The addiction of drug companies.
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Cost-Benefit Analysis↗
Biomedical subjects
A Stone
Publications and source records attributed to A Stone.
Progressive abrogation of TGF-beta 1 and EGF growth control is associated with tumour progression in ras-transfected human keratinocytes.
This study examined the response of human keratinocytes in different stages of transformation to exogenous TGF-beta 1 and EGF as well as their receptor and growth-factor expression. Cells of the spontaneously immortalized HaCaT cell line and c-Ha-ras transfected clones (I-6, I-7, II-3, II-4) exhibited different tumorigenic potentials when transplanted to athymic mice. HaCaT- and I-6 cells were non-tumorigenic, I-7 cells formed persisting epidermal cysts (benign tumours) and II-3 and II-4 cells developed into invasive squamous-cell carcinomas. TGF-beta 1 inhibited thymidine uptake in a dose-dependent manner, a progressive decrease in response being associated with an increasing malignant potential (HaCaT greater than I-6 greater than I-7 = II-4). HaCaT-cells and ras-clones expressed TGF-beta 1 mRNA at similar levels, but cells of increasing malignant potential secreted markedly less receptor-binding TGF-beta (HaCaT greater than I-6 = I-7 greater than II-3 greater than II-4) into the culture medium. Whilst ras-transfected cells expressed fewer TGF-beta receptors than HaCaT cells, there was little difference between TGF-beta receptor number or affinity between the 4 transfected cell clones. The same was true for the TGF-beta receptor types, but Type-II receptors were expressed at lower levels by the malignant clones II-3 and II-4. When HaCaT and ras-transfected cells were investigated for their response to exogenous EGF, cells were refractory (I-7, II-4), partially stimulated (I-6) or fully stimulated (HaCaT). Cells with increasing malignant potential produced increasing amounts of endogenous TGF-alpha (II-4 = II-3 greater than I-7 = I-6 greater than HaCaT). All tumorigenic ras clones expressed higher mRNA levels than HaCaT-cells. Ras-transfected clones expressed fewer high- and low-affinity EGF receptors than HaCaT cells with a tendency toward increased numbers of high-affinity EGF receptors associated with increasing malignant potential (II-4 = II-3 greater than I-7 greater than I-6) but these changes were associated with a progressive decrease in receptor affinity. The results indicate that tumour progression in human epidermal keratinocytes transfected with c-Ha-ras is associated with a progressive abrogation of TGF-beta 1 and EGF growth control. They suggest that the increased autonomous growth potential associated with advanced stages of epithelial tumour progression can be defined more closely using a cellular profile of TGF-beta and EGF.
Cell Division↗
Thermospray high-performance liquid chromatography/mass spectrometric determination of cyclosporins.
The cyclic undecapeptides cyclosporin (Csp) A, CspD and dihydro CspC (HCspC) were analyzed by high-performance liquid chromatography/thermospray-mass spectrometry (HPLC/TSP-MS) on line with a UV detector. Positive ion partial (1000-1300 u) mass spectra of these compounds could be obtained with 1-2 pmol injected on column. Mass spectra were characterized by signals corresponding to the [M+H] ions as well as fragment ions derived from the loss of 112 (CspA and CspD) or 44, 114 and 114 + 44 (HCspC) mass units from the parent ion. The same qualitative profile was observed for negative-ion acquisition where the ions were formed by proton abstraction. The application of the technique to the characterization of CspA and its major hydroxylated and dealkylated metabolites in human blood samples is presented.
Chromatography, High Pressure Liquid↗
N-benzyl-N-lactyl dithiocarbamate treatment of mice after chronic cadmium administration.
Administration of N-benzyl-N-lactyl dithiocarbamate (BLDTC) to mice after chronic cadmium (Cd) administration evoked a prompt, dose-dependent reduction of the whole body burden; 75% of the retained Cd was mobilized and excreted after 20 i.p. injections of BLDTC at 1.0 mmol/kg/injection. This same dose regimen produced 71% and 98% reductions of the renal and hepatic Cd concentrations, respectively. There was no reduction by BLDTC of the endogenous level of any of seven other metals measured: iron, magnesium, selenium, copper, calcium, zinc, and manganese. Renal proximal tubular damage in mice which received Cd followed by BLDTC was much less than that observed in kidneys from mice which received Cd alone. Chronic Cd administration led to substantial epithelial vacuolar damage to renal distal tubules, and this process was not apparently reversed or antagonized by BLDTC treatment to the extent observed in proximal tubules.
Animals↗
The Mary Lasker Conference, on growth factors in hormone-related tumors.
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Animals↗
Hazards of handling chemotherapeutic agents known but not heeded.
