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Biomedical subjects

G C Davies

Publications and source records attributed to G C Davies.

At least 19 recordsLinked to original sources
PubMed2006

EGFRvIII undergoes activation-dependent downregulation mediated by the Cbl proteins.

The overexpression or mutation of tyrosine kinases (TKs), such as the epidermal growth factor receptor (EGFR), can lead to the development of cancer. The most common mutation of the EGFR in glioblastomas is the deletion of exons 2-7 known as the EGFRvIII. This mutant receptor cannot bind EGF but, instead, is constitutively active. The Cbl family of ubiquitin ligases (Cbl, Cbl-b, and Cbl-c) targets the activated EGFR for degradation. As the EGFRvIII is transforming, we investigated whether it could be downregulated by the Cbl proteins. The overexpression of all three Cbl proteins resulted in the ubiquitination and degradation of the EGFRvIII. As with the wild-type EGFR, the TK-binding domain and the RING finger of Cbl-b are sufficient for the downregulation of the EGFRvIII. Also, we found that Cbl-b is recruited to the EGFRvIII and inhibits the transformation of NIH 3T3 cells by the EGFRvIII. Mutation of the Cbl-binding site (Y1045F) in the EGFRvIII inhibits its ubiquitination and downregulation by Cbl-b and enhances its ability to transform. Furthermore, the EGFR TK inhibitor, AG 1478, prevents the downregulation of the EGFRvIII by the Cbl proteins and antagonizes the ability of an immunotoxin directed against the EGFRvIII to kill cells expressing this receptor. In conclusion, the EGFRvIII does not transform by escaping regulation by Cbl proteins and this activation-induced downregulation of the EGFRvIII has an important role in mediating the toxicity of anti-EGFRvIII immunotoxins.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Adverse events reported by postmenopausal women in controlled trials with raloxifene.

OBJECTIVE: To assess the incidence of adverse events in postmenopausal women treated with raloxifene compared with placebo, hormone replacement therapy (HRT), or unopposed estrogen. METHODS: Common treatment groups were pooled across eight randomized, parallel clinical trials (6-30 months' duration) of raloxifene to create the following three databases: placebo-controlled, HRT-controlled, and estrogen-controlled databases. Incidence and severity of all treatment-emergent adverse events, defined as events that first occurred or worsened during treatment, were compared among groups in each of the databases. RESULTS: Discontinuation rates overall, and those related to adverse events, were not significantly different between treatment groups in any database. There was no significant difference in incidence of vaginal bleeding or breast discomfort between women treated with raloxifene (60 mg/d) or placebo. Both of these events were reported more frequently in women receiving HRT or estrogen. Vaginal bleeding was responsible for significantly more discontinuations from the HRT groups compared with the raloxifene group. Hot flashes was the only event common to all three databases that was significantly increased in the raloxifene group, but this event did not increase the discontinuation rates. The incidence of leg cramps was greater in raloxifene-treated women compared with placebo-treated women in the placebo-controlled database, but did not cause any discontinuations of therapy. Raloxifene had no effect on the incidence of vaginal symptoms or central nervous system events. CONCLUSION: Raloxifene had an adverse event profile distinct from HRT and unopposed estrogen and was well tolerated by postmenopausal women.

Adult↗
PubMed1999

Endometrial response to raloxifene compared with placebo, cyclical hormone replacement therapy, and unopposed estrogen in postmenopausal women.

OBJECTIVE: To determine the endometrial effects of raloxifene 60 mg/day in postmenopausal women as assessed by vaginal bleeding and endometrial thickness. DESIGN: Data from 1157 postmenopausal women were analyzed from a database consisting of four independent, double-blind, randomized, placebo-controlled trials (range = 6-30 months duration), a 24-month open-label randomized, cyclical hormone replacement therapy (HRT)-controlled trial, and a 6-month double-blind, randomized, unopposed estrogen-controlled trial. Vaginal bleeding rate was derived from self-reported adverse events collected at least every 6 months. Endometrial thickness was measured by ultrasonography at regular intervals. RESULTS: Raloxifene 60 mg/day was not significantly different from placebo with regard to the incidence of vaginal bleeding, the baseline-to-endpoint change in endometrial thickness, or the proportion of women experiencing an increase in endometrial thickness above baseline after either 12 or 24 months of therapy. Unexpected bleeding was reported significantly more frequently in the unopposed estrogen groups compared with the raloxifene group (raloxifene 60 mg/day, 0% versus estrogen, 50%; p = 0.002). A significantly greater baseline-to-endpoint increase in endometrial thickness was observed in both the HRT and estrogen groups compared with their respective raloxifene comparison group (raloxifene 60 mg/day, 0.01 +/- 2.0 mm versus HRT, 1.8 +/- 3.2; p < 0.001; raloxifene 60 mg/day, 1.1 +/- 1.7 mm versus estrogen, 7.8 +/- 3.8; p < 0.001). No cases of endometrial hyperplasia or cancer were diagnosed in the placebo or raloxifene 60 mg/day groups. Endometrial hyperplasia was diagnosed in one case in the HRT group and in two cases in the estrogen group. CONCLUSION: Raloxifene 60 mg/day for up to 30 months is not associated with vaginal bleeding or increased endometrial thickness in postmenopausal women.

