Patients with pT1 renal cell carcinoma who die from disease after nephrectomy may have unrecognized renal sinus fat invasion

Prior studies suggest that the renal sinus permits early tumor spread in otherwise localized renal cell carcinoma (RCC) tumors. We hypothesized that renal sinus fat invasion may be unrecognized in pT1 patients who subsequently die from RCC. Between 1985 and 2002, we identified 577 patients who underwent radical nephrectomy for localized pT1 clear cell RCC as reviewed by a single urologic pathologist (J.C.C.). Among these patients, 49 died from RCC including 33 who had their original nephrectomy specimen stored in formalin. These specimens were then resectioned with thin cuts of the renal sinus and reviewed by the same pathologist. For comparison, 33 patients who did not die from RCC (controls) also had their original nephrectomy specimen resectioned. Among the 33 patients who died from seemingly localized RCC, 14 (42%) had previously unrecognized renal sinus fat invasion compared with 2 (6%) of the controls (P<0.001). In addition, 19 (58%) patients who died from RCC had renal sinus small vein (microscopic venous) invasion, a pathologic feature not currently incorporated into the TNM staging system for RCC. This feature was present in 7 (21%) of the controls (P=0.003). In total, 22 (67%) patients who died from RCC had unrecognized renal sinus fat or small vein invasion compared with 7 (21%) of the controls (P<0.001). We conclude that renal sinus fat invasion is an important adverse pathologic feature that is clearly underreported in the literature. Appropriate assessment of nephrectomy specimens should include proper sampling of the renal sinus even for seemingly localized tumors.     

Shikimate kinase: a potential target for development of novel antitubercular agents

Tuberculosis (TB) remains the leading cause of mortality due to a bacterial pathogen, Mycobacterium tuberculosis. However, no new classes of drugs for TB have been developed in the past 30 years. Therefore there is an urgent need to develop faster acting and effective new antitubercular agents, preferably belonging to new structural classes, to better combat TB, including MDR-TB, to shorten the duration of current treatment to improve patient compliance, and to provide effective treatment of latent tuberculosis infection. The enzymes in the shikimate pathway are potential targets for development of a new generation of antitubercular drugs. The shikimate pathway has been shown by disruption of aroK gene to be essential for the Mycobacterium tuberculosis. The shikimate kinase (SK) catalyses the phosphorylation of the 3-hydroxyl group of shikimic acid (shikimate) using ATP as a co-substrate. SK belongs to family of nucleoside monophosphate (NMP) kinases. The enzyme is an alpha/beta protein consisting of a central sheet of five parallel beta-strands flanked by alpha-helices. The shikimate kinases are composed of three domains: Core domain, Lid domain and Shikimate-binding domain. The Lid and Shikimate-binding domains are responsible for large conformational changes during catalysis. More recently, the precise interactions between SK and substrate have been elucidated, showing the binding of shikimate with three charged residues conserved among the SK sequences. The elucidation of interactions between MtSK and their substrates is crucial for the development of a new generation of drugs against tuberculosis through rational drug design.     

Probing the role of the proximal heme ligand in cytochrome P450cam by recombinant incorporation of selenocysteine

The unique monooxygenase activity of cytochrome P450cam has been attributed to coordination of a cysteine thiolate to the heme cofactor. To investigate this interaction, we replaced cysteine with the more electron-donating selenocysteine. Good yields of the selenoenzyme were obtained by bacterial expression of an engineered gene containing the requisite UGA codon for selenocysteine and a simplified yet functional selenocysteine insertion sequence (SECIS). The sulfur-to-selenium substitution subtly modulates the structural, electronic, and catalytic properties of the enzyme. Catalytic activity decreases only 2-fold, whereas substrate oxidation becomes partially uncoupled from electron transfer, implying a more complex role for the axial ligand than generally assumed.     

Functional analysis of an Orc6 mutant in Drosophila

The origin recognition complex (ORC) is a 6-subunit complex required for the initiation of DNA replication in eukaryotic organisms. ORC is also involved in other cell functions. The smallest Drosophila ORC subunit, Orc6, is important for both DNA replication and cytokinesis. To study the role of Orc6 in vivo, the orc6 gene was deleted by imprecise excision of P element. Lethal alleles of orc6 are defective in DNA replication and also show abnormal chromosome condensation and segregation. The analysis of cells containing the orc6 deletion revealed that they arrest in both the G₁ and mitotic stages of the cell cycle. Orc6 deletion can be rescued to viability by a full-length Orc6 transgene. The expression of mutant transgenes of Orc6 with deleted or mutated C-terminal domain results in a release of mutant cells from G₁ arrest and restoration of DNA replication, indicating that the DNA replication function of Orc6 is associated with its N-terminal domain. However, these mutant cells accumulate at mitosis, suggesting that the C-terminal domain of Orc6 is important for the passage through the M phase. In a cross-species complementation experiment, the expression of human Orc6 in Drosophila Orc6 mutant cells rescued DNA replication, suggesting that this function of the protein is conserved among metazoans.     

Correlations between postural stability and strength of lower body extremities of women population living in long-term care facilities

The present study was aimed at analyzing correlation between strength of lower body extremities and postural stability in function of age. A pool of 180 women divided into 6 age groups (65-69, 70-74, 75-79, 80-84, 85-89 and 90-94 years) was examined. They all were informed-consent participants. The results suggest that age is negatively correlated with lower body strength and positively correlated with decrease of postural balance. There is also an exponential correlation between the strength of lower body part and postural balance. The conclusion was derived that postural stability is at least partially controlled by the strength of lower body. The age of 75 in women population seems to be a threshold above which the neurodegenerative and muscle degeneration processes are responsible for significant increase of risk of fall.