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Biomedical subjects

M E Flanagan

Publications and source records attributed to M E Flanagan.

At least 19 recordsLinked to original sources
PubMed1995

Netropsin and spermine conjugates of a water-soluble quinocarcin analog: analysis of sequence-specific DNA interactions.

BACKGROUND: Quinocarcin is the simplest of the bioxalmycin/naphthyridinomycin/tetrazomine/saframycin class of anti-tumor antibiotics, which damage DNA in a process that is inhibited by superoxide dismutase (SOD). The oxazolidine moiety of this class of anti-tumor antibiotics undergoes a redox self-disproportionation reaction of the Cannizzaro type. The reaction is proposed to proceed via an intermediate carbon-centered radical, which then reduces molecular oxygen to give superoxide. We set out to determine whether the DNA-cleavage properties of these anti-tumor antibiotics could be retained in less complex analogs of quinocarcin. RESULTS: A totally synthetic, water-soluble analog of quinocarcin has been prepared. This analog produced superoxide, but had considerably reduced ability to cleave supercoiled circular DNA compared to quinocarcin or tetrazomine. When conjugated to the DNA-binding molecule spermine, however, it cleaved DNA as effectively as quinocarcin at less than 1/10 the concentration. A conjugate with netropsin displayed selective cleavage around the sequence 5'-d(ATTT)-3'. Molecular modeling of the interaction between the conjugate and DNA, together with the pattern of cleavage, indicates that a non-diffusable oxidant is involved in sequence-selective DNA cleavage. The spermine conjugate displayed weak antimicrobial activity. CONCLUSIONS: Knowledge of the stereoelectronic requirements for superoxide production by quinocarcin has allowed us to design a structurally less complex analog which has many of the same physical properties, including water solubility, the ability to produce superoxide and the ability to cleave DNA. Covalently attaching known DNA-binding molecules to this analog gave a compound that produced sequence-specific DNA damage. Our results suggest that a mechanism other than superoxide production can mediate DNA damage by the netropsin conjugate.

Aerobiosis↗
PubMed1994

O2-dependent cleavage of DNA by tetrazomine.

A mechanism for the reduction of molecular oxygen that results in the O2-dependent cleavage of both single-stranded and double-stranded DNA by the antitumor antibiotic tetrazomine (1) is presented. The results are discussed in the context of a redox self-disproportionation of the oxazolidine moiety of tetrazomine. Comparisons are made to the structurally analogous natural product quinocarcin (2) in which, like tetrazomine, the oxazolidine moiety is invoked in redox chemistry, which ultimately results in the reduction of molecular oxygen to superoxide.

DNA↗
PubMed1991

Primary central nervous system T-cell lymphoma. Case report.

Primary central nervous system (CNS) T-cell lymphoma is extremely rare. The present case report provides immunocytochemical evidence for a cerebellar CNS T-cell lymphoma. The patient underwent surgery followed by radiation therapy and is alive and well 36 months postoperatively. The clinical and pathological features of primary CNS T-cell lymphoma as well as diagnostic measures and treatment options are discussed, together with a compilation of all previous case reports of primary CNS T-cell lymphomas.

Adult↗
PubMed1990

The Major Trauma Outcome Study: establishing national norms for trauma care.

The Major Trauma Outcome Study (MTOS) is a retrospective descriptive study of injury severity and outcome coordinated through the American College of Surgeons' Committee on Trauma. From 1982 through 1987, 139 North American hospitals submitted demographic, etiologic, injury severity, and outcome data for 80,544 trauma patients. Motor vehicle related injuries were most frequent (34.7%). Twenty-one per cent of patients had penetrating injuries. The overall mortality rate was 9.0%. The mortality rate for direct admissions was strongly related to the presence of serious head injury, 5.0% and 40.0%, when head injuries were less than or equal to AIS (Abbreviated Injury Scale) 3 or greater than or equal to AIS 4, respectively. Survival probability norms use the Revised Trauma Score, Injury Severity Score, patient age, and injury mechanism. Patients with unexpected outcomes were identified and statistical comparisons of actual and expected numbers of survivors made for each institution. Results provide a description of injury and outcome and support evaluation and quality assurance activities.

Adolescent↗
PubMed1989

Chemistry on solid supports: defining events and titers by use of cleavable, assayable linking molecules.

The cleavable diamines cystamine, 5, and 1,6-diamino-3,4-dihydroxyhexane, 1, were bonded to solid supports and, with a simple, newly developed dinitrofluorobenzene-based assay, were used to define (a) titers of ligands and (b) chemistry distal to the support. Compound 1, which is cleavable with periodate, becomes a linking molecule which is stable to almost all conditions encountered in biochemistry and enjoys considerable hydrophilic character. Compound 5, which is cleavable with dithiothreitol, can be usefully applied to those systems which do not require reducing agents. These nucleophilic linking moieties were converted to cleavable electrophilic linkers by succinylation and p-nitrophenyl ester activation. The first preparation of a polysaccharide-linked support is described. The method also allows the chemical definition of ligands containing amino groups which are prepared by deblocking of protecting groups while on the support. The methodology should promote greater understanding of affinity chromatography materials and processes.

Amines↗
PubMed1989

A revision of the Trauma Score.

The Trauma Score (TS) has been revised. The revision includes Glasgow Coma Scale (GCS), systolic blood pressure (SBP), and respiratory rate (RR) and excludes capillary refill and respiratory expansion, which were difficult to assess in the field. Two versions of the revised score have been developed, one for triage (T-RTS) and another for use in outcome evaluations and to control for injury severity (RTS). T-RTS, the sum of coded values of GCS, SBP, and RR, demonstrated increased sensitivity and some loss in specificity when compared with a triage criterion based on TS and GCS values. T-RTS correctly identified more than 97% of nonsurvivors as requiring trauma center care. The T-RTS triage criterion does not require summing of the coded values and is more easily implemented than the TS criterion. RTS is a weighted sum of coded variable values. The RTS demonstrated substantially improved reliability in outcome predictions compared to the TS. The RTS also yielded more accurate outcome predictions for patients with serious head injuries than the TS.

Blood Pressure↗
PubMed1989

Major trauma in geriatric patients.

Contemporary trauma to the elderly, its severity and associated mortality and morbidity in 111 United States and Canadian trauma centers are described. Three-thousand eight-hundred thirty-three (3,833) trauma patients age 65 years or older are compared to 42,944 injured patients under age 65. Although both groups had equivalent measures of injury severity, the older group had higher case fatality and complication rates and longer hospital stays. The results raise important questions regarding the triage, acute care, accurate prediction of outcome, and hospital reimbursement for the elderly injured patient, with implications for care evaluation, quality assurance, and the long-term viability of trauma centers and systems of care.

Adolescent↗