Enhancement of camptothecin-induced topoisomerase I cleavage complexes by the acetaldehyde adduct N2-ethyl-2'-deoxyguanosine.

The activity of DNA topoisomerase I (Top1), an enzyme that regulates DNA topology, is impacted by DNA structure alterations and by the anticancer alkaloid camptothecin (CPT). Here, we evaluated the effect of the acetaldehyde-derived DNA adduct, N2-ethyl-2'-deoxyguanosine (N2-ethyl-dG), on human Top1 nicking and closing activities. Using purified recombinant Top1, we show that Top1 nicking-closing activity remains unaffected in N2-ethyl-dG adducted oligonucleotides.

Novel autoxidative cleavage reaction of 9-fluoredenes discovered during synthesis of a potential DNA-threading indenoisoquinoline.

The indenoisoquinolines are a novel class of cytotoxic non-camptothecin topoisomerase I inhibitors. A potential DNA-threading agent was designed by attaching different amine side chains on the lactam nitrogen as well as on the C11 position of the indenoisoquinoline ring system. It was hypothesized that substituents on the lactam nitrogen could protrude out toward the DNA major groove while those on the C11 project out toward the DNA minor groove in the ternary "cleavage complex.

Position- and orientation-specific enhancement of topoisomerase I cleavage complexes by triplex DNA structures.

Topoisomerase I (Top1) activities are sensitive to various endogenous base modifications, and anticancer drugs including the natural alkaloid camptothecin. Here, we show that triple helix-forming oligonucleotides (TFOs) can enhance Top1-mediated DNA cleavage by affecting either or both the nicking and the closing activities of Top1 depending on the position and the orientation of the triplex DNA structure relative to the Top1 site. TFO binding 1 bp downstream from the Top1 site enhances cleavage by inhibiting religation and to a lesser extent DNA nicking.

Apoptotic topoisomerase I-DNA complexes induced by staurosporine-mediated oxygen radicals.

Topoisomerase I (Top1), an abundant nuclear enzyme expressed throughout the cell cycle, relaxes DNA supercoiling by forming transient covalent DNA cleavage complexes. We show here that staurosporine, a ubiquitous inducer of apoptosis in mammalian cells, stabilizes cellular Top1 cleavage complexes. These complexes are formed indirectly as staurosporine cannot induce Top1 cleavage complexes in normal DNA with recombinant Top1 or nuclear extract from normal cells.

Design, synthesis, and biological evaluation of cytotoxic 11-aminoalkenylindenoisoquinoline and 11-diaminoalkenylindenoisoquinoline topoisomerase I inhibitors.

The cytotoxic indenoisoquinolines are a novel class of noncamptothecin topoisomerase I inhibitors having certain features that compare favorably with the camptothecins. A new strategy was adopted to attach aminoalkenyl substituents at C-11 of the indenoisoquinoline ring system, which, according to molecular modeling, would orient the side chains toward the DNA minor groove. All of the newly synthesized compounds were more cytotoxic than the parent indenoisoquinoline NSC 314622.

Expression profiling of sodium butyrate (NaB)-treated cells: identification of regulation of genes related to cytokine signaling and cancer metastasis by NaB.

Histone deacetylase (HDAC) inhibitors induce growth arrest and apoptosis in a variety of human cancer cells. Sodium butyrate (NaB), a short chain fatty acid, is a HDAC inhibitor and is produced in the colonic lumen as a consequence of microbial degradation of dietary fibers. In order to dissect out the mechanism of NaB-induced growth inhibition of cancer cells, we carried out expression profiling of a human lung carcinoma cell line (H460) treated with NaB using a cDNA microarray.

A retrospective study: clinical experience using vacuum-assisted closure in the treatment of wounds.

We report the results of our wound care experience using the wound vac as an adjunct therapy in the treatment of sternal, spinal, and lower-extremity wounds. This is a retrospective study in which 42 patients were evaluated between 1999 and 2002 for nonhealing sternal, spinal, and lower-extremity wounds. There were 12 patients with sternal wounds with a variety of pathogens who were treated with antimicrobials along with the wound VAC.

Synthesis of nitrated indenoisoquinolines as topoisomerase I inhibitors.

