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J S Lewis

Publications and source records attributed to J S Lewis.

At least 37 records · Page 2Linked to original sources
PubMed2001

Tumor uptake of copper-diacetyl-bis(N(4)-methylthiosemicarbazone): effect of changes in tissue oxygenation.

UNLABELLED: We showed previously that, in vitro, copper-diacetyl-bis(N(4)-methylthiosemicarbazone) (Cu-ATSM) uptake is dependent on the oxygen concentration (pO2). We also showed that, in vivo, Cu-ATSM uptake is heterogeneous in animal tumors known to contain hypoxic fractions. This study was undertaken to confirm the pO2 dependence of this selective uptake in vivo by correlating Cu-ATSM uptake with measured tumor pO2. METHODS: Experiments were performed with the 9L gliosarcoma rat model using a needle oxygen electrode to measure tissue pO2. Using PET and electronic autoradiography, Cu-ATSM uptake was measured in tumor tissue under various pO2 levels. The oxygen concentration within implanted tumors was manipulated by chemical means or by altering the inhaled oxygen content. RESULTS: A good correlation between low pO2 and high Cu-ATSM accumulation was observed. Hydralazine administration in animals caused a decrease in the average tumor pO2 from 28.61 +/- 8.74 mm Hg to 20.81 +/- 7.54 mm Hg in untreated control animals breathing atmospheric oxygen. It also caused the tumor uptake of Cu-ATSM to increase by 35%. Conversely, in animals breathing 100% oxygen, the average tumor pO2 increased to 45.88 +/-15.9 mm Hg, and the tumor uptake of Cu-ATSM decreased to 48% of that of the control animals. PET of animals treated in a similar fashion yielded time-activity curves showing significantly higher retention of the tracer in hypoxic tissues than in oxygenated tissues. CONCLUSION: These data confirm that Cu-ATSM uptake in tissues in vivo is dependent on the tissue pO2, and that significantly greater uptake and retention occur in hypoxic tumor tissue. Therefore, the possible use of Cu-ATSM PET as a prognostic indicator in the management of cancer is further validated.

Animals↗
PubMed2001

PET imaging of hypoxia.

Hypoxia in tumors has been related to poor response to conventional therapies. This paper will discuss the methods, both invasive and non-invasive, used to determine hypoxia levels within tumors. PET imaging with two lead compounds 18F-fluoromisonidazole (18FMISO) and Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone (Cu-ATSM) and their relative effectiveness in delineating hypoxic regions will be discussed. The advantages of Cu-ATSM-PET over existing imaging agents will be discussed along with its potential application as a direct- and/or surrogate marker for the determination of oncological hypoxia in vivo.

Cell Hypoxia↗
PubMed2000

Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas.

Angiogenesis is essential to the growth and metastasis of solid tumours. Vascular endothelial growth factor (VEGF) is a potent pro-angiogenic cytokine that is overexpressed in malignant tumours such as invasive carcinoma of the breast. The low oxygen tensions (hypoxia) present in these tumours are known to up-regulate the expression of VEGF by tumour cells. Human macrophages also respond to hypoxia by increasing their release of VEGF in vitro, although the effect of hypoxia on VEGF expression by macrophages in vivo has yet to be demonstrated. The present study compared the expression of VEGF by macrophages in areas of low and high vascularity in 24 invasive breast carcinomas (12 lobular, 12 ductal). The cellular distributions of VEGF protein, CD31 (vessels), and CD68 (macrophages) were compared in sequential sections for each tumour. In ten tumours, both tumour cells and macrophages were immunoreactive for VEGF protein. Use of non-isotopic in situ hybridization to localize VEGF mRNA showed that these cell types also expressed VEGF mRNA. No significant differences in the cellular distribution of VEGF protein were found between lobular and ductal carcinomas. In all tumours, macrophages accumulated in higher numbers in poorly vascularized than in highly vascularized areas. In VEGF-positive tumours, macrophages were immunoreactive for VEGF only in avascular areas where tumour cells also expressed VEGF. This suggests that VEGF expression by these two cell types may be regulated by the same microenvironmental stimuli in breast carcinomas. In addition, significantly more macrophages were present in poorly vascularized areas of VEGF-positive than VEGF-negative tumours. This suggests that VEGF may exert a chemotactic action on macrophages in vivo and guide their migration into avascular tumour sites.

