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Biomedical subjects

K M Anderson

Publications and source records attributed to K M Anderson.

At least 19 recordsLinked to original sources
PubMed2006

To what extent are the "sets" of biologic properties expressed by hypoxic cancer cells and by cancer "stem" cells equivalent, intersecting, disjoint or complementary? Some implications for the design of cancer therapies.

Resistance to various cancer therapies with survival or recurrence of a malignancy has been ascribed to the inability to "kill" hypoxic cancer cells. The reported resistance of cancer "stem" cells has also been proposed as a major reason for this outcome. In planning therapy, it should be important to know whether these two categories "overlap": do "hypoxic" cells subsume cancer "stem" cells; alternately, are "stem" cells somewhat hypoxic or are these categories distinct? If the former is true and these categories overlap, to what extent do their properties share biochemical elements in common; if the latter is the case, should both properties be "targeted" independently? The inability of a proposed therapy to suppress these foci of resistance could preclude a successful outcome. Results from pre-clinical and clinical laboratory determination of the stem cell/hypoxic cell response may reflect the likely outcome of the proposed clinical treatment.

Animals↗
PubMed2005

Disparate forms of MK 886-induced programmed death in BCL-2 (+) blood and BCL-2 (-) solid cancer cells and a putative "nuclear" Ca2+ channel: "soil" trumps "seed"?

UNLABELLED: The five-lipoxygenase inhibitor, MK 886, in micromolar concentration induces a "type 1" form of programmed cell death in U937 human monoblastoid cells and a "type 2" form in Panc-1 pancreatic and PC3 prostate cell lines. The latter two lines originate from epithelial-derived solid human cancers. An acute rise in Ca(2+) occurs in U937 and HL 60 myeloid cells, in U937 cells located in their nuclei (HL 60 not tested), both of which are Bcl-2 positive. The two solid cancer cell lines express neither of these features. Solid tumor-derived Bcl-2-positive HeLa cervical cancer cells exhibit an acute increase in Ca(2+) after challenge with MK 886. In U937, PC3 and Panc-1 cells tested, the agent acutely increases oxidative stress and decreases mitochondrial membrane potential, indicating that neither event is directly determinative for the form of PCD. The role of mitochondria and the mechanism by which increased oxidative stress initiates the acute rise in U937 "nuclear" Ca(2+), the contribution, if any, of Bcl-2 in initiating the Ca(2+) signal and the latter in mandating the type of PCD, presumably through differential modulation of transcription, remain to be determined. Lastly, these results demonstrate that "soil" trumps "seed". HYPOTHESIS: Despite similarities in response, including those of the mitochondria to micromolar concentrations of MK 886, hematopoietic and epithelial-derived non-hematopoietic solid cancer cell lines exhibit dissimilar forms of programmed cell death. These differences may depend upon the presence of Bcl-2 or a related protein participating in a juxta-nuclear/nuclear Ca(2+) ion-channel. Evidence for this supposition is discussed.

Apoptosis↗
PubMed2005

Constraint-induced therapy for moderate chronic upper extremity impairment after stroke.

PRIMARY OBJECTIVE: To explore the effectiveness of constraint-induced therapy (CIT) in the treatment of individuals with moderate chronic upper extremity paresis. RESEARCH DESIGN: Multiple case reports, pre-post-treatment comparisons as well as long-term follow-ups at 1 and 6 months after intervention. METHODS AND PROCEDURES: Seven subjects, each greater than 12 months post-stroke, participated in an intensive 3 weeks CIT programme. The Wolf Motor Function Test (WMFT), Motor Activity Log (MAL) and Fugl-Meyer Evaluation (FM) were used to measure outcomes. MAIN OUTCOMES AND RESULTS: Subjects exhibited notable improvements in mean WMFT scores (0.25 point increase post-treatment, 0.38 point increase at 1-month follow-up, 0.44 point increase at 6-month follow-up). Similarly, improvements were seen for mean MAL (1.71 points for AS, 1.77 points for HW) and FM scores (6 points FM-UE, 6 points FM-TOT) post-treatment. Additional improvements were seen at some follow-up assessments. CONCLUSIONS: Subjects demonstrated gains in objective measures, however, did not regain normal functional ability of their paretic upper extremities. Further investigation of the effects of CIT in this population, as well the functional significance of the objective measures used is warranted.