Indenoisoquinolines and dihydroindenoisoquinolines have been synthesized possessing a nitro-substituted isoquinoline ring in an effort to explore the effects of electron-withdrawing substituents on biological activity. The in vitro anticancer activities of these molecules have been tested in the National Cancer Institute's screen of 55 cell lines. The compounds have also been tested for topoisomerase I (top1) inhibition.

Topoisomerase I-DNA complexes contribute to arsenic trioxide-induced apoptosis.

Topoisomerase I is an essential enzyme that relaxes DNA supercoiling by forming covalent DNA cleavage complexes, which are normally transient. Topoisomerase I-DNA complexes can be trapped by anticancer drugs (camptothecins) as well as by endogenous and exogenous DNA lesions. We show here that arsenic trioxide (a potent inducer of apoptosis that induces the intracellular accumulation of reactive oxygen species and targets mitochondria) induces cellular topoisomerase I cleavage complexes.

Apoptosis defects and chemotherapy resistance: molecular interaction maps and networks.

Intrinsic (innate) and acquired (adaptive) resistance to chemotherapy critically limits the outcome of cancer treatments. For many years, it was assumed that the interaction of a drug with its molecular target would yield a lethal lesion, and that determinants of intrinsic drug resistance should therefore be sought either at the target level (quantitative changes or/and mutations) or upstream of this interaction, in drug metabolism or drug transport mechanisms. It is now apparent that independent of the factors above, cellular responses to a molecular lesion can determine the outcome of therapy.

ABCG2 mediates differential resistance to SN-38 (7-ethyl-10-hydroxycamptothecin) and homocamptothecins.

One activity potentially limiting the efficacy of camptothecin anticancer agents is their cellular efflux by the ATP-binding cassette half-transporter, ABCG2. Homocamptothecins are novel anticancer drugs that inhibit topoisomerase 1 with a greater potency than camptothecins. Homocamptothecins differ from camptothecins by their E-ring, which is seven-membered instead of the six-membered ring of camptothecins.

Editing and publishing of a medical journal. Success of an unconventional workflow.

Regional journals often face constraints that threaten their growth, calling for novel coping strategies. This paper outlines the problems and challenges in editing and publishing the SQU Journal for Scientific Research: Medical Sciences, the only peer-reviewed medical journal in the Sultanate of Oman. These included the absence of secretarial support and the consequent need to reduce paperwork, the fact that most papers required substantial editing even after peer review, and the lack of a single workflow for creating documents for the press and the Internet.

Design, synthesis, and biological evaluation of indenoisoquinoline topoisomerase I inhibitors featuring polyamine side chains on the lactam nitrogen.

The indenoisoquinolines are a class of noncamptothecin topoisomerase I inhibitors that display significant cytotoxicity in human cancer cell cultures. They offer a number of potential advantages over the camptothecins, including greater chemical stability, formation of more persistent cleavage complexes, and induction of a unique pattern of DNA cleavage sites. Molecular modeling has suggested that substituents on the indenoisoquinoline lactam nitrogen would protrude out of the DNA duplex in the ternary cleavage complex through the major groove.

Repair of and checkpoint response to topoisomerase I-mediated DNA damage.

Topoisomerase I (Top1) catalyzes two transesterification reactions: single-strand DNA cleavage and religation that are normally coupled for the relaxation of DNA supercoiling in transcribing and replicating chromatin. A variety of endogenous DNA modifications, potent anticancer drugs and carcinogens uncouple these two reactions, resulting in the accumulation of Top1 cleavage complexes. Top1 cleavage complexes damage DNA and kill cells by generating replication-mediated DNA double-strand breaks (DSBs) and by stalling transcription complexes.

Use of liposomal amphotericin B in the treatment of disseminated coccidioidomycosis.

Disseminated fungal infection is an important cause of morbidity and mortality, especially in immunocompromised hosts. Amphotericin B is an important part of the therapy and treatment of invasive and life-threatening mycoses. We present a case of disseminated coccidioidomycosis in a patient who was successfully treated with liposomal amphotericin B (AmBisome) on steroid therapy.

