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As it emerges from the literature, electricity access in rural contexts is deeply intertwined with socioeconomic dynamics. However, the advent of a reliable and sufficient source of electricity is not the sole driver that might contribute to local development. Indeed, complementary activities might have a crucial role in sustaining the development of rural communities as well as the electricity access. The current research addresses the lack of counterfactual scenarios in which the impact of complementary activities on electrification projects can be investigated. The authors introduce the case study of Matembwe village, a rural community in the Njombe region of Tanzania. The data collection includes the electricity consumption, number of electricity connections, and number of income-generating activities in a timespan ranging from 1989 to 2015. The analysis is based on system dynamics. The study considers different scenarios representing the dynamics related to the following complementary actions: access to market measures, access to credit measures, and access to usable skills. On the one hand, the study reveals that the effectiveness of the considered complementary actions is limited except from the access to microcredit which fosters an increase in electricity connections by 17%. On the other hand, both access to microcredit and the starting up of a local cooperative by CEFA Onlus that reinvests its profits in the local market impact the socio-economic dimension by 69% and 22%, respectively. [ABSTRACT FROM AUTHOR]

Abstract: The pathogenic role of antibodies in multiple sclerosis (MS) is still controversial. We transferred to mice with experimental autoimmune encephalomyelitis (EAE), animal model of MS, IgG antibodies purified from a MS patient presenting a dramatic clinical improvement during relapse after selective IgG removal with immunoadsorption. Passive transfer of patient's IgG exacerbated motor paralysis and increased mouse central nervous system (CNS) inflammation and demyelination. Binding of patient's IgG was demonstrated in mouse CNS, with a diffuse staining of white matter oligodendrocytes. These data support a growing body of evidence that antibodies can play an important role in the pathobiology of MS. [Copyright &y& Elsevier]

The decarbonisation of residential heat through integration with the power system and deployment of refurbishment policies is at the core of European energy policies. Yet, heat-electricity integration may be challenged, in practice, by the large variability of heat demand across weather years. Current approaches for residential heat demand simulation fail to provide insights about the extent of such variability across many weather years and about the benefits potentially brought about by nearly zero-energy buildings. To fill this gap, this work develops an open-source space-heating demand simulation workflow that is applicable to any country's building stock. The workflow, based on a well-established lumped-parameter thermodynamic model, allows capturing sub-national weather-year variability and the mitigation effects of refurbishment. For Italy, different weather years lead to variations in heat demand up to 2 TWh/day, lasting for several days. Moreover, some weather regimes produce spatial asymmetries that may further complicate heat-electricity integration. The refurbishment of about 55% of buildings constructed before 1975 could substantially mitigate such oscillations, leading to a 31–37% reduction of yearly heat demand, primarily in colder regions. Intra-day heat demand variations, driven by user behaviour, are not substantially impacted by refurbishment, calling for the simultaneous deployment of flexible heat generating technologies. • Heat demand models fail to capture weather variability and refurbishment benefits. • This study provides an open, context-adaptable workflow that allows to do so. • For Italy, large and long-lasting demand variations occur across weather regimes. • Refurbishment can reduce absolute demand by up to 37% and mitigate oscillations. • All such effects vary spatially and must be evaluated at sub-national resolution. [ABSTRACT FROM AUTHOR]

Aims. To investigate the postprandial changes in serum lipoproteins and blood glucose and to verify whether different nutrient composition of the meal elicits different response in patients with (MetS+) and without (MetS-) metabolic syndrome. Research Design and Methods. 50MetS- patients and 50 age- and sex-matchedMetS- consumed a regular lunch chosen among those more similar to their usual diet. Blood was drawn in the morning after 12-hour fasting and 2 and 4:30 hours after the meal. Results. Serum triglycerides increased more in MetS+ (35%, 4:30 hours after the meal) than in MetS- (29%), HDL-cholesterol decreased 2 hours after the meal in both groups (-4% and -5%, resp.). Blood sugar similarly increased in both groups (19%, 2 hours after the meal in MetS+ and 17% in MetS-) and plasma insulin increased more and remained high longer in MetS+ (73.5 and 52.3 μU/mL, 2 and 4:30 hours after the meal) than in MetS- (46.7 and 21.6 μU/mL). Difference in nutrient composition of the meal (carbohydrate 57%, fat 28% versus carbohydrate 45%, fat 35%) was not associated with differences in postprandial levels of triglycerides, HDL-cholesterol, glucose, and insulin within each group. Conclusions. As compared with MetS-, MetS+ patients show a greater hypertriglyceridemic and hyperinsulinemic response to a regular lunch whatever the carbohydrate or fat content of the meal. [ABSTRACT FROM AUTHOR]