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Antineoplastic Agents↗
Analysis of the responses evoked in the cutaneous circulation of one hand by heating the contralateral hand.
In 9 healthy human subjects, cutaneous red cell flux in the thenor eminence of the left hand was measured by a Laser Doppler meter, while the right hand was transferred sequentially from water at 33 degrees C, to water at 42 degrees C for 5 min, to water at 33 degrees C (first experimental run) and then to water at 42 degrees C for 2 min (second experimental run). Red cell flux increased significantly by the end of the 2nd min of heating and had increased further by the end of the 5th min. Mean arterial pressure, measured by sphygmomanometry from the left arm, had not changed at either times indicating that the changes in red cell flux reflected progressive cutaneous vasodilation. Meanwhile heart rate was significantly increased by the 5th min. By contrast, when these experiments were carried out on 8 subjects with a cuff on the right arm inflated to approximately 60 mmHg to impede venous outflow from the heated limb, red cell flux in the contralateral hand showed a significant increase by the 5th min of heating, but this was accompanied by a fall in arterial pressure and no change in heart rate. By the 5th min after release of the occlusion and while the right arm was still in warm water, there was a further increase in red cell flux in the contralateral hand, but arterial pressure was not significantly different from the original control level and heart rate was significantly increased. Occlusion per se had no effect on red cell flux.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Changes in EGF and TGE-beta receptor expression reflects differentiation of rat malignant oral keratinocytes.
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4-Nitroquinoline-1-oxide↗
Differentiation of malignant oral rat keratinocytes reflects changes in EGF and TGF-beta receptor expression but not growth factor dependence.
This study examined the characteristics of keratinocytes from 4-nitroquinoline N-oxide-treated rat oral epithelium that formed well differentiated carcinomas or spindle cell tumours when transplanted s.c. to athymic mice. Small polygonal-type cells in early culture passage gave rise to xenografts that were well differentiated carcinomas with keratin positivity and a differential reactivity with two anti-vimentin antibodies (positive Vim Dako, negative Vim 3B4). Progressive culture of the polygonal cells resulted in cells of a more stellate-like morphology which, when transplanted, formed spindle cell tumours that were keratin negative and vimentin positive (Vim Dako and Vim 3B4). The staining pattern of the xenografts was similar to that of the cultured cell derivatives. By contrast to normal oral keratinocytes which were stimulated by epidermal growth factor (EGF), the parental and xenograft-derived cells were markedly less responsive and at times refractory to EGF. Low affinity EGF receptors characterized normal keratinocytes whilst parental and xenograft-derived cells from well differentiated carcinomas and spindle cell tumours expressed diminished numbers of low and high affinity and high affinity EGF receptors respectively. Normal keratinocytes and parental tumour cells were inhibited by transforming growth factor (TGF-beta) whereas xenograft-derived cell lines from both well differentiated carcinomas and spindle cell tumours were refractory to TGF-beta. TGF-beta receptors were predominantly of high affinity although xenograft-derived cells, particularly from spindle cell tumours, expressed increased numbers of receptors which were of lower affinity. The results indicate that spindle cell tumours are a variant of well differentiated carcinomas and express an aberrant pattern of differentiation. Resistance to EGF-induced stimulation and TGF-beta-induced inhibition appears not to be an integral part of the tumour phenotype but the pattern of EGF and TGF-beta receptor expression closely follows the degree of tumour differentiation.
Animals↗
Hepatic parenchymal oxygen tension following injury and sepsis.
Hepatic blood flow and splanchnic oxygen consumption were measured in 16 injured (n = 6) or septic (n = 10) patients and compared with values in 16 normal volunteers. Sepsis and injury appeared to stimulate an increase in blood flow and oxygen utilization, with the highest levels observed in the septic group. Patients with sepsis exhibited a 72% and 60% increase in hepatic blood flow and splanchnic oxygen consumption, respectively, compared with normal volunteers. Application of these data to the Krogh-Erlang tissue model indicates that despite an increase in oxygen delivery to the splanchnic bed during sepsis, it becomes more sensitive to hypoxic/ischemic events compared with other patient groups. This is indicated by a reduced centrilobular and increased critical oxygen tension. The major factor responsible for this is the regional hypermetabolism present in sepsis. This analysis emphasizes the critical importance of maintaining oxygen transport in critically ill patients with sepsis.
Humans↗
Enhanced glycosyltransferase activity during thermotolerance development in mammalian cells.
