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Biomedical subjects

Christopher Anderson

Publications and source records attributed to Christopher Anderson.

14 recordsLinked to original sources
PubMed2006

Antitumor effects of aminobisphosphonates on renal cell carcinoma cell lines.

PURPOSE: Bisphosphonates are established as a supportive therapy for a number of malignancies that metastasize to bone. Previous reports have also suggested potent antitumor and anti-angiogenic properties. We investigated the in vitro activity of the 2 aminobisphosphonates pamidronate (Faulding Pharmaceuticals, Paramus, New Jersey) and zoledronic acid (Novartis, Basel, Switzerland) on the growth and survival of the 3 renal cell carcinoma cell lines Caki-2, 769-P (American Type Culture Collection, Manassas, Virginia) and D69581. MATERIALS AND METHODS: Cell lines were exposed to bisphosphonates in vitro and evaluated by MTS (3-(4,5-dimethylahiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay and cell cycle analysis. Mechanisms of apoptotic cell death were investigated by ApoDIRECT assay (BioVision, Mountain View, California) and Kinetworks analysis. RESULTS: Zoledronic acid was consistently more potent than pamidronate for inducing apoptotic cell death. Zoledronic acid was capable of overcoming resistance to pamidronate in 1 cell line. Although it was ultimately less potent, the inhibitory effects of pamidronate appeared earlier than those of zoledronic acid. The pro-apoptotic effect of zoledronic acid was achieved through nonmitochondrial pathways and it was associated with the activation of caspase 6 and 3, and poly adenosine diphosphate-ribosyltransferase polymerase cleavage. Furthermore, we observed a marked decrease in and intracellular distribution of MSH2, a protein involved in DNA mismatch repair, as well as evidence of a greater cellular response to zoledronic acid as increased expression of superoxide dismutase. CONCLUSIONS: These findings add further support to the clinical use of aminobisphosphonates, particularly zoledronic acid, in patients with renal cell carcinoma with disease metastatic to bone.

Antineoplastic Agents↗
PubMed2005

Interstrand and intrastrand DNA-DNA cross-linking by 1,2,3,4-diepoxybutane: role of stereochemistry.

1,2,3,4-Diepoxybutane (DEB) is a bifunctional electrophile capable of forming DNA-DNA and DNA-protein cross-links. DNA alkylation by DEB produces N7-(2'-hydroxy-3',4'-epoxybut-1'-yl)-guanine monoadducts, which can then form 1,4-bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD) lesions. All three optical isomers of DEB are produced metabolically from 1,3-butadiene, but S,S-DEB is the most cytotoxic and genotoxic. In the present work, interstrand and intrastrand DNA-DNA cross-linking by individual DEB stereoisomers was investigated by PAGE, mass spectrometry, and stable isotope labeling. S,S-, R,R-, and meso-diepoxides were synthesized from l-dimethyl-2,3-O-isopropylidene-tartrate, d-dimethyl-2,3-O-isopropylidene-tartrate, and meso-erythritol, respectively. Total numbers of bis-N7G-BD lesions (intrastrand and interstrand) in calf thymus DNA treated separately with S,S-, R,R-, or meso-DEB (0.01-0.5 mM) were similar as determined by capillary HPLC-ESI(+)-MS/MS of DNA hydrolysates. However, denaturing PAGE has revealed that S,S-DEB produced the highest number of interchain cross-links in 5'-GGC-3'/3'-CCG-5' sequences. Intrastrand adduct formation by DEB was investigated by a novel methodology based on stable isotope labeling HPLC-ESI(+)-MS/MS. Meso DEB treatment of DNA duplexes containing 5'-[1,7, NH(2)-(15)N(3),2-(13)C-G]GC-3'/3'-CCG-5' and 5'-GGC-3'/3'-CC[(15)N(3),2-(13)C-G]-5' trinucleotides gave rise to comparable numbers of 1,2-intrastrand and 1,3-interstrand bis-N7G-BD cross-links, while S,S DEB produced few intrastrand lesions. R,R-DEB treated DNA contained mostly 1,3-interstrand bis-N7G-BD, along with smaller amounts of 1,2-interstrand and 1,2-intrastrand adducts. The effects of DEB stereochemistry on its ability to form DNA-DNA cross-links may be rationalized by the spatial relationships between the epoxy alcohol side chains in stereoisomeric N7-(2'-hydroxy-3',4'-epoxybut-1'-yl)-guanine adducts and their DNA environment. Different cross-linking specificities of DEB stereoisomers provide a likely structural basis for their distinct biological activities.

Cross-Linking Reagents↗
PubMed2005

Loss of Usp14 results in reduced levels of ubiquitin in ataxia mice.

