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D J Kwiatkowski

Publications and source records attributed to D J Kwiatkowski.

At least 91 records · Page 5Linked to original sources
PubMed1995

A phase I study of ifosfamide/carboplatin/etoposide/paclitaxel in advanced lung cancer.

A phase I study was conducted to define the maximally tolerated dose and toxicity profile of the ifosfamide/carboplatin/etoposide/paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) (ICE-T) regimen in advanced lung cancer. This chemotherapy program uses paclitaxel given as a 24-hour continuous infusion in conjunction with full-dose ICE chemotherapy with growth factor support. The dosage of paclitaxel was escalated from 75 to 225 mg/m2. Thirty-four patients have been accrued to date onto this study. Because hematologic dose-limiting toxicity was defined in terms of neutropenia and/or thrombocytopenia exceeding 7 days' duration, no patient demonstrated what was defined by the protocol as dose-limiting toxicity. Nonetheless, substantial hematologic toxicity was observed. Overall, 26% had fever and neutropenia, 56% had grade 4 neutropenia, and 26% had grade 4 thrombocytopenia. In all cases, hematologic toxicity was short term and reversible. While grade 3 and 4 myelosuppression was frequently observed, it was not dose related (in terms of paclitaxel dosage). Nonhematologic toxicity also was not dose related and, with only a few exceptions, was not clinically significant. Among 27 patients evaluable for response, 41% achieved an objective response, including 15% with a complete response. All of five patients with small cell lung cancer responded (including two with a complete response). Among 22 patients with non-small cell lung cancer, 27% achieved an objective response (also including two with a complete response). The results of this study suggest that with growth factor support, it is possible to safely administer full-dose, single-agent paclitaxel in conjunction with full-dose ICE chemotherapy. We will soon be initiating a phase II study of the ICE-T regimen using paclitaxel at 225 mg/m2 as a 24-hour continuous infusion in advanced lung cancer. We will also conduct a phase I study of ICE-T, with paclitaxel administered as a 3-hour continuous infusion.

Adult↗
PubMed1994

The human actin-regulatory protein cap G: gene structure and chromosome location.

Cap G (formerly called macrophage capping protein or gCap39) is a member of the gelsolin/villin family of actin-regulatory proteins. Unlike all other members of this family, Cap G caps the barbed ends of actin filaments, but does not sever them. This protein is half the molecular weight and contains half the number of repeat subunits (3 vs 6) of gelsolin and villin, suggesting that these two proteins may have arisen by gene duplication of the Cap G gene. To investigate this possibility we have cloned and sequenced the human Cap G gene (gene symbol CAPG). The gene is 16.6 kb in size, contains 10 exons and 9 introns, and is located on the proximal short arm of chromosome 2. The open reading frame is 6.9 kb, having 9 exons and 8 introns. This region contains 3 splice sites that are nearly identical to the human gelsolin gene, but shares only one with villin, indicating that CAPG is more closely related to gelsolin. Further comparisons of these three genes, however, indicate that the evolutionary steps resulting in human gelsolin and villin are likely to have been more complex than a simple tandem duplication of the Cap G gene.

Animals↗
PubMed1994

Tuberous sclerosis.

BACKGROUND AND DESIGN: Tuberous sclerosis (TS) is a genetic disease with prominent cutaneous and brain involvement whose clinical and molecular genetics are reviewed. OBSERVATIONS: Tuberous sclerosis is a systemic disorder (incidence one in 10,000) characterized by benign growths (hamartias and hamartomas) in multiple organ systems. Involvement of the brain can result in persistent seizures and mental retardation; skin involvement includes facial angiofibromas, subungual fibromas, hypomelanotic macules, forehead fibrous plaques, and Shagreen's patches. Approximately 60% of TS occurs as apparent sporadic cases. In families, it has autosomal dominant inheritance with high penetrance (approximately 95%), with careful clinical and radiologic evaluation. Genetic linkage analysis indicates that about half of all TS families show linkage to chromosome 9q34, and about half to chromosome 16p13. There are no distinguishing features in the two groups of families showing linkage to the two genomic regions, nor strong evidence for a third causative gene. Positional cloning efforts for both chromosomal regions have limited the region containing the gene to about 1 to 2 million bases. CONCLUSIONS: Identification of the two TS genes should illuminate the pathogenesis of TS and provide opportunities for genetic counseling, prenatal diagnosis, and therapeutic intervention.

