An MDM2 antagonist (MI-319) restores p53 functions and increases the life span of orally treated follicular lymphoma bearing animals

<p>Abstract</p> <p>Background</p> <p>MI-319 is a synthetic small molecule designed to target the MDM2-P53 interaction. It is closely related to MDM2 antagonists MI-219 and Nutlin-3 in terms of the expected working mechanisms. The purpose of this study was to evaluate anti-lymphoma activity of MI-319 in WSU-FSCCL, a B-cell follicular lymphoma line. For comparison purpose, MI-319, MI-219 and Nutlin-3 were assessed side by side against FSCCL and three other B-cell hematological tumor cell lines in growth inhibition and gene expression profiling experiments.</p> <p>Results</p> <p>MI-319 was shown to bind to MDM2 protein with an affinity slightly higher than that of MI-219 and Nutlin-3. Nevertheless, cell growth inhibition and gene expression profiling experiments revealed that the three compounds have quite similar potency against the tumor cell lines tested in this study. <it>In vitro</it>, MI-319 exhibited the strongest anti-proliferation activity against FSCCL and four patient cells, which all have wild-type p53. Data obtained from Western blotting, cell cycle and apoptosis analysis experiments indicated that FSCCL exhibited strong cell cycle arrest and significant apoptotic cell death; cells with mutant p53 did not show significant apoptotic cell death with drug concentrations up to 10 μM, but displayed weaker and differential cell cycle responses. In our systemic mouse model for FSCCL, MI-319 was tolerated well by the animals, displayed effectiveness against FSCCL-lymphoma cells in blood, brain and bone marrow, and achieved significant therapeutic impact (p < 0.0001) by conferring the treatment group a > 28% (%ILS, 14.4 days) increase in median survival days.</p> <p>Conclusion</p> <p>Overall, MI-319 probably has an anti-lymphoma potency equal to that of MI-219 and Nutlin-3. It is a potent agent against FSCCL <it>in vitro </it>and <it>in vivo </it>and holds the promises to be developed further for the treatment of follicular lymphoma that retains wild-type p53.</p

SMI of Bcl-2 TW-37 is active across a spectrum of B-cell tumors irrespective of their proliferative and differentiation status

The Bcl-2 family of proteins is critical to the life and death of malignant B-lymphocytes. Interfering with their activity using small-molecule inhibitors (SMI) is being explored as a new therapeutic strategy for treating B-cell tumors. We evaluated the efficacy of TW-37, a non-peptidic SMI of Bcl-2 against a range spectrum of human B-cell lines, fresh patient samples and animal xenograft models. Multiple cytochemical and molecular approaches such as acridine orange/ethidium bromide assay for apoptosis, co-immunoprecipitation of complexes and western blot analysis, caspase luminescent activity assay and apoptotic DNA fragmentation assay were used to demonstrate the effect of TW-37 on different B-cell lines, patient derived samples, as well as in animal xenograft models. Nanomolar concentrations of TW-37 were able to induce apoptosis in both fresh samples and established cell lines with IC50 in most cases of 165–320 nM. Apoptosis was independent of proliferative status or pathological classification of B-cell tumor. TW-37 was able to block Bim-Bcl-XL and Bim-Mcl-1 heterodimerization and induced apoptosis via activation of caspases -9, -3, PARP and DNA fragmentation. TW-37 administered to tumor-bearing SCID mice led to significant tumor growth inhibition (T/C), tumor growth delay (T-C) and Log10kill, when used at its maximum tolerated dose (40 mg/kg × 3 days) via tail vein. TW-37 failed to induce changes in the Bcl-2 proteins levels suggesting that assessment of baseline Bcl-2 family proteins can be used to predict response to the drug. These findings indicate activity of TW-37 across the spectrum of human B-cell tumors and support the concept of targeting the Bcl-2 system as a therapeutic strategy regardless of the stage of B-cell differentiation

Saudi-KAU Coupled Global Climate Model: Description and Performance

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Bayesian profiling of molecular signatures to predict event times

BACKGROUND: It is of particular interest to identify cancer-specific molecular signatures for early diagnosis, monitoring effects of treatment and predicting patient survival time. Molecular information about patients is usually generated from high throughput technologies such as microarray and mass spectrometry. Statistically, we are challenged by the large number of candidates but only a small number of patients in the study, and the right-censored clinical data further complicate the analysis. RESULTS: We present a two-stage procedure to profile molecular signatures for survival outcomes. Firstly, we group closely-related molecular features into linkage clusters, each portraying either similar or opposite functions and playing similar roles in prognosis; secondly, a Bayesian approach is developed to rank the centroids of these linkage clusters and provide a list of the main molecular features closely related to the outcome of interest. A simulation study showed the superior performance of our approach. When it was applied to data on diffuse large B-cell lymphoma (DLBCL), we were able to identify some new candidate signatures for disease prognosis. CONCLUSION: This multivariate approach provides researchers with a more reliable list of molecular features profiled in terms of their prognostic relationship to the event times, and generates dependable information for subsequent identification of prognostic molecular signatures through either biological procedures or further data analysis

