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PubMed1976

Effect of a large dose of thyrotrophin releasing factor on pituitary and thyroid function in patients with Parkinsonism.

Thyrotrophin releasing factor (TRF) was given intravenously in doses of 0-5 mg and 20 mg to six patients with Parkinsonism treated with L-dopa. Plasma thyrotrophin (TSH), prolactin, lutenizing hormone (LH), follicle stimulating hormone (FSH), thyroxine (T4) and triiodothyronine (T3) were measured before and after TRF infusion. The observation that FSH and LH did not change in response to either dose of TRF confirmed specificity of the effects TRF for certain anterior pituitary functions. The plasma TSH and prolactin levels achieved after 20 mg TRF were considerably greater and were maintained longer than those after 0-5 mg TRF. However, despite a seven fold increase in the overall TSH response, the T4 and T3 responses to 20 mg TRF were not significantly greater than those to 0-5 mg TRF. The explanation for this discrepancy between immunoreactive TSH levels and apparent biologic effect is unclear.

Adult↗
PubMed2006

Reduced telomere length in rheumatoid arthritis is independent of disease activity and duration.

BACKGROUND: Rheumatoid arthritis (RA) is associated with reduced lifespan and shortened telomere length in lymphocytes, but the mechanism underlying this is unclear. Telomere loss in white blood cells (WBC) is accelerated by oxidative stress and inflammation in vitro. It was postulated that the accelerated WBC telomere shortening in RA occurs as a result of exposure to chronic inflammation. OBJECTIVES: To measure telomere terminal restriction fragment (TRF) length in a large cohort of RA cases and healthy controls, to explore associations of TRF length with features of disease and with RA-associated HLA-DRB1 alleles. METHODS: WBC and TRF length were measured by Southern blot in DNA from 176 hospital-based RA cases satisfying the 1987 American College of Rheumatology criteria and from 1151 controls. TRF length was compared between cases and controls, and the effects of disease duration, severity and HLA-DRB1 alleles encoding the shared epitope (SE) were assessed. RESULTS: Age- and sex-adjusted TRF length was significantly shorter in RA cases compared with controls (p<0.001). There was no association between age- and sex-adjusted TRF length and disease duration, C reactive protein or Larsen score. The presence of one or more SE-encoding alleles was associated with reduced adjusted TRF length in RA cases (SE positive vs SE negative cases, p=0.038), but not in controls. CONCLUSION: The reduced TRF length in a large group of patients with RA compared with controls has been shown. The reduction is apparently independent of disease duration and markers of disease severity, but is influenced by HLA-DRB1 genotype.

Age Factors↗
PubMed2026

Changes in weight and metabolic health during and after cessation of a time-restricted feeding plus aerobic training in Swiss mice fed a high-fat diet.

Obesity is a chronic disease, representing a significant health problem worldwide. Unhealthy eating habits and sedentarism are key contributors to the development of obesity. Dietary and exercise strategies are the first-line therapies for weight loss or maintenance and have proven effective in controlling weight. However, long-term adherence is challenging, and rapid weight regain often follows intervention cessation. In mice, time-restricted feeding (TRF) and exercise (EXE) independently prevent weight gain and maintain metabolic health, yet weight regain is observed upon cessation. Whether combining TRF and EXE provides longer-lasting benefits remains unclear. Here, we assessed weight and metabolic parameters in Swiss male mice fed with a high-fat diet (HFD) during an 8-wk intervention of TRF (8-h food access in the active phase) or TRF combined with EXE (60-min treadmill running daily) and after cessation and transfer to ad libitum feeding. TRF and EXE interventions successfully mitigate weight gain, improve glycemic homeostasis, and attenuate lipid accumulation in the liver and adipose tissue hypertrophy compared to mice fed HFD ad libitum. However, cessation of both strategies led to rapid weight regain, impaired glycemic control, and increased circulating lipid levels. Although the combination of TRF and EXE led to the lowest body weight and best metabolic health, this group showed no protection against the metabolic impairments observed after TRF cessation alone. In conclusion, TRF and EXE are complementary strategies for managing metabolic health, but cessation of these interventions leads to rapid weight regain and metabolic deterioration, with only partial preservation of select metabolic adaptations. These findings underscore the critical need for sustained adherence to lifestyle interventions in obesity management.NEW & NOTEWORTHY This study demonstrates that combining time-restricted feeding with aerobic training improves weight and metabolic health in Swiss mice fed a high-fat diet. Importantly, we show that most metabolic benefits are lost after intervention cessation. However, insulin sensitivity and aspects of hepatic lipid metabolism are partially maintained after cessation of the intervention. These findings provide new insight into the durability of metabolic improvements induced by lifestyle interventions and highlight the potential of combined dietary and exercise strategies to counteract diet-induced obesity and metabolic dysfunction.

