid (PUFA) enriched in phospholipids in the brain and retina, is known to play multi-functional roles in brain health and diseases. While ...arachidonic acid (AA) is released from membrane phospholipids by cytosolic phospholipase A2 (cPLA2 ), DHA is linked to action of the Ca2+ -independent iPLA2. DHA undergoes enzymatic conversion by 15-lipoxygenase (Alox 15) to form oxylipins including resolvins and neuroprotectins, which are powerful lipid mediators. DHA can also undergo non-enzymatic conversion by reacting with oxygen free radicals (ROS), which cause the production of 4-hydoxyhexenal (4-HHE), an aldehyde derivative which can form adducts with DNA, proteins and lipids. In studies with both animal models and humans, there is evidence that inadequate intake of maternal n-3 PUFA may lead to aberrant development and function of the central nervous system (CNS). What is less certain is whether consumption of n-3 PUFA is important in maintaining brain health throughout one's life span. Evidence mostly from non-human studies suggests that DHA intake above normal nutritional requirements might modify the risk/course of a number of diseases of the brain. This concept has fueled much of the present interest in DHA research, in particular, in attempts to delineate mechanisms whereby DHA may serve as a nutraceutical and confer neuroprotective effects. Current studies have revealed ability for the oxylipins to regulation of cell redox homeostasis through the Nuclear factor (erythroid-derived 2)-like 2/Antioxidant response element (Nrf2/ARE) anti-oxidant pathway, and impact signaling pathways associated with neurotransmitters, and modulation of neuronal functions involving brain-derived neurotropic factor (BDNF). This review is aimed at describing recent studies elaborating these mechanisms with special regard to aging and Alzheimer's disease, autism spectrum disorder, schizophrenia, traumatic brain injury, and stroke.
Farming and pesticide use have previously been linked to non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). We evaluated agricultural use of specific ...insecticides, fungicides, and fumigants and risk of NHL and NHL-subtypes (including CLL and MM) in a U.S.-based prospective cohort of farmers and commercial pesticide applicators. A total of 523 cases occurred among 54,306 pesticide applicators from enrollment (1993-97) through December 31, 2011 in Iowa, and December 31, 2010 in North Carolina. Information on pesticide use, other agricultural exposures and other factors was obtained from questionnaires at enrollment and at follow-up approximately five years later (1999-2005). Information from questionnaires, monitoring, and the literature were used to create lifetime-days and intensity-weighted lifetime days of pesticide use, taking into account exposure-modifying factors. Poisson and polytomous models were used to calculate relative risks (RR) and 95% confidence intervals (CI) to evaluate associations between 26 pesticides and NHL and five NHL-subtypes, while adjusting for potential confounding factors. For total NHL, statistically significant positive exposure-response trends were seen with lindane and DDT. Terbufos was associated with total NHL in ever/never comparisons only. In subtype analyses, terbufos and DDT were associated with small cell lymphoma/chronic lymphocytic leukemia/marginal cell lymphoma, lindane and diazinon with follicular lymphoma, and permethrin with MM. However, tests of homogeneity did not show significant differences in exposure-response among NHL-subtypes for any pesticide. Because 26 pesticides were evaluated for their association with NHL and its subtypes, some chance finding could have occurred. Our results showed pesticides from different chemical and functional classes were associated with an excess risk of NHL and NHL subtypes, but not all members of any single class of pesticides were associated with an elevated risk of NHL or NHL subtypes. These findings are among the first to suggest links between DDT, lindane, permethrin, diazinon and terbufos with NHL subtypes.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Lymph node metastases in cancer patients are associated with tumor aggressiveness, poorer prognoses, and the recommendation for systemic therapy. Whether cancer cells in lymph nodes can seed distant ...metastases has been a subject of considerable debate. We studied mice implanted with cancer cells (mammary carcinoma, squamous cell carcinoma, or melanoma) expressing the photoconvertible protein Dendra2. This technology allowed us to selectively photoconvert metastatic cells in the lymph node and trace their fate. We found that a fraction of these cells invaded lymph node blood vessels, entered the blood circulation, and colonized the lung. Thus, in mouse models, lymph node metastases can be a source of cancer cells for distant metastases. Whether this mode of dissemination occurs in cancer patients remains to be determined.
