Identifying novel therapeutic inhibitors to target FMS-like tyrosine kinase-3 (FLT3) against acute myeloid leukemia: a molecular docking, molecular dynamics, and DFT study.

Around 30% of acute myeloid leukemia (AML) patients have triggering mutations in Feline McDonough Sarcoma (FMS)-like tyrosine kinase 3 (FLT3), which has been suggested as a possible therapeutic candidate for AML therapy. Many tyrosine kinase inhibitors are available and have a wide variety of applications in the treatment of cancer by inhibiting subsequent steps of cell proliferation. Therefore, our study aims to identify effective antileukemic agents against FLT3 gene. Initially, well-known antileukemic drug candidates have been chosen to generate a structure-based pharmacophore model to assist the virtual screening of 217,77,093 compounds from the Zinc database. The final hits compounds were retrieved and evaluated by docking against the target protein, where the top four compounds have been selected for the analysis of ADMET. Based on the density functional theory (DFT), the geometry optimization, frontier molecular orbital (FMO), HOMO-LUMO, and global reactivity descriptor values have been evaluated that confirming a satisfactory profile and reactivity order for the selected candidates. In comparison to control compounds, the docking results revealed that the four compounds had substantial binding energies (-11.1 to -11.5 kcal/mol) with FLT3. The physicochemical and ADMET (adsorption, distribution, metabolism, excretion, toxicity) prediction results corresponded to the bioactive and safe candidates. Molecular dynamics (MD) confirmed the better binding affinity and stability compared to gilteritinib as a potential FLT3 inhibitor. In this study, a computational approach has been performed that found a better docking and dynamics score against target proteins, indicating potent and safe antileukemic agents, furthermore in-vivo and in-vitro investigations are recommended.Communicated by Ramaswamy H. Sarma.

Organoboron Complexes as Thermally Activated Delayed Fluorescence (TADF) Materials for Organic Light-Emitting Diodes (OLEDs): A Computational Study.

We report on organoboron complexes characterized by very small energy gaps (ΔEST) between their singlet and triplet states, which allow for highly efficient harvesting of triplet excitons into singlet states for working as thermally activated delayed fluorescence (TADF) devices. Energy gaps ranging between 0.01 and 0.06 eV with dihedral angles of ca. 90° were registered. The spin-orbit couplings between the lowest excited S1 and T1 states yielded reversed intersystem crossing rate constants (KRISC) of an average of 105 s-1. This setup accomplished radiative decay rates of ca. 106 s-1, indicating highly potent electroluminescent devices, and hence, being suitable for application as organic light-emitting diodes.

Epidemiology of elderly fractures in a tertiary hospital in Northern Ghana: a 3-year retrospective descriptive review.

PURPOSE: The incidence of elderly fractures is closely related to the increasing proportion of the elderly population in sub-Saharan Africa, making it a relevant public health concern. Epidemiological profiles of these fractures and treatment options are necessary for resource-poor settings to optimise planning and patient care. METHODS: A retrospective descriptive cross-sectional study was conducted at Tamale Teaching Hospital. Data of 69 elderly patients (60 years and above) with fractures admitted to the trauma and orthopaedic unit from January 2017 to December 2019 were collected. Simple descriptive and bivariate analysis was conducted on some variables, whereas the Chi-square was used to test for some associations for categorical data. RESULTS: The mean age of the study participants was 70.3(± 8.6). Elderly males (55.1%) were three times more likely to sustain fractures than females. The primary mechanism of injury was a road traffic accident (RTA) (59.4%), followed by falls from slips (29.0%). There was a significant association between gender and mechanisms (RTA and Falls from slips) of injury (p = 0.002). The most fractured bone was the femur (50.7%). Hip fractures (33.3%) were more common among females than males and mainly among the (71-80) age group. Open fractures were more common among males than females. CONCLUSION: RTAs were the most typical cause of fractures in the elderly. Contrary to other studies, males were more commonly involved in accidents than females, albeit females were the majority for hip fractures. Therefore, significant public health policies with resource allocation should address the unmet health needs of this unique age group in our growing populations in low- and middle-income countries.