Animals↗
PubMed1997

Role of the autonomic nervous system in the thermogenic response to food in lean individuals.

The aim of this study was to determine the role of the autonomic nervous system (ANS) in obligatory and facultative components of the thermogenic response to food (TRF). Nineteen lean, healthy subjects participated in this study, which comprised two protocols, each exploring one component of the ANS. In the first experimental group, propranolol (prime: 80 micrograms/kg; continuous: 1 microgram.kg-1.min-1) was infused intravenously to inhibit sympathetic nervous activity (SNA), whereas in the second group atropine (prime: 5 micrograms/kg; continuous: 5 micrograms.kg-1.min-1) was used to inhibit parasympathetic nervous activity (PNA). The TRF was measured on four occasions: 1) after oral ingestion of a breakfast, during 0.9% NaCl perfusion, 2) after oral ingestion of the same breakfast, during the perfusion of one of the drugs, 3) after intragastric injection of a pureed form of the same meal as in part 1, during 0.9% NaCl perfusion, and 4) after intragastric feeding, during the administration of one of the drugs. Energy expenditure was measured by indirect calorimetry for 30 min before and 6 h after ingestion of the meal. Facultative TRF was defined as the difference between oral and intragastric TRF. Intragastric feeding significantly reduced TRF in both studies: 6.6 +/- 1.0 vs. 8.7 +/- 0.8% of the ingested energy in the SNA study and 5.5 +/- 1.6 vs. 7.4 +/- 3.1% in the PNA study. During propranolol infusion, TRF was significantly lower than it was during saline infusion after oral feeding (6.9 +/- 1.0% vs. 8.7 +/- 0.8% of ingested energy) but not after intragastric feeding. During atropine administration, TRF was reduced after both oral and intragastric feeding, although statistical significance was not reached in the latter. Atropine administration decreased gastric emptying (measured with an isotopic method) 2 h postingestion by 50%. These results show that the SNA is necessary for the facultative component of TRF to occur in humans. The role of the PNA appears to be related to its action on gastric emptying.

Adolescent↗
PubMedDate not supplied

Pro-inflammatory alterations and status of blood plasma iron in a model of blast-induced lung trauma.

Impact of blast shock waves (SW) with the body wall produces blast lung injuries characterized by bilateral traumatic hemorrhages. Such injuries often have no external signs, are difficult to diagnose, and therefore, are frequently underestimated. Predictive assessment of acute respiratory distress syndrome outcome in SW-related accidents should be based on experimental data from appropriate animal models. Blood plasma transferrin is a major carrier of blood iron essential for proliferative "emergency" response of hematopoietic and immune systems as well as injured tissue in major trauma. Iron-transferrin complexes (Fe3+ TRF) can be quantitatively analyzed in blood and tissue samples with low-temperature EPR techniques. We hypothesized that use of EPR techniques in combination with assays for pro-inflammatory cytokines and granulocytes in the peripheral blood and BAL would reveal a pattern of systemic sequestration of (Fe3+)TRF that could be useful for development of biomarkers of the systemic inflammatory response to lung injury. With this goal we (i) analyzed time-dependent dynamics of (Fe3+)TRF in the peripheral blood of rats after impacts of SW generated in a laboratory shock-tube and (ii) assayed the fluctuation of granulocyte (PMN) counts and expression of CD11b adhesion molecules on the surface of PMNs during the first 24 h after SW induced injury. Sham-treated animals were used as control. Exposure to SW led to a significant decrease in the amount of blood (Fe3+)TRF that correlated with the extent of lung injury and developed gradually during the first 24 h. Thus, sequestration of (Fe3+)TRF occurred as early as 3 h post-exposure. At that time, the steady state concentration of (Fe3+)TRF in blood samples decreased from 19.7+/-0.6 microM in controls to 7.5+/-1.3 microM in exposed animals. The levels of (Fe3+)TRF remained decreased throughout the entire study period. PMN counts increased 5-fold and 3.5-fold over controls respectively, at 3 and 6 h postexposure. These effects were accompanied by an increase in expression of CD11b on the surface membrane of PMNs. Extensive release of cytokines IL-1, IL-6, MCP-1, and MIP-2 was observed in BAL fluid and blood plasma during 24 h postexposure. We conclude that EPR monitoring of blood (Fe3+)TRF can be a useful approach for assessment of systemic pro-inflammatory alterations due to SW-induced lung injury.

