Biomedical subjects

D Small

Publications and source records attributed to D Small.

At least 37 records · Page 2Linked to original sources

PubMed2000

Constitutive activation of FLT3 stimulates multiple intracellular signal transducers and results in transformation.

Aberrant expression of FLT3 has been found in most cases of B-lineage ALL and AML, and subsets of T cell ALL, CML in blast crisis and CLL. In 20% of patients with AML the receptor has small internal tandem duplications of the juxtamembrane region which appear to contitutively activate the receptor. To investigate whether FLT3 activation could play a role in leukemia, we generated a constitutively activated FLT3 by fusing its cytoplasmic domain to the helix-loop-helix domain of TEL in analogy to the fusion that occurs with TEL-PDGFR in CMML. In vitro translation assays demonstrated oligomerization and intrinsic tyrosine kinase activity of the TEL-FLT3 chimeric receptor. Constitutively activated TEL-FLT3 conferred IL-3 independence and long-term proliferation to transfected Ba/F3 cells. Immunoblot analyses showed that JAK 2, STAT 3, STAT 5a, STAT 5b and CBL were tyrosine-phosphorylated in TEL-FLT3 expressing Ba/F3 cells in the absence of IL-3. These data suggest a possible role for the JAK/STAT pathway in FLT3 signaling. Transplantation of TEL-FLT3 expressing Ba/F3 cells into syngeneic mice caused mortality in all mice by 3 weeks after injection. Histopathologic analysis demonstrated a massive infiltration of mononuclear cells in the liver, spleen and bone marrow. The mimicking of naturally occurring TEL fusions provides an approach to assess aspects of the biology of activated FLT3, or other receptor-type tyrosine kinases (RTKs) in leukemic transformation.

Animals↗

PubMed2000

Comparison of tear sampling techniques for pharmacokinetics analysis: ofloxacin concentrations in rabbit tears after sampling with schirmer tear strips, capillary tubes, or surgical sponges.

This study compared the precision and accuracy of 4 tear sampling methods. In vivo, albino rabbits were treated with single bilateral eye drops ofofloxacin 0.3% solution, 3 hr after which tear samples were collected using capillary tubes (CT), surgical sponges (SS), or tear strips for 15 sec (15sTS) or 60 sec (60sTS). In vitro, CT, SS, and tear strips were spiked with known volumes of ofloxacin solution in order to assess the bioanalytical accuracy of each technique. Ofloxacin levels were quantified by HPLC in all samples. Results showed that tear volumes and ofloxacin masses sampled in vivo depended on sampling method. Tear volume followed the rank order 60sTS > 15sTS > SS > CT. The volume collected by 60sTS exceeded precorneal tear volume. Ofloxacin mass followed the order 60sTS approximately 15sTS > SS > CT. Tear concentrations (mean +/- SD; N = 12) were 3.28 +/- 3.76 microg/g for 60sTS, 10.3 +/- 10.0 microg/g for 15sTS, 9.75 +/- 8.04 microg/g for SS, and 5.83 +/- 3.35 microg/g for CT. In vitro, SS, 15sTS, and 60sTS yielded accuracies of 103-107% and coefficients of variation (CV) < 9%. CT was only 85% accurate with a CV of 31%, indicating incomplete extraction during analysis. We concluded from this study that: 1) rabbit tear sampling by SS was rapid, easy, accurate, precise, and easily analyzable; 2) sampling by CT or 15sTS was accurate, but may require aggressive extraction (for CT) or be affected by tear flow rate (for 15sTS); and 3) tear sampling by 60sTS underestimated actual tear concentrations.

Animals↗

PubMed1999

SZF1: a novel KRAB-zinc finger gene expressed in CD34+ stem/progenitor cells.