Aged↗
PubMed1993

Release characteristics, ovarian activity and menstrual bleeding pattern with a single contraceptive implant releasing 3-ketodesogestrel.

The properties of a single contraceptive subdermal implant releasing 3-ketodesogestrel were assessed in fifteen women over twelve months. Serum levels of 3-ketodesogestrel were monitored regularly following insertion and after removal. The mean serum level of 3-ketodesogestrel was 245 pg/ml after 72 h (steady state) and 176 pg/ml after twelve months. All volunteers demonstrated ovulation inhibition throughout the study. Transient oestradiol peaks occurred during the study. No luteal activity was noted. The cervical mucus was rapidly rendered hostile to sperm migration. Two women withdrew from the study during the first six months for medical reasons. Both volunteers cited bleeding irregularity as the main cause, one complaining of oligomenorrhoea, the other of prolonged bleeding/spotting episodes. A small but significant increase in weight was noted during the study period.

Adolescent↗
PubMed1992

A review of the effects of long-acting progestogen-only contraceptives on ovarian activity.

Progestogen-only contraception acts mainly by blocking cervical mucus and preventing sperm penetration through it does have a variable pattern of contraceptive effects on the endometrium and ovary. In contrast with the complete suppression of ovarian function with combined pill or injectable use, a variable degree of endocrine activity is demonstrated in women choosing a long-acting progestogen-only contraceptive. This degree of suppression of ovarian activity explains the decrease in systemic side-effects, the rapid resumption of ovulation and recovery of fertility following the discontinuation of the method. New delivery systems of progestogens, the vaginal ring and implant, offer better and more consistent contraceptive effects.

Cervix Mucus↗
PubMed1992

Ovarian activity and bleeding patterns during extended continuous use of a combined contraceptive vaginal ring.

A combined contraceptive vaginal ring with a mean release rate of 0.015 mg of ethinyloestradiol and 0.120 mg of 3-ketodesogestrel per day was used by female volunteers, for either 28, 42, 56 or 84 days. Contraceptive efficacy was assessed by pelvic ultrasound scanning, endocrine monitoring and cervical mucus assessment. Menstrual diary cards were analysed to assess the effect on cycle control. Ovulation inhibition was seen in all treatment groups. Following removal of the ring, a return to an ovulatory cycle was observed in all volunteers. With extension of the treatment cycle beyond the recommended 21 days, there is an increase in the occurrence of bleeding and spotting episodes. This can be compared to patterns obtained during continuous use of combined oral contraceptives.

Administration, Intravaginal↗
PubMed1992

The effects of a combined contraceptive vaginal ring releasing ethinyloestradiol and 3-ketodesogestrel on vaginal flora.

Fifty nine women with documented normal ovulatory cycles and with no symptoms of vaginal infection were divided into four groups. Each group used a combined contraceptive vaginal ring (CCVR) with a mean daily release rate of 0.015 mg of ethinyloestradiol (EE) and 0.120 mg of 3-ketodesogestrel (3-KDG) per day, for one cycle of either 21, 28, 42, or 56 days. Cultures from the posterior vaginal fornix and from the endocervical canal were obtained immediately before insertion of the ring and on removal of the ring. Changes in the numbers of vaginal cells, aerobic and anaerobic bacteria, Chlamydia trachomatis, Gardnerella vaginalis, yeasts and Trichomonas vaginalis were documented at the end of each treatment. Intra- and inter- group changes in the vaginal flora were assessed at the end of each treatment. The comparison between the number and type of flora showed no significant change between the pre-treatment population and the post-treatment population. The results of this study suggest that the use of this CCVR for 21, 28, 42 and 56 days is not associated with an increase in inflammatory cells or pathogenic bacteria.

Administration, Intravaginal↗
PubMed1988

The effect of age and smoking on vascular prostaglandin production in men and women.

6-Keto-PGF1 alpha, PGF2 alpha and PGE2 production by homogenates of aorta was unaffected by age, sex or smoking habits. Homogenates of saphenous vein from women aged 51-60 years produced greater and smaller amounts of 6-keto- PGF1 alpha and PGF2 alpha, respectively, than from women aged 41-50 and 61-70 years. In the 41-50 and 61-70 age groups, the amounts of 6-keto-PGF1 alpha and PGF2 alpha produced by homogenates of saphenous vein were smaller and greater, respectively, in women than in men. Cigarette smoking had no effect on PG production by homogenates of female saphenous vein. 6-Keto-PGF1 alpha production by homogenates of male saphenous vein was 20% lower in smokers and ex-smokers than in non-smokers, although this reduction was statistically significant only for ex-smokers. The amounts of PGE2 and PGF2 alpha produced by homogenates of male saphenous vein were smaller in smokers and ex-smokers, respectively, than in non-smokers. In spite of these changes in PG production by homogenates of saphenous vein, the basal outputs of PGs, particularly of 6-keto-PGF1 alpha, from the saphenous vein were little affected by age, sex or smoking habits.

