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Biomedical subjects

S Kaplan

Publications and source records attributed to S Kaplan.

At least 127 records · Page 7Linked to original sources
PubMed1997

Phase II trial of the oral platinum complex JM216 in non-small-cell lung cancer: an EORTC early clinical studies group investigation.

BACKGROUND: JM216 is a new oral platinum complex with dose-limiting toxicity myelosuppression, now undergoing phase II evaluation. PATIENTS AND METHODS: JM216 was evaluated as first line therapy in non-small-cell lung cancer. Seventeen patients received 120 mg/m2/day for five days repeated every three weeks. RESULTS: Toxicity was manageable, the commonest side-effects being nausea, vomiting, diarrhoea, constipation and asthenia. Myelososuppression was generally grade < 2 and there were no cases of neutropenic sepsis or bleeding. Thirteen patients were fully evaluable for response. No sustained objective responses were reported. One patient was reported as stable disease had a partial response after three courses but was progressing again after four. An additional five patients had stable disease (46.2%). CONCLUSIONS: Although some patients may have had useful palliation, JM216 did not appear to have significant antitumour activity in non-small-cell lung cancer.

Administration, Oral↗
PubMed1997

Development of a criteria set and a structured interview for disorders of extreme stress (SIDES).

Data regarding the development of a structured interview measuring alterations that may accompany extreme stress are presented. A list of 27 criteria often seen in response to extreme trauma and not addressed by DSM-IV criteria for posttraumatic stress disorder (PTSD) were generated based on a systematic review of the literature and a survey of 50 experts. A structured interview for disorders of extreme stress (SIDES) measuring the presence of these criteria was administered to 520 subjects as part of the DSM-IV PTSD field trials. Inter-rater reliability as measured by Kappa coefficients for lifetime Disorders of Extreme Stress was .81. Internal consistency using coefficient alpha ranged from .53 to .96. Results indicate that the SIDES is a useful tool for investigation of response to extremes stress.

Adolescent↗
PubMed1997

Low-resolution sequencing of Rhodobacter sphaeroides 2.4.1T: chromosome II is a true chromosome.

The photosynthetic bacterium Rhodobacter sphaeroides 2.4.1T has two chromosomes, CI (approximately 3.0 Mb) and CII (approximately 0.9 Mb). In this study a low-redundancy sequencing strategy was adopted to analyse 23 out of 47 cosmids from an ordered CII library. The sum of the lengths of these 23 cosmid inserts was approximately 495 kb, which comprised approximately 417 kb of unique DNA. A total of 1145 sequencing runs was carried out, with each run generating 559 +/- 268 bases of sequence to give approximately 640 kb of total sequence. After editing, approximately 2.8% bases per run were estimated to be ambiguous. After the removal of vector and Escherichia coli sequences, the remaining approximately 565 kb of R. sphaeroides sequences were assembled, generating approximately 291 kb of unique sequences. BLASTX analysis of these unique sequences suggested that approximately 131 kb (45% of the unique sequence) had matches to either known genes, or database ORFs of hypothetical or unknown function (dORFs). A total of 144 strong matches to the database was found; 101 of these matches represented genes encoding a wide variety of functions, e.g. amino acid biosynthesis, photosynthesis, nutrient transport, and various regulatory functions. Two rRNA operons (rrnB and rrnC) and five tRNAs were also identified. The remaining 160 kb of DNA sequence which did not yield database matches was then analysed using CODONPREFERENCE from the GCG package. This analysis suggested that 122 kb (42% of the total unique DNA sequence) could encode putative ORFs (pORFs), with the remaining 38 kb (13%) possibly representing non-coding intergenic DNA. From the data so far obtained, CII does not appear to be specialized for encoding any particular metabolic function, physiological state or growth condition. These data suggest that CII contains genes which are functionally as diverse as those found on any other bacterial chromosome and also contains sequences (pORFs), which may prove to be unique to this organism.

Base Sequence↗
PubMed1997

Identification and molecular genetic analysis of multiple loci contributing to high-level tellurite resistance in Rhodobacter sphaeroides 2.4.1.

