Determining the 3-substituted Coumarins inhibitory potential against the HslV protease of E. coli.

OBJECTIVE: The growing bacterial resistance towards classical antibiotics demands the development of novel approaches for the effective treatment of potentially fatal bacterial infections in humans. Proteostasis is crucial for the survival of every living cell, as several important physiological functions depend on well-regulated proteostasis. Within bacteria, the regulation of proteostasis relies on AAA+ (Adenosine 5'-triphosphatases associated with diverse cellular activities), ATPases, such as the HslVU complex (heat shock locus gene products U and V), along with other proteases. The HslVU protease/chaperon complex is thought to be the progenitor of the eukaryotic proteasome that regulates proteostasis mostly in prokaryotes. This study aimed to determine the inhibitory potential of 3-substituted coumarin derivatives against Escherichia coli heat shock locus V (HslV) protease. MATERIALS AND METHODS: In this study, twenty-three derivatives of 3-substituted coumarin were assessed for their inhibitory potential against E. coli HslV protease using both in-vitro and in-silico techniques. RESULTS: Among all the tested compounds, US-I-64, US-I-66, US-I-67, and US-I-68 displayed notable inhibitory potential against the HslV protease, showing IC50 (half maximal inhibitory concentration) values ranging from 0.2 to 0.73 µM. Additionally, the inhibitory potential of these compounds against the eukaryotic proteasome was also evaluated using a separate in-silico study. It was found that these compounds did not bind with the proteasomal active site, suggesting no apparent side effects of these lead molecules. CONCLUSIONS: These identified HslV protease inhibitors can be used for the development of novel and safer anti-bacterial drugs.

Presenting features, treatment patterns and outcomes of patients with breast cancer in Pakistan: Experience at a university hospital.

BACKGROUND: Breast cancer is the most common cancer in Pakistani women. We report the presenting features, treatment patterns and survival of breast cancer from a University Hospital in Southern Pakistan and compare the data with international population based studies. MATERIALS AND METHODS: Medical records of patients diagnosed to have breast cancer between January 1999 and November 2008 were reviewed retrospectively. RESULTS: A total of 845 patients were identified. Median age of diagnosis was 48 years (range 18-92). Clinical stage was as follows: Stage I 9.9%; Stage II 48.5%; Stage III 26.2%; Stage IV 13.8%; data not available 1.5%. Approximately, half (51.6%) were estrogen receptor (ER) positive and 17.5% over-expressed Her2/neu. Nearly 23% patients received neo-adjuvant chemotherapy while 68.9% received adjuvant chemotherapy. Anthracycline based treatment was the most common treatment until 2003 while later on, patients also received taxanes and trastuzumab based therapy. Age, stage, tumor size, lymph node status, tumor grade, ER status, treatment with hormonal therapy and radiation were the major predictive factors for overall survival (OS). We report an impressive 5 year OS of 75%, stage specific survival was 100%, 88% and 58% for Stages I, II and III respectively. CONCLUSION: The majority of patients present at a younger age and with locally advanced disease. However, short term follow-up reveals that the outcomes are comparable with the published literature from developed countries. Long-term follow-up and inclusion of data from population-based registries are required for accurate comparison.

Down's syndrome: prospects for prevention by antenatal diagnosis.

UNLABELLED: The results of a prospective study on cytogenetic analysis of Chorionic Villus Samples (CVS) taken in early pregnancy (after 10 weeks) from pregnant ladies aged between 22 and 50 years are being presented. OBJECTIVE: To find out the prevalence of chromosomal defects with advancing age of the mother. SETTING: Department of Medical Genetics, Armed Forces Institute of Pathology, Rawalpindi. METHODS: A total of 48 samples have been studied. Ten patients were above the age of 35 years and 38 were below the age of 35 years. Chorionic villus samples were obtained after 10th week of pregnancy through transabdominal approach. Cytogenetic cultures were set up both by the direct and routine methods. RESULTS: Three out of the seven samples taken from expecting mothers aged above 35 and one culture from a patient aged less than 35, showed trisomy 21. CONCLUSION: This study highlights the fact that incidence of chromosomal aberrations and the Down's syndrome in particular, increases with the advancing maternal age. Prenatal studies can therefore be utilized to decrease the incidence of various chromosomal abnormalities.