456 research outputs found
Ubiquitin-mediated protein degradation and methylation-induced gene silencing cooperate in the inactivation of the INK4/ARF locus in Burkitt`s lymphoma cell lines
No full textBurkitt lymphoma is one of the most aggressive tumors affecting humans. Together with the characteristic chromosomal translocation that constitutively activates the c-Myc oncogene, alterations in cellular tumor suppressor pathways are additionally required in order to allow the cells to overcome anti-oncogenic barriers and proliferate in an uncontrolled manner. The INK4a/ARF locus on chromosome 9p21 is considered a safeguard locus since it encodes the two important tumor suppressor proteins, p14(ARF) and p16(INK4a). By regulating the p53 and Rb pathways p14(ARF) and p16(INK4a) respectively act as pro-apoptotic and cell cycle inhibitor proteins. The importance of the INK4a/ARF locus has been well documented in several human tumors as well as in Burkitt lymphoma. Although the mechanisms responsible for the transcriptional regulation of the INK4a/ARF locus have been thoroughly characterized, less is known about its posttranscriptional control. In this study we found that p16(INK4a) and p14(Arf) are concurrently inactivated in a panel of BL cell lines. We demonstrate that along with the epigenetic silencing of the p16INK4a gene, the complete inactivation of the locus is achieved by the improper turnover of INK4/ARF proteins by the ubiquitin-proteasome system (UPS), as the proteasome inhibitor MG-132 blocks p14(ARF) degradation and induces a dramatic stabilization of the p16(INK4a) protein. We establish that the simultaneous deregulation of both DNA methylation patterns and the ubiquitin-dependent proteolysis system is required to completely inactive the INK4/ARF locus, opening new prospects for the understanding and treatment of Burkitt lymphoma
The international consensus classification of myeloid and lymphoid neoplasms
No full textDeveloped by 149 experts in the field, The International Consensus Classification of Myeloid and Lymphoid Neoplasms provides key information for use at the microscope to assist in arriving at a swift and accurate diagnosis. Drs. Daniel Arber, Michael J. Borowitz, James Cook, Laurence de Leval, John Goodlad, Robert Hasserjian, Rebecca L. King, Hans-Michael Kvasnicka, and Attilio Orazi lead a team of authors who focus on diagnostic criteria and the clinical significance of each disease entity
Toward optimal hemodynamics: computer modeling of the fontan circuit
No full textThe construction of efficient designs with minimal
energy losses is especially important for cavopulmonary
connections. The science of computational fluid dynamics
has been increasingly used to study the hemodynamic performance of surgical operations. Three-dimensional
computer models can be accurately constructed of typical
cavopulmonary connections used in clinical practice based
on anatomic data derived from magnetic resonance scans,
angiocardiograms, and echocardiograms. Using these
methods, the hydraulic performance of the hemi-Fontan,
bidirectional Glenn, and a variety of types of completion
Fontan operations can be evaluated and compared. This
methodology has resulted in improved understanding and
design of these surgical operations
Ten years of modelling to achieve haemodynamic optimisation of the total cavopulmonary connection.
No full textThe techniques of computational fluid dynamics are among the most powerful tools available to engineers dealing with the
motion of fluids and the exchange of mass, momentum,
and energy. They have recently been shown to
have an increasing number of applications to the
human cardiovascular system, including the fluid
dynamics of surgical reconstruction of congenitally
malformed parts of the cardiovascular system. In
vitro models are the alternative laboratory tools with
which to study fluid dynamics. The advantages of
computational fluid dynamics over the in vitro models
are the easy quantification of haemodynamic variables,
such as rates of flow, pressure, and distribution
of shear stress, and changes in geometric and fluid
dynamics parameters. Furthermore, using computational
fluid dynamics allows the development of
three-dimensional models to reproduce both the
complex anatomy of the investigated region and the
details of the surgical reconstruction, especially with
the recent developments in magnetic resonance
imaging. On the basis of the results, it is possible
quantitatively to evaluate the surgical correction.
This technology, which benefits greatly from the
continuous improvement in hardware and software,
enables cardiovascular experts and bioengineers to
look at the fluid dynamics of various cardiovascular
regions with increasing sophistication..
Expression of bcl-6 and CD10 in primary mediastinal large B-cell lymphoma - Evidence for derivation from germinal center B cells?
No full textComputational fluid dynamics simulations in realistic 3-D geometries of the total cavopulmonary anastomosis: the influence of the inferior caval anastomosis.