IMPORTANCE: Health care services that support the hospital-to-home transition can improve outcomes in patients with heart failure (HF). OBJECTIVE: To test the effectiveness of the Patient-Centered ...Care Transitions in HF transitional care model in patients hospitalized for HF. DESIGN, SETTING, AND PARTICIPANTS: Stepped-wedge cluster randomized trial of 2494 adults hospitalized for HF across 10 hospitals in Ontario, Canada, from February 2015 to March 2016, with follow-up until November 2016. INTERVENTIONS: Hospitals were randomized to receive the intervention (n = 1104 patients), in which nurse-led self-care education, a structured hospital discharge summary, a family physician follow-up appointment less than 1 week after discharge, and, for high-risk patients, structured nurse homevisits and heart function clinic care were provided to patients, or usual care (n = 1390 patients), in which transitional care was left to the discretion of clinicians. MAIN OUTCOMES AND MEASURES: Primary outcomes were hierarchically ordered as composite all-cause readmission, emergency department (ED) visit, or death at 3 months; and composite all-cause readmission or ED visit at 30 days. Secondary outcomes were B-PREPARED score for discharge preparedness (range: 0 most prepared to 22 least prepared); the 3-Item Care Transitions Measure (CTM-3) for quality of transition (range: 0 worst transition to 100 best transition); the 5-level EQ-5D version (EQ-5D-5L) for quality of life (range: 0 dead to 1 full health); and quality-adjusted life-years (QALY; range: 0 dead to 0.5 full health at 6 months). RESULTS: Among eligible patients, all 2494 (mean age, 77.7 years; 1258 50.4% women) completed the trial. There was no significant difference between the intervention and usual care groups in the first primary composite outcome (545 49.4% vs 698 50.2% events, respectively; hazard ratio HR, 0.99 95% CI, 0.83-1.19) or in the second primary composite outcome (304 27.5% vs 408 29.3% events, respectively; HR, 0.93 95% CI, 0.73-1.18). There were significant differences between the intervention and usual care groups in the secondary outcomes of mean B-PREPARED score at 6 weeks (16.6 vs 13.9; difference, 2.65 95% CI, 1.37-3.92; P < .001); mean CTM-3 score at 6 weeks (76.5 vs 70.3; difference, 6.16 95% CI, 0.90-11.43; P = .02); and mean EQ-5D-5L score at 6 weeks (0.7 vs 0.7; difference, 0.06 95% CI, 0.01 to 0.11; P = .02) and 6 months (0.7 vs 0.6; difference, 0.06 95% CI, 0.01-0.12; P = .02). There was no significant difference in mean QALY between groups at 6 months (0.3 vs 0.3; difference, 0.00 95% CI, −0.02 to 0.02; P = .98). CONCLUSIONS AND RELEVANCE: Among patients with HF in Ontario, Canada, implementation of a patient-centered transitional care model compared with usual care did not improve a composite of clinical outcomes. Whether this type of intervention could be effective in other health care systems or locations would require further research. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02112227
The purpose of this study was to assess the diagnostic accuracy of TAG320 in predicting functional stenosis severity evaluated by fractional flow reserve (FFR).
Coronary computed tomography ...angiography (CCTA) has limited specificity for predicting functionally significant stenoses. Recent studies suggest that contrast gradient attenuation along an arterial lesion, or transluminal attenuation gradient (TAG), may provide assessment of functional significance of coronary stenosis. The use of 320-detector row computed tomography (CT), enabling near isophasic, single-beat imaging of the entire coronary tree, may be ideal for TAG functional assessment of a coronary arterial stenosis.