The ataxia (ax(J)) mutation is a spontaneous recessive mutation that results in reduced expression of ubiquitin-specific protease 14, Usp14. Mice homozygous for the ax(J) mutation are retarded for growth and exhibit several behavioral disorders, including a resting tremor and hindlimb paralysis. Although pathological defects appear to be limited to the central nervous system, reduction of Usp14 expression was widespread in the ax(J) mice. Usp14 co-fractionated with proteasomes isolated from livers and brains of wild-type mice. Proteasomes isolated from the ax(J) brains still possessed deubiquitinating activity and were functionally competent to hydrolyze 20S proteasomal substrates in vitro. However, the levels of monomeric ubiquitin were reduced approximately 35% in most of the ax(J) tissues examined. These results indicate that Usp14 functions to maintain the cellular levels of monomeric ubiquitin in mammalian cells, and that alterations in the levels of ubiquitin may contribute to neurological disease.

Animals↗
PubMed2004

The clamp-loader-helicase interaction in Bacillus. Atomic force microscopy reveals the structural organisation of the DnaB-tau complex in Bacillus.

The clamp-loader-helicase interaction is an important feature of the replisome. Although significant biochemical and structural work has been carried out on the clamp-loader-clamp-DNA polymerase alpha interactions in Escherichia coli, the clamp-loader-helicase interaction is poorly understood by comparison. The tau subunit of the clamp-loader mediates the interaction with DnaB. We have recently characterised this interaction in the Bacillus system and established a tau(5)-DnaB(6) stoichiometry. Here, we have obtained atomic force microscopy images of the tau-DnaB complex that reveal the first structural insight into its architecture. We show that despite the reported absence of the shorter gamma version in Bacillus, tau has a domain organisation similar to its E.coli counterpart and possesses an equivalent C-terminal domain that interacts with DnaB. The interaction interface of DnaB is also localised in its C-terminal domain. The combined data contribute towards our understanding of the bacterial replisome.

Adenosine Triphosphatases↗
PubMed2004

Guanine-adenine DNA cross-linking by 1,2,3,4-diepoxybutane: potential basis for biological activity.

1,2,3,4-Diepoxybutane (DEB) is a prominent carcinogenic metabolite of 1,3-butadiene (1,3-BD), an important industrial chemical and an environmental pollutant found in cigarette smoke and automobile exhaust. DEB is capable of inducing a variety of genotoxic effects, including point mutations, large deletions, and chromosomal aberrations. The mutagenicity and carcinogenicity of DEB are thought to result from its ability to form bifunctional DNA-DNA adducts by sequentially alkylating two nucleobases within the DNA double helix. We recently reported that DEB-induced DNA-DNA cross-linking leads to the formation of 1,4-bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD) adducts [Park, S., and Tretyakova, N. (2004) Structural characterization of the major DNA-DNA cross-link of 1,2,3,4-diepoxybutane. Chem. Res. Toxicol. 17 (2), 129-136]. However, guanine-guanine cross-linking by DEB cannot explain the development of A:T base pair mutations following exposure to DEB and 1,3-BD. In the present work, four asymmetrical DNA-DNA cross-links involving both adenine and guanine nucleobases were identified in double-stranded DNA treated with racemic DEB. These novel lesions were assigned the structures of 1-(aden-1-yl)-4-(guan-7-yl)-2,3-butanediol (N1A-N7G-BD), 1-(aden-3-yl)-4-(guan-7-yl)-2,3-butanediol (N3A-N7G-BD), 1-(aden-7-yl)-4-(guan-7-yl)-2,3-butanediol (N7A-N7G-BD), and 1-(aden-N6-yl)-4-(guan-7-yl)-2,3-butanediol (N6A-N7G-BD), based on the comparison of their MS/MS spectra, HPLC retention times, and UV spectra with those of the corresponding authentic standards prepared independently. Although guanine-adenine lesions are approximately 10 times less abundant in DEB-treated double-stranded DNA than the corresponding bis-N7G cross-links, N1A-N7G-BD and N6A-N7G-BD are more hydrolytically stable and, if formed in vivo, may accumulate in target tissues. HPLC-ESI-MS/MS analysis of guanine-adenine DEB cross-links induced in synthetic DNA duplexes 5'-(GGT)5, 5'-(GT)7G, and 5'-(GAA)5 (+-strand) demonstrate that G-A cross-linking by DEB produces primarily 1,3-interstrand N1A-N7G lesions. The formation of bifunctional guanine-adenine adducts is likely to contribute to AT base pair substitutions and deletion mutations following DEB exposure.

Adenine↗
PubMed2004

Seizure expression during electroconvulsive therapy: relationships with clinical outcome and cognitive side effects.