Hydroaminoalkylation of alkenes using transition metals complexes grafted on silica SBA15 as catalysts.

The gas-phase hydroaminoalkylation reaction of propene catalyzed by group 4 (M = Ti, Zr and Hf) metal amido complexes [(≡Si-O-)(M(-NMe2)3] was investigated by using PBE0-D3/SVP//TZVP level of theory. The geometrical analysis traced the formation of the metallaaziridines and the azametallacyclopentanes as key intermediates in these reactions. The metallaaziridines were simulated through the activation of α-C-H bonds of the amido groups; while the azametallacyclopentanes were configured by slotting the propene double bond onto the M - C bonds of the metallaaziridines. The latter reaction was considered the rate-determining step. Thermochemical calculations showed that the order of catalytic activity is: Ti ≥ Zr > Hf; while the preference of the azametallacyclopentanes is: Hf > Zr ≥ Ti.

Computational Identification of Druggable Bioactive Compounds from Catharanthus roseus and Avicennia marina against Colorectal Cancer by Targeting Thymidylate Synthase.

Colorectal cancer (CRC) is the second most common cause of death worldwide, affecting approximately 1.9 million individuals in 2020. Therapeutics of the disease are not yet available and discovering a novel anticancer drug candidate against the disease is an urgent need. Thymidylate synthase (TS) is an important enzyme and prime precursor for DNA biosynthesis that catalyzes the methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) that has emerged as a novel drug target against the disease. Elevated expression of TS in proliferating cells promotes oncogenesis as well as CRC. Therefore, this study aimed to identify potential natural anticancer agents that can inhibit the activity of the TS protein, subsequently blocking the progression of colorectal cancer. Initially, molecular docking was implied on 63 natural compounds identified from Catharanthus roseus and Avicennia marina to evaluate their binding affinity to the desired protein. Subsequently, molecular dynamics (MD) simulation, ADME (Absorption, Distribution, Metabolism, and Excretion), toxicity, and quantum chemical-based DFT (density-functional theory) approaches were applied to evaluate the efficacy of the selected compounds. Molecular docking analysis initially identified four compounds (PubChem CID: 5281349, CID: 102004710, CID: 11969465, CID: 198912) that have better binding affinity to the target protein. The ADME and toxicity properties indicated good pharmacokinetics (PK) and toxicity ability of the selected compounds. Additionally, the quantum chemical calculation of the selected molecules found low chemical reactivity indicating the bioactivity of the drug candidate. The global descriptor and HOMO-LUMO energy gap values indicated a satisfactory and remarkable profile of the selected molecules. Furthermore, MD simulations of the compounds identified better binding stability of the compounds to the desired protein. To sum up, the phytoconstituents from two plants showed better anticancer activity against TS protein that can be further developed as an anti-CRC drug.

Zn2+-Schiff's Base Complex as an "On-Off-On" Molecular Switch and a Fluorescence Probe for Cu2+ and Ag+ Ions.

The present study presents a thorough theoretical analysis of the electronic structure and conformational preference of Schiff's base ligand N,N-bis(2-hydroxybenzilidene)-2,4,6-trimethyl benzene-1,3-diamine (H2L) and its metal complexes with Zn2+, Cu2+ and Ag+ ions. This study aims to investigate the behavior of H2L and the binuclear Zn2+ complex (1) as fluorescent probes for the detection of metal ions (Zn2+, Cu2+ and Ag+) using density functional theory (DFT) and time-dependent density functional theory (TDDFT). The six conformers of the H2L ligand were optimized using the B3LYP/6-311 + + G** level of theory, while the L-2-metal complexes were optimized by applying the B3LYP functional with the LANL2DZ/6-311 + + G** mixed basis set. The gas-phase and solvated Enol-cis isomer (E-cis) was found to be the most stable species. The absorption spectra of the E-cis isomer and its metal complexes were simulated using B3LYP, CAM-B3LYP, M06-2X and ωB97X functionals with a 6-311 + + G** basis set for C, O, N and H atoms and a LANL2DZ basis set for the metal ions (Zn2+, Cu2+ and Ag+). The computational results of the B3LYP functional were in excellent agreement with the experimental results. Hence, it was adopted for performing the emission calculations. The results indicated that metal complex (1) can act as a fluorescent chemosensor for the detection of Ag+ and Cu2+ ions through the mechanism of intermolecular charge transfer (ICT) and as a molecular switch "On-Off-On" via the replacement of Cu2+ by Ag+ ions, as proved experimentally.

