Regulation of p53 and Its Targets During Involution of the Mammary Gland

Post-lactational involution of the mammary glandprovides a system in which to study the expression andfunction of genes that regulate apoptosis in the contextof a normal tissue. The functions of the p53 tumor suppressor gene have been extensivelystudied as a mediator of apoptosis in response to DNAdamage, but its regulation in normal physiologicprocesses has been poorly characterized. Expression of p53 mRNA was shown to be among the firstgenes to be induced in mammary tissue following weaningof neonates. Although involution proceeds in the absenceof a functional p53 gene, it is delayed compared to normal individuals. Therefore, involutioncan be viewed as biphasic with initial responses beingsensitive to p53, whereas secondary responses beingp53-independent. These observations can be exploited to determine the subset of genes that arep53-responsive and that mediate the effects of p53 innormal mammary tissue.     

Comparative investigations on the bioavailability of cefuroxime axetil.

In a three-way cross-over study the bioavailability of cefuroxime was determined in 12 healthy volunteers after oral administration of 250 mg as cefuroxime axetil (Elobact; CAS 64544-07-6) in a plain aqueous suspension and as tablets from different batches. The tablet formulations showed nearly identical pharmacokinetic parameters and were bioequivalent. The mean maximum serum concentration was 4.7 micrograms/ml, achieved after 2.1 h. The serum half-live was 1.2-1.4 h, the area under the serum concentration-time curve was 14.3-14.4 micrograms/ml.h and the urinary recovery of unchanged cefuroxime was 54%. The bioavailability of cefuroxime after administration of cefuroxime axetil in aqueous suspension was lower, but bio-inequivalence was not demonstrated.     

PSYCHOLOGICAL EFFECTS OF AN EPIDEMIOLOGICAL STUDY OF BENIGN PROSTATIC HYPERTROPHY

SUMMARY The psychological impact of an epidemiological study of benign prostatic hypertrophy (BPH) was assessed in a representative sample of practice list patients. Of the 889 men completing a general health self-report questionnaire previously validated in a screening programme, 75% knew nothing of problems of the prostate, and 84.5% were not at all worried about prostate problems prior to commencement of the study. Receiving the letter of invitation and the procedures neither increased nor reduced anxiety levels for 69% and 70% respectively. In the 227 men referred to hospital for further investigation the procedure increased anxiety in 28%, decreased anxiety in 20%, and had no effect on the remainder. The sample of 137 (16%) men who, prior to interview, were in some way worried about problems of the prostate had significantly more urinary tract symptoms than those who were not at all worried about prostatic problems. Despite being worried about prostatic problems and having significant urinary symptoms, this group was no more likely to have attended a GP for investigation and/or treatment. Results are discussed in relation to the possible psychological effects of general health screening and the reluctance of men to attend for consultation despite awareness and concern regarding urinary symptomatology.     

Coexpression of platelet-derived growth factor (PDGF) and PDGF-receptor genes by primary human astrocytomas may contribute to their development and maintenance.

The present studies investigated the expression of the two PDGF genes (c-sis/PDGF-2 and PDGF-1) and the PDGF-receptor b gene (PDGF-R) in 34 primary human astrocytomas. Northern blot analysis demonstrated the coexpression of the c-sis/PDGF-2 protooncogene and the PDGF-R gene in all astrocytomas examined. The majority of the tumors also expressed the PDGF-1 gene. There was no correlation between the expression of the two PDGF genes. Nonmalignant human brain tissue expressed the PDGF-R and PDGF-1 genes but not the c-sis/PDGF-2 protooncogene. In situ hybridization of astrocytoma tissue localized the expression of the c-sis and PDGF-R mRNA's in tumor cells. Capillary endothelial cells also expressed c-sis mRNA. In contrast, nonmalignant human brain tissue expressed only PDGF-R mRNA but not c-sis/PDGF-2 mRNA. The coexpression of a potent mitogenic growth factor protooncogene (c-sis) and its receptor gene in astrocytoma tumor cells suggests the presence of an autocrine mechanism that may contribute to the development and maintenance of astrocytomas. The expression of c-sis mRNA in tumor cells but not in nonmalignant brain cells may serve as an additional diagnostic criterion for the detection of astrocytomas in small tissue specimen using in situ hybridization for the detection of c-sis mRNA and/or immunostaining for the recognition of its protein product.     