Adult↗
PubMed1988

The management of patients with locally advanced colorectal cancer.

Patients who have colorectal tumours which involve neighbouring organs or tissues either by direct invasion or by an inflammatory response, in the absence of obvious dissemination at the time of operation, may be suitable for radical en-bloc resection, producing good survival rates.

Colorectal Neoplasms↗
PubMed1987

111In-platelet and 125I-fibrinogen deposition in the lungs in experimental acute pancreatitis.

An experimental model of acute pancreatitis in rats has been used to study intrapulmonary 125I-fibrinogen and 111In-platelet deposition. Pancreatitis caused a significant increase in wet lung weight compared to normal, and this could be abolished by heparin or aspirin pretreatment. 125I-fibrinogen was deposited in the lungs of animals to a significantly greater degree than in controls (P less than 0.01). 125I-fibrinogen deposition was reduced to control levels by pretreatment with aspirin or heparin (P less than 0.05). The uptake of radiolabeled platelets was greater in pancreatitis than in controls (P less than 0.001). Pancreatitis appears to be responsible for platelet entrapment in the lungs. Platelet uptake was reduced by heparin treatment but unaffected by aspirin therapy.

Acute Disease↗
PubMed1986

Bacteriology of the closed duodenal loop model of acute pancreatitis and ultrastructural changes induced in the lungs.

Injection of infected human bile into a closed duodenal loop in the rat consistently produces lethal pancreatitis with severe pulmonary damage. Lung abnormalities, resembling the human adult respiratory distress syndrome (ARDS) are frequently seen in this model and are usually ascribed to the pancreatitis. Similar pulmonary problems are seen in the human form of acute pancreatitis. Recently, it has been suggested, that the lung changes in the experimental animal are more likely to be due to bacteremia than to the pancreatitis. The aim of this study was to determine whether bacteremia occurred in this model, and if so, to determine whether bacteremia alone, in the absence of pancreatitis could produce this lung damage. A group of rats underwent induction of acute pancreatitis by a closed duodenal loop method and were compared to two groups comprising a closed small bowel loop bile infusion preparation, isolated from the pancreas, and a control group of rats undergoing a "sham" gastrotomy. Both pancreatitis and closed small bowel groups of animals were found to be bacteremic when sacrificed at 6 hr. The lungs from the animals with pancreatitis were significantly heavier than those in the other groups and scanning electron micrographs of the lungs in pancreatitis showed gross abnormalities, with marked increases in the alveolar wall thickness. The lungs in the closed small bowel loop preparation were indistinguishable from a control sham gastrotomy group of non-bacteremic rats. These results indicate that although the closed duodenal loop model of pancreatitis produces bacteremia, pancreatitis is necessary for development of pulmonary abnormalities.

Animals↗
PubMed1985

Gastric surgery and the risk of subsequent colorectal cancer.

A matched case control study has been conducted in order to determine whether an association exists between gastric surgery and the subsequent development of colorectal carcinoma. Two hundred and eighty-nine patients (151 women and 138 men) presenting with large bowel cancer have been studied. Case controls were matched according to age, sex and date of admission. The case notes of each patient in the study were reviewed to determine the prevalence of peptic ulceration and gastric surgery. Significantly more patients with colorectal carcinoma had undergone gastric surgery P less than 0.05, although the prevalence of peptic ulceration was similar in both groups. Colorectal carcinoma is more common in patients who have undergone gastric surgery for benign peptic ulcer disease than in the general population.

Adenocarcinoma↗
PubMed1985

Free perforation in Crohn's colitis. A ten-year review.

A review of 198 patients with Crohn's disease of the colon who presented over a ten-year period identified six patients with free perforation of the colon (3 percent). Five were females and all were known to have pre-existing Crohn's disease. Four were taking oral corticosteroids at the time of perforation. The sole male presented with acute toxic dilatation of the colon and had not received previous steroids. Pneumoperitoneum was seen in five of the six patients. Subtotal colectomy with ileostomy appears to be the optimum treatment in patients presenting with this complication of Crohn's disease.

Adult↗
PubMed1985

The role of Robertson's cooked-meat broth in the bacteriological evaluation of surgical specimens.

The results were compared of submitting simple swabs, swabs in Stuart's Transport Medium (STM) and swabs in Robertson's cooked-meat broth (RCMB), from 100 potentially or definitely infected sites in patients undergoing general surgery. Significantly more positive bacterial cultures were obtained from swabs sent in RCMB (65), than from swabs sent either in STM (39) or as simple swabs (32). The isolation of potentially significant organisms from only the RCMB series could influence clinical management. The conventional reluctance of bacteriologists to accept evidence obtained from RCMB cultures seeded directly in the ward or at operation is challenged.

Abscess↗