The ability of the facultative photoheterotroph Rhodobacter sphaeroides to tolerate and reduce high levels of tellurite in addition to at least 10 other rare earth metal oxides and oxyanions has considerable potential for detoxification and bioremediation of contaminated environments. We report the identification and characterization of two loci involved in high-level tellurite resistance. The first locus contains four genes, two of which, trgAB, confer increased tellurite resistance when introduced into the related bacterium Paracoccus denitrificans. The trgAB-derived products display no significant homology to known proteins, but both are likely to be membrane-associated proteins. Immediately downstream of trgB, the cysK (cysteine synthase) and orf323 genes were identified. Disruption of the cysK gene resulted in decreased tellurite resistance in R. sphaeroides, confirming earlier observations on the importance of cysteine metabolism for high-level tellurite resistance. The second locus identified is represented by the telA gene, which is separated from trgAB by 115 kb. The telA gene product is 65% similar to the product of the klaB (telA) gene from the tellurite-resistance-encoding kilA operon from plasmid RK2. The genes immediately linked to the R. sphaeroides telA gene have no similarity to other components of the kilA operon. R. sphaeroides telA could not functionally substitute for the plasmid RK2 telA gene, indicating substantial functional divergence between the two gene products. However, inactivation of R. sphaeroides telA resulted in a significant decrease in tellurite resistance compared to the wild-type strain. Both cysK and telA null mutations readily gave rise to suppressors, suggesting that the phenomenon of high-level tellurite resistance in R. sphaeroides is complex and other, as yet uncharacterized, loci may be involved.

Amino Acid Sequence↗
PubMed1997

Molecular genetic analysis suggesting interactions between AppA and PpsR in regulation of photosynthesis gene expression in Rhodobacter sphaeroides 2.4.1.

The AppA protein plays an essential regulatory role in development of the photosynthetic apparatus in the anoxygenic phototrophic bacterium Rhodobacter sphaeroides 2.4.1 (M. Gomelsky and S. Kaplan, J. Bacteriol. 177:4609-4618, 1995). To gain additional insight into both the role and site of action of AppA in the regulatory network governing photosynthesis gene expression, we investigated the relationships between AppA and other known regulators of photosynthesis gene expression. We determined that AppA is dispensable for development of the photosynthetic apparatus in a ppsR null background, where PpsR is an aerobic repressor of genes involved in photopigment biosynthesis and puc operon expression. Moreover, all suppressors of an appA null mutation thus far isolated, showing improved photosynthetic growth, were found to contain mutations in the ppsR gene. Because ppsR gene expression in R. sphaeroides 2.4.1 appears to be largely independent of growth conditions, we suggest that regulation of repressor activity occurs predominately at the protein level. We have also found that PpsR functions as a repressor not only under aerobic but under anaerobic photosynthetic conditions and thereby is involved in regulating the abundance of the light harvesting complex II, depending on light intensity. It seems likely therefore, that PpsR responds to an integral signal (e.g., changes in redox potential) produced either by changes in oxygen tension or light intensity. The profile of the isolated suppressor mutations in PpsR is in accord with this proposition. We propose that AppA may be involved in a redox-dependent modulation of PpsR repressor activity.

Aerobiosis↗
PubMed1997

Analysis of the fnrL gene and its function in Rhodobacter capsulatus.

The fnr gene encodes a regulatory protein involved in the response to oxygen in a variety of bacterial genera. For example, it was previously shown that the anoxygenic, photosynthetic bacterium Rhodobacter sphaeroides requires the fnrL gene for growth under anaerobic, photosynthetic conditions. Additionally, the FnrL protein in R. sphaeroides is required for anaerobic growth in the dark with an alternative electron acceptor, but it is not essential for aerobic growth. In this study, the fnrL locus from Rhodobacter capsulatus was cloned and sequenced. Surprisingly, an R. capsulatus strain with the fnrL gene deleted grows like the wild type under either photosynthetic or aerobic conditions but does not grow anaerobically with alternative electron acceptors such as dimethyl sulfoxide (DMSO) or trimethylamine oxide. It is demonstrated that the c-type cytochrome induced upon anaerobic growth on DMSO is not synthesized in the R. capsulatus fnrL mutant. In contrast to wild-type strains, R. sphaeroides and R. capsulatus fnrL mutants do not synthesize the anaerobically, DMSO-induced reductase. Mechanisms that explain the basis for FnrL function in both organisms are discussed.

Amino Acid Sequence↗
PubMed1997

A quorum-sensing system in the free-living photosynthetic bacterium Rhodobacter sphaeroides.