Since electroconvulsive therapy (ECT) can result in generalized seizures that lack efficacy, physiological markers of treatment adequacy are needed. Specific electroencephalographic (EEG) features differentiate seizures produced with barely suprathreshold right unilateral (RUL) ECT, an ineffective treatment, from effective forms of ECT. This study determined whether EEG features are sensitive to treatment condition using a broad dosing range for RUL ECT, as well as predictive of clinical and cognitive outcomes. Quantitative EEG measures and observer ratings were compared in predictive power. From a larger study, 54 in-patients with major depression were randomized to low (1.5 x seizure threshold (ST)), moderate (2.5 x ST), or high-dose (6 x ST) RUL ECT, or high-dose (2.5 x ST) bilateral (BL) ECT. High dosage RUL and BL ECT were comparable in efficacy, and superior to low and moderate dosage RUL ECT. In the slow frequency bands (delta), BL ECT resulted in greater ictal power, ictal coherence, and postictal suppression than each RUL ECT condition, but the EEG measures failed to discriminate the RUL ECT groups. EEG measures were modestly associated with clinical outcome, with greater ictal power, delta coherence, and postictal suppression positive predictors. None of the EEG measures were associated with cognitive outcomes. Inability to distinguish forms of RUL ECT differing markedly in dosage and efficacy suggests that EEG measures have limited potential as markers of treatment adequacy. Rather than assaying treatment adequacy, the EEG features associated with efficacy may reflect individual differences in the strength of inhibitory processes that terminate the seizure, and can help isolate the biological variability that predisposes to positive or negative clinical response to ECT.

Adult↗
PubMed2004

Eukaryotic initiation factor 4E staining as a clinical marker in pediatric neuroblastoma.

OBJECTIVES: Neuroblastoma (NBL) has several well-established prognostic factors. Eukaryotic initiation factor 4E (4E) has shown promise as a prognostic marker in other cancers. We hypothesize that a correlation exists between 4E staining and NBL clinical outcome. METHODS: Eleven adrenal NBL patient charts were reviewed for data, including age, stage, MYCN amplification, Shimada classification, and mortality. These patients' surgical specimens were stained with 4E antibody and scored for staining density. 4E expression, quantified by staining density, was compared to clinical data. CONCLUSION: 4E staining significantly correlates with age at diagnosis. The remaining prognostic factors lack statistically significant correlation. Increasing sample size may further establish statistically significant correlations. 4E could become an additional prognostic factor of NBL.

Adrenal Gland Neoplasms↗
PubMed2003

Reversed activity of mitochondrial adenine nucleotide translocator in ischemia-reperfusion.

BACKGROUND: Graft dysfunction as a result of preservation injury remains a major clinical problem in liver transplantation. This is related in part to accumulation of mitochondrial calcium. In an attempt to sustain cell and mitochondrial integrity during ischemia, intramitochondrial F(0)F(1) adenosine triphosphate (ATP) synthase reverses its activity and hydrolyzes ATP to maintain the mitochondrial transmembrane potential (mdeltapsi). It is not known how cytoplasmic ATP becomes available for hydrolysis by this enzyme. The authors hypothesized that mitochondrial adenine nucleotide translocator (ANT) reverses its activity during ischemia, making cytoplasmic ATP available for hydrolysis by F(0)F(1) ATP synthase. METHODS: Rat livers were perfused with cold University of Wisconsin solution at 4 degrees C (39.2 degrees F)through the portal vein and processed immediately or after 24 hr of cold storage. Mitochondria were separated by differential centrifugation. ATP-dependent mitochondrial calcium-45 (45Ca)2+ uptake was determined after incubation with ATP (5 mM) or adenosine diphosphate (ADP) (5 mM) with or without 15 microM of bongkrekic acid (BA), an ANT blocker; the nonhydrolyzable analog of ATP (adenosine 5'-beta,gamma-imidotriphosphate [AMP-PNP]) served as the negative control. All measurements were performed in triplicate. Student t test, P<0.05 was taken as significant. RESULTS: Inhibition of ANT by BA prevents mitochondrial Ca2+ accumulation in the presence of ATP and high 45Ca2+ concentrations, and increased extramitochondrial 45Ca2+ stimulated mitochondrial 45Ca2+ uptake in the presence of ATP but not ADP, AMP-PNP, or BA. CONCLUSIONS: These data demonstrate that ANT plays an important role in mitochondrial Ca2+ uptake under ischemic conditions by reversing its activity and allowing transport of extramitochondrial ATP into the matrix for hydrolysis by reversed F(0)F(1) ATP synthase.

Adenosine Triphosphate↗
PubMed2003

Altered ATP-dependent mitochondrial Ca2+ uptake in cold ischemia is attenuated by ruthenium red.

