ARID1B, a member of the human SWI/SNF chromatin remodeling complex, exhibits tumour-suppressor activities in pancreatic cancer cell lines.

BACKGROUND: The human ATP-dependent SWItch/sucrose nonfermentable (SWI/SNF) complex functions as a primary chromatin remodeler during ontogeny, as well as in adult life. Several components of the complex have been suggested to function as important regulators of tumorigenesis in various cancers. In the current study, we have characterised a possible tumour suppressor role for the largest subunit of the complex, namely the AT-rich interaction domain 1B (ARID1B). METHODS: We performed Azacytidine and Trichostatin A treatments, followed by bisulphite sequencing to determine the possible DNA methylation-induced transcription repression of the gene in pancreatic cancer (PaCa) cell lines. Functional characterisation of effect of ARID1B ectopic expression in MiaPaCa2 PaCa cell line, which harboured ARID1B homozygous deletion, was carried out. Finally, we evaluated ARID1B protein expression in pancreatic tumour samples using immunohistochemistry on a tissue microarray. RESULTS: ARID1B was transcriptionally repressed due to promoter hypermethylation, and ectopic expression severely compromised the ability of MiaPaCa2 cells to form colonies in liquid culture and soft agar. In addition, ARID1B exhibited significantly reduced/loss of expression in PaCa tissue, especially in samples from advanced-stage tumours, when compared with normal pancreas. CONCLUSION: The results therefore suggest a possible tumour-suppressor function for ARID1B in PaCa, thus adding to the growing list of SWI/SNF components with a similar function. Given the urgent need to design efficient targeted therapies for PaCa, our study assumes significance.

Primary myelodysplastic syndrome: clinical spectrum of 53 cases.

Fifty three (45 males, 8 females) patients with primary meylodysplastic syndrome were seen between January 1990 and June, 1996. Fifteen (28%) patients had refractory anaemia (RA), 9 (17%) refractory anaemia with ring sideroblast (RARS), 21 (40%) refractory anaemia with excess blasts (RAEB), 5 (9%) refractory anaemia with excess blasts in transformation (REABt) and 3 (6%) had chronic myelomonocytic leukemia (CMML). The mean age for the whole cohort was 59 years. Patients with RAEB and RAEBt were significantly younger than other FAB types with a mean age of 53.5 and 45 years respectively. Among the FAB types RAEB appeared to be over represented. Symptomatic anaemia (66% cases) was the major cause to seek medical attention. The commonest laboratory findings was anaemia; Hb < 8 g/dl in 31 (59%) patients. Only two patients had Hb > 12 g/dl at presentation. Twenty four (45%) patients had normocytic anaemia, mainly in RAEB group (61%). Macrocytosis was a dominant finding in patients with RA (53%) and RARS (53%). Bicytopenia (72%) was a more common finding than pancytopenia (8%). Bone marrow was normocellular in 32 (60%) patients and hypoplastic in 11 (21%). Dyserythropoiesis predominantly affected RA (80%), RARS (55%) and RAEB (43%) groups. Bilineage dysplasia (21%) was commoner than trilineage dysplasia (19%). Increased bone marrow fibrosis was seen in about half of the available trephines, mainly in RAEB patients. Median survival of patients was ten months with a follow up duration of 2-55 months. Four patients transformed to acute leukemia (M1 or M2) and died subsequently. However, infection was major complication and cause of death (10 cases). The preponderance of younger people to acquire the disease (especially the RAEB and RAEBt variants), the emergence of RAEB as the major group of MDS and increased prevalence of hypoplastic MDS point towards non-therapeutic genotoxin (s) in the causation of disease. Shortened survival and low rate of acute transformation points that patients did not withstand cytopenias and died earlier.

The impact of nutritional counselling on serum lipids, dietary and physical activity patterns of school children.

Eighty-eight school children and their parents who had been counselled regarding appropriate dietary and activity patterns aimed at reducing serum cholesterol were followed-up 21 months later to determine changes in dietary and activity patterns and in serum lipid levels. The decline in serum total cholesterol ranged from 8 to 14% in the different age and sex groups (P < 0.05 to P < 0.001). Serum triglycerides did not change significantly. Cholesterol intake decreased 36% and 54% in 10-14 year old boys and girls respectively (P > 0.001). The activity level increased significantly in both the 5-9 year and 10-14 year olds (P < 0.05 to P < 0.005). These results show that nutrition education can bring about a change in dietary and activity patterns, resulting in a decline in serum cholesterol levels.

Anaemia in pregnancy--a study of 709 women in Karachi.

PIP: To determine contributory factors of anemia in pregnant women, 709 pregnant women in Karachi were studied from November 1986 to June 1988. Of the 709 patients, 400 were at a private institution while 309 were from governmental clinics. All subjects were attending the hospitals for their 1st antenatal care visit. Information was collected concerning socioeconomic status, age, parity, diet, and date of last menstrual period. The women ranged in age from 16 to 45 years and 17% were anemic. Anemia was common among primipara (16%), gravida 2-6 (16%, and gravida 7 (38%). Furthermore, it was found in 23% of the women in their 3rd trimester. Comparing patients in the private clinics and in the free clinics, 8% of the private clinic patients and 29% of the free clinic patients were anemic. Among fee clinic patients, anemia was shown 6% of the women having an adequate diet, 24% of those having a poor diet, and 58% of those having a very poor diet. Therefore, risk factors for anemia include low socioeconomic status, poor diets, gravida 7, and being in the 3rd trimester of pregnancy.^ieng

Methotrexate clearance and clinical toxicity in osteosarcoma following high-dose methotrexate therapy.

Two patients with osteogenic sarcoma were treated with high-dose methotrexate (MTX) followed by leucovorin 'rescue'. Profiles of MTX clearance from plasma and erythrocytes were obtained. Clearance of the drug from plasma during the first 36 hours appears to be biphasic with the first phase of elimination of the drug being appreciably more rapid than the second phase. The drug had also incorporated into the bone marrow precursor cells and reappeared after a few days in the circulating mature erythrocytes which may later serve as a slow-changing compartment for MTX. Nonspecific binding of the drug to plasma proteins may have been one of the causes of delayed clearance of plasma MTX observed in one of the patients. However, delayed clearance does not appear to correlate with the severity of clinical toxicity which was found to be more pronounced in a patient with a better clearance of the drug. Our results support the more recent concept that enhanced clinical toxicity may not be predictable by monitoring plasma MTX alone.