Oncogene-induced senescence (OIS) is a barrier for tumor development. Oncogene-dependent DNA damage and activation of the ARF/p53 pathway play a central role in OIS and, accordingly, ARF and p53 are frequently mutated in human cancer. A number of leukemia/lymphoma-initiating oncogenes, however, inhibit ARF/p53 and only infrequently select for ARF or p53 mutations, suggesting the involvement of other tumor-suppressive pathways. We report that NPM-ALK, the initiating oncogene of anaplastic large cell lymphomas (ALCLs), induces DNA damage and irreversibly arrests the cell cycle of primary fibroblasts and hematopoietic progenitors. This effect is associated with inhibition of p53 and is caused by activation of the p16INK4a/pRb tumor-suppressive pathway. Analysis of NPM-ALK lymphomagenesis in transgenic mice showed p16INK4a-dependent accumulation of senescent cells in premalignant lesions and decreased tumor latency in the absence of p16INK4a. Accordingly, human ALCLs showed no expression of either p16INK4a or pRb. Up-regulation of the histone-demethylase Jmjd3 and de-methylation at the p16INK4a promoter contributed to the effect of NPM-ALK on p16INK4a, which was transcriptionally regulated. These data demonstrate that p16INK4a/pRb may function as an alternative pathway of oncogene-induced senescence, and suggest that the reactivation of p16INK4a expression might be a novel strategy to restore the senescence program in some tumors. [ABSTRACT FROM AUTHOR]

Linker histone H1 plays an essential role in chromatin organization. Proper deposition of linker histone H1 as well as its removal is essential for chromatin dynamics and function. Linker histone chaperones perform this important task during chromatin assembly and other DNA-templated phenomena in the cell. Our in vitro data show that the multifunctional histone chaperone NPM1 interacts with linker histone H1 through its first acidic stretch (residues 120-132). Association of NPM1 with linker histone H1 was also observed in cells in culture. NPM1 exhibited remarkable linker histone H1 chaperone activity, as it was able to efficiently deposit histone H1 onto dinucleosomal templates. Overexpression of NPM1 reduced the histone H1 occupancy on the chromatinized template of HIV-1 LTR in TZM-bl cells, which led to enhanced Tat-mediated transactivation. These data identify NPM1 as an important member of the linker histone chaperone family in humans. [ABSTRACT FROM AUTHOR]

Thanks to their modularity and their capacity to adapt to different contexts, hybrid microgrids are a promising solution to decrease greenhouse gas emissions worldwide. To properly assess their impact in different settings at country or cross-country level, microgrids must be designed for each particular situation, which leads to computationally intractable problems. To tackle this issue, a methodology is proposed to create surrogate models using machine learning techniques and a database of microgrids. The selected regression model is based on Gaussian Processes and allows to drastically decrease the computation time relative to the optimal deployment of the technology. The results indicate that the proposed methodology can accurately predict key optimization variables for the design of the microgrid system. The regression models are especially well suited to estimate the net present cost and the levelized cost of electricity (R 2 = 0.99 and 0.98). Their accuracy is lower when predicting internal system variables such as installed capacities of PV and batteries (R 2 = 0.92 and 0.86). A least-cost path towards 100% electrification coverage for the Bolivian lowlands mid-size communities is finally computed, demonstrating the usability and computational efficiency of the proposed framework. • A novel methodology to create surrogate models for energy planning is presented. • Gaussian regression is compared to multi-variable regression. • The surrogate models for Economic indicators have a high prediction accuracy. • PV and Batteries installed capacity have lower prediction accuracy. • Surrogate models are created and coupled to a rural energy planning tool. [ABSTRACT FROM AUTHOR]

The Myc-associated zinc-finger protein, Miz1, is a negative regulator of cell proliferation and induces expression of the cell-cycle inhibitors p15Ink4b and p21Cip1. Here we identify the ribosomal protein L23 as a negative regulator of Miz1-dependent transactivation. L23 exerts this function by retaining nucleophosmin, an essential co-activator of Miz1 required for Miz1-induced cell-cycle arrest, in the nucleolus. Mutant forms of nucleophosmin found in acute myeloid leukaemia fail to co-activate Miz1 and re-localize it to the cytosol. As L23 is encoded by a direct target gene of Myc, this regulatory circuit may provide a feedback mechanism that links translation of Myc target genes and cell growth to Miz1-dependent cell-cycle arrest. [ABSTRACT FROM AUTHOR]

