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Biomedical subjects

J E Harris

Publications and source records attributed to J E Harris.

At least 19 recordsLinked to original sources
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↗
PubMed2003

Fenceline contact of beef calves with their dams at weaning reduces the negative effects of separation on behavior and growth rate.

The purpose of this study was to examine the hypothesis that fenceline contact between beef calves and cows at weaning reduces indices of behavioral distress and associated temporary reductions in weight gain. One hundred Angus/Hereford-cross calves were randomly assigned to five treatments for 7 d in each of 3 yr to determine the effect of different weaning techniques on their behavior and subsequent growth. Treatments were 1) fenceline separation from dams on pasture (F-P), 2) total separation from dams on pasture (S-P), 3) total separation from dams in a drylot (corral) preconditioned to hay (S-D-P), 4) total separation from dams in a drylot not preconditioned to hay (S-D-NP), and 5) nonweaned controls on pasture (C-P). At the end of the 7-d postweaning period, all calves were placed on pasture in large groups. Calves were weighed weekly for 10 wk. In the days following weaning, F-P and C-P calves spent more time eating (grazing or eating hay) than S-P and S-D-NP calves (P < 0.05). The S-P calves spent more time walking (pacing) than calves in the other four treatments (P < 0.05), which did not differ. The S-P calves also spent less time lying down than C-P, F-P, and S-D-P calves (P < 0.05); S-P and S-D-NP calves did not differ in lying time. The F-P calves vocalized less than S-P and S-D-NP calves (P < 0.05). In general, treatment differences were greatest during the first 3 d following weaning with d 2 (20 to 30 h after weaning) showing the greatest disparity. The F-P calves spent approximately 60% of their time within 3 m of the fence separating them from their dams during the first 2 d following weaning, whereas F-P cows spent about 40% of their time within 3 m of the fence during this period. Postweaning cumulative body weight gains of the F-P calves were greater than the gains recorded for the calves in the three totally separated treatments (which did not differ). The F-P calves gained 95% more weight than the average calf in the three totally separated treatments in the first 2 wk and were still heavier at 10 wk (21.4 vs 11.0 kg, respectively, at 2 wk and 50.0 vs 38.2 kg, respectively, at 10 wk; P < 0.05). It was concluded that providing fenceline contact between beef calves and cows for 7 d following weaning reduces behavioral indices of distress seen in the totally separated calves. In addition, fenceline contact with dams at weaning minimizes losses in weight gain in the days following separation. Totally separated calves did not compensate for these early losses in weight gain even after 10 wk.

Animals↗
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

Chiral separations of transition metal complexes using capillary zone electrophoresis.

Several buffer additives that may facilitate chiral separation for optically active transition metal (TM) systems are investigated using capillary zone electrophoresis. The TM complexes evaluated exhibit considerable heterogeneity with respect to total complex charge (0 to 4+), ligand type, and identity of the central metal including Ru2+, Ni2+, Cr3+, and Co3+, threo-D[+]-Isocitrate, potassium antimonyl-d-tartrate and dibenzoyl-L-tartrate are identified as the most efficient chiral selectors. Interestingly, TM complexes exhibiting a (3+) total complex charge exhibit a reversal of enantiomer elution order versus all other complexes when separated using the tartrate additives. Operating parameters including pH, temperature, and capillary length are discussed, and chiral separations of complex mixtures are demonstrated.

Electrophoresis, Capillary↗
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

Adjuvant active specific immunotherapy of stage II and stage III colon cancer with an autologous tumor cell vaccine: first randomized phase III trials show promise.

We performed three multi-institutional, prospectively randomized, controlled clinical trials, assessing the therapeutic effect of post-resection adjuvant active specific immunotherapy in patients with stage II and stage III colon cancer. In each study four outcomes were considered: time-to-disease recurrence, overall survival intervals, disease-free survival intervals, and recurrence-free survival intervals using the Kaplan-Meir method for generating curves and the log-rank test used to compare efficacy distributions. In addition, a meta-analysis of the three phase III trials was performed since the trials had proven homogeneity. Two main analyses were performed: (1) the intent-to-treat colon cancer patients from all three studies; and (2) analyzable colon cancer patients in all three studies. The conclusion of these analyses is that adjuvant active specific immunotherapy provided significant clinical benefits in patients with stage II colon cancer and appears to be an important new adjuvant treatment for these patients.