Adult↗
PubMed2003

Distress and concerns in couples referred to a specialist infertility clinic.

OBJECTIVES: The aims of this study were to examine emotional distress and infertility-related concerns in male and female members of couples referred to a specialist infertility clinic and to determine changes in these over time. METHODS: A prospective cohort study with a 6-month follow-up. Emotional distress was measured using the Hospital Anxiety and Depression Scale, and concerns by a specially designed questionnaire. RESULTS: The response rate achieved was 38%. At baseline, 25.7% of women and 8.9% of men had scores of greater than 10 on the Hospital Anxiety and Depression Scale (HADS) Anxiety subscale, and 2.7% of women and 1.8% of men had scores of greater than 10 on the HADS Depression subscale. At 6-month follow-up the HADS scores were substantially unchanged. Females reported a significantly greater infertility-related concerns regarding life satisfaction, sexuality, self-blame, self-esteem and avoidance of friends compared with males. CONCLUSIONS: The prevalence of emotional disorder identified was low. There were gender differences in the nature of the specific concerns reported. The degree of distress and concerns did not change significantly over time. There are a minority of patients, mainly females, with clinically significant distress and infertility-related concerns amongst patients attending infertility clinics who deserve psychological attention.

Adult↗
PubMed2002

Addendum to a note regarding the success of biological and medical science.

Much like mathematics, the biological and medical sciences seem unreasonably successful, considering many potential obstacles to this outcome. A recent suggestion that data should be viewed as 'quantized', that each 'elementary system' contains a single 'bit' of information (A. Zeilinger, A foundational principle for quantum mechanics, Foundations of Physics 29 (1999) 631), would seem ultimately to underlie the coherent relationships between the perceived physical universe and mental constructs within and among mathematics, logic, the 'hard' sciences and those 'softer' sciences directly based on biochemical and physiologic mechanisms (A. Zeilinger, A foundational principle for quantum mechanics, Foundations of Physics 29 (1999) 631; H. C. Von Baeyer, In the beginning was the bit, New Scientist, 17 (2000) 26-30).

Biological Science Disciplines↗
PubMed2002

Increased cytosol Ca(2+) and type 1 programmed cell death in Bcl-2-positive U937 but not in Bcl-2-negative PC-3 and Panc-1 cells induced by the 5-lipoxygenase inhibitor MK 886.

MK 886, an arachidonic acid-related analog which inhibits the enzyme, 5-lipoxygenase by an indirect mechanism involving the 5-lipoxygenase activating protein, rapidly increased U937 cytosol Ca(2+), much of which localized around the cell nuclei. Five-lipoxygenase activity was not directly involved since the direct redox-dependent 5-LPOx inhibitor, SC-41661A did not increase Ca(2+). U937 cells subsequently undergo classic type 1 programmed cell death. At least initially the ionized calcium originates from internal stores. Coincident with the rise in U937 ionized calcium, MK 886 rapidly increased reactive oxygen species and reduced mitochondrial membrane potential, as judged by several fluorescent probes. The Ca(2+) response of myeloid leukemia-derived HL-60 cells to MK 886 was similar and both cell lines express Bcl-2 protein. Bcl-2-negative Panc-1 and PC-3 cells did not respond to MK 886 with a Ca(2+) signal but did develop oxidative stress and a decline in mitochondrial membrane potential; these events are thought to contribute to the inhibition of cell proliferation and induction of a type 2 PCD. In addition to its marked inhibition of Bcl-2 mRNA synthesis, an interesting hypothesis is that MK 886, serving as a low molecular weight ligand, either by direct or indirect inhibition of U937 Bcl-2 protein function, possibly related to an ion channel activity, alters the distribution of intracellular, possibly nuclear Ca(2+), thereby promoting the development of type 1 programmed cell death.

Apoptosis↗
PubMed2001

Control over directional metal-metal charge transfer in cyanide-bridged dimanganese complexes: effects of mu-CN linkage isomerism and ancillary ligand set.

Synthesis and characterisation of cyano-bridged complexes of the form [(eta-C5R4Me)L(ON)Mn(mu-XY)Mn(CO)2-L'(dppm)]z (X,Y = C,N; z = 1-3) shows that systematic variation of the orientation of the CN bridge and the nature and geometric arrangement of the ancillary ligands affords control of the direction and energy of metal-metal charge transfer in the mixed valence dications.