Air Pressure↗
PubMed1987

Bipolar secretion of androgen-binding protein and transferrin by Sertoli cells cultured in a two-compartment culture chamber.

The influence of various medium supplements on Sertoli cell (Sc) monolayer permeability to [3H]inulin and polarized secretion of transferrin (Trf) and androgen-binding protein (ABP) was investigated in a two-compartment culture chamber. Sc from 14- and 18-day-old rats were maintained for 13 days in one of the following media: Modified Eagle's Medium-Ham's F-12 (DFM), DFM plus insulin, epidermal growth factor, progesterone, hydrocortisone, and vitamins A and E (6F), 6F plus testosterone (7F), 7F plus FSH (8F), 6F plus 2% fetal bovine serum (6F2S), 6F plus 5% fetal bovine serum (6F5S). The monolayer permeability to [3H]inulin decreased rapidly during the initial 3-5 days of culture for the Sc isolated from 18- and 14-day old animals, then remained stable in all media except DFM. Morphological examination revealed the presence of tight junctions between neighbouring Sc in both age groups, indicating their de novo formation. Secretion of Trf was lowest in DFM and steadily declined. In all other media, Trf secretion peaked on day 5 and remained relatively constant after day 7. Medium 7F only slightly and inconsistently increased the secretion, whereas 8F was always highly stimulatory compared to 6F. Supplementation of 6F with serum resulted in the greatest Trf secretion. In the case of ABP, three different secretion patterns were noted depending on the medium composition; secretion was greatest in the presence of 5% fetal bovine serum. The medium supplements also differentially affected the polarity of Trf and ABP secretion. The ratio of Trf secreted to the outer and inner compartments (OC/IC) was approximately 2.0 in DFM and was not influenced by supplements in 6F, 7F, and 8F. However, in serum-containing media, the OC/IC ratio gradually increased with time to about 5.0 on day 13. The average OC/IC ratio of ABP was 1.7 in DFM and, in contrast to Trf, declined to 0.7 in other serum-free media. Serum supplementation reversed and increased the ABP ratio to about 6.0 on day 13. These data indicate that Sc grown on permeable supports form confluent monolayers that limit the diffusion of macromolecules, most likely due to the formation of tight junctions. The monolayer permeability as well as the total and polarized secretion of Trf and ABP are differentially regulated by hormones and serum factors.

Age Factors↗
PubMed2000

Teacher-assessed behavior of children prenatally exposed to cocaine.