Image quality and dose evaluation of MVCT TomoTherapy acquisitions: A phantom study.

BACKGROUND: The aim of this study is to evaluate the dose delivered and the image quality of pre-treatment MVCT images with Hi-Art TomoTherapy system, varying acquisition and reconstruction parameters. MATERIALS AND METHODS: Catphan 500 MVCT images were acquired with all acquisition pitch and reconstruction intervals; image quality was evaluated in terms of noise, uniformity, contrast linearity, contrast-to-noise ratio (CNR) and spatial resolution with the Modulation Transfer Function (MTF). Dose was evaluated as Multi Slice Average Dose (MSADw) and measurements were performed with the Standard TomoTherapy® Quality Assurance Kit composed by the TomoTherapy Phantom, the Exradin A1SL ion chamber and TomoElectrometer. For each pitch-reconstruction interval, acquisitions were repeated 5 times. RESULTS: Differences in noise and uniformity, though statistically significant in some cases, were very small: noise ranged from 2.3% for Coarse - 3 mm to 2.4% for Coarse - 6 mm, while uniformity passed from 99.5% for Coarse - 6 mm to 99.8% for Normal - 4 mm. No differences at all were found for CNR for high and low density inserts, while MTF was higher for pitch Coarse, even if no differences in spatial resolution were observed visually (spatial resolution was up to 4 lp/cm for all combinations of pitch and reconstruction interval). Dose was dependent on pitch, being 1.0 cGy for Coarse, 1.5 cGy for Normal and 2.85 cGy for Fine. CONCLUSIONS: We observed negligible differences in image quality among different pitch and reconstruction interval, thus, considerations regarding pre-treatment imaging modalities should be based only on dose delivered and on the desired resolution along the cranio-caudal axis for image-guided radiotherapy and adaptive radiotherapy purposes.

Active surveillance as a successful management strategy for patients with clinical stage I germ cell testicular cancer.

BACKGROUND: Cancer-specific survival for patients with clinical stage I (CSI) germ cell testicular cancer (GCTC) is outstanding after inguinal orchidectomy regardless the treatment utilized. This study evaluated whether active surveillance (AS) of such patients yielded similar health outcomes to other therapeutic strategies such as adjuvant chemotherapy, radiotherapy or primary retroperitoneal lymphadenectomy as described in the literature. PATIENTS AND METHODS: Patients with CSI GCTC were screened between January 2012 and December 2016. Patients had previously undergone inguinal orchidectomy as the primary treatment and chosen AS as their preferred management strategy after receiving information about all available strategies. RESULTS: Out of 91 patients screened, 82 patients selected AS as their preferred management strategy. Relapse rate in the overall population was 20% (95% CI 12-30) and median time to relapse was 11.5 months (range 1.0-35.0). In patients with seminomatous tumors, relapse rate decreased to 13% and median time to relapse was 13 months; whereas in patients with non-seminomatous tumors, relapse rate was 33% (IA) or 29% (IB) and median time to relapse was 12 months in stage IA and 4.5 months in stage IB patients. All relapses were rescued with three or four cycles of chemotherapy and two also required a retroperitoneal lymphadenectomy. All patients are currently alive and free of disease. CONCLUSIONS: The clinical outcomes of patients with CSI GCTC managed by AS in this series were excellent. This strategy limited the administration of active treatments specifically to the minority of patients who relapsed without compromising performance.

Non-specific skin purpura.

Essential thrombocythemia is one of the myeloproliferative neoplasms. Palpable purpura is a rare manifestation that may delay diagnosis and treatment. We report a case of essential thrombocythemia in a 50-year-old man, who presented with recurrent thigh pain for the past one year with nonspecific localized purpura. His full blood count revealed isolated thrombocytosis of 880,000/µL with an impression of myeloproliferative disorder from peripheral blood film. He was referred urgently to the hematology team, which proceeded with a venesection. His condition improved with hydroxyurea. This was a rare case of chronic presentation of myeloproliferative neoplasm detected at a primary care clinic.