Adult↗
PubMed1993

Suppression of tumorigenicity in simian virus 40-transformed 3T3 cells transfected with alpha-actinin cDNA.

Human cytoskeletal alpha-actinin cDNA was transfected into highly malignant simian virus 40-transformed BALB/c 3T3 (SVT2) cells that express 6-fold lower levels of alpha-actinin than nontransformed BALB/c 3T3 cells. SVT2 clones expressing various levels of alpha-actinin were isolated and their structure and tumorigenic properties were determined. Transfected SVT2 clones expressing alpha-actinin at levels found in nontumorigenic 3T3 cells displayed a flatter phenotype, a decreased ability to grow in suspension culture in soft agar, and a marked reduction in their ability to form tumors in syngeneic BALB/c mice and in athymic nude mice. Clones overexpressing alpha-actinin at the highest level (about 2-fold higher than 3T3 cells) were completely suppressed in their ability to form tumors in syngeneic BALB/c mice. The results suggest that alpha-actinin, an actin-crosslinking protein that is also localized in cell junctions, may have an effective suppressive ability on the transformed phenotype.

3T3 Cells↗
PubMed1993

Actin-binding protein (ABP-280) filamin gene (FLN) maps telomeric to the color vision locus (R/GCP) and centromeric to G6PD in Xq28.

Actin-binding protein-280 (ABP-280) is a dimeric actin filament crosslinking protein that promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins. We have mapped the ABP-280 filamin gene (FLN) to Xq28 by Southern blot analysis of somatic cell hybrid lines, by fluorescence in situ hybridization, and through identification of portions of the FLN gene within cosmids and YACs mapped to Xq28. The FLN gene is found within a 200-kb region centromeric to the G6PD locus and telomeric to DSX52 and the color vision locus.

Blotting, Southern↗
PubMed1993

A high-resolution linkage map of human 9q34.1.

A map comprising 16 distinct markers with heterozygosities of 0.61-0.92 for a 10-cM region of human 9q34.1 is presented. The map incorporates four genes and has a maximum intermarker interval of 2.1 cM. Markers were analyzed in the Venezuelan reference pedigrees and all were placed uniquely in the map with a minimum likelihood of 676:1. The map should prove useful in analysis of families segregating dystonia and tuberous sclerosis, as the DYT1 and TSC1 loci map within this region.

ABO Blood-Group System↗
PubMed1993

An index marker map of chromosome 9 provides strong evidence for positive interference.

An index marker map of chromosome 9 has been constructed using the Centre d'Etude du Polymorphisme Humain reference pedigrees. The map comprises 26 markers, with a maximum intermarker interval of 13.1 cM and only two intervals > 10 cM. Placement of all but one marker into the map was achieved with > 10,000:1 odds. The sex-equal length is 151 cM, with male length of 121 cM and female length of 185 cM. The map extends to within 2%-3% of physical length at the telomeres, and its coverage therefore is expected to be within 20-30 cM of full map length. The markers are all of the GT/CA repeat type and have average heterozygosity .77, with a range of .60-.89. The map shows both marked contraction of genetic distance relative to physical distance in the pericentromeric region and expansion in the telomeric regions. Genotypic data were carefully examined for errors by using the crossover routine of the program DATAMAN. Five new mutations were observed among 17,316 meiotic events examined. There were two double-crossover events occurring within an interval of 0-10 cM, and another eight were observed within an interval of 10-20 cM. Many of these could be due to additional mutational events in which one parental allele converted to the other by either gene conversion or random strand slippage. When there was no correction for these possible mutational events, the number of crossovers displayed by the maternal and paternal chromosomes was significantly different (P < .001) from that predicted by the Poisson distribution, which would be expected in the absence of interference. In addition, the observed crossover distribution for paternally derived chromosomes was similar to that predicted from cytogenetic chiasma frequency observations. In all, the data strongly support the occurrence of strong positive interference on human chromosome 9 and suggest that flanking markers at an interval of < or = 20 cM are generally sufficient for disease gene inheritance predictions in presymptomatic genetic counseling by linkage analysis.

Base Sequence↗