Adult↗
PubMed2000

Copper bis(diphosphine) complexes: radiopharmaceuticals for the detection of multi-drug resistance in tumours by PET.

Experience with imaging of the multi-drug resistance (MDR) phenotype in tumours using technetium-99m sestamibi, a substrate of the P-glycoprotein (Pgp) transporter, suggests that better quantification of images and separation of MDR from other variables affecting tracer uptake in tumours are required. One approach to these problems is the development of short half-life positron-emitting tracers which are substrates of Pgp. Several lipophilic cationic copper(I) bis(diphosphine) complexes labelled with copper-64 have been synthesised and evaluated in vitro as substrates for Pgp. The synthesis is rapid and efficient with no need for purification steps. The chemistry is suitable for use with very short half-life radionuclides such as copper-62 (9.7 min) and copper-60 (23.7 min). Incubation of the complexes with human serum in vitro showed that they are sufficiently stable in serum to support clinical imaging, and the more lipophilic members of the series are taken up rapidly by cells (Chinese hamster ovary and human ovarian carcinoma) in vitro with great avidity. Uptake in human ovarian carcinoma cells is significantly reduced after several months of conditioning in the presence of doxorubicin, which induces increased Pgp expression. Uptake in hooded rat sarcoma (HSN) cells, which express Pgp, is significantly increased in the presence of the MDR modulator cyclosporin A. Biodistribution studies in hooded rats show rapid blood clearance, excretion through both kidneys and liver, and low uptake in other tissues. The one complex investigated in HSN tumour-bearing rats showed uptake in tumour increasing up to 30 min p.i. while it was decreasing in other tissues. We conclude that diphosphine ligands offer a good basis for development of radiopharmaceuticals containing copper radionuclides, and that this series of complexes should undergo further evaluation in vivo as positron emission tomography imaging agents for MDR.

Animals↗
PubMed2000

Effect of macrolides as part of initial empiric therapy on medical outcomes for hospitalized patients with community-acquired pneumonia.

OBJECTIVE: The goal of this study was to compare the outcomes of hospitalized patients receiving a nonpseudomonal third-generation cephalosporin with or without a macrolide for the treatment of community-acquired pneumonia (CAP). BACKGROUND: The initial treatment of CAP is usually based on empirically selected antibiotic therapy. The need for coverage of atypical pathogens in hospitalized patients is widely debated, and regional variations may exist. METHODS: All patients admitted to a community hospital or to a university hospital for 1 year who were aged > or =18 years and had a principal discharge diagnosis of pneumonia with no organism specified according to the International Classification of Diseases, Ninth Revision, Clinical Modification were evaluated. Each patient's medical chart was reviewed by a clinical pharmacist at each facility. The following information was collected for each patient using a standardized form: demographic characteristics, coexisting illnesses, length of hospital and intensive care unit stays, antibiotic regimens, length of parenteral and oral therapy, laboratory and radiographic findings (ie, blood urea nitrogen, glucose, hematocrit, sodium, PO2, pH, and pleural effusion), physical examination results, and mortality. Patients treated with a nonpseudomonal third-generation cephalosporin with or without a macrolide were included in this analysis. Categoric variables were compared using the chi-square test or the Fisher exact test, and continuous variables were compared using the Mann-Whitney U test. A P value < 0.05 was considered statistically significant. RESULTS: A total of 213 patients met the entry criteria and were treated with a nonpseudomonal third-generation cephalosporin with (116 patients) or without (97 patients) a macrolide. The mean (+/- SD) age of the patients was 62.2+/-19.6 years; 47% were male. The most common comorbid conditions were chronic obstructive pulmonary disease, diabetes mellitus, congestive heart failure, and cerebrovascular accident (CVA). Of the 116 patients who received a macrolide, the majority (66%) received erythromycin. Other macrolides used were clarithromycin (19%) and oral azithromycin (15%). There were no statistical differences between patients who did and did not receive a macrolide in terms of comorbid illnesses, length of hospital stay (5.2+/-2.8 vs 5.2+/-3.4 days, respectively), length of intravenous antibiotic therapy (4.4+/-2.5 vs 4.1+/-2.3 days, respectively), or mortality (0.9% vs 3.1%, respectively; P = 0.333). The only difference between the groups was in age. Those patients who received a macrolide were significantly younger than those who received only a nonpseudomonal third-generation cephalosporin (57.4+/-19.2 years vs 67.9+/-18.5 years; P < 0.001). However, when age and severity of illness were taken into account, no difference existed between the patients who received a nonpseudomonal third-generation cephalosporin alone or in combination with a macrolide. CONCLUSIONS: We concluded that the addition of a macrolide to a nonpseudomonal third-generation cephalosporin as initial therapy for the treatment of CAP may not be necessary. A randomized, prospective clinical trial comparing a nonpseudomonal third-generation cephalosporin alone and in combination with a macrolide is warranted.