Detection of Undiagnosed Coeliac Disease with Atypical Features Using Antireticulin and Antigliadin Antibodies

Eighteen patients with a variety of non-gastrointestinal symptomswere incidentally found to have circulating antireticulin antibodyand on subsequent testing were also positive for antigliadinantibody. They prospectively underwent jejunal biopsy to determinewhether or not they had coeliac disease. Their age range was21–79 years (mean 42 years). Enteropathy was present in13 (72 per cent) and was always associated with circulatingIgA antigliadin antibody. Enteropathy was not present in thefive cases who had only IgG antibody. Clinical improvement occurredin eight of 11 patients who complied with a gluten-free dietand was paralleled by an improvement in the mucosal histologyin seven of eight who were re-biopsied. The most remarkablecases were two patients who presented with severe debility andno apparent haematological or biochemical abnormalities, andwho subsequently made a dramatic recovery on a gluten-free diet.It is concluded that antireticulin antibody detected by routineautoantibody screening and confirmed to have IgA antigliadinantibody specificity is a useful indicator of an otherwise undiagnosedenteropathy. This serves to emphasize that the condition cansometimes be associated with atypical features and significantmorbidity.     

In vitro and in vivo activity of murine lymphokine-activated killer cells after cryopreservation

The in vitro and in vivo effects of cryopreservation on the cytotoxic activity of murine lymphokine-activated killer (LAK) cells were studied. LAK cells were generated by incubation of spleen lymphocytes of BALB/c mice for 3 days with recombinant interleukin-2 (rIL-2) and subsequent cryopreservation. Cytotoxicity was determined in a 51Cr release assay. After thawing, cytotoxic activity was reduced (40.4% 51Cr release at an effector:target cell ratio of 40:1 as compared to 68.5% 51Cr release before freezing) and could be restored to precryopreserved levels by reincubation with rIL-2 for 2 days after thawing (78.8% 51Cr release). These cells were then tested in BALB/c mice injected with RAW 112 cells, a pre-B-cell lymphoma line. The results demonstrate that the survival rate of mice injected with cryopreserved and restimulated LAK cells (50% survival greater than 180 days after injection) did not differ significantly from that of mice injected with fresh unfrozen LAK cells (60% survival greater than 120 days, 50% survival greater than 180 days). Cryopreserved LAK cells have potential use in adoptive immunotherapy.     

The selective Aurora B kinase inhibitor AZD1152 is a potential new treatment for multiple myeloma

Aurora kinases are potential targets for cancer therapy. Previous studies have validated Aurora kinase A as a therapeutic target in multiple myeloma (MM), and have demonstrated in vitro anti-myeloma effects of small molecule Aurora kinase inhibitors that inhibit both Aurora A and B. This study demonstrated that Aurora B kinase was strongly expressed in myeloma cell lines and primary plasma cells. The selective Aurora B inhibitor AZD1152-induced apoptotic death in myeloma cell lines at nanomolar concentrations, with a cell cycle phenotype consistent with that reported previously for Aurora B inhibition. In some cases, AZD1152 in combination with dexamethasone showed increased anti-myeloma activity compared with the use of either agent alone. AZD1152 was active against sorted CD138(+) BM plasma cells from myeloma patients but also, as expected, was toxic to CD138(-) marrow cells from the same patients. In a murine myeloma xenograft model, AZD1152-inhibited tumour growth at well-tolerated doses and induced cell death in established tumours, with associated mild, transient leucopenia. AZD1152 shows promise in these preclinical studies as a novel treatment for MM.