Differential induction of topoisomerase I-DNA cleavage complexes by the indenoisoquinoline MJ-III-65 (NSC 706744) and camptothecin: base sequence analysis and activity against camptothecin-resistant topoisomerases I.

Camptothecin (CPT) and its derivatives target mammalian DNA topoisomerase I (top1) and are among the most effective novel anticancer drugs. However, the activity of CPTs is limited by several factors, including drug inactivation by lactone ring opening, tumor drug resistance, and toxicity in patients. Novel top1 inhibitors are being searched to overcome such limitations and expand the anticancer spectrum of camptothecins.

Design, synthesis, and biological evaluation of cytotoxic 11-alkenylindenoisoquinoline topoisomerase I inhibitors and indenoisoquinoline-camptothecin hybrids.

The indenoisoquinolines are a novel class of topoisomerase I (top1) inhibitors that are cytotoxic in cancer cell cultures and are therefore under development as potential anticancer agents. As inhibitors of the DNA religation reaction occurring after DNA cleavage by the enzyme, they are classified as top1 poisons, similar to the camptothecins. Two strategies were employed in order to further develop the structure-activity relationships of the indenoisoquinolines and enhance their therapeutic potential.

The role of propofol as a general anaesthetic agent in surgery for sinonasal diseases.

Propofol is known to he a better drug when used for induction of general anaesthesia. But when it is used for induction as well as maintenance of general anaesthesia in the surgery for sinonasal diseases, it significantly reduces the blood loss thereby improving the risibility of the endonasal structures and minimises the chance of complications related to endoseopic sinus surgery.

Profile of child and adolescent psychiatry in Oman.

Objective: To find the common behavioral problems in youth, their co-morbidity, treatment, and other variables in Oman.

Methods: All patients who attended the child psychiatric clinic in Sultan Qaboos University Hospital (SQUH), Muscat, (the only child psychiatry clinic in Sultanate of Oman) for a 3-month period were investigated for behavioral problems, particularly hyperactivity (by Conners' Questionnaire). The diagnosis was based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition.

Is human herpesvirus 6 linked to kikuchi-fujimoto disease? The importance of consistent molecular and serologic analysis.

Background: Kikuchi-Fujimoto disease, also called histiocytic necrotizing lymphadenitis, is a self-limiting lymphadenopathy of unknown cause. The patient often presents with fever, malaise, and lymphadenopathy primarily involving the cervical lymph nodes. Laboratory findings are nonspecific, and the diagnosis is established by identifying characteristic pathologic features from lymph node biopsy.

Clinical experience with linezolid in the treatment of resistant gram-positive infections.

This study presents our clinical experience with linezolid in 19 patients with serious resistant gram-positive infections enrolled as part of the compassionate study. In this prospective, non-randomized, noncomparative study, 19 patients were enrolled as part of the National Compassionate Study Protocol conducted by Pharmacia-Upjohn. At the time of this writing, these patients had not been published in the literature.

Vipassana meditation:: A naturalistic, preliminary observation in Muscat.

Objectives: To assess the effects of Vipassana meditation on the physical and psychological health in a multi-ethnic population in the city of Muscat.

Method: The subjects were participants of a Vipassana meditation course taught in a ten-day residential retreat. Self-assessments of health-related parameters and physical and psychological symptomatology were collected from them before and immediately after the course.

Eikenella corrodens: an unusual cause of severe parapneumonic infection and empyema in immunocompetent patients.

Over the past 25 years, Eikenella corrodens has increasingly been recognized for its pathogenic potential. Previously identified as an organism most likely to cause opportunistic infection in the immunocompromised host, Eikenella more recently has been implicated in a number of clinical infections in non-immunocompromised patients. We report a case of community-acquired pneumonia, caused by Eikenella, in a patient with diabetes mellitus and a past history of testicular cancer.

Evolution of force distribution in three-dimensional granular media.

Based on the discrete element method, the nature of normal contact force distribution and the effect of microstructure (contact fabric) on stresses in granular media sheared under constant mean stress condition is analyzed. The particles are tested in a periodic cell, having a nearly monodispersed system of spherical particles ("hard" and "soft"). The granular systems were initially isotropically compressed to have different solid fractions in order to obtain "dense" and "loose" samples.