The identification and study of genes expressed in hematopoietic stem/progenitor cells should further our understanding of hematopoiesis. Transcription factors in particular are likely to play important roles in maintaining the set of genes that define the stem/progenitor cell. We report here the identification of a putative KRAB-zinc finger gene (SZF1) from a cDNA library prepared from human bone marrow CD34+ cells. Characterization of SZF1 implicates its role in hematopoiesis. The predicted protein contains a highly conserved KRAB domain at the NH2 terminus and four zinc fingers of the C2H2 type at the COOH terminus. Two alternatively spliced products of SZF1 were isolated, which predict proteins of 421 (SZF1-1) and 361 (SZF1-2) amino acids, differing from each other only at the carboxy terminus. The two transcripts of SZF1 have different expression patterns. SZF1-2 is ubiquitously expressed, as indicated by Northern blot, RNase protection, and reverse transcriptase polymerase chain reaction. SZF1-1 expression, in contrast, was detected only in CD34+ cells. We recently isolated the promoter region for the stem/progenitor cell expressed FLT3/FLK-2/STK-1 gene and used this region to generate a reporter construct to test the effect of SZF1 expression. Cotransfection of the reporter construct with SZF1 constructs showed that SZF1-2 repressed transcription three- to fourfold, whereas SZF1-1 showed a lower level of repression. The expression pattern of SZF1 transcripts and the transcriptional repression of a CD34+-specific promoter demonstrate a possible role for SZF1 in hematopoietic stem/progenitor cell differentiation.

Alternative Splicing↗

PubMed1998

Comparison of flow cytometry and laser scanning cytometry for the intracellular evaluation of adenoviral infectivity and p53 protein expression in gene therapy.

The determination of recombinant adenoviral (rAd) infectivity and p53 protein expression is important for the evaluation of rAd vectors containing the p53 gene (rAd-CMV-p53) for gene therapy. We have previously reported that rAd5-CMV-p53 vectors can be assessed for infectivity and concomitant p53 protein expression in single- and two-color assays using intracellular staining methodology and flow cytometric analysis. We have compared the flow cytometry-based assays for rAd infectivity (hexon protein) and p53 protein expression with the new slide-based laser scanning cytometry (LSC). We report that LSC analysis of rAd-CMV-p53-infected human 293 cells correlated very well with flow cytometric analysis across a wide range of viral infectivity for both infectivity assessment (r2 = 0.97) and p53 protein expression (r2 = 0.96). Absolute values for infective titer and p53 protein expression titer from an rAd5-CMV-p53 production batch were similar and within experimental error with the two different analytical methods. Finally, bivariate format analysis of rAd-CMV-p53-infected cells revealed comparable results between LSC and flow cytometric analysis. LSC is a reliable and useful tool for the intracellular staining for adenoviral hexon protein expression for determining infectivity and for p53 protein expression from an expressed p53 transgene.

Adenoviruses, Human↗

PubMed1998

Flt3high and Flt3low CD34+ progenitor cells isolated from human bone marrow are functionally distinct.

We generated monoclonal antibodies against the human Flt3 receptor and used them to study the characteristics of normal human bone marrow cells resolved based on Flt3 expression. Human CD34+ or CD34+lin- marrow cells were sorted into two populations: cells expressing high levels of Flt3 receptor (Flt3high) and cells with little or no expression of Flt3 receptor (Flt3low). Flt3 receptor was detected on a subset of CD34+CD38- marrow cells, as well as on CD34+CD19+ B lymphoid progenitors and CD34+CD14+CD64+ monocytic precursors. Flt3 receptor was also present on more mature CD34-CD14+ monocytes. In colony-forming assays, Flt3high cells gave rise mainly to colony-forming unit-granulocyte-macrophage (CFU-GM) colonies, whereas Flt3low cells produced mostly burst-forming unit-erythroid colonies. There was no difference in the number of multilineage CFU-Mix colonies between the two cell fractions. Cell cycle analysis showed that a large number of the Flt3low cells were in the G0 phase of the cell cycle, whereas Flt3high cells were predominantly in G1. Cell numbers in the suspension cultures initiated with Flt3high cells were maintained in the presence of Flt3 ligand (FL) alone, and increased in response to FL plus kit ligand (KL). In contrast, cell numbers in the suspension cultures started with Flt3low cells did not increase in the presence of FL, or FL plus KL. Upregulation of Flt3 receptor on Flt3low cells was not detected during suspension culture. CD14+ monocytes were the major cell type generated from CD34+lin-Flt3high cells in liquid suspension culture, whereas cells generated from CD34+lin-Flt3low cells were mainly CD71+GlycA+ erythroid cells. These results show clear functional differences between CD34+Flt3high and CD34+Flt3low cells and may have implications concerning the in vitro expansion of human hematopoietic progenitor cells.