Adult↗
PubMed2000

Self-assembly of an oligodeoxyribonucleotide harboring the estrogen response element in the presence of polyamines: ionic, structural, and DNA sequence specificity effects.

Estrogenic regulation of gene expression is mediated by the binding of the hormone to its specific receptor, estrogen receptor (ER), which undergoes structural and conformational alterations to recognize specific DNA sequences, estrogen response elements (ERE), in responsive genes to trigger a series of events culminating in the transcription of these genes. Polyamines are ubiquitous cellular cations that are important for cell growth and differentiation, and have been shown to participate in estrogenic regulation of gene expression. Polyamine-mediated DNA condensation/aggregation has been studied to understand the ionic and structural requirements for the compaction of DNA. DNA condensation/decondensation may also play a role in transcription and replication. We studied the aggregation of a 38-mer oligonucleotide duplex (ODN) in the presence of natural and synthetic polyamines under different ionic conditions (NaCl, KCl, and K glutamate). Our results showed that an ODN harboring the consensus ERE (ODN1) was 2-fold more susceptible to precipitation by spermine compared to ODN2 containing scrambled sequences, or a mutant ODN (ODN3). The nature of the monovalent cations (Na+ vs K+), and anions (Cl- vs glutamate) also played an important role in the efficacy of a polyamine to precipitate ODNs: potassium glutamate being the least effective in suppressing the ability of spermine to precipitate ODNs. The concentration of polyamines required for precipitating the ODNs increased with monovalent ion concentration in the buffer. With ODN1, a plot of log[spermine4+] at the 50% precipitation concentrations against log[Na+/K+] yielded a straight line, with a slope of 1.8 +/- 0.18, a value comparable to that predicted by the counterion condensation theory (1.85). We also observed significant structural specificity effects of spermine and its analogues [NH2(CH2)3NH(CH2)nNH(CH2)3NH2, where n = 2-9; n = 4 for spermine] on aggregating the ODN1. These results demonstrate DNA sequence and polyamine structural specificity effects on the aggregation of ODNs, and suggest that the gene regulatory function of ERE may be linked to its ability to undergo facile condensation/decondensation in the presence of biological cations, such as polyamines.

Base Sequence↗
PubMed2000

Comparative dosimetry of copper-64 and yttrium-90-labeled somatostatin analogs in a tumor-bearing rat model.

90Y-DOTA-tyrosine3-octreotide (90Y-DOTA-Y3-OC) is currently being evaluated as a radiotherapy agent for trials in patients with somatostatin-receptor positive cancer. In this study, we compared the estimated absorbed doses to human organs, as well as to a CA20948 rat tumor, of 90Y- and 64Cu-labeled DOTA-Y3-OC and DOTA-Y3-octreotate (DOTA-Y3-TATE). Assuming that the radiopharmaceutical biodistributions are the same in rodents and humans, human absorbed dose estimates were obtained from rat biodistribution data. The absorbed doses of 90Y-DOTA-Y3-TATE were determined from the biodistribution of the 88Y-labeled peptide, with and without co-injection of a therapeutic amount of the 90Y-labeled peptide. Additionally, the absorbed doses of 90Y-DOTA-Y3-TATE were determined from data using two different biodistribution endpoints, 48 h and 168 h. Human absorbed dose estimates were calculated using MIRD methodology assuming that rats and humans have the same biodistribution. The biodistribution of the radiolabeled somatostatin analogs was dependent on the peptide and the radiometal. For 90Y-DOTA-Y3-TATE, the tumor dose was dependent on both the administration of therapeutic 90Y-peptide and the biodistribution endpoint. Our data suggested that, for both radionuclides, the TATE derivatives imparted a higher absorbed dose to the tumor than the OC analogs. 90Y-DOTA-Y3-OC and 64Cu-DOTA-Y3-OC were comparable with respect to their tumor-to-normal tissue dose ratios, while 90Y-DOTA-Y3-TATE appeared to have distinct advantages over 64Cu-DOTA-Y3-TATE.

