Prognostic impact of Additional Chromosomal Abnormalities in Egyptian Chronic Myeloid Leukemia Patients

BACKGROUND: Emergence of additional chromosomal abnormalities (ACAs) in chronic myeloid leukemia (CML) is associated with disease progression to advanced phases and reflects the genetic instability of CML. AIM: Is to evaluate the frequency of ACAs in chronic phase (CP) and advanced disease (AP) CML patients and study their impact on patient’s outcome, overall survival (OS) and event-free survival (EFS). RESULTS: The studied group (n = 73) included 31 males (43%) and 42 females (57%). Median age of patients at diagnosis was 37 years (17–76). Median TLC was 208×109/L (2.1–784.2), median Hb was 9.4 g/dL (5.7–13), and median platelets count was 290.5×109/L (13–1271). We identified 32 patients (44%) with ACAs. ACAs emergence was significantly associated with advanced phases of CML (13/21, 62%) compared to CP (19/52, 36%) (p = 0.048). ACAs were associated with lower median OS and EFS in CP compared to AP (38 vs. 120 ms) and (58.3 vs. 77 ms) (p = 0.026 and p = 0.065, respectively). Early molecular responders (6/17, 35%) at 3 months, and 6 months (10/26, 38%) developed ACAs less than nonoptimal responders. Disease phase, hepatomegaly and bone marrow eosinophilia were significant predictors of OS (p < 0.001, p = 0.02, p = 0.04, respectively). CONCLUSION: Early identification of ACAs in Ph+ metaphases at diagnosis and during therapy predicts CML outcome. ACAs emergence occurred at a higher frequency and at a younger age in our CML patients and are related to inferior EFS and OS

Aven and Survivin Expression in Egyptian Acute Leukemia and Their Relation to Apoptosis

Background: Several anti apoptotic signals have been recently identified. Aven and Survivin are broadly expressed and are conserved in mammalian species. Patients and Methods: 39 AML and 25 ALL were tested. Aven and Survivin expression were detected by RT-PCR. DNA fragmentation was carried out daily after treatment..Results: Survivin was expressed (P=0.06) more in AML (74%) than in ALL (52%). While, Aven was equally expressed in both leukemias. Patients were categorized into 3 groups based on DNA fragmentation. Absence of Aven significantly (p‹0.001) contributed to DNA fragmentation,but Survivin did not contribute as much. None of the concordant both positive Survivin and Aven were in group III (the good 5 day fragmentation, (P< 0.001). Survivin was statistically related to CD7 expression (P<0.001) in AML only. There was a significant dissociation between Aven and Survivin in AML (p=0.03) and near significant dissociation in ALL (p=0.07). Conclusion: Aven seems to be more important as an inhibitor of apoptosis than survivin in acute leukemia. The presence of both confers a survival disadvantage and a significantly worse DNA fragmentation pattern suggesting a synergistic inhibition of apoptosis. The highly significant relation between CD7 and survivin expression might suggest their involvement in a common signal transduction pathway

Synthesis, structure diversity, and antimicrobial studies of Ag(i) complexes with quinoline-type ligands

Compounds [Ag(5NO2Qu)2]BF4 (1) and [Ag(Qu3CN)(H2O)]BF4 (2) were prepared and studied from a structural perspective and screened for antimicrobial activity. The Ag(i) in the monomeric complex 1 is coordinated to two 5-nitroquinoline (5NO2Qu) ligands via the N-atoms of the quinoline rings with equidistant Ag-N bonds (2.146(2) \uc5) and a N-Ag-N# bond angle of 171.42(8)\ub0. The 2D coordination polymer 2 contains tetracoordinated Ag(i) with two N-atoms (N1 and N2#1) from two quinoline-3-carbonitrile (Qu3CN) ligands and two O-atoms (O1 and O1#1) from two water molecules. The Qu3CN ligand acts as a connector between the Ag(i) sites along the b-direction via two short Ag1-N1 (2.185(4) \uc5) and Ag1-N2#1 (2.204(4) \uc5) bonds. In addition, the Ag(i) is coordinated with two symmetry related water molecules which are also acting as connectors between the Ag(i) sites along the a-direction via two longer Ag1-O1 (2.470(4) \uc5) and Ag1-O1#2 (2.546(4) \uc5) bonds. Hirshfeld surface analysis confirmed the significance of the polar F⋯H contacts in the molecular packing of 1 (25.9%) and 2 (39.9%). In addition, the crystal packing of 1 showed a significant amount of polar O⋯H (23.5%) contacts. Also, both complexes displayed π-π stacking interactions. The Ag(i) complexes and the free ligand were assessed for their antimicrobial activities. It was found that 1 (MIC = 7.8 μg mL−1) and 2 (MIC = 31.25 μg mL−1) have higher antifungal potency against C. albicans than their free ligands (MIC = 125 μg mL−1). Interestingly, 1 has better antifungal activity than the standard nystatin (15.6 μg mL−1). Also, both Ag(i) complexes and the free ligands as well have better activity against P. mirabilis than the common antibiotic amoxicillin