The cellular heat shock response leads to the enhanced synthesis of a family of heat shock proteins and the development of thermotolerance. In CHO cells, however, heat shock also leads to enhanced synthesis of a 50 kD glycoprotein and elevated activity of N-acetylgalactosaminyltransferase (GalNAcT). In this study we showed increased GalNAcT activity during thermotolerance expression in all of five mammalian cell lines included in the study. However, there was no simple correlation between cellular heat sensitivity of unheated control cells and basal levels of GalNAcT activity, measured toward the same exogenous acceptor apomucin. Although GalNAcT was elevated in thermotolerant cells, GalNAcT activity itself did not exhibit thermotolerance in terms of reduced sensitivity to heat inactivation. The increase in GalNAcT activity after heating was similar in exponentially growing and plateau-phase cultures and was inhibited neither by cycloheximide nor actinomycin D. However, the inhibitors by themselves also increased GalNAcT activity in unheated control cells. Chemical inducers of thermotolerance (arsenite and diamide) increased GalNAcT activity, but the increase was modest when compared to that following hyperthermia. In addition to GalNAcT, two other glycosyltransferases with specificity for O-glycans, alpha 1,2-fucosyltransferase and alpha 2,6-sialyltransferase, also showed increased activity after hyperthermia and during thermotolerance development. Together with previously published data, these results support the hypothesis that heat-induced activation of O-glycan-specific glycosyltransferases plays a physiological role in the cellular heat shock response and in thermotolerance development.
Animals↗
The behaviour of human oral squamous cell carcinoma in cell culture.
This study examined the initial behaviour of 48 human oral squamous cell carcinomas (SCC) in cell culture. The early outcome of these cultures (contamination, absence of cell growth, epithelial cell senescence/fibroblast overgrowth, extended keratinocyte growth) did not reflect the clinical characteristics of the tumours of origin. Four new human oral SCC cell lines were characterized more extensively. Each cell line was immortal, 3T3-independent, and expressed low degrees of anchorage independence (CFE less than 4 per cent). Two of the four cell lines were tumorigenic in athymic mice. All of the cell lines expressed keratin intermediate filaments and two showed weak co-expression of vimentin. A wide range of keratins were expressed by the tumour xenografts; cornified keratins (K1, K10) were only expressed in the absence of K19 and vimentin, and vice versa. The nuclear:cytoplasmic ratio and the degree of serum independence correlated with each other and with the STNMP clinical grading of the tumours of origin.
Adult↗
Analysis of vascular responses evoked in the cutaneous circulation of one hand by cooling the contralateral hand.
In 11 healthy human subjects, cutaneous red cell flux in the thenar eminence of the left hand was measured by a Laser Doppler meter, while the right hand was transferred sequentially from water at 33 degrees C, to water at 16 degrees C for 5 min, to water at 33 degrees C (1st experimental run) and then to water at 16 degrees C for 2 min (2nd experimental run). Red cell flux decreased from 33 +/- 10 (mean +/- SEM) to 19 +/- 5* perfusion units (pu) by the end of the 2nd min of cooling (* P less than 0.05 paired t-test), but had returned to 27 +/- 8 pu by the 5th min. Arterial pressure, measured by sphygmomanometry from the left arm at the 5th min (1st run) and 2nd min (2nd run) did not change, indicating the changes in red cell flux reflected changes in cutaneous vascular resistance. By contrast, when these experiments were repeated with a cuff on the right arm inflated to 56-62 mmHg to impede venous outflow from the cooled limb, there were no changes in red cell flux in the contralateral hand, nor in arterial pressure. Occlusion per se had no effect on red cell flux. Thus, we propose that cooling one hand evokes a short-lasting reflex constriction in the cutaneous circulation of the contralateral hand which is mainly mediated by core thermoreceptors affected by a reduction in blood temperature, rather than by peripheral thermoreceptors in the cooled hand. The contrast between this proposal and views based on earlier studies is discussed.
Adult↗
Tumour progression in experimental oral carcinogenesis is associated with changes in EGF and TGF-beta receptor expression and altered responses to these growth factors.
This study examined the characteristics of premalignant oral epithelial cell lines derived from non-invasive palatal and lingual mucosa of rats painted with the carcinogen 4-nitroquinoline N-oxide (4NQO) in vivo. In contrast to normal keratinocytes, premalignant epithelial cells had an extended life span, were independent of 3T3 fibroblast support, and expressed variable anchorage independence in gel culture and tumorigenicity in athymic mice. The expression of these functional phenotypes did not correlate with the duration of 4NQO treatment. Keratinocytes from 4NQO-treated tissues predominantly had fewer epidermal growth factor (EGF) receptors than normal controls. The expression of high-affinity EGF receptors paralleled the emergence of the anchorage-independent phenotype and was markedly elevated in tumorigenic cell lines. Cell lines with an extended life span expressed fewer transforming growth factor beta 1 (TGF-beta) receptors than their normal counterparts though the loss of these receptors appeared to be unrelated to either anchorage independence or tumorigenicity. Normal keratinocytes were stimulated and inhibited, in a dose-dependent manner, by EGF and TGF-beta respectively. By contrast, a cell line that was immortal, anchorage dependent and non-tumorigenic showed reduced sensitivity to stimulation by EGF and was inhibited only by high concentrations of TGF-beta. Cells that were immortal, anchorage independent and tumorigenic, however, were refractory to EGF and were inhibited only by high concentrations of TGF-beta. There was no correlation between the expression of EGF or TGF-beta cell surface receptors and the response to ligand binding. The results show that tumour progression in rat oral epithelial cells is associated with a progressive independence of growth factor control. The number and distribution of EGF and TGF-beta receptors may be useful markers in more closely defining the stages of epithelial tumour progression.