We assessed the diagnostic accuracy of TAG320 using 320-row CCTA with FFR for the evaluation of functional stenosis severity in consecutive patients undergoing invasive coronary angiography and FFR for stable chest pain. The luminal radiological contrast attenuation (Hounsfield units HU) was measured at 5-mm intervals along the artery from ostium to a distal level where the cross-sectional area decreased to <2.0 mm(2). TAG320 was defined as the linear regression coefficient between luminal attenuation and axial distance. Functionally significant coronary stenosis was defined as ≤0.8 on FFR.
In our cohort of 54 patients (age 62.7 ± 8.7 years, 35 men, 78 vessels), TAG320 in FFR-significant vessels was significantly lower when compared with FFR nonsignificant vessels (-21 -27; -16 vs. -11 -16; -3 HU/10 mm, p < 0.001). On receiver-operating characteristic analysis, a retrospectively determined TAG320 cutoff of -15.1 HU/10 mm predicted FFR ≤0.8 with (a bootstrapped resampled) a sensitivity of 77%, specificity of 74%, positive predictive value of 67%, and negative predictive value of 86%. The combined TAG320 and CCTA assessment had an area under the curve of 0.88. There was incremental value of adding TAG320 to CCTA assessment for detection of significant FFR by Wald test (p = 0.0001) and integrated discrimination improvement index (0.11, p = 0.002).
Assessment of TAG320 with a 320-detector row CT provides acceptable prediction of invasive FFR and may provide a noninvasive modality for detecting functionally significant coronary stenoses. Combined TAG320 and CCTA assessment may have incremental predictive value over CCTA alone for detecting functionally significant coronary arterial stenoses; however, larger studies are required to determine the benefit of combined TAG320 and CCTA assessment.
Successful organizations adapt their marketing strategies to marketplace changes. Boundary spanners, such as salespeople, because they are able to embed themselves in social networks outside the ...organization, play a key role in developing marketplace knowledge. However, if this knowledge remains solely with the boundary spanners, it cannot be used effectively to improve firm performance. This study investigates tacit knowledge exchange between sales and marketing and its ability to enhance marketing success (i.e., marketing program innovativeness, relative efficiency, and relative effectiveness). In addition, by examining five antecedents hypothesized to influence tacit knowledge exchange, it provides guidance to sales and marketing managers, who desire to improve tacit knowledge exchange, and, in turn, marketing success.
Cervical cancer remains one of the leading causes of cancer-related deaths worldwide. Here we report the extensive molecular characterization of 228 primary cervical cancers, one of the largest ...comprehensive genomic studies of cervical cancer to date. We observed notable APOBEC mutagenesis patterns and identified SHKBP1, ERBB3, CASP8, HLA-A and TGFBR2 as novel significantly mutated genes in cervical cancer. We also discovered amplifications in immune targets CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2), and the BCAR4 long non-coding RNA, which has been associated with response to lapatinib. Integration of human papilloma virus (HPV) was observed in all HPV18-related samples and 76% of HPV16-related samples, and was associated with structural aberrations and increased target-gene expression. We identified a unique set of endometrial-like cervical cancers, comprised predominantly of HPV-negative tumours with relatively high frequencies of KRAS, ARID1A and PTEN mutations. Integrative clustering of 178 samples identified keratin-low squamous, keratin-high squamous and adenocarcinoma-rich subgroups. These molecular analyses reveal new potential therapeutic targets for cervical cancers.
Context-dependent inhibition of N-methyl-D-aspartate (NMDA) receptors has important therapeutic implications for the treatment of neurological diseases that are associated with altered neuronal ...firing and signaling. This is especially true in stroke, where the proton concentration in the afflicted area can increase by an order of magnitude. A class of allosteric inhibitors, the 93-series, shows greater potency against GluN1-GluN2B NMDA receptors in such low pH environments, allowing targeted therapy only within the ischemic region. Here we map the 93-series compound binding site in the GluN1-GluN2B NMDA receptor amino terminal domain and show that the interaction of the N-alkyl group with a hydrophobic cage of the binding site is critical for pH-dependent inhibition. Mutation of residues in the hydrophobic cage alters pH-dependent potency, and remarkably, can convert inhibitors into potentiators. Our study provides a foundation for the development of highly specific neuroprotective compounds for the treatment of neurological diseases.
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