The Prognostic Value of International Prognostic Index and MIB-1 Immunostaining of Peripheral Lymphoid Tissues and Bone Marrow in Patients with High-Grade Non-Hodgkin's Lymphoma

ling index and with the known clinical variables included within the IPI. Patients with high intermediate or high IPI who expressed high Ki-67 labelling index had a worse overall survival compared with patients with low or low intermediate IPI and low Ki-67 index (p < 0.001). BM infiltration as detected by MIB-1 was correlated in univariate analysis (p = 0.04), although not confirmed in multivariate analysis, with poor survival. Conclusion: In conclusion, the MIB-1 monoclonal antibody immunostaining appears to be a simple and reproducible method of determining tumour proliferative index and provides useful prognostic information in patients with high-grade NHL. We recommend using apoptotic markers in addition for proper assessment of the impact of detecting MIB-1 positive cells in BM on disease outcome. INTRODUCTION Non-Hodgkin's lymphomas (NHL) represent a spectrum of haematological malignancies characterized by a highly diverse clinical behaviour in terms of clinical presentation, histology, immunophenotype, genetic alternation, prognosis and response to therapy. Although the International Prognostic Factor Project was developed to provide a model system for predicting the outcome of patients with aggressive NHL depending on some clinical parameters (age, stage, performance status, number of extranodal sites and serum lactic dehyrogenase level) The identification of proliferating cells in ABSTRACT Background: Cell kinetic data are important indicator of the aggressiveness of tumour and clinical response. The Ki-67 antigen plays a pivotal role in maintaining cell proliferation and the expression of this antigen was found to be a valuable indicator for aggressive disease in a variety of neoplastic disorders. Aim of the study: This study aimed to assess the prognostic significance of the expression of Ki-67 antigen in peripheral lymphoid tissues and bone marrow, using the monoclonal antibody MIB-1 that is applicable in formaline-fixed paraffin embedded samples in cases with high-grade non-Hodgkin's lymphomas. Material and methods: The MIB-1 immunostaining was performed on 96 samples from 48 patients with high-grade non-Hodgkin's lymphomas. The study was performed on tissue sections, nodal or extranodal, as well as on BM smears or BM paraffin embedded sections of same patients. Ki-67 index was determined using image analyzer. Results: Forty-five out of the studied 48 cases (93.8%) were positive with a median labelling index of 20.425% (Range, 0-58%). We were able to detect bone marrow involvement by detecting MIB-1 positive cells in BM samples of 29 patients who were not morphologically diagnosed to have BM infiltration. There was a strong correlation between BM positivity for Ki-67 and Ki-67 labelling index (p < 0.001). Twenty-eight (58.3%) out of the studied 48 cases achieved complete remission (CR). The median duration of CR was 35 months (range, 8-42 months) and the overall survival at 48 months was 35.4% (median 22 months, 95% CI, 13-31 months). The median Ki-67 index (20.425%) was chosen as a cut-off level for statistical analysis of the variables that influence clinical outcome. The probability of inducing CR was associated with low and low intermediate International Prognostic Index (IPI) whereas a low growth fraction was associated, although not significant, with a trend toward a higher probability of inducing a CR. In univariate analysis, high MIB-1 labelling index and increased IPI were associated with shorter duration of complete remission and overall survival time. Multivariate analysis showed that an extended overall survival time was associated with low MIB-1 label

New Bioprecursor Prodrugs of Sulfadiazine : Synthesis, X-ray Structure and Hirshfeld Analysis