OBJECTIVE: Prenatal cocaine exposure has been associated with alterations in neonatal behavior and more recently a dose-response relationship has been identified. However, few data are available to address the long-term behavioral effects of prenatal exposures in humans. The specific aim of this report is to evaluate the school-age behavior of children prenatally exposed to cocaine. METHODS: All black non-human immunodeficiency virus-positive participants in a larger pregnancy outcomes study who delivered singleton live born infants between September 1, 1989 and August 31, 1991 were eligible for study participation. Staff members of the larger study extensively screened study participants during pregnancy for cocaine, alcohol, cigarettes, and other illicit drugs. Prenatal drug exposure was defined by maternal history elicited by structured interviews with maternal and infant drug testing as clinically indicated. Cocaine exposure was considered positive if either history or laboratory results were positive. Six years later, 665 families were contacted; 94% agreed to participate. The child, primary caretaker (parent), and, when available, the biologic mothers were tested in our research facilities. Permission was elicited to obtain blinded teacher assessments of child behavior with the Achenbach Teacher's Report Form (TRF). Drug use since the child's birth was assessed by trained researchers using a structured interview. RESULTS: Complete laboratory and teacher data were available for 499 parent-child dyads, with a final sample size for all analyses of 471 (201 cocaine-exposed) after the elimination of mentally retarded subjects. A comparison of relative Externalizing (Aggressive, Delinquent) to Internalizing (Anxious/Depressed, Withdrawn, Somatic Complaints) behaviors of the offspring was computed for the TRF by taking the difference between the 2 subscales to create an Externalizing-Internalizing Difference (T. M. Achenbach, personal communication, 1998). Univariate comparisons revealed that boys were significantly more likely to score in the clinically significant range on total TRF, Externalizing-Internalizing, and Aggressive Behaviors than were girls. Children prenatally exposed to cocaine had higher Externalizing-Internalizing Differences compared with controls but did not have significantly higher scores on any of the other TRF variables. Additionally, boys prenatally exposed to cocaine were twice as likely as controls to have clinically significant scores for externalizing (25% vs 13%) and delinquent behavior (22% vs 11%). Gender, prenatal exposures (cocaine and alcohol), and postnatal risk factors (custody changes, current drug use in the home, child's report of violence exposure) were all related to problem behaviors. Even after controlling for gender, other prenatal substance exposures, and home environment variables, cocaine-exposed children had higher Externalizing-Internalizing Difference scores. Prenatal exposure to alcohol was associated with higher total score, increased attention problems, and more delinquent behaviors. Prenatal exposure to cigarettes was not significantly related to the total TRF score or any of the TRF subscales. Postnatal factors associated with problem behaviors included both changes in custody status and current drug use in the home. Change in custody status of the cocaine-exposed children, but not of the controls, was related to higher total scores on the TRF and more externalizing and aggressive behaviors. Current drug use in the home was associated with higher scores on the externalizing and aggressive subscales. CONCLUSIONS: Results of this study suggest gender-specific behavioral effects related to prenatal cocaine exposure. Prenatal alcohol exposure also had a significant impact on the TRF. Postnatal exposures, including current drug use in the home and the child's report of violence exposure, had an independent effect on teacher-assessed child behavioral problems. (ABSTRACT TRUNCATE

Black or African American↗
PubMedDate not supplied

[Chronic renal failure in children in Yugoslavia].

UNLABELLED: The aim of this study was to analyse the demographic variables of chronic non-terminal (CRF) and terminal (TRF) renal failure patients (pts) younger than 19 years treated in Serbia in June 2001. The prevalence of CRF pts was registered as 4.7 per million total population (pmtp) or 14.1 per million child population (pmcp) while corresponding values for TRF pts were 4.5 pmtp or 13.5 pmcp. The incidence of TRF pts during the period Jan. 2000-Jan. 2002 was 4.35 pmcp. Boys dominated only among CRF pts (34:14); 60.4% being between the ages of 6 and 19 yrs while at the time of diagnosis of HBI, 33.3% of boys were yanger than 2 yrs. The causes of CRF were: reflux nephropathy 58.3%, congenital kidney disease 16.7%, familial/hereditary 14.6%, glomerulonephritis 6.2% and Willms tu 4.1%. Reflux nephropathy was also the most common underlying disease of TRF accounted for 36.9% of total cases, while glomerulonephritis was responsible for 23.9%. Reflux nephropathy was associated with neural tube defect in 53.3% and with congenital lower urinary tract obstruction in 66.7%. The most of CRF (81.25%) and TRF pts (95.6%) were from Serbia, the others were from Monte Negro and Republic Srpska. The most of CRF (65%) and TRF (80%) pts were treated in University Children's Hospital in Belgrade. Of CRF pts 46% had serum creatinine 100-200 mumol/l, in 11% of pts it was 400-600 mumol/l and 2% of pts were in pre-terminal CRF. One third of CRF pts had proteinuria 150-500 mg/l, and second third had proteinuria greater of 1000 mg/l. Anemia was present in 54% of CRf pts, and arterial hypertension in 56%. Hemodialysis was dominant treatment modality for TRF pts and only 23.9% had functioning transplant. CONCLUSION: This is the first national study of demographic characteristics of pediatric CRF in Serbia. Since its prevalence is considerably lower than that in Western and North European countries the true prevalence is some what higher. The increasing incidence of pediatric TRF from 2.85 pmcp to 4.35 pmcp reflect better diagnosis and treatment of these patients in the recent years.

Adolescent↗
PubMed1993

Binding of doxorubicin-conjugated transferrin to U937 cells.

