Hussein A. Abbas

Mdm2 Is Required for Survival of Hematopoietic Stem Cells/Progenitors via Dampening of ROS-Induced p53 Activity

Mdm2 is an E3 ubiquitin ligase that targets p53 for degradation. p53(515C) (encoding p53R172P) is a hypomorphic allele of p53 that rescues the embryonic lethality of Mdm2(-/-) mice. Mdm2(-/-) p53(515C/515C) mice, however, die by postnatal day 13 resulting from hematopoietic failure. Hematopoietic stem cells and progenitors of Mdm2(-/-) p53(515C/515C) mice were normal in fetal livers but were depleted in postnatal bone marrows. After birth, these mice had elevated reactive oxygen species (ROS) thus activating p53R172P. In the absence of Mdm2, stable p53R172P induced ROS and cell cycle arrest, senescence, and cell death in the hematopoietic compartment. This phenotype was partially rescued with antioxidant treatment and upon culturing of hematopoietic cells in methycellulose at 3% oxygen. p16 was also stabilized because of ROS, and its loss increased cell cycling and partially rescued hematopoiesis and survival. Thus, Mdm2 is required to control ROS-induced p53 levels for sustainable hematopoiesis.

The p53–Mdm2 feedback loop protects against DNA damage by inhibiting p53 activity but is dispensable for p53 stability, development, and longevity

The p53-Mdm2 feedback loop is perceived to be critical for regulating stress-induced p53 activity and levels. However, this has never been tested in vivo. Using a genetically engineered mouse with mutated p53 response elements in the Mdm2 P2 promoter, we show that feedback loop-deficient Mdm2(P2/P2) mice are viable and aphenotypic and age normally. p53 degradation kinetics after DNA damage in radiosensitive tissues remains similar to wild-type controls. Nonetheless, DNA damage response is elevated in Mdm2(P2/P2) mice. Enhanced p53-dependent apoptosis sensitizes hematopoietic stem cells (HSCs), causing drastic myeloablation and lethality. These results suggest that while basal Mdm2 levels are sufficient to regulate p53 in most tissues under homeostatic conditions, the p53-Mdm2 feedback loop is critical for regulating p53 activity and sustaining HSC function after DNA damage. Therefore, transient disruption of p53-Mdm2 interaction could be explored as a potential adjuvant/therapeutic strategy for targeting stem cells in hematological malignancies.

The ups and downs of p53 regulation in hematopoietic stem cells.

Hematopoietic stem cells provide an indispensible source for replenishing the blood with all its constituents throughout the organisms lifetime. Mice with a compromised hematopoietic stem cell compartment cannot survive. p53, a major tumor suppressor gene, has been implicated in regulation of hematopoiesis. In particular, p53 plays a role in homeostasis by regulating HSC quiescence and self renewal. We recently utilized a hypomorphic p53515C allele in conjunction with Mdm2, a negative regulator of p53 to gain insights into the role of p53 in hematopoietic regulation. Our analyses revealed that p53515C/515CMdm2-/- double mutant mice die soon after birth due to hematopoietic failure. Further mechanistic studies revealed that in the absence of Mdm2, ROS induced postnatal p53 activity depletes hematopoietic stem cells, progenitors and differentiated cells.

Cross-species identification of genomic drivers of squamous cell carcinoma development across preneoplastic intermediates

Cutaneous squamous cell carcinoma (cuSCC) comprises 15–20% of all skin cancers, accounting for over 700,000 cases in USA annually. Most cuSCC arise in association with a distinct precancerous lesion, the actinic keratosis (AK). To identify potential targets for molecularly targeted chemoprevention, here we perform integrated cross-species genomic analysis of cuSCC development through the preneoplastic AK stage using matched human samples and a solar ultraviolet radiation-driven Hairless mouse model. We identify the major transcriptional drivers of this progression sequence, showing that the key genomic changes in cuSCC development occur in the normal skin to AK transition. Our data validate the use of this ultraviolet radiation-driven mouse cuSCC model for cross-species analysis and demonstrate that cuSCC bears deep molecular similarities to multiple carcinogen-driven SCCs from diverse sites, suggesting that cuSCC may serve as an effective, accessible model for multiple SCC types and that common treatment and prevention strategies may be feasible.