No full textManagement of Patients With Hematologic Malignancies During the COVID-19 Pandemic: Practical Considerations and Lessons to Be Learned
No full textThe COVID-19 pandemic has created unprecedented hurdles to the delivery of care to patients with cancer. Patients with hematologic malignancies appear to have a greater risk of SARS-CoV-2 infection and severe disease due to myelosuppression and lymphopenia. The first challenge, therefore, is how to continue to deliver effective, curative therapy to vulnerable patients and at the same time avoid exposing them, and their health care teams (HCT), to SARS-CoV-2. An additional challenge is the timely completion of the diagnostic and staging studies required to formulate appropriate treatment plans. Deferred procedures and avoidance of multiple trips to the surgical, diagnostic, and laboratory suites require same day consolidation of all procedures. With laboratory medicine absorbed by the need to deploy large scale COVID-testing, the availability of routine molecular tests is affected. Finally, we are increasingly faced with the challenge of making complex treatment decisions in SARS-CoV-2 positive patients with aggressive but potentially curable blood cancers. When to treat, how to treat, when to wait, how long to wait, how to predict and manage toxicities, and how to avoid compromising cure rates remains unknown. We present an outline of the scientific, medical, and operational challenges posed by the COVID-19 pandemic at selected American and European institutions and offer our current view of the key elements of a response. While the peak of the pandemic may be past us, in the absence of a vaccine risks remain, and our alertness and response to future challenges need to be refined and consolidated
Global mathematical modelling of the Norwood circulation: a multiscale approach for the study of the pulmonary and coronary arterial perfusions.
No full textThe Norwood procedure involves three separate stages of operative corrections. The first stage involves re-fashioning the pulmonary trunk into a neo-aorta so that it is possible to
establish an unrestricted systemic circulation. An
interpositional, or systemic-to-pulmonary arterial,
shunt is then created between the neo-aorta and the
pulmonary arteries to allow pulmonary perfusion and
gas exchange. Two of the available options for the
systemic-to-pulmonary shunt are the central shunt
and the right modified Blalock-Taussig shunt. In the
setting of a central shunt, pulmonary perfusion is
derived from a conduit placed between the pulmonary
arterial bed and the neo-aorta whereas, in the modified
Blalock-Taussig shunt, the conduit is interposed
between one of the pulmonary arteries and the brachiocephalic
artery. In subsequent stages, pulmonary
perfusion is provided directly by deoxygenated blood.
This is achieved by connecting, first, the superior
caval vein, and then the inferior caval vein, to the pulmonary
arteries. It is usually during the second stage
that the systemic-to-pulmonary shunt is removed...
Computational fluid dynamics in the evaluation of hemodynamic performance of cavopulmonary connections after the Norwood procedure for hypoplastic left heart syndrome
No full textAbstractObjectiveComputational fluid dynamics have been used to study the hemodynamic performance of surgical operations, resulting in improved design. Efficient designs with minimal energy losses are especially important for cavopulmonary connections. The purpose of this study was to compare hydraulic performance between the hemi-Fontan and bidirectional Glenn procedures, as well as the various types of completion Fontan operations.MethodsThree-dimensional models were constructed of typical hemi-Fontan and bidirectional Glenn operations according to anatomic data derived from magnetic resonance scans, angiocardiograms, and echocardiograms. Boundary conditions were imposed, and fluid dynamics were calculated from a mathematic code. Power losses, flow distribution to each lung, and pressures were measured at three predetermined levels of pulmonary arteriolar resistance. Models of the lateral tunnel, total cavopulmonary connection, and extracardiac conduit completion Fontan operations were constructed, and power losses, total flow distribution, vena caval and pulmonary arterial pressures, and flow distribution of inferior vena caval return were calculated.ResultsThe hemi-Fontan and bidirectional Glenn procedures performed nearly identically, with similar power losses and nearly equal flow distributions to each lung at all levels of pulmonary arteriolar resistance. However, the lateral tunnel Fontan procedure as performed after the hemi-Fontan operation had lower power losses (6.9 mW, pulmonary arteriolar resistance 3 units) than the total cavopulmonary connection (40.5 mW) or the extracardiac conduit (42.9 mW), although the inclusion of an enlargement patch toward the right in the total cavopulmonary connection was effective in reducing the difference (10.0 mW). Inferior vena caval flow to the right lung was 52% for the lateral tunnel, compared with 19%, 30%, 19%, and 15% for the total cavopulmonary connection, total cavopulmonary connection with right-sided enlargement patch, extracardiac conduit, and extracardiac conduit with a bevel to the left lung, respectively.ConclusionsAccording to these methods, the hemi-Fontan and bidirectional Glenn procedures performed equally well, but important differences in energy losses and flow distribution were found after the completion Fontan procedures. The superior hydraulic performance of the lateral tunnel Fontan operation after the hemi-Fontan procedure relative to any other method may be due to closer to optimal caval offset achieved in the surgical reconstruction
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