Animals↗
PubMed1999

Comparison of four 64Cu-labeled somatostatin analogues in vitro and in a tumor-bearing rat model: evaluation of new derivatives for positron emission tomography imaging and targeted radiotherapy.

Previous studies have shown that modification of the somatostatin analogue octreotide (OC), by substitution of tyrosine for phenylalanine at position 3 and of a C-terminal carboxylic acid for an alcohol, to give Tyr3-octreotate (Y3-TATE) improved uptake of the peptide in somatostatin receptor-positive tissues. To determine which substitution best accounts for increased target tissue uptake, the peptides containing single modifications, Tyr3-octreotide (Y3-OC) and octreotate (TATE), were synthesized. These peptides were conjugated to the macrocyclic chelating agent 1,4,8, 11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid (TETA) and radiolabeled with 64Cu(II). The in vitro receptor binding, in vitro tumor cell uptake, and in vivo distribution properties of 64Cu-labeled TETA-Y3-OC and TETA-TATE were compared to those of [64Cu]TETA-OC and [64Cu]TETA-Y3-TATE. Cu-TETA-TATE (IC50 = 0.297 +/- 0.0055 nM) and Cu-TETA-Y3-TATE (IC50 = 0.308 +/- 0.0375 nM) displayed significantly higher binding affinity to somatostatin receptors on CA20948 rat pancreatic tumor membranes than Cu-TETA-Y3-OC (IC50 = 0.397 +/- 0.0206 nM) and Cu-TETA-OC (IC50 = 0. 498 +/- 0.039 nM). Similarly, the uptakes of [64Cu]TETA-Y3-TATE (60. 75 +/- 1.21%) and [64Cu]TETA-TATE (55.62 +/- 0.16%) into AR42J rat pancreatic tumor cells over a 2-h time period were higher than those of [64Cu]TETA-Y3-OC (47.20 +/- 1.20%) and [64Cu]TETA-OC (34.07 +/- 2. 24%). The in vitro results suggest that the C-terminal carboxylate may contribute more to enhanced receptor binding and tumor cell uptake than the substitution at the 3-position. Biodistributions in CA20948 tumor-bearing rats showed receptor-mediated uptake of the 64Cu-labeled peptides in somatostatin-rich tissues, including the pituitary, adrenals, pancreas, and tumor. The structure-activity relationships of the four 64Cu-labeled peptides did not show consistent trends in all target tissues, but [64Cu]TETA-Y3-TATE exhibited tumor uptake 1.75-3.5 times higher than the other derivatives at 4 h postinjection. The greater tumor retention of [64Cu]TETA-Y3-TATE justifies the selection of this agent for future PET imaging and targeted radiotherapy studies.

Adrenal Glands↗
PubMed1999

Macrophage responses to hypoxia: relevance to disease mechanisms.

Macrophages are ubiquitous in the stromal compartment of tissues under normal physiological conditions and the number of these cells increases markedly with the onset and progression of many pathological states. The mechanisms underlying this response are well described in such conditions as wound healing and malignant tumors, where tissue-specific signals enhance the extravasation of blood monocytes and their subsequent differentiation into macrophages. Recent evidence suggests that macrophages may also be stimulated by microenvironmental factors present in diseased tissues to perform distinct, tissue-specific activities. One such factor, hypoxia (low oxygen tension), results from insufficient vascular perfusion of a given tissue. Various studies have shown that experimental hypoxia alters the morphology, expression of cell surface markers, viability, phagocytosis, metabolic activity, and release of cytokines by macrophages. Here we review the evidence for these macrophage responses to hypoxia, the involvement of co-stimuli, and their implications for the role of macrophages in various disease processes. Because the intracellular mechanisms mediating the effects of hypoxia on gene expression in other cell types have been characterized recently, we discuss their possible involvement in the effects of hypoxia on gene expression in macrophages.

Animals↗
PubMed1999

In vitro and in vivo evaluation of 64Cu-TETA-Tyr3-octreotate. A new somatostatin analog with improved target tissue uptake.