Endocrine and Bone Complications in β-Thalassemia Intermedia: Current Understanding and Treatment

Thalassemia intermedia (TI), also known as nontransfusion dependent thalassemia (NTDT), is a type of thalassemia where affected patients do not require lifelong regular transfusions for survival but may require occasional or even frequent transfusions in certain clinical settings and for defined periods of time. NTDT encompasses three distinct clinical forms: β-thalassemia intermedia (β-TI), Hb E/β-thalassemia, and α-thalassemia intermedia (Hb H disease). Over the past decade, our understanding of the molecular features, pathophysiology, and complications of NTDT particularly β-TI has increased tremendously but data on optimal treatment of disease and its various complications are still lacking. In this paper, we shall review a group of commonly encountered complications in β-TI, mainly endocrine and bone complications.

The effect of consanguinity on neonatal outcomes and health.

Consanguineous marriages constitute a significant fraction of marriages worldwide and confer a major public health concern on newborns. In addition to the risk of acquiring a recessive genetic disease, the offspring of consanguineous parents are plausibly at an increased risk of preterm birth, decreased anthropometric measurements, congenital defects and mortality. How consanguinity confers such an increased risk is still largely unknown. In this review, we discuss the effect of consanguinity on selected gestational outcomes by delineating the different studies that have led to such findings. We also investigate the different conclusions that have emerged regarding the effect of consanguinity on gestational outcomes.

One‐year results from a prospective randomized trial comparing phlebotomy with deferasirox for the treatment of iron overload in pediatric patients with thalassemia major following curative stem cell transplantation

Iron overload is well documented in patients with β‐thalassemia major, and patients who have undergone hematopoietic stem cell transplantation (HSCT) remain at risk as a result of pre‐ and immediate post‐HSCT transfusions.

Prevalence of glucose-6-phosphate dehydrogenase deficiency among neonates at a tertiary care centre in Lebanon

In this study we aimed to determine the prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency in a Lebanese population and the clinical outcomes and associated adverse events encountered amongst affected patients. Newborn screening in a tertiary care centre in North Lebanon showed a prevalence of 2.1% (62 out of 3009), significantly higher in males than females, and in Muslims than Christians. Among 45 infants followed for a median of 2.2 years from birth, 12 (27%) were admitted to hospital for severe haemolytic crises, despite a programme of early family education and close follow-up. A nationwide newborn screening program to identify afflicted individuals, and to augment vigilance about this disease, should be considered in countries where the disorder is prevalent.

Transfusion Therapy in Children With Sickle Cell Disease.

Hydroxyurea, blood transfusions, and hematopoietic stem cell transplantation represent the 3 disease-modifying therapies in children with sickle cell disease (SCD). Blood transfusions play an increasingly important role in both prevention and management of SCD complications in this age group. This review will focus on the indications of blood transfusion in children with SCD and modalities of its administration. It will also highlight the complications of this life-saving therapy and ways of optimizing transfusion to minimize its associated risks.

Cynicism and other attitudes towards patients in an emergency department in a middle eastern tertiary care center.

BackgroundA caring, compassionate practitioner of the medical arts is the idealized version of what makes a good doctor. If asked to think of a painting of a doctor we most likely conjure an image of a physician sitting at a patient’s bedside checking the pulse with a concerned look on his face. The reality is however that cynicism, among other negative attitudes, is becoming more prominent among physicians and medical staff. The causes and extent of cynicism likely vary among medical departments and different cultures. In this study, we aimed to assess attitudes of medical students and physicians in an Emergency Department (ED) in Lebanon that accommodates both local patients and is also known to attract patients from around the Middle East.MethodsA total of 30 students, residents and attending physicians at the American University of Beirut Medical Center were invited to participate. All participants underwent semi-structured interviews that were recorded, transcribed and then analyzed for common themes.ResultsMore negative emotions were expressed among participants than positive ones. Negative emotions were more frequently expressed among medical students, interns and residents than attending physicians. Cynicism in the ED was commonly reported however, maintenance of professionalism and adequate patient care were underscored. While empathy was recurrently found among participants, a trend towards a decrease in empathy with career progression was noted among attending physicians. Further, negative feelings towards patient families were prominent. Participants tended to categorize patients based on willingness to cooperate, gender, age, case acuity, ethnic origins and social status.ConclusionsCynicism emerged as a prominent theme among medical students and staff in our study. However, participants were also empathetic. These attitudes were generally attributed to the peculiar stressors associated with the Lebanese culture, low acuity cases and “VIP” patients. It is crucial to explore methods in order to decrease cynicism and improve patient care. Also, the implications of these attitudes on patient care remain to be discovered.