Comparison of survival between dialysis patients with incident high-flux hemodialysis versus on-line hemodiafiltration: A single center experience in Saudi Arabia.

Conventional hemodialysis (HD) is the most common treatment modality used for renal replacement therapy. The concept of HD is based on the diffusion of solutes across a semipermeable membrane. Hemofiltration (HF) is based on convective transport of solutes; hemodiafiltration (HDF) is based on combined convective and diffusive therapies. Data about survival benefit of on-line HDF (OL-HDF) over high-flux HD (HF-HD) is conflicting. We conducted this study to investigate if there is a survival difference between the two treatment modalities. This study is a retrospective, single-center study in which 78 patients were screened; 18 were excluded and 60 patients were analyzed. The study patients were aged 47.5 ± 20.7 years, 33 patients (55%) were on HF-HD, and 27 patients (45%) were on OL-HDF. A total of 24 patients (40%) of both groups were diabetic and, the mean duration on dialysis was 43.5 ±21.3 months in the HF-HD group and 41.2 ± 22.0 months in the OL-HDF group. The mean substitution volume for OL-HDF was 22.3 ± 2.5 L. Survival was 73% [95%, confidence interval (CI) 60-84] in the HF-HD group and 65% (95%, CI 54-75) in the OL-HDF group by the end of the study period. The unadjusted hazard ratio (HR) with 95% CI comparing HF-HD to high-volume postdilution OL-HDF was 0.78 (0.10-5.6; P = 0.810). Kaplan-Meier analysis for patient survival over five years showed no significant difference between the two modalities. Prospective controlled trials with a larger number of patients will be needed to assess the long-term clinical outcome of postdilution OL-HDF over HF-HD.

DFT Study of the Structure, Reactivity, Natural Bond Orbital and Hyperpolarizability of Thiazole Azo Dyes.

The structure, reactivity, natural bond orbital (NBO), linear and nonlinear optical (NLO) properties of three thiazole azo dyes (A, B and C) were monitored by applying B3LYP, CAM-B3LYP and ωB97XD functionals with 6-311++G** and aug-cc-pvdz basis sets. The geometrical parameters,dipolemoments,HOMO-LUMO(highest occupied molecular orbital,lowest unoccupied molecular orbital) energy gaps, absorption wavelengths and total hyperpolarizabilities were investigated in carbon tetrachloride (CCl4) chloroform (CHCl3), dichloromethane (CH2Cl2) and dimethlysulphoxide (DMSO). The donor methoxyphenyl group deviates from planarity with the thiazole azo moiety by ca. 38◦; while the acceptor dicyanovinyl, indandione and dicyanovinylindanone groups diverge by ca. 6◦. The HOMOs for the three dyes are identical. They spread over the methoxyphenyl donor moiety, the thiazole and benzene rings as π-bonding orbitals. The LUMOs are shaped up by the nature of the acceptor moieties. The LUMOs of the A, B and C dyes extend over the indandione, malononitrile and dicyanovinylindanone acceptor moieties, respectively, as π-antibonding orbitals. The HOMO-LUMO splittings showed that Dye C is much more reactive than dyes A and B. Compared to dyes A and B, Dye C yielded a longer maximum absorption wavelength because of the stabilization of its LUMOs relative to those of the other two. The three dyes show solvatochromism accompanied by significant increases in hyperpolarizability. The enhancement of the total hyperpolarizability of C compared to those of A and B is due to the cumulative action of the long π-conjugation of the indanone ring and the stronger electron-withdrawing ability of the dicyanovinyl moiety that form the dicyanovinylindanone acceptor group. These findings are facilitated by a natural bond orbital (NBO) technique. The very high total hyperpolarizabilities of the three dyes define their potent nonlinear optical (NLO) behaviour.