Adult↗

PubMed1998

Frequent detection of tumor cells in hematopoietic grafts in neuroblastoma and Ewing's sarcoma.

Many poor-risk neuroblastomas and tumours of the Ewing's sarcoma family (ET) recur despite autologous transplants. Recurrence may be due to tumor cells contained in the BM harvests or PBSC harvests. The objectives of this prospective study were to: (1) determine the incidence and degree of tumor cell contamination in paired BM and PBSC harvests; and (2) determine the efficacy of tumor cell purging by immunomagnetic CD34+ cell selection. 198 samples from 11 consecutive patients with neuroblastoma or Ewing's sarcoma were analyzed. We assayed tumor contamination by RT-PCR assay for PGP 9.5, plus immunohistochemistry for neuroblastoma-specific antigens (the latter in neuroblastoma only). None of these patients had tumor cells detected in their BM by clinical histology immediately before BM or PBSC harvests. However, 82% of PBSC and 89% of backup BM harvests were contaminated with tumor by RT-PCR and/or immunocytochemistry assays. Unselected PBSC and BM harvests contained similar quantities of tumor cells (median, approximately 200000 cells). Cyclophosphamide plus G-CSF mobilization did not affect the incidence or level of contamination in PBSC harvests, as compared to blood obtained before mobilization. Immunomagnetic CD34+ cell selection depleted tumor cells by a median of 3.0 logs for PBSC, and 2.6 logs for BM harvests.

Adolescent↗

PubMed1998

An ovarian teratoma in a cat.

A 5-month-old, intact female, domestic shorthaired cat was presented for evaluation of abdominal distension. Abdominal radiographs revealed a midabdominal mass that contained multiple, irregular, mineralized opacities. The mass was surgically removed, and an ovariohysterectomy performed. The mass was located at the tip of the left uterine horn and was covered partially by haired skin. Histologically, the mass was diagnosed as a mature ovarian teratoma based on the presence of well-differentiated somatic structures derived from three primary embryonal germ-cell layers. Germ-cell tumor classification and feline ovarian teratomas are reviewed.

Animals↗

PubMed1998

Evaluation of right ventricular systolic pressure during incremental exercise by Doppler echocardiography in adults with atrial septal defect.

STUDY OBJECTIVES: Pulmonary hypertension is the most important complication in patients with atrial septal defect (ASD), but its role in limiting exercise has not been examined. This study sought to evaluate exercise performance in adults with ASD and determine the contribution of elevated pulmonary artery pressure in limiting exercise capacity. DESIGN: We used Doppler echocardiography during exercise in 10 adults (aged 34 to 70 years) with isolated ASD (New York Heart Association class I, II) and an equal number of matched control subjects. Incremental exercise was performed on an electrically braked upright cycle ergometer. Expired gases and VE were measured breath-by-breath. Two-dimensional and Doppler echocardiographic images were obtained at rest prior to exercise to determine ASD size, stroke volume (SV), shunt ratio (Qp:Qs), right ventricular outflow tract (RVOT) size, and right ventricular systolic pressure at rest (RVSPr). Doppler echocardiography was repeated at peak exercise to measure right ventricular systolic pressure during exercise (RVSPex). RESULTS: Resting echocardiography revealed that RVOT was larger (21+/-4 vs 35+/-8 mm, mean+/-SD; p=0.0009) and RVSPr tended to be higher (17+/-8 vs 31+/-8 mm Hg; p=0.08) in ASD; however, left ventricular SV was not different (64+/-23 vs 58+/-23 mL; p>0.05), compared with control subjects. Despite normal resting left ventricular function, ASD patients had a significant reduction in maximum oxygen uptake (VO2max) (22.9+/-5.4 vs 17.3+/-4.2 mL/kg/min; p=0.005). RVSPex was higher (19+/-8 vs 51+/-10 mm Hg; p=0.001) and the mean RVSP-VO2 slope (1+/-2 vs 18+/-3 mm Hg/L/min; p=0.003) and intercept (17+/-4 vs 27+/-4 mm Hg; p=0.05) were higher in the ASD group. VO2max correlated inversely with both RVSPr (r=-0.69; p=0.007) and RVSPex (r=-0.67; p=0.01). CONCLUSION: These findings suggest that adults with ASD have reduced exercise performance, which may be associated with an abnormal increase in pulmonary artery pressure during exercise.