Mutations leading to aberrant cytoplasmic localization of nucleophosmin (NPM) are the most frequent genetic alteration in acute myelogenous leukemia (AML). NPM binds the Arf tumor suppressor and protects it from degradation. The AML-associated NPM mutant (NPMmut) also binds p19Arf but is unable to protect it from degradation, which suggests that inactivation of p19Arf contributes to leukemogenesis in AMLs. We report here that NPM regulates turnover of the c-Myc oncoprotein by acting on the F-box protein Fbw7γ, a component of the E3 ligase complex involved in the ubiquitination and proteasome degradation of c-Myc. NPM was required for nucleolar localization and stabilization of Fbw7γ. As a consequence, c-Myc was stabilized in cells lacking NPM. Expression of NPMmut also led to c-Myc stabilization because of its ability to interact with Fbw7γ, and delocalize it to the cytoplasm, where it is degraded. Because Fbw7 induces degradation of other growth-promoting proteins, the NPM-Fbw7 interaction emerges as a central tumor suppressor mechanism in human cancer. [ABSTRACT FROM AUTHOR]

In response to DNA damage, p53 activates a G1 cell cycle checkpoint, in part through induction of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). Here we report the identification of a new direct p53 target, Ptprv (or ESP), encoding a transmembrane tyrosine phosphatase. Ptprv transcription is dramatically and preferentially increased in cultured cells undergoing p53-dependent cell cycle arrest, but not in cells undergoing p53-mediated apoptosis. This observation was further confirmed in vivo using a Ptprv null-reporter mouse line. A p53-responsive element is present in the Ptprv promoter and p53 is recruited to this site in vivo. Importantly, while p53-dependent apoptosis is intact in mice lacking Ptprv, Ptprv-null fibroblasts and epithelial cells of the small intestine are defective in G1 checkpoint control. Thus, Ptprv is a new direct p53 target and a key mediator of p53-induced cell cycle arrest. Finally, Ptprv loss enhances the formation of epidermal papillomas after exposure to chemical carcinogens, suggesting that Ptprv acts to suppress tumor formation in vivo. [ABSTRACT FROM AUTHOR]