Journal Article↗
PubMed2001

In situ synthesis of oligonucleotide arrays by using surface tension.

This work describes the in situ synthesis of oligonucleotide arrays on glass surfaces. These arrays are composed of features defined and separated by differential surface tension (surface tension arrays). Specifically, photolithographic methods were used to create a series of spatially addressable, circular features containing an amino-terminated organosilane coupled to the glass through a siloxane linkage. Each feature is bounded by a perfluorosilanated surface. The differences in surface energies between the features and surrounding zones allow for chemical reactions to be readily localized within a defined site. The aminosilanation process was analyzed using contact angle, X-ray photoelectron spectroscopy (XPS), and time-of-flight/secondary ion mass spectroscopy (TOF-SIMS). The efficiency of phosphoramidite-based oligonucleotide synthesis on these surface tension arrays was measured by two methods. One method, termed step-yields-by-hybridization, indicates an average synthesis efficiency for all four (A,G,C,T) bases of 99.9 +/- 1.1%. Step yields measured for the individual amidite bases showed efficiencies of 98.8% (dT), 98.0% (dA), 97.0% (dC), and 97.6% (dG). The second method for determining the amidite coupling efficiencies was by capillary electrophoresis (CE) analysis. Homopolymers of dT (40- and 60mer), dA (40mer), and dC (40mer) were synthesized on an NH(4)OH labile linkage. After cleavage, the products were analyzed by CE. Synthesis efficiencies were calculated by comparison of the full-length product peak with the failure peaks. The calculated coupling efficiencies were 98.8% (dT), 96.8% (dA), and 96.7% (dC).

Glass↗
PubMed2001

Long-term mortality benefit with abciximab in patients undergoing percutaneous coronary intervention.

OBJECTIVES: The goal of this study was to test: 1) if platelet glycoprotein IIb/IIIa (GP IIb/IIIa) blockade with abciximab bolus plus 12-h infusion reduces mortality after percutaneous coronary intervention (PCI); 2) if prevention of early myocardial infarction (MI) after PCI is a mechanism for reducing mortality; and 3) for risk factors for mortality after PCI. BACKGROUND: Studies of PCI suggest that MI after intervention is predictive of mortality. Abciximab, a platelet GP IIb/IIIa receptor inhibitor, has consistently reduced the incidence of MI among PCI patients in several trials. The presumed mechanism is prevention of platelet thrombus associated with vessel wall injury and downstream embolization into the microcirculation. METHODS: In eight trials, 5,154 patients were randomized to a regimen comprising conventional therapy plus a bolus of abciximab within 1 h before PCI followed by a 12-h infusion; 4,136 controls were randomized to conventional therapy alone. Patient follow-up from six months to three years was available. Survival differences are examined using proportional hazards regression and survival curves. RESULTS: A hazard ratio of 0.71 (95% confidence interval 0.57 to 0.89; p = 0.003) suggests a mortality benefit with abciximab. The absolute reduction in mortality was estimated to be 0.5% through 30 days, 0.7% through six months, 0.9% through one year and 1.8% through three years. Early MI explained 18% of the observed mortality benefit at one year. Multivariate regression suggests that patients with advanced cardiovascular disease may derive the greatest mortality benefit from abciximab. CONCLUSIONS: The evidence from 9,290 randomized PCI patients shows a mortality benefit provided by abciximab bolus plus 12-h infusion.

Abciximab↗
PubMed2001

The mode of cell death in H-358 lung cancer cells cultured with inhibitors of 5-lipoxygenase or the free radical spin trap, NTBN.

The 5-lipoxygenase inhibitors SC41661A and MK886 with different mechanisms of action and the free radical spin trap, NTBN inhibit proliferation of the human bronchiolar lung cancer cell line NCI H-358 (5807 CRL). With continued culture, the agents induced a form of programmed cell death in which DNA laddering was not detected and ultrastructural changes were not characteristic of classic 'type 1' cellular suicide. The changes were more consistent with a type 2 cytosolic, autophagic form of PCD. MK886 induced strikingly abnormal mitochondrial morphology. Since the lipoxygenase inhibitors and NTBN induce classic type 1 PCD in U937 monoblastoid cells, these agents can activate either pathway, depending upon cell type. It is not certain whether activation of type 1 or 2 pathways depends entirely upon cell lineage and/or initiating agent, if all cells retain both pathways, and if type 1 PCD a more effective mediator of the process. These are all relevant questions for assessing the impact of PCD on malignant cell survival and considering ways in which it might be enhanced.