Sulphonamide motif is found extensively in numerous chemotherapeutic drug candidates, it acts by stopping the production of folate inside the bacterial cell. Current research has established the synthesis and characterization of new bioprecursor prodrugs of sulfadiazine. The first prodrug, 3, was synthesized via the coupling of diazonium salt of sulfadiazine with ethyl acetoacetate in AcONa at 0 °C. The second prodrug, sulfadiazine-pyrazole, 5, was furnished via cyclocondensation of the hydrazono derivative, 3, and 2-pyridyl hydrazine, 4. The generated data from the X-ray analysis is interpreted and refined to obtain the crystal structure of the target compound, 5. Density functional theory (DFT) method was used to calculate the optimized geometrical parameters, electronic state (HOMO–LUMO), and the electronic properties. Moreover, Hirshfeld analysis revealed that the most important contributions to the crystal packing of the prodrug 5 are H···H, O···H and H···C contacts.peerReviewe

Efficient Consecutive Synthesis of Ethyl-2-(4-Aminophenoxy) Acetate, a Precursor for Dual GK and PPARγ Activators, X-ray Structure, Hirshfeld Analysis, and DFT Studies

Herein, we report a facile synthesis of ethyl-2-(4-aminophenoxy)acetate 4 as a building synthon for novel dual hypoglycemic agents. This building template was synthesized by alkylation of 4-nitrophenol with ethyl bromo-acetate followed by selective reduction of the nitro group. This reduction methoddoes not require nascent hydrogen or any reaction complexity; it goes easily via consecutive reaction in NH4Cl/Fe to yield our target synthon as very pure crystals. This product was characterized by 1HNMR, 13CNMR, COSY, NOESY NMR spectroscopy, and elemental analysis. Additionally, its structure was studied and approved by X-ray single crystal structure determination. The unit cell parameters are a = 8.2104(6)Å, b = 10.3625(9)Å, c = 11.9562(9)Å, α = 101.787(7), β = 91.849(6), and γ = 102.755(7)°, indicating that 4 was crystallized in the triclinic crystal system. The cooperative non-covalent interactions are also discussed with the aid of Hirshfeld surface analysis. The H…H, H…C, and O…H interactions have a major contribution in the molecular packing of 4. Moreover, different quantum chemical parameters were computed and discussed based on DFT calculations. The experimental UV/Vis spectra showed two bands at 299 and 234 nm, which were calculated using the TD-DFT method at 286 (f = 0.068) and 226 nm (f = 0.294), respectively. These bands were assigned to HOMO→LUMO (95%) and HOMO→LUMO+2 (86%) transitions, respectively.peerReviewe

A Novel Na(I) Coordination Complex with <i>s</i>-Triazine Pincer Ligand: Synthesis, X-ray Structure, Hirshfeld Analysis, and Antimicrobial Activity

The pincer ligand 2,4-bis(3,5-dimethyl-1H-pyrazol-1-yl)-6-methoxy-1,3,5-triazine (bpmt) was used to synthesize the novel [Na(bpmt)2][AuCl4] complex through the self-assembly method. In this complex, the Na(I) ion is hexa-coordinated with two tridentate N-pincer ligands (bpmt). The two bpmt ligand units are meridionally coordinated to Na(I) via one short Na-N(s-triazine) and two slightly longer Na-N(pyrazole) bonds, resulting in a distorted octahedral geometry around the Na(I) ion. In the coordinated bpmt ligand, the s-triazine core is not found to be coplanar with the two pyrazole moieties. Additionally, the two bpmt units are strongly twisted from one another by 64.94°. Based on Hirshfeld investigations, the H···H (53.4%) interactions have a significant role in controlling the supramolecular arrangement of the [Na(bpmt)2][AuCl4] complex. In addition, the Cl···H (12.2%), C···H (11.5%), N···H (9.3%), and O···H (4.9%) interactions are significant. Antimicrobial investigations revealed that the [Na(bpmt)2][AuCl4] complex has promising antibacterial and antifungal activities. The [Na(bpmt)2][AuCl4] complex showed enhanced antibacterial activity for the majority of the studied gram-positive and gram-negative bacteria compared to the free bpmt (MIC = 62.5–125 µg/mL vs. MIC = 62.5–500 µg/mL, respectively) and Amoxicillin (MIC > 500 µg/mL) as a positive control. Additionally, the [Na(bpmt)2][AuCl4] complex had better antifungal efficacy (MIC = 125 µg/mL) against C. albicans compared to bpmt (MIC = 500 µg/mL)