Simvastatin has been reported to improve endotheliumdependent vascular relaxation in patients with hypercholesterolemia. The consequent decrease in arterial stiffness might be associated with a decrease in blood pressure (BP).The aim of this study was to determine whether simvastatin 20 and 40 mg/d have an effect on systolic and diastolic blood pressure (SBP and DBP, respectively) in patients with hypercholesterolemia, and, if so, whether the effect is dose dependent and/or is related to the changes in the serum lipid profile.This 6-month, open-label study was conducted at the Lipid Clinics of the Department of Internal Medicine, University of Milan, Maggiore Hospital IRCCS, and of the Department of Internal Medicine 1, G. Salvini Hospital, Garbagnate Milanese (Milan, Italy). Patients aged 18 to 80 years with primary hypercholesterolemia who were following a low-fat, low-cholesterol diet for >2 months before the study were enrolled. Patients at high risk for cardiovascular disease (CVD), according to the National Cholesterol Education Program Adult Treatment Panel II guidelines, were given simvastatin 20 mg (tablet) QD for 3 months, and those at low risk for CVD continued with diet only for 3 months (controls). Efficacy variables included body weight, SBP, DBP, and serum lipid levels (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high density lipoprotein cholesterol [HDL-C], and triglycerides [TG]). At 3 months, patients in the simvastatin + diet group who reached their therapeutic goal continued to receive simvastatin 20 mg/d for 3 additional months. In simvastatintreated patients who were normotensive at baseline or who became normotensive at 3 months but who did not reach the therapeutic goal, the simvastatin dosage was increased to 40 mg/d. Patients in both groups who remained hypertensive at 3 months were switched to hypotensive therapy. In the diet-only group, patients who were formerly normotensive or who became normotensive at 3 months but who did not reach their therapeutic goal continued with diet only or started lipid-lowering therapy. All other patients in the diet-only group continued to be treated with diet only, for 3 additional months. Efficacy variables were measured again at 6 months. Tolerability of simvastatin was assessed at each visit using patient interview and measurement of serum aminotransferase and creatine phosphokinase levels.The study population comprised 222 patients (132 women, 90 men; mean [SEM] age, 53.9 [0.95] years [range, 23–76 years]); 115 high-risk patients (57 with untreated stage 1 hypertension) were assigned to the simvastatin + diet group, and 107 low-risk patients (29 with untreated stage 1 hypertension) were assigned to the diet-only group. In the simvastatin group, after 3 months of therapy, mean SBP was decreased by 3.9 (1.49) mm Hg (change, −2.9%), mean DBP decreased by 3.0 (0.87) mm Hg (change, −3.7%), mean TC decreased by 90.6 (3.98) mg/dL (change, −27.0%), mean LDL-C decreased by 88.9 (3.88) mg/dL (change, −35.6%), and mean TG decreased by 26.3 (7.34) mg/dL (change, −15.8%) (all, P < 0.001). Mean HDL-C increased by 3.6 (1.16) mg/dL (change, 6.9%; P < 0.001). The BP-lowering effect was found only in patients with hypertension at baseline (n = 57); in these patients, mean SBP decreased by 7.2 (2.44) mm Hg (change, −4.8%; P < 0.005 vs baseline) and DBP decreased by 4.8 (1.29) mm Hg (change, −5.6%; P < 0.001 vs baseline). Also in the simvastatin group, 26 patients (22.6%) achieved their target SBP/DBP. In patients with normotension at baseline (n = 58), neither SBP nor DBP was changed significantly (changes, −0.8 [1.65] and −1.4 [1.15] mm Hg, respectively [−0.6% and −1.8%, respectively]). The changes in serum lipid levels were similar between hypertensive and normotensive patients in the simvastatin group. Forty-one patients (18 hypertensive and 23 normotensive at baseline) were treated with simvastatin 40 mg/d plus diet between months 3 and 6. At 6 months, no further significant decrease was observed in mean BP. In contrast, the expected dose-dependent response was observed for TC and LDL-C levels. In the diet-only group, no significant changes occurred in BP or serum lipid levels. Changes in BP, TC, LDL-C, TG, and HDL-C were significantly greater in the simvastatin + diet group than in the diet-only group (all, P < 0.001). Body weight did not change significantly in either group.In this group of patients with hypercholesterolemia, the starting dosage of simvastatin (20 mg/d) was associated with reductions in SBP and DBP within 3 months of treatment in patients with hypertension, and this effect was independent of the lipid-lowering properties of the drug. Although the decrease in BP was modest, it is likely clinically relevant. Further studies on this topic are advisable. [Copyright &y& Elsevier]

• Production- and Consumption-based carbon emissions taxation schemes are revised. • Carbon policies are applied to Europe, assessing economic and environmental impacts. • The World Trade Model coupled with Exiobase MRIO database is used for the analysis. • Application of Production-based carbon taxation leads to carbon leakage. • Results of Production- and Consumption-based schemes are comparatively analysed. Policy initiatives towards reduction of CO 2 emissions implemented so far are grounded on the so-called Production-Based paradigm: this approach allocates responsibility of emissions to countries that directly caused such emissions, without taking into account all the indirect contributions to CO 2 emissions caused outside country's borders, eventually leading to the so-called carbon leakage phenomenon. In this paper, the alternative Consumption-Based approach is proposed, and its effectiveness assessed: according to this approach, policy initiatives allocates responsibility for CO 2 emissions proportionally to the CO 2 emissions embedded in goods and services required by industries as inputs for production. Global environmental and economic consequences of carbon emissions reduction policies, applied at the European level based on both Production- and Consumption-Based paradigms, are comparatively assessed based on the World Trade Model with Bilateral Trades. Results of this study suggest that defining CO 2 emissions policies based on a Consumption-Based paradigm seems to be the most effective way to reduce the global carbon emissions, avoiding the carbon leakage phenomenon which may occur in economies regulated by Production-Based policies. Indeed, an imposed reduction in CO 2 emissions embedded in EU final demand through a Consumption-Based Accounting policy would result in a global CO 2 emissions reduction up to almost 1.2 Gton. On the other hand, an imposed reduction in direct EU CO 2 emissions according to a PBA approach would result in an overall increase in global carbon emissions up to almost 0.8 Gton. [ABSTRACT FROM AUTHOR]