Hair Trace Element and Electrolyte Content in Women with Natural and In Vitro Fertilization-Induced Pregnancy

The objective of the present study was to perform comparative analysis of hair trace element content in women with natural and in vitro fertilization (IVF)-induced pregnancy. Hair trace element content in 33 women with IVF-induced pregnancy and 99 age- and body mass index-matched control pregnant women (natural pregnancy) was assessed using inductively coupled plasma mass spectrometry. The results demonstrated that IVF-pregnant women are characterized by significantly lower hair levels of Cu, Fe, Si, Zn, Ca, Mg, and Ba at p < 0.05 or lower. Comparison of the individual levels with the national reference values demonstrated higher incidence of Fe and Cu deficiency in IVF-pregnant women in comparison to that of the controls. IVF pregnancy was also associated with higher hair As levels (p < 0.05). Multiple regression analysis revealed a significant interrelation between IVF pregnancy and hair Cu, Fe, Si, and As content. Hair Cu levels were also influenced by vitamin/mineral supplementation and the number of pregnancies, whereas hair Zn content was dependent on prepregnancy anthropometric parameters. In turn, planning of pregnancy had a significant impact on Mg levels in scalp hair. Generally, the obtained data demonstrate an elevated risk of copper, iron, zinc, calcium, and magnesium deficiency and arsenic overload in women with IVF-induced pregnancy. The obtained data indicate the necessity of regular monitoring of micronutrient status in IVF-pregnant women in order to prevent potential deleterious effects of altered mineral homeostasis

Perception and acceptance of senior medical students at King Abdulaziz University of the use of Objective Structured Clinical Examination as a tool of assessment

Abstract Introduction: The faculty of Medicine at King Abdulaziz University (KAU) introduced the Objective Structured Clinical Examination (OSCE) as a tool of assessing medical students in the last decade. In our study, we aimed to assess the perception and acceptance of OSCE among students and to interpret rating of OSCE in relation to other assessment methods. Methodology: A cross-sectional survey using electronic validated questionnaire, was distributed through different methods which included Short Message Service, social media website, and posters. The questionnaire contained various domains about students&apos; perception of OSCE validity and reliability, and rating of OSCE in relation to other assessment methods. Results: Among 246 students who responded to the survey, 52% of them denied that OSCE provided opportunity to learn real life scenarios. Interestingly, more than 80% of students showed concern about inter-evaluator and interpatient variability as bias factors that could affect their scores. Passing or failing the OSCE was not a true measure of clinical skills as 77% of students admitted. Conclusion: Although OSCE exam is supposed to be standardized and fair to students, our survey raised concerns regarding the conduction of OSCE especially regarding inter-evaluator and inter-patient variability

Impact of elevated red cell distribution width on patients with acute myocardial infarction

Background: Red cell distribution width (RDW) is an important parameter that has a critical impact on the severity of coronary artery disease, especially on that of acute myocardial infarction (AMI). Objective: This study was aimed to determine the effect of elevated RDW on the outcome of AMI. Materials and Methods: This is a retrospective, case–control study conducted on two groups of participants; the first group (cases) comprised 87 patients suffering from AMI, while the second one (controls) comprised an equal number of patients having stable angina. Matching of controls to patients was done according to age (within 5 years) and gender. The study extended from the beginning of October 2017 to the end of March 2018. Participants in both groups were collected from Al-Sadr Teaching Hospital and Merjan Medical City at Iraqi Najaf and Babylon Governorates, respectively. RDW values were determined by the use of hematological auto-analyzer. Results: Statistically significant differences found between the study groups regarding RDW (P = 0.0001, odds ratio [OR] = 9.481, 95% confidence interval [CI] = 5.127–17.535) and cardiac troponin I (cTnI) (P = 0.0001, OR = 1.325, 95% CI = 1.109–1.584). Strong positive correlation was found between RDW and cTnI (r = 0.272, P = 0.0001). Other measured parameters which are age, gender, history of hypertension, diabetes and smoking, body mass index, hemoglobin (Hb), packed cell volume, mean cell volume, and mean cell Hb concentration all showed no significant differences between the study groups regarding them. Conclusion: RDW owns substantial diagnostic and prognostic value that can aid in the management of AMI patients

Turning flows at motorway service areas

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