Binding of transferrin (Trf) and its doxorubicin-conjugated forms (Conj) to U937 cells at 0 degrees C were compared using 125I-labelled Trf or Conj. The apparent binding affinity (Ka) of Conj to the surface of U937 cells was (1.9 +/- 0.4).10(8) l/mol; it is about 40% of that of Trf [(5.0 +/- 1.2).10(8) l/mol]. Binding of 125I-labelled ligands was blocked by the unlabelled ligands to the same degree, however, it was not blocked by a great excess of doxorubicin (Dox). N-ethylmaleimide caused about 10% inhibition while dithiothreitol was without effect. Dissociation of 125I-labelled ligands in the presence of different concentrations of unlabelled ligands (Trf and Conj in the all 4 variations) resulted in different R50 values (the concentration of the unlabelled ligand where 50% of the radiolabelled ligand was released). While Trf displaced Trf with an R50 value close to the binding affinity, Conj displacement by Conj occurred with much lower efficiency. The heterolog displacement experiments yielded R50 values in between the two extrema. These results suggest that 1) binding of Conj to the surface of cells is governed by the binding of the Trf part of Conj to the transferrin receptor, 2) -SH groups are not involved in the binding, and 3) a second interaction between the Conj and some constituent(s) of the plasma membrane may modify the binding of Conj in comparison to that of Trf.

Doxorubicin↗
PubMed2004

Tocotrienol-rich fraction of palm oil activates p53, modulates Bax/Bcl2 ratio and induces apoptosis independent of cell cycle association.

Anti-cancer properties of palm oil have been attributed to the presence of tocotrienols and carotenoids. Studies from various laboratories have shown that tocotrienol-rich fraction (TRF) of palm oil inhibits cell growth and induces apoptosis in both preneoplastic and neoplastic cells. However, the mechanism by which TRF induces apoptosis remains largely unknown. Since several chemopreventive agents have been shown to utilize p53 pathway in negative regulation of cell growth, using human colon carcinoma RKO cells which express wild type p53, we investigated the effect of TRF on components of p53 signaling network. Treatment of cells with TRF resulted in a dose- and time- dependent inhibition of growth and colony formation. Further, TRF treatment of RKO cells resulted in the induction of WAF1/p21 which appears to be independent of cell cycle regulation and is transcriptionally upregulated in p53 dependent fashion. These results were further confirmed by using cells that express luciferase from a p53 responsive promoter where TRF treatment leads to activation of p53 reporter activity. TRF treatment also resulted in alteration in Bax/Bcl2 ratio in favor of apoptosis, which was associated with the release of cytochrome c and induction of apoptotic protease-activating factor-1. This altered expression of Bcl2 family members triggered the activation of initiator caspase-9 followed by activation of effector caspase-3. These signaling cascades lead to condensed chromatin, DNA fragmentation and shrinkage of cell membrane resulting into apoptosis. Our data suggest that TRF-induced apoptosis in colon carcinoma cells is mediated by p53 signaling network which appears to be independent of cell cycle association.

Antioxidants↗
PubMed2002

[Epidemiology of care demands].

SOME FIGURES: Terminal renal failure (TRF) is a major public health problem in France in view of its increasing incidence (110 pmi/year), prevalence (700 pmi) and the costs of treatments supplied. In France, more than 6,500 new patients started treatment for TRF in 2001; around 42,000 patients with renal failure have been treated. The mean cost of treatment per patient is estimated to be of 350 KF per annum for dialysis, 450 KF for transplantation the first year and 50 KF per annum thereafter. Hence, more than 10 billion francs are spent every year on treating TRF, i.e., 1.5% of the Health Scheme. However, these costs do not include expensive treatments (erythropoietin), transport or hospitalisation. RECENT TENDENCIES: Our information system concerning TRF is fragmented and not coordinated. Identification of the cases is incomplete, their declaration is not always systematic and the quality control of the data has not been formalized. Nonetheless, major tendencies can be identified. The notable facts of the last 10 years are an aging TRF population and an increase in associated comorbidity. The diseases leading to TRF are changing. Vascular nephropathies predominate; ischemic renal diseases have become the first cause of TRF in elderly patients. The incidence of type 2 diabetes is increasing and strangely in the French overseas territories. Glomerular nephropathies are the third cause of TRF, particularly in the young. However, compared with other causes, their prevalence is decreasing. INSUFFICIENCIES: The morbidity and mortality with dialysis is dominated by cardiac and vascular causes. Renal transplantation has stagnated; the waiting lists increase and donations are insufficient. Conversely, transplantation survival is progressing. In a second part, we will examine the elements of health strategy necessary to adapt the supply of care and the organization of preventive measures.

France↗
PubMed1991

Differentiation between the effects of IGF-1 and GH on PMSG-induced progesterone production by rat granulosa cells.