Rhodobacter sphaeroides is a free-living, photoheterotrophic bacterium known for its genomic and metabolic complexity. We have discovered that this purple photosynthetic organism possesses a quorum-sensing system. Quorum sensing occurs in a number of eukaryotic host-associated gram-negative bacteria. In these bacteria there are two genes required for quorum sensing, the luxR and luxI homologs, and there is an acylhomoserine lactone signal molecule synthesized by the product of the luxI homolog. In R. sphaeroides, synthesis of a novel homoserine lactone signal, 7,8-cis-N-(tetradecenoyl)homoserine lactone, is directed by a luxI homolog termed cerI. Two open reading frames immediately upstream of cerI are proposed to be components of the quorum-sensing system. The first of these is a luxR homolog termed cerR, and the second is a small open reading frame of 159 bp. Inactivation of cerI in R. sphaeroides results in mucoid colony formation on agar and formation of large aggregates of cells in liquid cultures. Clumping of CerI mutants in liquid culture is reversible upon addition of the acylhomoserine lactone signal and represents a phenotype unlike those controlled by quorum sensing in other bacteria.

4-Butyrolactone↗
PubMed1997

Characterization of genes encoding dimethyl sulfoxide reductase of Rhodobacter sphaeroides 2.4.1T: an essential metabolic gene function encoded on chromosome II.

Rhodobacter sphaeroides 2.4.1T is a purple nonsulfur facultative phototrophic bacterium which exhibits remarkable metabolic diversity as well as genomic complexity. Under anoxic conditions, in the absence of light and the presence of dimethyl sulfoxide (DMSO) or trimethylamine N-oxide (TMAO), R. sphaeroides 2.4.1T utilizes DMSO or TMAO as the terminal electron acceptor for anaerobic respiration, which is mediated by the molybdoenzyme DMSO reductase. Sequencing of a 13-kb region of chromosome II revealed the presence of 10 putative open reading frames, of which 5 possess homology to genes encoding the TMAO reductase (the tor system) of Escherichia coli. The dorS and dorR genes encode a sensor-regulator pair of the two-component sensory transduction protein family, homologous to the torS and torR gene products. The dorC gene was shown to encode a 44-kDa DMSO-inducible c-type cytochrome. The dorB gene encodes a membrane protein of unknown function homologous to the torD gene product. The dorA gene encodes DMSO reductase, containing the molybdopterin active site. Mutations were constructed in each of these dor genes, and the resulting mutants were shown to be impaired for DMSO-dependent anaerobic growth in the dark. The mutant strains exhibited negligible levels of DMSO reductase activity compared to the wild-type strain under similar growth conditions. Further, no DorA protein was detected in DorS and DorR mutant strains with anti-DorA antisera, suggesting that the products of these genes are required for the positive regulation of dor expression in response to DMSO. This characterization of the dor gene cluster is the first evidence that genes of chromosome CII encode metabolic functions which are essential under particular growth conditions.

Chromosomes, Bacterial↗
PubMed1997

Evidence for the role of redox carriers in photosynthesis gene expression and carotenoid biosynthesis in Rhodobacter sphaeroides 2.4.1.

Previous work from this laboratory revealed that alterations in the structure of the ccoNOQP operon of Rhodobacter sphaeroides 2.4.1 could lead to induction of the photosynthetic apparatus under aerobic growth conditions. Immediately downstream of the ccoNOQP operon is the rdxB gene, the first gene of the rdxBHIS cluster. The rdxB gene product is predicted to encode a membrane protein which can bind two [4Fe-4S] clusters. The ccoP gene product is a diheme cytochrome which is a component of the cbb3-type cytochrome oxidase. Under aerobic growth conditions, strains possessing ccoP and rdxB mutations both singly and in combination produced light-harvesting complexes, suggesting that normal functioning of these proteins is required to maintain repression of photosynthesis gene expression in the presence of oxygen. Analysis of the expression of puc::lacZ fusions under aerobic conditions revealed an approximately 12-fold increase in puc operon expression in the RDXB1 and CCOP1 mutant strains compared with that for wild-type 2.4.1. Similarly, puf::lacZ activity was observed to be elevated fourfold above wild-type levels. Further indication of the importance of the RdxB and CcoP proteins was derived from studies of mutant and wild-type cells grown under anoxygenic photosynthetic and nitrogen-fixing conditions. These mutant strains were observed to accumulate spheroidenone to approximately 50% or more of the total carotenoid. In wild-type cultures, spheroidenone normally accumulates to approximately 10 to 20% of the total carotenoid under the same growth conditions. This effect was most pronounced when both the rdxB and the ccoP mutations were present together in cells cultured under nitrogen-fixing photosynthetic growth conditions in which spheroidenone represented approximately 90% of the total carotenoid. We propose that mutations in the rdxB or ccoP gene may lead to changes in a membrane-generated redox signal or the accumulation of a critical redox intermediate in the mutant strains which results in increased photosynthesis gene expression under aerobic conditions by alteration of the activity of a transcriptional regulator(s) of photosynthesis gene expression. Mutations in these genes also appear to posttranscriptionally influence the terminal step of carotenoid biogenesis. Potential regulators interacting with an aberrant redox signal in the mutants and the possible nature of such a redox signal are discussed.