Amides↗
PubMed2001

Comments on the unreasonable effectiveness of the biological and especially medical sciences.

About 50 years ago it was pointed out by Dr. Eugene Wigner that applications of mathematics to a wide range of physical problems were inexplicably effective in both their immediate practical results and predictive power. The reasons for this remain elusive. In a loosely analogous sense, parallels can be drawn between such an effectiveness and the evolving power of the biological sciences, leading to the accomplishment of many practical and theoretical goals. We consider some of the similarities and differences that distinguish these two modalities with which certain features of physical reality are apprehanded, analyzed and manipulated.

Biology↗
PubMed2001

Is induction of type 2 programmed death in cancer cells from solid tumors directly related to mitochondrial mass?

Many solid cancers respond to chemo or radiotherapy with a type 2 form of programmed cell death. This requires direct participation of mitochondria with release of cytochrome c and other factors that activate the 'execution' phase of the process. It is believed that as solid cancers progress, less differentiated clones containing fewer mitochondria evolve. Consequently, the mitochondrial 'switch' that activates the type 2 process will become less effective, as the number of elements available and their mass-effect declines. The opportunity for successful therapy, considered to depend upon the ability to activate programmed cell death, therefore becomes progressively less probable.

Apoptosis↗
PubMed2001

Enrasentan improves survival, limits left ventricular remodeling, and preserves myocardial performance in hypertensive cardiac hypertrophy and dysfunction.

Evidence suggests that endothelin receptor antagonists may have therapeutic potential for the chronic treatment of heart failure. In the current study, the effects of an orally active mixed endothelin-A/endothelin-B (ETA /ETB ) receptor antagonist (enrasentan) were assessed in a model of cardiac hypertrophy and dysfunction (spontaneously hypertensive stroke prone rats) maintained on a high-salt/high-fat diet. Echocardiography was used to quantify cardiac performance and left ventricular dimensions. Enrasentan (1,200 and 2,400 parts per million in the high-salt/high-fat diet) had no significant effects on body weight and systolic blood pressure. However, increases in heart rate were not observed in the enrasentan-treated groups at 12 weeks (p < 0.05). Enrasentan-treated groups exhibited significantly improved survival (90-95% vs. 30% [control rats] at 18 weeks; p < 0.001). Enrasentan treatments also increased stroke volume (at 8, 12, and 16 weeks) and cardiac index (at 8 and 16 weeks) 33-50% and 45-63%, respectively. Enrasentan treatments reduced the relative wall thickness (14-27% at 8 and 12 weeks), ratio of left ventricular mass to body weight (20% at 12 weeks), and ratio of terminal heart weight to body weight (16-23%, p < 0.05). Finally, circulating aldosterone concentration (54-57%) and proANF fragment (33%) were reduced in enrasentan-treated groups (54-57% and 33%, respectively). Mixed ETA /ETB receptor antagonism improves cardiac performance and attenuates ventricular remodeling and premature mortality in an aggressive hypertension model.

Aldosterone↗
PubMed2001

Selected features of nonendocrine pancreatic cancer.

We survey some interesting features of gene expression in nonendocrine pancreatic cancer, the response to some less widely known agents as they impact on pancreatic cell proliferation and programmed death, and several developing approaches to therapy. The proliferative and cellular suicide responses of Panc-1 cells to the free radical spin trap, NTBN, and to the 5-lipoxygenease inhibitor, MK 886, the latter assessed with CLONTECH Atlas Human cDNA Array 1, are reviewed. Difficulties in identifying those factors whose suppression or augmentation could result in inhibition of malignantly transformed cell properties are considered.

Animals↗
PubMed2000

Economic assessment of platelet glycoprotein IIb/IIIa receptor blockade with abciximab and low-dose heparin during percutaneous coronary revascularization: results from the EPILOG randomized trial. Evaluation in PTCA to Improve Long-term Outcome with abciximab GP IIb/IIIa blockade.