The role of electricity availability in promoting the economic growth of low-income countries is a highly debated issue. Taking the Tanzanian government's view that a lack of infrastructure for power generation, together with a low electrification rate, are a limitation to growth, this paper studies the implications on the country's sustainable development of expanding the electricity sector. The analysis is based on the joint use of the OSeMOSYS open-source power system optimization model and the Leontief Input-Output model (based on the Tanzanian Social Accounting Matrix). Four scenarios are considered, representative of alternative technological and environmental policies, characterized by different timing to achieve full electrification. Results indicate that while an expansion of the electricity sector can contribute significantly to economic growth, the associated direct and indirect growth in carbon emissions is equally remarkable. Relying on the country's renewable generation potential would be important but might not be sufficient to lower the economy-wide carbon intensity, particularly under the assumption of reaching full access already in 2030. Targeting energy efficiency and/or decarbonization efforts in the industrial sectors as well as in the provisions of services would also be necessary. The latter is particularly relevant as, per effect of an average income increase, household consumption habits contributes to drive the economy away from its traditional, agricultural base. • Four different electrification scenarios for Tanzania are proposed and analysed. • OSeMOSYS model is soft-linked with the Leontief Input-Output model. • Implications on the country's economic growth and carbon emissions are remarkable. • Change in households' consumption due to income increase impact mainly emissions. • Joint efforts in different sectors are necessary to achieve a reduction of carbon intensity. [ABSTRACT FROM AUTHOR]

• Analysis of different sector-coupling options and their contributions to system flexibility. • Flexibility provided by individual sector-coupling options stacks up in fully integrated systems. • Open-source soft linking framework between the JRC-EU-TIMES and the Dispa-SET model. • Highly detailed large-scale multi-sector unit commitment and power dispatch model. • Greenhouse gas emission reduction not possible without multi-sector integration. The relevance of sector coupling is increasing when shifting from the current highly centralised and mainly fossil fuel-based energy system to a more decentralized and renewable energy system. Cross-sectoral linkages are already recognized as a cost-effective decarbonisation strategy that provides significant flexibility to the system. Modelling such cross-sectoral interconnections is thus highly relevant. In this work, these interactions are considered in a long-term perspective by uni-directional soft-linking of two models: JRC-EU-TIMES, a long term planning multisectoral model, and Dispa-SET, a unit commitment and optimal dispatch model covering multiple energy sectors such as power, heating & cooling, transportation etc. The impact of sector coupling in future Europe-wide energy systems with high shares of renewables is evaluated through five scenarios. Results show that the contributions of individual sectors are quite diverse. The transport sector provides the highest flexibility potential in terms of power curtailment, load shedding, congestion in the interconnection lines and resulting greenhouse gas emissions reduction. Nevertheless, allowing combinations of multiple flexibility options such as hydro for the long-term, electric vehicles and flexible thermal units for the short-term provides the best solution in terms of system adequacy, greenhouse gas emissions and operational costs. [ABSTRACT FROM AUTHOR]

Integrated systems modelling has provided insights on pathways for the sustainable use of energy, land and water resources. Among the existing modelling tools, some have been widely used to engage policy makers, due to their open source and basic structure. Yet, in the attempt of simplifying the representation of integrated systems, essential features significantly influencing the dynamics between systems may have been left aside. This study proposes an improved formulation of the Open Source Energy Modelling System (OSeMOSYS), for a better representation of energy and resource storage processes. In particular, the focus of this work is the storage losses introduction for both dams for hydropower generation and batteries for electricity storage. The modifications were applied to a case study representing key features of both a developed and developing country. The results highlight that, with low additional computational effort, a much more accurate representation of the storage technologies can be achieved. Despite the introduction of losses, renewable energy technologies tend to have a high penetration in the future energy mix thanks to storage applications that remedy their unpredictability and seasonality. • An improved storage formulation in the OSeMOSYS modelling framework is proposed. • Storage losses for water dams and batteries have been implemented in OSeMOSYS. • The improved formulation has been tested and verified through the Atlantis case study. • An accurate storage representation can be performed with few computational effort. [ABSTRACT FROM AUTHOR]

Efforts towards ensuring clean and affordable electricity for all have been progressing slowly in rural, off grid areas of developing countries. In this context, hybrid microgrids may offer reliable and potentially clean electricity for isolated locations. Nevertheless, the process of planning and operation of these systems faces several challenges, often due to the uncertainties related to the renewable resources and to the stochastic nature of electricity consumption in rural contexts. This paper tackles this problem and contributes to the literature in bridging the gap between field practices and two-stage stochastic modeling approaches by identifying an open-source modeling framework which is then applied to real local data. As reference case-study, we consider a microgrid built in 2015 in Bolivia. Overall, the optimal system results from a compromise between the Net Present Cost, the peak capacity installed and the flexibility (to balance variable generation). Different approaches to size isolated microgrids are tested, with the conclusion that methods accounting for the uncertainty in both demand and renewable generation may lead to a more robust configuration with little impacts on the final cost for the community. • The historical monitoring data from a remote PV-diesel microgrid in Bolivia for rural electrification is presented. • A novel two-stage optimization framework is developed for the robust design of such systems under uncertainty. • Components models and performance curves are derived from the monitoring data. • Among different model formulations, stochastic MILP models generate the most robust system configuration. • Recommendations are formulated regarding the optimal configuration with respect to the existing system. [ABSTRACT FROM AUTHOR]