Autoantigens↗
PubMed2001

Comparison of 5-fluorouracil alone, 5-fluorouracil with levamisole, and 5-fluorouracil with hepatic irradiation in the treatment of patients with residual, nonmeasurable, intra-abdominal metastasis after undergoing resection for colorectal carcinoma.

BACKGROUND: The authors conducted a randomized Phase III trial of three treatment regimens for patients with residual, nonmeasurable, intra-abdominal metastatic disease after undergoing resection for primary colorectal carcinoma. METHODS: To be eligible for this study, patients had to be both free of other malignancies and capable of starting their therapy within 3-6 weeks after surgery. They were required to have an Eastern Cooperative Oncology Group performance status < 3; to be chemotherapy, radiation, and immunotherapy naïve; to have adequate bone marrow, renal, and hepatic function; and to provide written, informed consent. The patients were divided into two cohorts: patients with no demonstrable hepatic metastasis (Group A) and patients with hepatic metastasis (Group B). RESULTS: The 229 patients in Group A were randomized to receive either 5-fluorouracil (5-FU) (n = 116 patients) or 5-FU with levamisole (n = 113 patients). The median survival (15.4 months and 15.3 months, respectively, for Groups A and B) was virtually identical. The two groups also were similar in terms of time to treatment progression, which was 7.9 months for group that received 5-FU alone 7.7 months for the group that received levamisole with 5-FU. The 168 patients in Group B with hepatic metastasis underwent a three-way randomization: 5-FU alone (n = 60 patients), 5-FU with levamisole (n = 54 patients), and 5-FU with hepatic irradiation (n = 54 patients). The median overall survival for the three treatment arms were similar, with 17.3 months for the group that received 5-FU alone, 16 months for the group that received 5-FU with levamisole, and 14.4 months for the group that received hepatic irradiation in addition to 5-FU: The time to treatment failure was 6.7 months, 6.8 months, and 8.3 months, respectively, for the three groups. The toxicity experienced by patients was as expected with the regimens, and no differences were observed between any of the treatment groups. The primary toxicities were hematologic and gastrointestinal. There was one treatment-related death due to adult respiratory distress syndrome, which occurred on the first day of the fourth cycle of 5-FU and levamisole. Other Grade 4 toxicities included nine patients with Grade 4 leukopenia, one patient with Grade 4 sepsis, and one patient with Grade 4 gastrointestinal toxicity, including blood loss and diarrhea. CONCLUSIONS: This study showed no treatment advantage for any of the combined modalities over 5-FU alone in this group of patients with intra-abdominal, nonmeasurable disease.

Abdominal Neoplasms↗
PubMed2001

Identification of two novel transmembrane gamma-carboxyglutamic acid proteins expressed broadly in fetal and adult tissues.

The proline-rich gamma-carboxyglutamic acid (Gla) proteins (PRGPs) 1 and 2 are the founding members of a family of vitamin K-dependent single-pass integral membrane proteins characterized by an extracellular amino terminal domain of approximately 45 amino acids that is rich in Gla. The intracellular carboxyl terminal region of these two proteins contains one or two copies of the sequence PPXY, a motif present in a variety of proteins involved in such diverse cellular functions as signal transduction, cell cycle progression, and protein turnover. In this report, we describe the cloning of the cDNAs for two additional human transmembrane Gla proteins (TMG) of 20-24 kDa named TMG3 and TMG4. These two proteins possess extracellular Gla domains with 13 or 9 potential Gla residues, respectively, followed by membrane-spanning hydrophobic regions and cytoplasmic carboxyl terminal regions that contain PPXY motifs. This emerging family of integral membrane Gla proteins includes proline-rich Gla protein (PRGP) 1, PRGP2, TMG3, and TMG4, all of which are characterized by broad and variable distribution in both fetal and adult tissues. Members of this family can be grouped into two subclasses on the basis of their gene organization and amino acid sequence. These observations suggest novel physiological functions for vitamin K beyond its known role in the biosynthesis of proteins involved in blood coagulation and bone development. The identification and characterization of these proteins may allow a more complete understanding of the teratogenic consequences of exposure in utero to vitamin K antagonists, such as warfarin-based anticoagulants.

1-Carboxyglutamic Acid↗
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

Pelvic metastases from pancreatic carcinoma: a pattern observed on bone scan.