Aerobiosis↗
PubMed1997

Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group.

PURPOSE: To assess activity and toxicity of topotecan in previously treated small-cell lung cancer (SCLC) patients. PATIENTS AND METHODS: Patients with measurable SCLC, progressive after one first-line regimen, were eligible for the study. Two groups of patients were selected: (1) patients who failed first-line treatment < or = 3 months from chemotherapy discontinuation (refractory group); and (2) patients who responded to first-line treatment and progressed greater than 3 months after chemotherapy discontinuation (sensitive group). Topotecan was administered as a 30-minute daily infusion at a dose of 1.5 mg/m2 for 5 consecutive days, every 3 weeks. RESULTS: One hundred one patients were entered onto the study and 403 courses were administered. Ninety-two patients (47 refractory and 45 sensitive) were eligible and assessable for response. Among refractory patients, there were two partial responses (PRs) and one complete response (CR), for an overall response rate of 6.4% (95% confidence interval [CI], 1.3% to 17.6%), whereas in the sensitive group, there were 11 PRs and six CRs, for an overall response rate of 37.8% (95% CI, 23.8% to 53.5%). Overall median duration of response was 7.6 months. Median survival was 5.4 months; median survival of refractory patients was 4.7 months, whereas that of sensitive patients was 6.9 months (P = .002). Median survival of responding patients was 12.5 months. Toxicity was mainly hematologic. Leukopenia, although short-lived, was universal, with grade III and IV neutropenia occurring in 28% and 46.8% of cycles, respectively. Nonhematological toxicity was mild. Fatigue/malaise was reported in 39.3% of cycles and transient elevation of liver enzymes in 17%. CONCLUSION: Topotecan has significant activity in SCLC, particularly in patients sensitive to prior chemotherapy, with predictable and manageable toxicity. The incorporation of topotecan in combination chemotherapy regimens for future treatment of SCLC is warranted.

Aged↗
PubMed1997

Acute nicotine interactions with nicotinic and muscarinic antagonists: working and reference memory effects in the 16-arm radial maze.

In the 8-arm radial maze and other tests, acute nicotine administration has been found to improve memory performance significantly, whereas acute administration of the nicotinic antagonist mecamylamine has been found to impair memory performance. However, questions remain concerning the behavioral and pharmacological nature of acute nicotine effects on memory. In the current studies, we examined acute nicotine effects on working and reference memory in a 16-arm radial maze. In the first study, nicotine caused a significant improvement in working memory but not in reference memory. The muscarinic antagonist scopolamine caused significant deficits in working memory but not in reference memory. Nicotine did not significantly attenuate the scopolamine-induced deficit. In the second study, with rats trained to near-perfect performance, a low dose of mecamylamine (1.25 mg/kg) caused a significant working memory impairment in the 16-arm maze. This deficit was significantly attenuated by concurrent acute administration of nicotine. These studies show that acute nicotine, like chronic nicotine, preferentially improves working compared with reference memory in the radial-arm maze. Mecamylamine can impair working memory performance in the 16-arm maze at low doses which are less likely to have effects at N-methyl-D-aspartate receptors. Nicotine can selectively reverse mecamylamine-induced deficits.

Animals↗
PubMed1996

Usefulness of banding of the pulmonary trunk with single ventricle physiology at risk for subaortic obstruction.