BACKGROUND: In the EPILOG trial (Evaluation in PTCA to Improve Long-term Outcome with abciximab GP IIb/IIIa blockade), abciximab administered with weight-adjusted heparin diminished the risk of ischemic complications within 30 days by 56% among patients undergoing percutaneous coronary revascularization, without increased bleeding complications. METHODS AND RESULTS: A prospective economic assessment was performed in the 2792 patients enrolled in EPILOG. Patients were randomized to receive placebo with standard-dose weight-adjusted heparin, abciximab with low-dose weight-adjusted heparin, or abciximab with standard-dose weight-adjusted heparin during percutaneous coronary intervention. Hospital billing data for the baseline hospitalization were collected for 2581 patients (92.4% of total) and imputed for the remainder, with physician fees estimated from the Medicare Fee Schedule. For the baseline hospitalization, medical costs (hospitalization and physician fees) averaged $9632 for the placebo arm compared with $8758 (P:=0.005) and $9092 (P:=0.176) for the abciximab with low-dose and standard-dose heparin arms, respectively. Inclusive of average drug cost ($1454 to $1457), the net incremental baseline cost of these 2 abciximab strategies was $583 with low-dose weight-adjusted heparin and $914 with standard-dose weight-adjusted heparin. During 6-month follow-up, average hospital costs were not significantly different in the 3 treatment groups; cumulative net incremental costs were $1236 and $1268 in the abciximab with low-dose and standard-dose heparin groups, respectively. CONCLUSIONS: Treatment with abciximab and low-dose, weight-adjusted heparin during percutaneous coronary revascularization reduces ischemic events and associated costs, thereby offsetting some of the cost of the drug. The suppression of bleeding complications associated with this agent by heparin dose reduction optimizes the economic attractiveness of this treatment strategy.

Abciximab↗
PubMed2000

Cutting edge: heat shock protein gp96 induces maturation and migration of CD11c+ cells in vivo.

Immunization of mice with the heat shock protein (HSP) gp96 but not control proteins leads to 5- to 7-fold enlargement of draining lymph nodes (LNs) resulting from accumulation of large numbers of mature CD11c(+) cells, but not T or B lymphocytes in them. The increase in size and cellularity is time-dependent; the draining LNs reach their peak size between 12 and 24 h after injection and regress to their normal size between 48 and 72 h after injection. The increment is elicited specifically in the draining LN but not in other LNs. This observation uncovers a novel aspect of HSP-APC interaction and adds to the mechanistic explanation for the unusually high immunogenicity of HSP-peptide complexes.

Animals↗
PubMed2000

Molecular characterization of a human scavenger receptor, human MARCO.

Murine MARCO has been identified recently in subsets of macrophages located in the peritoneum, marginal zone of the spleen, and the medullary cord of lymph nodes, where it has been proposed that it serves as a bacteria-binding receptor. A scavenger receptor family member with an extended collagenous domain, murine MARCO has also been demonstrated in atherosclerotic lesions of susceptible mice. We report here the identification, tissue and chromosomal localization, and pharmacological characterization of human (h)MARCO. hMARCO was identified from a macrophage cDNA library by electronic screening with the murine MARCO sequence. Nucleotide sequence analysis confirmed that the full-length hMARCO clone encoded a 519-amino acid protein sharing 68.5% identity with murine MARCO. RNA blot analysis indicated that the hMARCO transcript is 2.0 kb in length and is predominantly expressed in human lung, liver, and lymph nodes. Radiation hybrid mapping localized hMARCO to chromosome 2q14. Ligand-binding studies of COS cells expressing hMARCO demonstrated significant specific binding of both Escherichia coli and Staphylococcus aureus. In contrast, the hMARCO receptor expressed in COS cells did not specifically bind the scavenger receptor ligand acetylated low-density lipoprotein (LDL), despite its similarity to the elongated collagen-like binding domain of the macrophage scavenger receptor. In addition, acetylated (Ac)LDL and oxidized (Ox)LDL did not inhibit E. coli binding to hMARCO. These data suggest that hMARCO may play an important role in host defense, but it has no obvious role in the accumulation of modified lipoproteins during atherogenesis.

Amino Acid Sequence↗