Adult↗

PubMed1998

Bilingual professionals in community mental health services.

OBJECTIVE: This paper presents results from research that explored the roles of bilingual professionals in community mental health services in the Sydney metropolitan area of New South Wales. There were two main objectives to the research: (i) to identify and describe the roles of bilingual professionals that are important in improving the quality of community mental health services for clients from non-English-speaking backgrounds (NESB); and (ii) to identify and describe the factors that facilitate and inhibit the conduct of these roles. METHOD: Data collection involved indepth interviews with bilingual professionals and team leaders in community mental health services and various other community health services; and various staff responsible for policy and service development with regard to cultural diversity. RESULTS: Bilingual mental health workers were found to have at least four critical roles. These were (i) direct clinical service provision to NESB clients; (ii) mental health promotion and community development; (iii) cultural consultancy; and (iv) service development. Respondents reported that the latter three roles were seriously underdeveloped compared to the clinical service provision role. CONCLUSIONS: It is critical that service managers implement strategies to make better use of the linguistic and cultural skills of bilingual professionals. In addition to their role in clinical service provision ways must be found to facilitate the community-focused, cultural consultancy and service development roles of bilingual professionals employed in mental health services.

Case Management↗

PubMed1997

International differences in epidemiology of lung adenocarcinoma.

In Europe, the squamous cell carcinoma is the most frequent non-small cell lung cancer (NSCLC) subtype and until now, no increase in incidence of lung adenocarcinoma (ADC) has been described (except in the Netherlands), in contrast to North America where ADC predominates. Our aim was to compare the percentage of ADC in Montreal (MTL), Canada, with that in Strasbourg (STBG), France. We prospectively identified patients with NSCLC in MTL and in STBG over an 8-month period and described the distribution of NSCLC by sex, age, subtype and smoking history. A total of 172 patients in MTL and 166 in STBG were identified. The male/female ratio was significantly different in STBG (12:1) and in MTL (2:1). The percentage of ADC was significantly higher in MTL (40%) than in STBG (30%). This difference is partly due to the higher number of women with NSCLC in Montreal combined with the predominance of ADC in women. The proportion of ADC decreased with age in STBG, but was similar in each age category in MTL. In STBG, most women with NSCLC had never smoked (69%), in contrast to MTL where only 16% of women had never smoked. In conclusion, ADC is more frequent in MTL than in STBG. This is partly due to the higher number of women with NSCLC in MTL combined with the predominance of ADC in women. The greatest proportion of ADC subtype in the youngest cohorts of men in STBG suggests that ADC may be on the rise in this city.

Adenocarcinoma↗

PubMed1997

Metabolic deesterification of tazarotene in human blood and rat and human liver microsomes.

Tazarotene is a novel acetylenic retinoid for the treatment of psoriasis and acne. We examined (1) the hydrolysis of tazarotene in blood from Japanese-American and Caucasian subjects, (2) the esterases responsible for this hydrolysis in human blood, and (3) tazarotene hydrolysis in rat and human liver microsomes. Tazarotene hydrolysis and enzyme inhibition were assessed by monitoring the disappearance of tazarotene and the appearance of its primary metabolite tazarotenic acid by HPLC. In blood, tazarotene was converted mainly to tazarotenic acid via first-order kinetics, and there was no statistically significant difference in the hydrolytic (metabolic) rate of tazarotene in uninhibited Japanese-American and Caucasian blood. Physostigmine (a cholinesterase inhibitor), bis(p-nitrophenyl) phosphate (a carboxylesterase inhibitor), and EDTA (an aromatic esterase inhibitor) did not significantly affect tazarotene hydrolysis in blood. Paraoxon, an inhibitor of all serine esterases including cholinesterase and carboxylesterase, decreased the hydrolysis of tazarotene to tazarotenic acid by 95% in both blood and liver microsomes. In conclusion, blood and liver esterases play a significant role in the hydrolysis of tazarotene to tazarotenic acid, and paraoxon-inhibitable forms of esterases are involved in this hydrolysis in humans.

