Epigenetic regulators as promising therapeutic targets in acute myeloid leukemia.

Acute myeloid leukemia (AML), the most prevalent acute leukemia in adults, is an aggressive hematological malignancy arising in hematopoietic stem and progenitor cells. With the exception of a few specific AML subtypes, the mainstays of treatment have not significantly changed over the last 20 years, and are still based on standard cytotoxic chemotherapy. As a result, clinical outcome remains poor for the majority of patients, with overall long-term survival in the region of 20-30%. Recent successes in characterizing the genetic landscape of AML have highlighted that, despite its heterogeneity, many cases of AML carry recurrent mutations in genes encoding epigenetic regulators. Transcriptional dysregulation and altered epigenetic function have therefore emerged as exciting areas in AML research and it is becoming increasingly clear that epigenetic dysfunction is central to leukemogenesis in AML. This has subsequently paved the way for the development of epigenetically targeted therapies. In this review, we will discuss the most recent advances in our understanding of the role of epigenetic dysregulation in AML pathobiology. We will particularly focus on those altered epigenetic programs that have been shown to be central to the development and maintenance of AML in preclinical models. We will discuss the recent development of therapeutics specifically targeting these key epigenetic programs in AML, describe their mechanism of action and present their current clinical development. Finally, we will discuss the opportunities presented by epigenetically targeted therapy in AML and will highlight future challenges ahead for the AML community, to ensure that these novel therapeutics are optimally translated into clinical practice and result in clinical improvement for AML patients.We would like to thank all the members of the Huntly laboratory and our funders Leukaemia Lymphoma Research, Kay Kendall Leukaemia fund, the Medical Research Council UK, the Wellcome Trust, the Cambridge NIHR Biomedical Research Centre, Leukemia & Lymphoma Society US, the Academy of Medical Sciences UK and Lady Tata Memorial Trust. We apologise to writers whose work we have failed to cite due to space constraints.This is the author accepted manuscript. The final version is available via SAGE at http://dx.doi.org/10.1177/204062071557761

Evaluation of demand in a rural English hospital emergency department

The purpose of this article is to analyse the patient demand placed on a rural district general hospital (DGH) emergency department within the context of the Purpose, Process, People (PPP) framework used in the private sector. This analysis was undertaken to inform wider evaluation of the implementation of the enterprise culture—the NHS policy to adopt private sector best practice to produce resource use, quality and efficiency improvements. The article concludes with a view that the PPP framework provides methods of calculating the level of discharge necessary to meet the four-hour wait target. Data describing the characteristics and patterns of attending patients can be used to develop an emergency department’s processes and people to achieve its time-based target

Should Radiology IT be Owned by the Chief Information Officer?

Considerable debate within the medical community has focused on the optimal location of information technology (IT) support groups on the organizational chart. The challenge has been to marry local accountability and physician acceptance of IT with the benefits gained by the economies of scale achieved by centralized knowledge and system best practices. In the picture archiving and communication systems (PACS) industry, a slight shift has recently occurred toward centralized control. Radiology departments, however, have begun to realize that no physicians in any other discipline are as dependent on IT as radiologists are on their PACS. The potential strengths and weaknesses of centralized control of the PACS is the topic of discussion for this month’s Point/Counterpoint

Impact of different radiation transfer parameterization schemes in a GCM on the simulation of the onset phase of Indian summer monsoon

The impact of two radiation parameterization schemes (NASA/Goddard and GFDL) in NCMRWF T80 model on the simulation of June, 1995 is presented in this paper. Our main aim here is to understand the sensitivity of different radiation schemes on the simulation of Indian summer monsoon onset phase. At Earth's surface, the simulation using NASA/Goddard scheme produces more reasonable balance between incoming and outgoing fluxes (radiative and the turbulent heat fluxes) compared to GFDL scheme. The inclusion of cloud scattering and hence the treatment of direct and diffused radiation separately in NASA/Goddard radiation scheme resulted in changes in the net shortwave flux at surface and hence in the surface temperature. Results also indicate the high sensitivity of surface temperature in the monsoon onset simulation. Both models reasonably simulate the mean June 1995 flow patterns. Comparison between the two simulations shows that T80 model with NASA/Goddard has less forecast errors at 200 hPa, whereas in 850 hPa this simulation has slightly higher forecast errors east of 75°E longitude over Indian latitudes

Compliance with follow up cytology after discharge from the colposcopy clinic.