Radiolabeled somatostatin analogs have demonstrated potential as cancer therapeutic agents. Many of these agents are based on the analog octreotide (OC). Recently it has been shown that substitution of a tyrosine for phenylalanine in the 3-position and changing the C-terminus from an alcohol to an acid improves the targeting of somatostatin-rich tissues. The compound, 1,4,8,11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid-Tyr3-octreotate (TETA-Y3-TATE), was synthesized and radiolabeled with 64Cu. The receptor binding properties of 64Cu-TETA-Y3-TATE showed an estimated Kd value of 549 pM in somatostatin receptor-positive CA20948 tissue membrane. High tumor uptake was observed in two animal tumor models. Tumor uptakes of 2.37 %ID/g in CA20948 tumor-bearing rats and 21.60 %ID/g in AR42J tumor-bearing SCID mice were observed at 1 h, compared with 1.09 %ID/g and 11.24 %ID/g for 64Cu-TETA-OC. Higher uptake in other somatostatin-receptor rich tissues was also observed, compared with 64Cu-TETA-OC. Positron emission tomography (PET) imaging with 64Cu-TETA-Y3-TATE in a baboon showed significant uptake in the pituitary and adrenals, and clearance through the kidneys. 64Cu-TETA-Y3-TATE, a new OC analog for binding somatostatin receptors, demonstrated significantly greater uptake in somatostatin-rich tissues in two tumor-bearing animal models, and demonstrated great potential as a radiopharmaceutical for imaging and therapy of somatostatin receptor-positive tissues.

Animals↗
PubMed1999

High purity production and potential applications of copper-60 and copper-61.

Previously we described the high yield production of 64Cu using a target system designed specifically for low energy, biomedical cyclotrons. In this study, the use of this target system for the production of 60Cu and 61Cu is described and the utility of these isotopes in the labeling of biomolecules for tumor and hypoxia imaging is demonstrated. 60Cu and 61Cu were produced by the 60Ni(p,n)60Cu, 61Ni(p,n)61Cu, and 60Ni(d,n)61Cu nuclear reactions. The nickel target (>99% enriched or natural nickel) was plated onto a gold disk as described previously (54-225 microm thickness) and irradiated (14.7 MeV proton beam and 8.1 MeV deuteron beam). The copper isotopes were separated from the nickel via ion exchange chromatography and the radioisotopic purity was assessed by gamma spectroscopy. Yields of up to 865 mCi of 60Cu have been achieved using enriched 60Ni. 61Cu has been produced with a maximum yield of 144 mCi using enriched 61Ni and 72 mCi using enriched 60Ni. Specific activities (using enriched material) ranged from 80 to 300 mCi/microg Cu for 60Cu and from 20 to 81 mCi/microg Cu for 61Cu. Bombardments of natural Ni targets were performed using both protons and deuterons. Yields and radioisotopic impurities were determined and compared with that for enriched materials. 60Cu was used to radiolabel diacetyl-bis(N4-methylthiosemicarbazone), ATSM. 60Cu-ATSM was injected into rats that had an occluded left anterior descending coronary artery. Uptake of 60Cu-ATSM in the hypoxic region of the heart was visualized clearly using autoradiography. In addition, 60Cu-ATSM was injected into dogs and excellent images of the heart and heart walls were obtained using positron emission tomography (PET). 61Cu was labeled to 1,4,8,11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid-octreotide (TETA-octreotide) and the PET images of tumor-bearing rats were obtained up to 2 h postinjection. After decay of the 61Cu, the same rat was injected with 64Cu-TETA-octreotide and the images were compared. The tumor images obtained using 61Cu were found to be superior to those using 64Cu as predicted based on the larger abundance of positrons emitted by 61Cu vs. 64Cu.

Animals↗
PubMed1999

Radiotherapy and dosimetry of 64Cu-TETA-Tyr3-octreotate in a somatostatin receptor-positive, tumor-bearing rat model.