The effects of insulin-like growth factor-1 (IGF-1) and growth hormone (GH) on pregnant mare serum gonadotropin (PMSG)-induced progesterone production by cultured granulosa cells have been studied. Rat granulosa cells were cultured in different concentrations of PMSG (0-100 mU/ml) plus or minus IGF-1 (4 nM) or GH (hGH, 2.5 or 10 nM) in the presence or absence of cortisol (2.4 micrograms/ml) and/or insulin (68 nM) in low (5 micrograms/ml) or high (50 micrograms/ml) concentrations of transferrin (TRF). IGF-1 augmented PMSG-induced progesterone production in both low and high TRF. The maximal increments were 6.6 and 4.5 times at 20 mU/ml PMSG respectively in low and high TRF. The enhancement by IGF-1 of PMSG-induced progesterone production was greater at low TRF concentrations. When cortisol was added in both low and high TRF, the enhancement by IGF-1 of PMSG-induced progesterone production was reversed and IGF-1 inhibited PMSG-induced progesterone production by 25.9% (low TRF) and 62.3% (high TRF) respectively. When a high dose of insulin was added instead of IGF-1, there was no obvious inhibition of the insulin stimulation by cortisol. In contrast, the IGF-1 inhibition in the presence of cortisol still existed in the presence of a high dose of insulin. These data indicate that insulin must have a direct effect of its own rather than simply acting as a surrogate IGF-1. GH inhibited PMSG-induced progesterone production by 37.2% and 61% respectively at 2.5 and 10 nM GH at low TRF concentration and 100 mU/ml PMSG.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Biochemical characterization of regulatory factors derived from T cell hybridomas and spleen cells. II. Evidence for glycosylation of T cell growth factor, T cell replacing factor, and granulocyte-macrophage colony-stimulating factor.

Isoelectric focusing demonstrated that T cell growth factor (TCGF), T cell replacing factor (TRF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) derived from concanavalin A-stimulated T cell hybridomas and spleen cells are heterogeneous with respect to charge. The spleen cell-derived TCGF and TRF activities focused with isoelectric points (pI) between 3.5 and 6.5 whereas the range for GM-CSF activity was broader (pI, 3.5 to 8.0). The T cell hybridoma-derived activities were slightly more acidic. Neuraminidase treatment of both hybridoma 123 and spleen cell-derived material resulted in a major peak of each activity (TRF/TCGF pI, 4.9; GM-CSF pI, 4.7). Neuraminidase treatment of hybridoma T6-derived material resulted in peaks of TRF and TCGF around 6.0 as well as one around 5.0, suggesting that this charge heterogeneity was due to causes other than variations in the level of sialic acid on the relevant molecules. Tunicamycin-treated spleen cells or hybridoma 123 cells released biologically active TCGF, TRF, and GM-CSF. Each of these three activities from tunicamycin-treated spleen cells focused with pI around 5.0. A major fraction of TRF, TCGF, and GM-CSF activities bound to wheat-germ agglutinin. GM-CSF also bound to concanavalin A and lentil lectin. These results suggest that the molecules responsible for TCGF, TRF, and GM-SCF activities are glycosylated and that the observed heterogeneity in charge and lectin-binding characteristics is due in part to variable glycosylation. Glycosylation was not critical for any of the three biologic activities. No conclusive separation of TRF and TCGF activities was observed in these experiments although GM-CSF differed from TRF and TCGF in that it bound to Concanavalin A.

Carbohydrate Metabolism↗
PubMed1995

Transformation-restoring factor: a low molecular weight secreted factor required for anchorage-independent growth of oncogene-resistant mutant cell lines.

We have previously described two independent mutant rat fibroblast cell lines that fail to form colonies in soft agar when infected with a v-H-ras-expressing retrovirus, yet still undergo transformation-related morphological alterations in response to this oncogene. We report here that conditioned medium (CM) from non-transformed rat fibroblasts contains an activity that specifically corrects this defect in the mutant cell lines, rendering them capable of anchorage-independent growth in response to ras. The major activity in CM, designated transformation-restoring factor (TRF), is approximately 1300 molecular weight, lipid insoluble, and heat, protease, acid and base stable. Latent activity, distinct from TRF, is also present in CM; several lines of evidence indicate that transforming growth factor (TGF) beta is responsible for this activity. TRF, however, cannot substitute for TGF beta in the phenotypic transformation of NRK cells. TRF activity is decreased in CM of control cells transformed by ras and this response to ras is retained by the mutant cell lines. We propose that whereas wild-type cells transformed by ras may constitutively activate a TRF-regulated pathway, thus becoming independent of TRF for growth in soft agar, these mutants have acquired dependence on an exogenous supply of TRF for this aspect of the transformed phenotype. Cellular activities regulated, directly or indirectly, by TRF may be effectors of the anchorage-independent growth property that is a hallmark of transformed rodent fibroblasts.