Cervical cancer represents the second common cancer in women and is a major public health issue in Ireland and worldwide. Despite appropriate treatment of precancerous lesions, women with dysplasia are at relatively increased risk, and require follow up. We aimed to evaluate the compliance rate with follow up cytology advice given to patients discharged from the colposcopy clinic and to identify predictive factors for poor compliance. This is a retrospective cohort study of patients initially managed in our institution in 2001. Patients were evaluated for adherence with the recommendations received at the time of discharge from the clinic. Of the 116 women that were initially contacted, 100 agreed to participate in the study (86% response rate). Sixty women (60%) were entirely compliant. While older patients (\u3e 40 years) were significantly less likely to show complete compliance (OR: 0.12; 950/ Cl: 0.02-0.58; p = 0.009)

Skills of different mesoscale models over Indian region during monsoon season: Forecast errors

Performance of four mesoscale models namely, the MM5, ETA, RSM and WRF, run at NCMRWF for short range weather forecasting has been examined during monsoon-2006. Evaluation is carried out based upon comparisons between observations and day-1 and day-3 forecasts of wind, temperature, speci.c humidity, geopotential height, rainfall, systematic errors, root mean square errors and specific events like the monsoon depressions. It is very difficult to address the question of which model performs best over the Indian region? An honest answer is 'none'. Perhaps an ensemble approach would be the best. However, if we must make a final verdict, it can be stated that in general, (i) the WRF is able to produce best All India rainfall prediction compared to observations in the day-1 forecast and, the MM5 is able to produce best All India rainfall forecasts in day-3, but ETA and RSM are able to depict the best distribution of rainfall maxima along the west coast of India, (ii) the MM5 is able to produce least RMSE of wind and geopotential fields at most of the time, and (iii) the RSM is able to produce least errors in the day-1 forecasts of the tracks, while the ETA model produces least errors in the day-3 forecasts

Supersymmetric geometries of IIA supergravity I

IIA supergravity backgrounds preserving one supersymmetry locally admit four types of Killing spinors distinguished by the orbits of $Spin(9,1)$ on the space of spinors. We solve the Killing spinor equations of IIA supergravity with and without cosmological constant for Killing spinors representing two of these orbits, with isotropy groups $Spin(7)$ and $Spin(7)\ltimes\mathbb{R}^8$. In both cases, we identify the geometry of spacetime and express the fluxes in terms of the geometry. We find that the geometric constraints of backgrounds with a $Spin(7)\ltimes\mathbb{R}^8$ invariant Killing spinor are identical to those found for heterotic backgrounds preserving one supersymmetry.Comment: 21 page

Acute response and chronic stimulus for cardiac structural and functional adaptation in a professional boxer.

The individual response to acute and chronic changes in cardiac structure and function to intense exercise training is not fully understood and therefore evidence in this setting may help to improve the timing and interpretation of pre-participation cardiac screening. The following case report highlights an acute increase in right ventricular (RV) size and a reduction in left ventricular (LV) basal radial function with concomitant increase at the mid-level in response to a week's increase in training volume in a professional boxer. These adaptations settle by the second week; however, chronic physiological adaptation occurs over a 12-week period. Electrocardiographic findings demonstrate an acute lateral T-wave inversion at 1 week, which revert to baseline for the duration of training. It appears that a change in training intensity and volume generates an acute response within the RV that acts as a stimulus for chronic adaptation in this professional boxer

Pre-operative diagnosis of an unusual complication of abdominal aortic aneurysm on multidetector computed tomography: a case report

Spontaneous fistulation of an abdominal aortic aneurysm (AAA) into the inferior vena cava (IVC) is an unusual and infrequently encountered complication in clinical practice. In the majority of cases, it is a diagnosis made on the operating table, during surgical repair of AAA. We report a patient with an aortocaval fistula diagnosed preoperatively on multidetector computed tomography (MDCT). Preoperative diagnosis of this rare complication is important as it allows appropriate anaesthetic and surgical planning thereby reducing morbidity and mortality