Target fishing of glycopentalone using integrated inverse docking and reverse pharmacophore mapping approach.

Glycopentalone isolated from Glycosmis pentaphylla (family Rutaceae) has cytotoxic and apoptosis inducing effects in various human cancer cell lines; however, its mode of action is not known. Therefore, target fishing of glycopentalone using a combined approach of inverse docking and reverse pharmacophore mapping approach was used to identify potential targets of glycopentalone, and gain insight into its binding modes against the selected molecular targets, viz., CDK-2, CDK-6, Topoisomerase I, Bcl-2, VEGFR-2, Telomere:G-quadruplex and Topoisomerase II. These targets were chosen based on their key roles in the progression of cancer via regulation of cell cycle and DNA replication. Molecular docking analysis revealed that glycopentalone displayed binding energies ranging from -6.38 to -8.35 kcal/mol and inhibition constants ranging from 0.758 to 20.90 µM. Further, the binding affinities of glycopentalone to the targets were in the order: Telomere:G-quadruplex > VEGFR-2 > CDK-6 > CDK-2 > Topoisomerase II > Topoisomerase I > Bcl-2. Binding mode analysis revealed critical hydrogen bonds as well as hydrophobic interactions with the targets. The targets were validated by reverse pharmacophore mapping of glycopentalone against a set of 2241 known human target proteins which revealed CDK-2 and VEGFR-2 as the most favorable targets. The glycopentalone was well mapped to CDK-2 and VEGFR-2 which involve six pharmacophore features (two hydrophobic centers and four hydrogen bond acceptors) and nine pharmacophore features (five hydrophobic, two hydrogen bond acceptors and two hydrogen bond donors), respectively. The present computational approach may aid in rational identification of targets for small molecules against large set of candidate macromolecules before bioassays validation.

Molecular docking of the anticancer bioactive compound proceraside with macromolecules involved in the cell cycle and DNA replication.

The bioactive compounds proceraside A, frugoside and calotropin, which were extracted from the root bark of Calotropis procera (Aiton) W.T. Aiton (family Asclepiadaceae), were recently reported to inhibit the growth of inhibition against various human cancer cell lines in vitro. However, their modes of action have not been clearly defined. Therefore, we attempted an in silico approach to gain insights into their binding modes against the following selected molecular targets: CDK-2, CDK-6, topoisomerase I, BCL-2, VEGFR-2, telomere: G-quadruplex, and topoisomerase II. These targets were selected based on their key roles in cancer progression via the regulation of the cell cycle and DNA replication. Molecular-docking analyses revealed that proceraside A was the best docked ligand against all the targets, with the exception of telomere-G: quadruplex. Furthermore, it displayed the lowest binding energies and inhibition constants, and critical hydrogen bonds and hydrophobic interactions with the targets were also revealed. The present study may aid in the identification of possible targets for proceraside A, and might provide a plausible explanation for its proven anti-tumor activities. Moreover, the result of this study may further guide structure-activity relationship studies used to generate more potent target-specific inhibitors.

Roseomonas bacteremia in a recipient of an allogeneic hematopoietic stem cell transplantation.

Roseomonas are pink-pigmented, oxidative, slowly growing, nonfermentative, gram-negative coccobacilli whose identification may require extensive biochemical testing and molecular profiling. Roseomonas infections vary in severity and clinical presentation, and they predominantly occur in immunocompromised and chronically ill patients. The organism is generally susceptible to carbapenems and aminoglycosides, but resistant to most of the cephalosporins and broad-spectrum penicillins. Reported here is a patient with lymphoblastic lymphoma who developed Roseomonas mucosa bacteremia after receiving her hematopoietic stem cell allograft. The bacteremic episode was successfully treated with imipenem and amikacin in addition to removal of the central venous catheter. To our knowledge, this is the first report of Roseomonas bacteremia in a stem cell transplantation recipient.

Embryo-feto-toxicity of anticancer drug, heptaplatin in laboratory mice.

The present study was conducted to test the possible teratogenic and toxic effects of anti-cancer drug heptaplatin (SKI 2053) on developing embryos and fetuses in gestating SWR/J mice. Dose levels of 5.0, 10.0 and 12.5 mg heptaplatin/kg b.wt. were intraperitoneally administered to pregnant mice on days 6-8, 9-11 and 12-14 of gestation. On day 17 of gestation, all fetuses were removed and examined for toxic phenomena (embryo-fetal toxicity) by taking observation on live fetuses and embryonic resorption. Fetuses were also examined for external, internal and skeletal malformations. None of the dams treated with heptaplatin at any of the dose levels used in the present study died during the experimental period. Higher doses of heptaplatin caused greater embryonic resorption and reduced number of live fetuses. However, no loss of body weight was noticed in fetuses at any of the dose levels administered. At highest dose of heptaplatin (12.5 mg kg(-1)), tail deformity was observed in the form of short and curve tails whereas no other anatomical or skeletal malformations were noticed in any of the fetuses. In addition to mild embryo-fetotoxicity, the study indicates mild teratogenic effects of hetaplatin as reflected in fetal abnormalities at low frequency. These results have significant implications for protracted use of this drug.

