Assessment of prognostic value of tissue inhibitors of metalloproteinase 3 (TIMP3) protein in ovarian cancer.

Background: TIMP3 is a multifunctional proteolytic enzyme belonging to TIMPs family and acts as a potent inhibitor of matrix metalloproteinases (MMPs). TIMP3 possesses a tumor suppresive function by directly promoting tumor cell apoptosis, preventing angiogenesis and extracellular matrix remodelling. The lower expression of TIMP3 was associated with poor prognosis and overall survival in various cancer types. The aim of this study was to evaluate the association of TIMP3 protein expression with ovarian cancer (OC) clinicopathological features and survival outcomes.Patients and Methods: One hundred forty four of OC FFPE samples were collected from King Abdulaziz University Hospital, Saudi Arabia and constructed in tissue microarray (TMA) slides. Automated Ventana immunostainer platform was used to evaluate TIMP3 protein expression patterns.Results: The study showed that TIMP3 exhibits cytoplasmic localisation. This TIMP3 protein expression was not associated with age, tumor size and the involvement of lymph nodes (p > 0.05). However, it was significantly correlated with tumor stage (p < 0.05) and borderline significant with endpoint status (p = 0.07). Interestingly, the Kaplan-Meier analysis of disease specific survival (DSS) outcomes showed a significant association (p = 0.02, log rank) between OC patients with higher TIMP3 expression compared to those with lower expression. In fact, OC patients with high TIMP3 expression had longer survivals. Multivariate Cox's regression analysis suggests that low TIMP3 protein expression pattern is an independent poor survival marker (p = 0.025).Conclusion: Cytoplasmic TIMP3 protein expression could be used as a good prognosticator to stratify poorly prognostic OC patients in order to personlaize their disease management.

Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies.

Telomeres maintain genomic integrity in normal cells, and their progressive shortening during successive cell divisions induces chromosomal instability. In the large majority of cancer cells, telomere length is maintained by telomerase. Thus, telomere length and telomerase activity are crucial for cancer initiation and the survival of tumors. Several pathways that regulate telomere length have been identified, and genome-scale studies have helped in mapping genes that are involved in telomere length control. Additionally, genomic screening for recurrent human telomerase gene hTERT promoter mutations and mutations in genes involved in the alternative lengthening of telomeres pathway, such as ATRX and DAXX, has elucidated how these genomic changes contribute to the activation of telomere maintenance mechanisms in cancer cells. Attempts have also been made to develop telomere length- and telomerase-based diagnostic tools and anticancer therapeutics. Recent efforts have revealed key aspects of telomerase assembly, intracellular trafficking and recruitment to telomeres for completing DNA synthesis, which may provide novel targets for the development of anticancer agents. Here, we summarize telomere organization and function and its role in oncogenesis. We also highlight genomic mutations that lead to reactivation of telomerase, and mechanisms of telomerase reconstitution and trafficking that shed light on its function in cancer initiation and tumor development. Additionally, recent advances in the clinical development of telomerase inhibitors, as well as potential novel targets, will be summarized.

Antistaphylococcal activity of WCK 771, a tricyclic fluoroquinolone, in animal infection models.

WCK 771, the arginine salt of S-(-)-nadifloxacin, was evaluated in animal models of staphylococcal infection and in vitro. For 302 methicillin-susceptible strains the MIC at which 50% of isolates are inhibited (MIC50) and the MIC90 of WCK 771 were 0.03 and 0.03 microg/ml, respectively, and for 198 methicillin-resistant strains the MIC50 and the MIC90 were 0.5 and 1.0 microg/ml, respectively. All methicillin-susceptible staphylococci were quinolone susceptible, and almost all methicillin-resistant staphylococci were quinolone resistant. WCK 771 was more potent than moxifloxacin, trovafloxacin, levofloxacin, and ciprofloxacin and had potency comparable to that of clinafloxacin. Only WCK 771 and clinafloxacin demonstrated strong potencies against vancomycin-intermediate Staphylococcus aureus strains (MICs = 1 microg/ml). WCK 771 is not a substrate of the NorA pump, as evident from the lack of an effect of reserpine on the MICs and similar protective doses against infections caused by efflux-positive and -negative staphylococci. WCK 771 was effective by both the oral and the subcutaneous routes in mice infected intraperitoneally with quinolone-susceptible methicillin-susceptible S. aureus (MSSA) strains. For infections caused by quinolone-resistant methicillin-resistant S. aureus (MRSA) strains, the activity of WCK 771 administered subcutaneously was superior to those of trovafloxacin and sparfloxacin, with a 50% effective dose range of 27.8 to 46.8 mg/kg of body weight. The activity of WCK 771 was superior to those of moxifloxacin, vancomycin, and linezolid in a mouse cellulitis model of infection caused by one MSSA and two MRSA strains, with effective doses of 2.5 and 5 mg/kg for the MSSA strain and 10-fold higher effective doses for MRSA strains. WCK 771, like vancomycin and linezolid, eradicated MRSA from mouse liver, spleen, kidney, and lung when it was administered subcutaneously at a dose of 50 mg/kg for four doses. These studies have demonstrated the effectiveness of WCK 771, administered orally and parenterally, for the treatment of diverse staphylococcal infections in mice, including those caused by quinolone-resistant strains.