The Thermodynamic and Kinetic Properties of 2-Hydroxypyridine/2-Pyridone Tautomerization: A Theoretical and Computational Revisit.

The gas-phase thermal tautomerization reaction between 2-hydroxypyridine (2-HPY) and 2-pyridone (2-PY) was investigated by applying 6-311++G** and aug-cc-pvdz basis sets incorporated into some density functional theory (DFT) and coupled cluster with singles and doubles (CCSD) methods. The geometrical structures, dipole moments, HOMO-LUMO energy gaps, total hyperpolarizability, kinetics and thermodynamics functions were monitored against the effects of the corrections imposed on these functionals. The small experimental energy difference between the two tautomers of 3.23 kJ/mol; was a real test of the accuracy of the applied levels of theory. M062X and CCSD methods predicted the preference of 2-HPY over 2-PY by 5-9 kJ/mol; while B3LYP functional favoured 2-PY by 1-3 kJ/mol. The CAM-B3LYP and ωB97XD functionals yielded mixed results depending on the basis set used. The source of preference of 2-HPY is the minimal steric hindrance and electrostatic repulsion that subdued the huge hyperconjugation in 2-PY. A 1,3-proton shift intramolecular gas-phase tautomerization yielded a high average activation of 137.152 kJ/mol; while the intermolecular mixed dimer interconversion gave an average barrier height of 30.844 kJ/mol. These findings are boosted by a natural bond orbital (NBO) technique. The low total hyperpolarizabilities of both tautomers mark out their poor nonlinear optical (NLO) behaviour. The enhancement of the total hyperpolarizability of 2-HPY over that of 2-PY is interpreted by the bond length alternation.

Physicochemical and Nonlinear Optical Properties of Novel Environmentally Benign Heterocyclic Azomethine Dyes: Experimental and Theoretical Studies.

Novel heterocyclic azomethine dyes were prepared by the reaction of anthracene-9-carbaldehyde with different heterocyclic amines under microwave irradiation. Structures of the azomethine dyes were confirmed by the elemental analysis, mass spectrometry and several spectroscopic techniques. We studied absorbance and fluorescence spectra of the azomethine dyes in various solvents. They are found to be good absorbers and emitters. We also report photophysical properties like, extinction coefficient, oscillator strength, stokes shift and transition dipole moment. This reflects physicochemical behaviors of synthesized dyes. In addition, their intramolecular charge transfer and nonlinear optical properties, supported by natural bond orbital technique, were also studied computationally by density functional theory. The negative nonlinear refractive index and nonlinear absorption coefficient were measured for these dyes using the closed and open aperture Z-scan technique with a continuous wave helium-neon laser. These are found to vary linearly with solution concentration.

Photophysical Behavior and Computational Investigation of Novel 1,4-Bis(2-(2-Phenylpyrimido[1,2-a]Benzimidazol-4-Yl)Phenoxy)Butan (BPPB) Macromolecule.

A new macromolecule pyrimido[l,2-a]benzimidazole derivative named 1,4-bis(2-(2-phenylpyrimido[1,2-a]benzimidazol-4-yl)phenoxy)butan (BPPB) has been synthesized in accepted yield using microwave assistance. The new compound BPPB has been formed by the interaction of 3,3'-((butane-1,4-diylbis(oxy))bis(2,1-phenylene))bis(1-phenylprop-2-en-1-one) (3) with 2- aminobenzimidazole (4) in the presence of potassium hydroxide as a basic catalyst in dimethylformamide (DMF) under microwave radiation for 20 min. The chemical structure of this novel compound was elucidated by elemental and spectral techniques including: FT-IR, (1)H-NMR, (13)C-NMR and mass spectra. The electronic absorption and emission spectra of BPPB were measured in different solvents. BPPB displayed a solvatochromic effect of the emission spectrum that is reflected by red shifts of its fluorescence emission maxima on increasing the solvent polarity, indicating a change of electronic charge distribution upon excitation. BPPB crystalline solids gave excimer-like emission at 535 nm with a bandwidth of ca. 60 nm. Ground and excited states electronic geometry optimizations using density functional theory (DFT) and time-dependent density functional theory (TD-DFT), respectively, complemented these spectral findings. The intramolecular charge transfer was investigated by natural bond orbital (NBO) technique.