Animals↗
PubMedDate not supplied

Transferrin directed delivery of adriamycin to human cells.

Transferrin was covalently conjugated to adriamycin (Trf-adr) by the formation of a schiff base. This conjugate was found to bind to cell membrane trf receptors in a variety of human tumor cell lines. The Trf-adr conjugate was found to be active against sensitive and resistant cell lines e.g. Lovo, HL-60, H-meso and Hep2. It was, however, found that Trf-adr conjugate was more potent against resistant human tumor cell lines as compared to sensitive cell lines (based on cytotoxicity assays). The Trf-adr conjugate was then tested against nude mice bearing human mesothelioma tumors in their peritoneal cavity. The Trf-adr conjugate prolonged the lifespan of advanced tumor bearing nude mice as compared to either adriamycin alone or adriamycin and trf unlinked. Our studies show that trf can be successfully used as an ligand for directing anticancer drugs to human tumor cells.

Animals↗
PubMed1995

Telomere repeat fragment sizes do not limit the growth potential of uterine leiomyomas.

We have compared the length of telomere repeat fragments (TRF's) in 19 uterine leiomyomas from 6 patients with the corresponding myometrium. The advantage of this study of TRF length is that cells from uterine leiymyoma and cells from corresponding myometrium do not contain any considerable proportions of other cells as revealed by analysis of clonality. In all tumor samples a loss of TRF length ranging from 1120 to 4690 bp was noted. There was no correlation between tumor volume or size of tumor population as revealed by histological examination and loss of TRF length. From the obtained TRF length data (an average myometrial TFR length of 13 kb and an average loss of TRF length in myoma cells of 83 bp per cell division) we concluded that TRF length reduction does not limit the growth potential of uterine leiomyomas.

Base Sequence↗
PubMed1995

Effect of tocotrienols on the growth of a human breast cancer cell line in culture.

The tocotrienol-rich fraction (TRF) of palm oil consists of tocotrienols and some alpha-tocopherol (alpha-T). Tocotrienols are a form of vitamin E having an unsaturated side-chain, rather than the saturated side-chain of the more common tocopherols. Because palm oil has been shown not to promote chemically-induced mammary carcinogenesis, we tested effects of TRF and alpha-T on the proliferation, growth, and plating efficiency (PE) of the MDA-MB-435 estrogen-receptor-negative human breast cancer cells. TRF inhibited the proliferation of these cells with a concentration required to inhibit cell proliferation by 50% of 180 microgram/mL whereas alpha-T had no effect at concentrations up to 1000 microgram/mL as measured by incorporation of [3H]thymidine. The effects of TRF and alpha-T also were tested in longer-term growth experiments, using concentrations of 180 and 500 microgram/mL. We found that TRF inhibited the growth of these cells by 50%, whereas alpha-T did not. Their effect on the ability of these cells to form colonies also was studied, and it was found that TRF inhibited PE, whereas alpha T had no effect. These results suggest that the inhibition is due to the presence of tocotrienols in TRF rather than alpha T.

Antioxidants↗
PubMed1984

Killing of human tumor cells in culture with adriamycin conjugates of human transferrin.

Receptors for human transferrin (Trf) in high density are found on reticulocytes and syncytiotrophoblast, but most unstimulated, normal adult cells do not bind Trf. In contrast, leukemia and breast adenocarcinoma cells have been shown to manifest Trf receptors, raising the possibility that these receptors might be employed to bind cytotoxic Trf conjugates. Trf was conjugated with adriamycin (Adr) and it was shown that the conjugates are bound by Trf receptors on plasma membranes of Daudi and HL-60 cells, following which Adr is identified in the nuclei of these cells. The biological effect of Adr is quantitated by the inhibition of tritiated thymidine uptake, and subsequent cell death is measured by trypan blue exclusion. The killing correlates directly with both the time of exposure and the amount of conjugate employed. These results suggest that such cytotoxic Trf conjugates hold promise for selective in vivo killing of some malignant cells.

Animals↗