Animals↗

PubMed1997

Evidence that the early loss of membrane protein kinase C is a necessary step in the excitatory amino acid-induced death of primary cortical neurons.

A rapid loss of protein kinase C (PKC) activity is a prognostic feature of the lethal damage inflicted on neurons by cerebral ischemia in vivo and by hypoxic and excitotoxic insults in vitro. However, it is not known if this inactivation of PKC is incidental or is an essential part of the neurodegenerative process driven by such insults. To address this issue, the effects of glutamate on PKC activity and neurotoxicity were studied in immature [8 days in vitro (DIV)] and mature (15-20 DIV) embryonic day 18 rat cortical neuronal cultures. Exposing 16 DIV neurons to as little as 20-50 microM glutamate for 15 min was neurotoxic and induced a rapid (approximately 1-2 h) Ca(2+)-dependent inactivation of membrane PKC. By contrast, neurons 8 DIV were resistant to > 800 microM glutamate, and no evidence of PKC inactivation was observed. Reverse transcription-polymerase chain reaction analysis of NMDA and AMPA receptor subtypes and fluorometric intracellular Ca2- concentration measurements of the effects of NMDA, AMPA, kainate, and metabotropic glutamate receptor activation demonstrated that this striking difference in vulnerability was not due to an absence of functional glutamate receptors on neurons 8 DIV. However, 8 DIV neurons became highly vulnerable to low (< 20 microM) concentrations of glutamate when PKC activity was inhibited by 50 nM staurosporine, 1 microM calphostin C, 5 microM chelerythrine, or chronic exposure to 100 nM PMA. A 15-min coapplication of 50 nM staurosporine with glutamate, NMDA, AMPA, or kainate killed between 50 and 80% of 8 DIV cells within the ensuing 24 h. Moreover, cell death was observed in these cells even when PKC inactivation was delayed up to 4 h after glutamate removal. The evidence indicates that a loss of PKC activity is an essential element of the excitotoxic death of neurons 8 DIV and that cellular event(s) responsible for linking glutamate-mediated Ca2+ influx to PKC inactivation in vulnerable neurons 16 DIV are undeveloped in resistant cells 8 DIV. These results also suggest that the loss of neuronal PKC activity observed in cerebral ischemia may indeed be an important part of the neurodegenerative process. The 8 DIV/16 DIV cortical cell model may prove to be valuable in discerning those intracellular signaling events critical to glutamate-mediated neuronal death.

Alkaloids↗

PubMed1997

The increasing incidence of lung adenocarcinoma: reality or artefact? A review of the epidemiology of lung adenocarcinoma.

Lung adenocarcinoma is the most common cell type in females (smokers or non-smokers) and in non-smoking males. Its incidence has been increasing in younger cohorts of males and females until very recent years. Changes in classification and in pathological techniques account for some of this increase. In females and non-smoker males, the increase could be partly due to a detection bias in former studies. Nevertheless, successive cohorts over time seem more likely to develop adenocarcinoma and less likely to develop squamous cell carcinoma. These differences between birth cohorts suggest that the increasing incidence of adenocarcinoma is not only due to changes in pathological diagnosis. Geographical differences are also observed: in Europe, the squamous cell type still predominates and an increase in incidence of adenocarcinoma has only been reported in the Netherlands. In Asia, in the 1960s and 1970s, the proportion of adenocarcinoma was higher than in North America or Europe and seems to be increasing. To what extent these differences are due to differences. In establishing diagnosis remains unknown. Despite these biases in temporal and geographical trends detailed in this review, there has probably been a true increase in incidence of adenocarcinoma. An explanation for this should be sought in studies on detailed smoking history and passive smoking exposure, occupational exposure, diet and cooking, pollution and other environmental factors.