64Cu [T1/2 = 12.8 h; beta+ = 0.655 MeV (19%); beta- = 0.573 MeV (40%)] has shown promise as a radioisotope for targeted radiotherapy. It has been demonstrated previously that the somatostatin analogue 64Cu-TETA-octreotide (64Cu-TETA-OC, where TETA is 1,4,8,11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid) significantly inhibited the growth of somatostatin receptor-positive CA20948 rat pancreatic tumors in Lewis rats (C. J. Anderson et al., J. Nucl. Med., 39: 1944-1951, 1998). In this study, we evaluated the radiotherapeutic efficacy of a new 64Cu-labeled somatostatin analogue, 64Cu-TETA-Tyr3-octreotate (64Cu-TETA-Y3-TATE), in CA20948 tumor-bearing rats. A single dose of 15 mCi (555 MBq) of 64Cu-TETA-Y3-TATE was shown to be more effective in reducing tumor burden than the same dose of 64Cu-TETA-OC. In multiple dose experiments, tumor-bearing rats were administered three doses of either 10 or 20 mCi (370 or 740 MBq) of 64Cu-TETA-Y3-TATE at 48-h intervals. Rats given 3x10 mCi (3x370 MBq) showed extended mean survival times compared with rats given a single dose; however, no complete regressions occurred. Complete regression of tumors was observed for all rats treated with 3x20 mCi (3x740 MBq), with no palpable tumors for approximately 10 days; moreover, the mean survival time of these rats was nearly twice that of controls. Toxicity was determined by physical appearance and hematological and enzyme analysis, which revealed no overt toxicity and only transient changes in blood and liver chemistry. Absorbed dose estimates showed the dose-limiting organ to be the kidneys. The radiotherapy results, along with absorbed dose estimates to target and clearance organs, confirm that 64Cu-labeled somatostatin analogues warrant continued consideration as agents for targeted radiotherapy.

Animals↗
PubMed1999

A review of alternative approaches in the management of iatrogenic femoral pseudoaneurysms.

The management of iatrogenic pseudoaneurysms (IPAs) demands close co-operation between radiologist, vascular surgeon and plastic surgeon. Ideally, each patient should be reviewed employing a team approach. Many IPAs require only observation; those with a volume greater than 6 cm3 will require treatment as spontaneous thrombosis is uncommon. Radiological treatment options include ultrasound guided compression repair (UGCR), embolisation, and covered stenting. Occasionally, these are unsuccessful or contra-indicated, and the vascular surgical approach is discussed in detail. Finally, the role of the plastic surgeon in dealing with skin ischaemia is detailed.

Aneurysm, False↗
PubMed1999

Evaluation of 64Cu-ATSM in vitro and in vivo in a hypoxic tumor model.

UNLABELLED: We have evaluated Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM), an effective marker for the delineation of hypoxic but viable tissue, in vitro in the EMT6 carcinoma cell line under varying degrees of hypoxia and compared it with the flow tracer 64Cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone) (Cu-PTSM) and the hypoxic tracer 18F-fluoromisonidazole (MISO). We have also compared the uptake of Cu-ATSM and Cu-PTSM in vivo and ex vivo in a murine animal model bearing the EMT6 tumor. METHODS: Uptake of 64Cu-ATSM, 64Cu-PTSM and 18F-MISO in vitro into EMT6 cells was investigated at the dissolved oxygen concentrations of 0, 1 x 10(3), 5 x 10(3), 5 x 10(4) and 2 x 10(5) ppm. Biodistribution performed at 1, 5, 10, 20 and 40 min compared 64Cu-ATSM with 64Cu-PTSM in BALB/c mice bearing EMT6 tumors. To determine long-term retention of 64Cu-ATSM, biodistribution was also performed at 1, 2 and 4 h. Ex vivo autoradiography of tumor slices after co-injection of 60Cu-PTSM (60Cu, T1/2 = 23.7 min) and 64Cu-ATSM (64Cu, t1/2 = 12.7 h) into the same animal was performed. RESULTS: After 1 h, 64Cu-ATSM was taken up by EMT6 cells: 90% at 0 ppm, 77% at 1 x 10(3) ppm, 38% at 5 x 10(3) ppm, 35% at 5 x 10(4) ppm and 31% at 2 x 10(5) ppm. 18F-MISO also showed oxygen concentration dependent uptake, but with lower percentages than 64Cu-ATSM. 64Cu-PTSM showed 83%-85% uptake into the cells after 1 h, independent of oxygen concentration. Biodistribution data of 64Cu-ATSM and 64Cu-PTSM showed optimal tumor uptake after 5 and 10 min, respectively (0.76% injected dose (ID)/organ for 64Cu-ATSM and 1.11%ID/organ for 64Cu-PTSM). Ex vivo imaging experiments showed 60Cu-PTSM uniform throughout the EMT6 tumor, but heterogeneous uptake of 64Cu-ATSM, indicative of selective trapping of 64Cu-ATSM into the hypoxic tumor cells. CONCLUSION: Cu-ATSM exhibits selectivity for hypoxic tumor tissue both in vivo and in vitro and may provide a successful diagnostic modality for the detection of tumor ischemia.

Animals↗
PubMed1998

Decline in sexually transmitted disease prevalence in female Bolivian sex workers: impact of an HIV prevention project.