The growing complexity and the many challenges related to fast-changing and highly de-carbonised electricity systems require reliable and robust open source energy modelling frameworks. Their reliability may be tested on a series of well-posed benchmarks that can be used and shared by the modelling community. This paper describes and integrates stand-alone, independent modules to compute the costs and benefits of flexible generation options in the open source energy investment modelling framework OSeMOSYS. The modules are applied to a case study that may work as a benchmark. The whole documentation of the modules and the test case study are retrievable, reproducible, reusable, interoperable, and auditable. They create a case to help establish a FAIR-compliant, user-friendly, and low-threshold model and data standards in modelling practices. As is well known, one of the options for balancing high shares of variable renewables is flexible power generation by dispatchable units. The associated costs need to be considered for short-term operational analyses and for long-term investment plans. The added modules contribute to extending the modelling capacity by introducing (a) costs of ramping, (b) non-linear decrease of efficiency at partial load operation, and (c) refurbishment of existing units in the cost minimisation objective function of OSeMOSYS. From application to the test case study, two main insights are drawn: costs of ramping and decreased partial load efficiency may influence the competitiveness of generation technologies in the provision of reserve capacity; and refurbishment of existing units may represent attractive investment options for increasing flexibility. Both effects are also seen in the long-term and may impact infrastructure investment decisions to meet decarbonisation targets. These effects would not be captured without the introduction of the modules. [ABSTRACT FROM AUTHOR]

Currently, about 2.7 billion people across the world still lack access to clean cooking means. Humanitarian emergencies and post-emergencies are among the most critical situations: the utilization of traditional devices such as three-stone fires have a huge negative impact not only on food security but also on the socio-economic status of people, their health and the surrounding environment. Advanced Cooking Stoves may constitute better systems compared to actual ones, however, financial, logistic and time constraints have strongly limited the interventions in critical contexts until now. The innovative, low-cost Mewar Angithi insert for improving energy efficiency of three-stone fires may play a role in the transition to better cooking systems in such contexts. In this paper, we rely on the Water Boiling Test 4.2.3 to assess the performances of the Mewar Angithi insert respect to a traditional three-stone fire and we analyse the results through a robust statistical procedure. The potentiality and suitability of this novel solution is discussed for its use in critical contexts. [ABSTRACT FROM AUTHOR]

Background: Nucleophosmin (NPM), a nucleocytoplasmic shuttling protein with prominent nucleolar localization, regulates the ARF-p53 tumor-suppressor pathway. Translocations involving the NPM gene cause cytoplasmic dislocation of the NPM protein. Methods: We used immunohistochemical methods to study the subcellular localization of NPM in bone marrow–biopsy specimens from 591 patients with primary acute myelogenous leukemia (AML). We then correlated the presence of cytoplasmic NPM with clinical and biologic features of the disease. Results: Cytoplasmic NPM was detected in 208 (35.2 percent) of the 591 specimens from patients with primary AML but not in 135 secondary AML specimens or in 980 hematopoietic or extrahematopoietic neoplasms other than AML. It was associated with a wide spectrum of morphologic subtypes of the disease, a normal karyotype, and responsiveness to induction chemotherapy, but not with recurrent genetic abnormalities. There was a high frequency of FLT3 internal tandem duplications and absence of CD34 and CD133 in AML specimens with a normal karyotype and cytoplasmic dislocation of NPM, but not in those in which the protein was restricted to the nucleus. AML specimens with cytoplasmic NPM carried mutations of the NPM gene that were predicted to alter the protein at its C-terminal; this mutant gene caused cytoplasmic localization of NPM in transfected cells. Conclusions: Cytoplasmic NPM is a characteristic feature of a large subgroup of patients with AML who have a normal karyotype, NPM gene mutations, and responsiveness to induction chemotherapy. N Engl J Med 2005;352:254-66. [ABSTRACT FROM AUTHOR]