Septic shock caused by Sphingomonas paucimobilis bacteremia in a patient with hematopoietic stem cell transplantation.

Sphingomonas paucimobilis is an aerobic gram-negative bacillus that causes a variety of infections in healthy as well as in immunocompromised individuals. The organism is usually susceptible to tetracycline, chloramphenicol, aminoglycosides, trimethoprim-sulfamethoxazole, and carbapenems. However, resistance to penicillins and the first-generation cephalosporins is commonly encountered. Reported here is a patient with acute myeloid leukemia who developed S. paucimobilis bacteremia complicated by septic shock just before receiving an autologous hematopoietic stem cell transplant (SCT) at King Faisal Specialist Hospital and Research Centre in Riyadh. The septic episode was successfully treated in the intensive care unit. To our knowledge, this is the first case report of septic shock caused by S. paucimobilis bacteremia in a hematopoietic SCT recipient.

Successful treatment of hepatic veno-occlusive disease after myeloablative allogeneic hematopoietic stem cell transplantation by early administration of a short course of methylprednisolone.

Hepatic veno-occlusive disease (VOD) is one of the most common and important regimen-related toxicities observed after hematopoietic stem cell transplantation (HSCT). There are no universally accepted preventative or therapeutic approaches for VOD. We prospectively evaluated the safety and efficacy of a short course of methylprednisolone (MP) in 48 patients undergoing allogeneic HSCT who were diagnosed with hepatic VOD. MP was administered at a dose of 0.5 mg/kg i.v. every 12 h for a total of 14 doses, and then discontinued without taper. Thirty (63%) patients responded with a reduction in total serum bilirubin of 50% or more after 10 days of treatment. In univariate analysis, non-responders had a higher total bilirubin at the start of MP therapy, more weight gain, evidence of fungal infection and platelet refractoriness. High SGPT and early engraftment were significant factors among responders. Twenty-five of the 30 responders survived up to day +100, whereas all but three non-responders died within 100 days post-HSCT, for a probability of survival of 58% among responders and 10% for non-responders. Prospective comparative studies are needed to confirm the observed encouraging outcome of MP therapy for VOD.

Complicated septic shock caused by Achromobacter xylosoxidans bacteremia in a patient with acute lymphoblastic leukaemia.

Infections caused by Achromobacter xylosoxidans cause significant morbidity and mortality in debilitated individuals. Eradication of these infections requires prolonged therapy with antimicrobial agents and removal of any infected central venous catheter. The outcome is usually poor in patients with high risk malignancy, septic complications, and/or multi-organ dysfunction.

Cytotoxic chemotherapy administered to two patients with partially refractory leukaemia while receiving intensive care treatment.

Administration of cytotoxic chemotherapy to a mechanically ventilated patient is a major undertaking. Induction of remission of leukaemia under such circumstances is an extremely rare event. We report two patients with partially refractory acute myeloid leukaemia who achieved remission of their leukaemia after receiving chemotherapy in the intensive care unit. Both patients were subsequently cured by allogeneic bone marrow transplant.

The experience of bone marrow transplantation at riyadh armed forces hospital.

This is a report about the program of bone marrow transplantation (BMT), which was established in 1989 at the Armed Forces Hospital in Riyadh, Saudi Arabia. We follow the strict international protocol of pre transplant assessment of the donor and the recipient, BMT conditioning by Cyclosphosphamide and Basulphan or body irradiation, BM harvest and processing, graft versus host disease prophylaxis by cyclosporin and methotrexate, and post-transplant care. Since the start of the BMT programme at the Armed Forces Hospitals in Riyadh in May 1989 and until the end of March 1996, fifty nine allogeneic and one autologous transplants have been performed. Chronic myelocytic and acute myeloid leukemia were the principal indications for BMT in our institute. The acturial five years survival of BMT in these two conditions was 67% and 47% respectively. Besides allografting, we finished the preparations for autologus BMT and peripheral blood stem cells transplantation, which may be used for treating patients with solid tumors and leukemias who are not suitable for allogenic transplantation due to older age or donor unavailability.