Fluorescence, Photophysical Behaviour and DFT Investigation of E,E-2,5-bis[2-(3-pyridyl)ethenyl]pyrazine (BPEP).

E,E-2,5-bis[2-(3-pyridyl)ethenyl]pyrazine (BPEP) has been prepared by aldol condensation between 2,5-dimethylpyrazine and pyridine-3-carboxaldehyde. It is characterized by IR, (1)H NMR, and (13)C NMR. The electronic absorption and emission properties of BPEP were studied in different solvents. BPEP displays a slight solvatochromic effect of the absorption and emission spectrum, indicating a small change in dipole moment of BPEP upon excitation. The dye solutions (1 × 10(-4) M) in CHCl3, EtOH and dioxane give laser emission in blue region upon excitation by a 337.1 nm nitrogen pulse (λ = 337 nm). The tuning range, gain coefficient (α) and emission cross - section (σe) have been determined. Ground and excited states electronic geometric optimizations were performed using density functional theory (DFT) and time-dependent density functional theory (TD-DFT), respectively. A DFT natural bond analysis complemented the ICT. The simulated maximum absorption and emission wavelengths are in line the observed ones in trend, and are proportionally red-shifted with the increase of the solvent polarity. The stability, hardness and electrophilicity of BPEP in different solvents were correlated with the polarity of the elected solvents. BPEP dye displays fluorescence quenching by colloidal silver nanoparticles (AgNPs). The fluorescence data reveal that radiative and non-radiative energy transfer play a major role in the fluorescence quenching mechanism.

Disease Management, Case Management, Care Management, and Care Coordination: A Framework and a Brief Manual for Care Programs and Staff.

UNLABELLED: With the changing landscape of health care delivery in the United States since the passage of the Patient Protection and Affordable Care Act in 2010, health care organizations have struggled to keep pace with the evolving paradigm, particularly as it pertains to population health management. New nomenclature emerged to describe components of the new environment, and familiar words were put to use in an entirely different context. PURPOSE/OBJECTIVES: This article proposes a working framework for activities performed in case management, disease management, care management, and care coordination. The author offers standard working definitions for some of the most frequently used words in the health care industry with the goal of increasing consistency for their use, especially in the backdrop of the Centers for Medicaid & Medicare Services offering a "chronic case management fee" to primary care providers for managing the sickest, high-cost Medicare patients. PRIMARY PRACTICE SETTINGS: Health care organizations performing case management, care management, disease management, and care coordination. FINDINGS/CONCLUSIONS: Road map for consistency among users, in reporting, comparison, and for success of care management/coordination programs. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: This article offers a working framework for disease managers, case and care managers, and care coordinators. It suggests standard definitions to use for disease management, case management, care management, and care coordination. Moreover, the use of clear terminology will facilitate comparing, contrasting, and evaluating all care programs and increase consistency. The article can improve understanding of care program components and success factors, estimate program value and effectiveness, heighten awareness of consumer engagement tools, recognize current state and challenges for care programs, understand the role of health information technology solutions in care programs, and use information and knowledge gained to assess and improve care programs to design the "next generation" of programs.

The Prognosis of Adult Burkitt's Cell Leukemia in Real-Life Clinical Practice.