BACKGROUND: Graft dysfunction as a result of preservation injury remains a major clinical problem in liver transplantation. This is related in part to accumulation of mitochondrial calcium (Ca(2+)), which has been linked to activation of proapoptotic factors. We hypothesized that cold ischemia increases mitochondrial Ca(2+) uptake in a concentration dependent fashion and that ruthenium red (RR) will attenuate these changes by inhibiting the mitochondrial Ca(2+) uniporter. METHODS: Rat livers perfused with cold University of Wisconsin (UW) solution (4 degrees C) with or without RR (10 microM) via the portal vein (n = 3 per group) were processed immediately (no ischemia) or after 24 h cold-storage (24 h cold ischemia). Mitochondria were separated by differential centrifugation, and adenosine triphosphate (ATP)-dependent (45)Ca(2+) uptake was determined in the presence of ATP (5 mM), adenosine diphosphate (ADP), or adenosine 5'-beta,gamma-imidotriphosphate (AMP-PNP); variable concentrations of extramitochondrial (45)Ca(2+) were used. All measurements were performed in triplicate. Student's t test with P < 0.05 was taken as significant. RESULTS: Our data demonstrate the following: 1) ATP-dependent (45)Ca(2+) uptake in mitochondria separated from livers following 24 h of cold ischemia in UW alone was higher than in mitochondria isolated from non-ischemic livers; the increased uptake was dependent on the concentration of (45)Ca(2+) in the incubation buffer. 2) There was no difference in ATP-dependent (45)Ca(2+) uptake between nonischemic mitochondria and those separated from livers stored in UW-RR for 24 h. 3) (45)Ca(2+) uptake in mitochondria from livers subjected to 24 h of cold ischemia in UW-RR was significantly lower compared to those from livers stored in UW alone when (45)Ca(2+) concentrations were greater than 1 microM. CONCLUSION: 1) Cold ischemia affects mitochondrial Ca(2+) handling, especially when it is challenged by high extramitochondrial Ca(2+) concentrations. 2) The addition of RR in preservation solution attenuates the effects of cold ischemia on mitochondrial Ca(2+) handling. 3) Inhibition of mitochondrial Ca(2+) uniporter with RR protects mitochondria from Ca(2+) overload at high Ca(2+) concentrations. These findings may offer a potentially effective strategy for prevention of ischemia-reperfusion injury in liver transplantation.

Adenosine Triphosphate↗
PubMed2002

BOTOX and physical therapy in the treatment of piriformis syndrome.

OBJECTIVE: This study evaluates the efficacy of botulinum toxin A injections used in conjunction with physical therapy for the treatment of piriformis syndrome. DESIGN: This a double-blind, placebo controlled clinical trial using electrophysiologic criteria for patient selection and a visual analog scale to assess treatment efficacy in relieving pain. RESULTS: As measured on the visual analog scale, patients injected with botulinum toxin A experienced more relief from pain than patients receiving lidocaine with steroid (P < 0.05) and more relief than patients receiving placebo (P = 0.001). CONCLUSIONS: Injection with botulinum toxin A is an effective adjunct to physical therapy in the treatment of piriformis syndrome. H-reflex prolongation by flexion, adduction, and internal rotation (FAIR test) beyond 1.86 msec (3 SD) of the mean is a clinical indication of piriformis syndrome.

Botulinum Toxins, Type A↗
PubMedDate not supplied

Impairment, activity, participation, life satisfaction, and survival in persons with locked-in syndrome for over a decade: follow-up on a previously reported cohort.

OBJECTIVE: To determine the long-term outcome of patients with stable locked-in syndrome. SETTING: The community. DESIGN: Retrospective phone survey. This study was further follow-up on a previously reported cohort. PARTICIPANTS: Twenty-nine persons with locked-in syndrome were included in an initial cohort 11 years prior to the current study. Records or contact with family showed that 16 were deceased. Telephone interviews were made with 1 living patient and the caregivers of 11 others. Public records documented survival of 1 nonrespondent. OUTCOME MEASURES: Survival, codified responses regarding functional activities, social activities, and satisfaction with life. RESULTS: Five-, 10-, and 20-year survival were 83%, 83%, and 40%, respectively. Ten subjects had not been hospitalized in the previous year. Eight lived with family. Little change in impairment occurred, but care was simplified. Improvements in communication related to technology, including computer and Internet access. Eleven left home at least monthly. Caregivers reported seven expressed satisfaction with life; five were occasionally depressed. No deaths could be attributed to euthanasia and no survivor had a "no code" status. One patient wished to die, seven had never considered euthanasia, six had considered and rejected it. CONCLUSIONS: Persons with initially stable locked-in syndrome can have prolonged survival, can live in the community if there is enough support, and have some measure of quality of life.

Adolescent↗