4-Nitroquinoline-1-oxide↗
The American Cancer Society's strategic plan for dietary change.
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American Cancer Society↗
The role of endoscopic retrograde pancreatography (ERP) in blunt abdominal trauma.
The diagnosis of pancreatic injury is often difficult because it lies retroperitoneally in a protected area. Delayed diagnosis and treatment of blunt pancreatic trauma can result in significant morbidity and mortality. Endoscopic Retrograde Pancreatography (ERP) is infrequently used in the diagnosis of pancreatic injury. We reviewed our experience with the use of ERP in patients with blunt pancreatic injury. Two stable patients with traumatic pancreatitis underwent ERP shortly after injury. CT scans revealed a transverse fracture of the distal pancrease in one and fluid accumulation in the other around the pancreas extending to the right kidney and left hepatic lobe. The absence of ductal disruption on ERP allowed nonoperative management of the pancreatitis. Resolution was documented by the absence of symptoms on regular oral intake, normal serum amylase levels, and normal follow-up CT scans. A third patient with persistent fistulae three months postinjury underwent preoperative ERP revealing ductal obstruction. This facilitated the planning of a distal pancreatectomy and subsequently the fistulae healed. A fourth patient underwent an exploratory laparotomy on the basis of clinical and CT scan findings that could have been circumvented with preoperative ERP. ERP in selected patients allows nonoperative treatment in the absence of ductal injury or earlier operative treatment of ductal injury. It also aids the treatment of late complications by delineating ductal anatomy.
Adult↗
Stage, transfer, and academic achievement in dialect-speaking Hawaiian adolescents.
The study reported here is concerned with certain dialect-speaking groups in the United States who do poorly in high school while giving their teachers an impression that they have great intellectual ability and doing well on formal operational tasks. We examined the relation between stage of cognitive development, transfer ability, production ability in Standard English, and school achievement among a sample of high school students in rural Hawaii, speakers of Hawaiian Creole English. A path analysis suggests that transfer ability is the missing ingredient in school performance, and that a habit of active encoding in the classroom, in turn, facilitates transfer.
Achievement↗
Effect of hyperthermia on activity of three glycosyltransferases in Chinese hamster ovary cells.
We measured activities of three glycosyltransferases at various times during heat-induced thermotolerance development. Glycosyltransferases are normally located in the Golgi apparatus and catalyze cellular glycosylation reactions. UDP-Gal:N-acetylglucosamine beta 1,4-galactosyltransferase (beta 1,4-GalT) is known to participate in the formation of N-linked glycoproteins; when compared to cell survival, beta 1,4-GalT activity was significantly more heat resistant (50% loss of activity: 80 min, 45 degrees C) and showed little elevation at a time when thermotolerance was fully expressed. However, beta 1,4-GalT activity increased twofold by 24-h postheating when thermotolerance had begun to decay. Activity of beta 1,4-GalT was compared with glycosyltransferase activities that are considered to be specific for O-linked glycoproteins: UDP-Gal:N-acetylgalactosamine-beta 1,3-galactosyltransferase (beta 1,3-GalT), and UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase (Gal-NAcT). Heat-inactivation experiments with heating times up to 60 min at 45 degrees C failed to reduce either activity below that of unheated control cells. Instead both beta 1,3-GalT and GalNAcT activity increased approximately twofold immediately after 10 min at 45 degrees C. Activity of beta 1,3-GalT rapidly decreased with time after heating and returned to control levels by 6-h postheating. In contrast, GalNAcT activity continued to increase with time after 10 min at 45 degrees C, and was 4.5-fold above unheated controls by 6-h postheating. GalNAcT activity returned to control levels 24- to 48-h postheating. A comparison with the cellular survival response showed that GalNAcT activity preceded thermotolerance expression by 2-4 h and also decayed more rapidly than heat resistance in thermotolerant cells. These data, together with other published results, suggest that expression of thermotolerance may be associated with enhanced glycosylation of intracellular proteins.
Animals↗