This study addresses the effects of early banding of the pulmonary trunk and subsequent management of subaortic obstruction on the attainment of acceptable pre-Fontan hemodynamics in patients with a single left ventricle and aorta arising from an outflow chamber. We report our experience with 26 patients seen at our institution between January 1984 and December 1994 with a diagnosis of double-inlet left ventricle or tricuspid atresia and transposed great arteries, who were initially managed with pulmonary artery banding in the first 6 months of life. Pulmonary artery band placement was performed at an age of 2.1 +/- 1.8 months (mean +/- SD). Associated aortic arch abnormalities were present in 8 patients (31%). There were 19 patients (73%) who underwent treatment with a Damus-Kaye-Stansel procedure or ventricular septal defect (VSD) enlargement for a significant subaortic gradient or morphologically small VSD, alone or in conjunction with a Glenn or Fontan procedure. Eighteen of 26 patients (69%) underwent cardiac catheterization to assess their candidacy for the Fontan operation. Of this group, 16 were classified as low to moderate risk and 2 as high-risk Fontan candidates, based on hemodynamic criteria. The cumulative mortality for the entire cohort was 19%. Our results suggest that this high-risk group of patients can undergo effective pulmonary artery banding as an initial palliative step, with subsequent intervention for subaortic ob- struction when it is documented or highly suspected, and that acceptable pre-Fontan hemodynamic parameters can be achieved.

Cardiac Catheterization↗
PubMed1996

Single agent activity of rhizoxin in non-small-cell lung cancer: a phase II trial of the EORTC Early Clinical Trials Group.

In a multicentre trial of the EORTC-Early Clinical Trials Group (ECTG) we treated 31 chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC) with rhizoxin, a novel tubulin-binding agent. The drug was given as an i.v. bolus injection at 2 mg m-2 once every 3 weeks in an outpatient setting. Prophylactic antiemetics were not routinely given. Of the 29 eligible patients, nine had been treated surgically and three had received radiotherapy. The main toxic effects observed were stomatitis (34% of cycles) and neutropenia (41% of cycles). Neutropenic fever was rare (3% of cycles). Twenty-seven patients were evaluable for response. There were four partial responses (15%), while 13 patients (48%) showed stabilisation of their disease. The median duration of response was 7 months (range 6.0-10.7 months) and median survival from the start of rhizoxin treatment was 6 months (range 2-14.7 months). Rhizoxin as single agent shows activity in patients with advanced NSCLC.

Adult↗
PubMed1996

Mild hypothermia, hypertension, and mannitol are protective against infarction during experimental intracranial temporary vessel occlusion.

A rabbit model of focal temporary ischemia was used to test the protection provided by mild hypothermia, hypertension, mannitol and the combination of the three methods. Twenty-four New Zealand White rabbits were divided into five groups as follows: a control group, a hypertension group (mean arterial blood pressure increased by 42 mm Hg), a hypothermic group (rectal temperature decreased by 6 degrees C), a mannitol group (1 g/kg of body weight, administered intravenously), and the triple-therapy group. The intracranial internal carotid artery, the middle cerebral artery, and the anterior cerebral artery were clipped for 2 hours and then underwent 4 hours of reperfusion. Blood pressure, rectal and brain temperature, blood glucose level, hematocrit, and arterial blood gases were monitored during the experiment. For measuring the infarction size, the brain was divided into 4-mm slices and stained with 2,3,5-triphenyltetrazolium chloride. The severity of the neuronal damage was also evaluated by conventional histological examination with hematoxylin and eosin staining. The infarct volume was 193.2 +/- 34.8 (standard error of the mean) mm3 for the control group, 32.3 +/- 22.6 mm3 for the hypertension group (P < 0.0005 versus control), 40.9 +/- 17.6 mm3 for the hypothermia group (P < 0.0005), 58.0 +/- 41.0 mm3 for the mannitol group (P < 0.005), and 0.9 +/- 0.9 mm3 for the triple-therapy group (P < 0.0001). The infarct volume of the triple-therapy group was smaller than that of the hypertension, hypothermia, and mannitol groups but the difference was not statistically significant. The combination of hypertension, mild hypothermia, and mannitol to protect against temporary focal ischemia provides a set of manipulations that is readily available for neurovascular procedures.

Animals↗