OBJECTIVE: To implement an HIV prevention intervention among female commercial sex workers (CSW), and to monitor key outcomes using routinely collected clinical and laboratory data. DESIGN: Cross-sectional and longitudinal analysis of data from an open-enrollment cohort. SETTING: One public sexually transmitted disease (STD) clinic and about 25 brothels in La Paz, Bolivia. PARTICIPANTS: A total of 508 female CSW who work at brothels and attend a public STD clinic. INTERVENTION: Improved STD clinical care, supported by periodic laboratory testing, and behavioral interventions performed by a local non-governmental organization. MAIN OUTCOME MEASURES: Prevalence of gonorrhea, syphilis (reactive plasma reagin titer > or = 1 : 16), genital ulcer disease, chlamydial infection, and trichomoniasis; self-reported condom use in the previous month; and HIV seroprevalence. RESULTS: From 1992 through 1995, prevalence of gonorrhea among CSW declined from 25.8 to 9.9% (P < 0.001), syphilis from 14.9 to 8.7% (P = 0.02), and genital ulcer disease from 5.7 to 1.3% (P = 0.006); trends in prevalence of chlamydial infection and trichomoniasis were not significant. Self-reported condom use during vaginal sex in the past month increased from 36.3 to 72.5% (P < 0.001). In a multivariate analysis, condom use was inversely associated with gonorrhea [odds ratio (OR), 0.63; 95% confidence interval (Cl), 0.41-0.97], syphilis (OR, 0.39; 95% Cl, 0.23-0.64), and trichomoniasis (OR, 0.44; 95% Cl, 0.32-0.71). In 1995, HIV seroprevalence among CSW was 0.1%. CONCLUSION: Effective prevention interventions for female CSW can be implemented through public services and non-governmental organizations while HIV rates are still low, and key outcomes can be monitored using data obtained from periodic screening examinations.

Adult↗
PubMed1998

Design of hypoxia-targeting radiopharmaceuticals: selective uptake of copper-64 complexes in hypoxic cells in vitro.

The well-known perfusion tracer CuPTSM, labelled with 62Cu or 64Cu, is believed to be trapped in cells non-selectively by a bioreductive mechanism. It is proposed that by modifying the ligand to increase its electron donor strength (for example by adding alkyl functionality or replacing sulphur ligands with oxygen ligands), the copper complexes will become less easily reduced and tracers with selectivity for hypoxic tissues could thus be developed. The aim of this work was to prepare 64Cu-labelled complexes of two series of ligands, based on the bis(thiosemicarbazone) (13 ligands) and bis(salicylaldimine) (3 ligands) skeletons, and to evaluate the hypoxia dependence of their uptake in cells. The complexes were incubated with Chinese hamster ovary cells under normoxic and hypoxic conditions, and the cells isolated by centrifugation to determine radioactivity uptake at various time points up to 90 min. Several members of both series demonstrated significant (P<0.05) or highly significant (P<0.01) hypoxia selectivity, indicating that both series of complexes offer a basis for development of hypoxia-targeting radiopharmaceuticals for positron emission tomography (60Cu, 61Cu, 62Cu, 64Cu) and targeted radiotherapy (64Cu, 67Cu).

Animals↗
PubMed1998

Etiology of genital ulcers and prevalence of human immunodeficiency virus coinfection in 10 US cities. The Genital Ulcer Disease Surveillance Group.

To determine the etiology of genital ulcers and to assess the prevalence of human immunodeficiency virus (HIV) infection in ulcer patients in 10 US cities, ulcer and serum specimens were collected from approximately 50 ulcer patients at a sexually transmitted disease clinic in each city. Ulcer specimens were tested using a multiplex polymerase chain reaction assay to detect Haemophilus ducreyi, Treponema pallidum, and herpes simplex virus (HSV); sera were tested for antibody to HIV. H. ducreyi was detected in ulcer specimens from patients in Memphis (20% of specimens) and Chicago (12%). T. pallidum was detected in ulcer specimens from every city except Los Angeles (median, 9% of specimens; range, 0%-46%). HSV was detected in >/=50% of specimens from all cities except Memphis (42%). HIV seroprevalence in ulcer patients was 6% (range by city, 0%-18%). These data suggest that chancroid is prevalent in some US cities and that persons with genital ulcers should be a focus of HIV prevention activities.

Female↗