Adenocarcinoma↗

PubMed1997

Recombinant 52 kDa Ro(SSA) ELISA detects autoantibodies in Sjögren's syndrome sera that go undetected by conventional serologic assays.

OBJECTIVE: To determine the utility of a recombinant 52 kDa Ro(SSA) ELISA for detecting Ro autoantibodies in Sjögren's syndrome (SS) sera. METHODS: Several different groups of SS sera previously tested for Ro and La(SSB) autoantibodies in clinical diagnostic labs were tested by ELISA with a recombinant human 52 kDa Ro fusion protein. RESULTS: Five of 18 primary SS sera (28%) that had undetectable Ro and La autoantibodies by conventional immunodiffusion (ID) or ELISA in clinical diagnostic laboratories had significant reactivity with a recombinant 52 kDa Ro (r52) ELISA. On repeat testing these 5 sera were again negative for Ro and La antibodies by ELISA with purified 60 kDa Ro and La antigens, but 3 of these sera were reactive with r52 by immunoblot, and immunoprecipitated a 52 kDa protein from human cell extracts. Twelve of 12 primary SS sera that had detectable Ro autoantibodies by ID also reacted with the r52 ELISA, whereas none of 11 normal sera and only one of 27 ID-defined Ro negative systemic lupus erythematosus sera did. Eleven of 28 sera from patients with suspected SS were Ro positive by ID and 60 kDa Ro ELISA. All 11 were also Ro positive by the r52 ELISA. Two of the 28 suspected SS sera were Ro positive by the r52 Ro ELISA, but were Ro and La negative by ID and 60 kDa Ro and La ELISA. CONCLUSION: Anti-52 kDa Ro autoantibodies are frequently present in primary SS sera, but may go undetected by commonly used Ro serologic assays. Our r52 ELISA is more sensitive in detecting Ro antibodies in SS than conventional ID and 60 kDA Ro ELISA.

Antibody Specificity↗

PubMed1997

JAK3: expression and mapping to chromosome 19p12-13.1.

We cloned JAK3, the most recently described member of the JAK family of intracellular tyrosine kinases, from normal human CD34+ RNA. JAK3 is involved in the signal transduction pathways of the IL-2, IL-4, IL7, IL-9, and IL-15 receptors by association with their common gamma-chain (gamma[c]). JAK3 is critical to lymphoid development, as recently established by the linking of mutations in JAK3 to a subgroup of patients with SCID and the generation of JAK3-null mice with severe disruptions in normal lymphocytic development. However, JAK3 expression is not restricted to the lymphocytic compartment of bone marrow but is found in a wide range of tissues of both hematopoietic and non-hematopoietic origin. Northern blot analysis indicates that JAK3 is also expressed in adult placenta, lung, liver, kidney, pancreas, spleen, thymus, ovary, and small intestine. RNAse protection assays and RT-PCR indicate that JAK3 is expressed in a variety of leukemic-derived hematopoietic cell lines with myeloid and/or lymphoid phenotypes. In normal human bone marrow, JAK3 is expressed in the CD34+/lineage- fraction, which is highly enriched in hematopoietic stem/progenitor cells. In addition, we found a splice variant of JAK3 which is formed by the splicing of JAK3 with exon II of the leydig insulin-like (LEY I-L) hormone. RT-PCR and RNAse protection assay analyses indicate that this variant (termed I-JAK3) is normally expressed in almost all hematopoietic and non-hematopoietic tissues shown to express JAK3. Using fluorescence in situ hybridization we have localized JAK3 to 19p12-13.1, the same region of chromosome 19 to which the LEY I-L hormone maps (19p12-13.2).

Adult↗

PubMed1996

Study of potency, kinetics of block and toxicity of NMDA receptor antagonists using fura-2.