OBJECTIVE: Many studies reported an improved prognosis in patients with Burkitt's lymphoma obviating the need of stem cell transplantation. However, prognosis of the advanced disease [i.e. Burkitt's cell leukemia (BCL)] has not been reported with current treatment modalities except for a few prospective trials. The aim of this study is to compare the prognoses of BCL patients with similarly treated and nontransplanted patients with other types of acute lymphoblastic leukemia (ALL) and with ALL patients that underwent allogeneic stem cell transplantation (ASCT) in their first remissions. MATERIALS AND METHODS: In this retrospective analysis, BCL patients aged between 16 and 63 who were admitted between 2000 and 2014 to the hospitals of Hacettepe or Gazi University and were treated with intensive therapies aimed at cure were included. All ALL patients who were treated with a similar protocol not including transplantation during the same period (NT-ALL group) and all ALL patients who underwent ASCT in the first complete remission during the same period (T-ALL group) served as control groups. RESULTS: The central nervous system or extramedullary involvement rates, lactate dehydrogenase levels, and white blood cell counts at diagnosis were higher in the BCL group than the NT-ALL group and these differences were significant. BCL patients had disease-free survival (DFS) durations comparable with the T-ALL cohort but NT-ALL patients had significantly shorter DFS durations. Both cumulative relapse incidence and cumulative nonrelapse mortality were higher in NT-ALL patients compared to the T-ALL group and BCL patients. CONCLUSION: DFS in BCL patients treated with a widely accepted modern regimen, R-HyperCVAD, is comparable to results in other ALL patients receiving allogeneic transplantation. Our results are in agreement with a few prospective noncomparative studies suggesting no further need for stem cell transplantation in BCL.

Expression Profiles of the Individual Genes Corresponding to the Genes Generated by Cytotoxicity Experiments with Bortezomib in Multiple Myeloma.

OBJECTIVE: Multiple myeloma (MM) is currently incurable due to refractory disease relapse even under novel anti-myeloma treatment. In silico studies are effective for key decision making during clinicopathological battles against the chronic course of MM. The aim of this present in silico study was to identify individual genes whose expression profiles match that of the one generated by cytotoxicity experiments for bortezomib. MATERIALS AND METHODS: We used an in silico literature mining approach to identify potential biomarkers by creating a summarized set of metadata derived from relevant information. The E-MTAB-783 dataset containing expression data from 789 cancer cell lines including 8 myeloma cell lines with drug screening data from the Wellcome Trust Sanger Institute database obtained from ArrayExpress was "Robust Multi-array analysis" normalized using GeneSpring v.12.5. Drug toxicity data were obtained from the Genomics of Drug Sensitivity in Cancer project. In order to identify individual genes whose expression profiles matched that of the one generated by cytotoxicity experiments for bortezomib, we used a linear regression-based approach, where we searched for statistically significant correlations between gene expression values and IC50 data. The intersections of the genes were identified in 8 cell lines and used for further analysis. RESULTS: Our linear regression model identified 73 genes and some genes expression levels were found to very closely correlated with bortezomib IC50 values. When all 73 genes were used in a hierarchical cluster analysis, two major clusters of cells representing relatively sensitive and resistant cells could be identified. Pathway and molecular function analysis of all the significant genes was also investigated, as well as the genes involved in pathways. CONCLUSION: The findings of our present in silico study could be important not only for the understanding of the genomics of MM but also for the better arrangement of the targeted anti-myeloma therapies, such as bortezomib.

Gas-Phase Thermal Tautomerization of Imidazole-Acetic Acid: Theoretical and Computational Investigations.

The gas-phase thermal tautomerization reaction between imidazole-4-acetic (I) and imidazole-5-acetic (II) acids was monitored using the traditional hybrid functional (B3LYP) and the long-range corrected functionals (CAM-B3LYP and ωB97XD) with 6-311++G** and aug-cc-pvdz basis sets. The roles of the long-range and dispersion corrections on their geometrical parameters, thermodynamic functions, kinetics, dipole moments, Highest Occupied Molecular Orbital-Lowest Unoccupied Molecular Orbital (HOMO-LUMO) energy gaps and total hyperpolarizability were investigated. All tested levels of theory predicted the preference of I over II by 0.750-0.877 kcal/mol. The origin of predilection of I is assigned to the H-bonding interaction (nN8→σ*O14-H15). This interaction stabilized I by 15.07 kcal/mol. The gas-phase interconversion between the two tautomers assumed a 1,2-proton shift mechanism, with two transition states (TS), TS1 and TS2, having energy barriers of 47.67-49.92 and 49.55-52.69 kcal/mol, respectively, and an sp³-type intermediate. A water-assisted 1,3-proton shift route brought the barrier height down to less than 20 kcal/mol in gas-phase and less than 12 kcal/mol in solution. The relatively high values of total hyperpolarizability of I compared to II were interpreted and discussed.