Metastases to the bony pelvis is an unusual pattern of the spread of primary pancreatic tumors. The authors report the presence of metastatic disease in the bony pelvis observed on bone scans in several patients who had been treated recently for pancreatic carcinoma. When bone scans that show metastatic disease in the pelvis are evaluated in patients with unknown primaries, the diagnosis of pancreatic carcinoma should be considered.

Bone Neoplasms↗
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↗
PubMed2001

Crohn's disease and Mycobacterium avium subsp. paratuberculosis: current issues.

Crohn's disease is a chronic debilitating inflammatory bowel disease of unknown etiology. Proposed causes include bacterial or viral infection, diet or exposure to tobacco smoke, genetic abnormality, and immune dysfunction. The bacterium Mycobacterium avium subsp. paratuberculosis (Map) has received much research attention as a potential cause of the disease. Map causes Johne's disease in ruminants. The pathology of Johne's disease superficially resembles that of Crohn's disease in humans. Some researchers have shown evidence of Map in intestinal tissues of Crohn's disease patients. Studies are in progress to investigate the possibility that Map exists in milk from infected cows and survives pasteurization. This is a controversial subject with the potential for media attention and public outcry. We examined the current literature and concluded that insufficient evidence exists at this time to implicate any one factor, including Map in milk, as the definitive cause of Crohn's disease. The high degree of uncertainty in this issue requires regulators to recognize the need for effective risk communication as ongoing research provides additional information about the disease.

Animals↗
PubMed2000

Impact of the Massachusetts tobacco control programme: population based trend analysis.

OBJECTIVE: To assess the impact of the Massachusetts tobacco control programme, which, since its start in January 1993, has spent over $200m-"the highest per capita expenditure for tobacco control in the world"-funded by an extra tax of 25 cents per pack of cigarettes. DESIGN: Population based trend analysis with comparison group. SUBJECTS: Adult residents of Massachusetts and other US states excluding California. MAIN OUTCOME MEASURES: Per capita consumption of cigarettes as measured by states' sales tax records; prevalence of smoking in adults as measured by several population-based telephone surveys. RESULTS: From 1988 to 1992, decline in per capita consumption of cigarettes in Massachusetts (15%) was similar to that in the comparison states (14%), corresponding to an annual decline of 3-4% for both groups. During 1992-3, consumption continued to decline by 4% in the comparison states but dropped 12% in Massachusetts in response to the tax increase. From 1993 onward, consumption in Massachusetts showed a consistent annual decline of more than 4%, whereas in the comparison states it levelled off, decreasing by less than 1% a year. From 1992, the prevalence of adult smoking in Massachusetts has declined annually by 0.43% (95% confidence interval 0.21% to 0.66%) compared with an increase of 0. 03% (-0.06% to 0.12%) in the comparison states (P<0.001). CONCLUSIONS: These findings show that a strongly implemented, comprehensive tobacco control programme can significantly reduce tobacco use.

Adult↗
PubMed2000

The value of prone imaging in CT pneumocolon.

AIM: To evaluate the value of prone imaging in computed tomography pneumocolon. MATERIALS AND METHODS: In the U.K., patients commonly undergo computed tomography (CT) pneumocolon in the supine position alone. A prospective analysis of both supine and prone CT images was performed. The degree of distension and the presence/absence of fluid/faecal residue were documented. RESULTS: Twenty-five patients were examined in total. In all cases, all five segments of the colon were well visualized on combined assessment of supine/prone images. Diagnostic distension was obtained in all five segments of the bowel in 69% of cases in the prone position, but in only 24% of patients in the supine position. The rectum and sigmoid colon were well distended in 100 and 88%, respectively, on prone CT, but in only 58 and 35% of cases, respectively, on supine CT. Problems encountered by fluid/faecal residue were eliminated on prone CT. CONCLUSION: Adjunctive prone pelvic CT should be performed in all patients undergoing CT pneumocolon unless the supine images can be fully reviewed and shown to be satisfactory before the patient leaves the CT department. If a single positional sequence is to be performed, then prone CT is the position of choice.

Colonic Diseases↗
PubMed2000

Widespread countervailing genomic responses induced by chemotherapy or radiation as a cause of therapeutic failure.

If chemotherapy or ionizing radiation induce widespread genomic responses tending to circumvent or antagonize their ability to kill malignant cells, an additional cause for therapeutic failure would be suggested. There is evidence that some agents evoke extensive countervailing genomic activity, the nature and extent of which can be assessed with the use of 'gene chips'.

Antineoplastic Agents↗