NMDA receptor antagonists reduced NMDA-triggered increases in [Ca2+]i measured by fura-2 and showed qualitative differences in the potency and kinetics of block. High potency antagonists produced a slow block which allowed an initial increase in [Ca2+]i that was greater than the steady-state level, while compounds with moderate to low potency produced a rapid block that was at steady-state from the first measurement. The more potent antagonists showed the slowest unblocking rates. Using this simple method, novel NMDA antagonists can be screened to ascertain potency, kinetics of block and relative toxicity, prior to animal testing.

Animals↗

PubMed1996

Treatment of small cell lung carcinoma in the elderly.

BACKGROUND: The number of elderly people with small cell lung carcinoma (SCLC) is increasing and currently nearly 25% are older than 70 years. Elderly patients may not tolerate intensive therapy and, therefore, often do not receive such treatment. Additionally, age may be an independent predictor for response and survival. We compared the investigation, staging procedure, and management of patients less than 60 years, 60 to 69, and older than 70 years who were diagnosed with SCLC between 1985 and 1991. We hypothesized that elderly patients were investigated and treated less aggressively, and that their outcome was poorer than that of younger patients with SCLC. METHODS: Information on weight loss, performance status, coexisting disease, staging investigations, and treatment was recorded. Treatment was categorized as optimal or suboptimal using predetermined criteria, and correlated with patient age. Toxicity grade, response to treatment, and survival were noted. RESULTS: There were no differences among the 3 age groups with respect to disease stage, and weight loss, although poorer performance status and comorbidity were more common in those patients older than 70 years. Elderly patients were investigated and treated less aggressively than the 2 younger patient groups. The oldest group received smaller chemotherapy dosage, fewer cycles, and had more dose reductions compared to the younger patients. Only 1 of 81 elderly patients was enrolled on an experimental protocol as compared with 19% and 28% of the younger patient groups. Furthermore, elderly patients had the highest frequency of supportive care alone. There was a significant relationship between advanced age and suboptimal treatment, with those older than 70 years having an odds ratio (OR) of 0.30 (95% confidence interval (CI) 0.15-0.61), for having received optimal treatment. Despite this, survival was similar for younger and older groups of patients (OR 0.89, CI 0.6-1.3). CONCLUSIONS: Elderly patients had poorer pre-treatment performance status, greater comorbidity, were more likely to have suboptimal therapy and were almost never entered into clinical trials. Despite this their survival did not differ from that of younger patients with SCLC. Randomized trials of treatment, with assessment of quality of life, are necessary to determine the effect of modified regimens for elderly patients with SCLC.

Aged↗

PubMed1996

Tnk1: a novel intracellular tyrosine kinase gene isolated from human umbilical cord blood CD34+/Lin-/CD38- stem/progenitor cells.

Degenerate PCR was employed to identify novel tyrosine kinase genes from an enriched population of human umbilical cord blood hematopoietic stem/progenitor cells. One novel tyrosine kinase gene, designated Tnk1, was cloned. The sequence of the complete Tnk1 coding region predicts a 72 kD protein. Comparison of Tnk1 to available sequences in protein databases reveals that it is most homologous to Ack, an intracellular tyrosine kinase which associates with the GTP-bound form of p21cdc42Hs. Like Ack, Tnk1 consists of an N-terminal kinase domain, a putative SH3 domain immediately C-terminal to the kinase domain, and a proline-rich C-terminal region. Analysis of Tnk1 mRNA expression demonstrates that Tnk1 is expressed in all cord blood, bone marrow and adult blood sub-populations, as well as in most of the leukemia cell lines examined (16 of 20). Hybridization to fetal multi-tissue Northern blots detected several different Tnk1 transcripts in all fetal tissues examined. In contrast, a single Tnk1 transcript was detected in only five of 16 adult tissues examined (prostate, testis, ovary, small intestine and colon). Fluorescence in situ hybridization (FISH) analysis of metaphase chromosomes localized the Tnk1 gene to the short arm of chromosome 17 (17p13.1), near the p53 locus. Thus, Tnk1 is a novel tyrosine kinase that may be involved in signalling pathways utilized broadly during fetal development, more selectively in adult tissues and in cell of the lymphohematopoietic system.

ADP-ribosyl Cyclase↗