Polo-Like Kinase 1(PLK1) Immunohistochemical Expression in Triple Negative Breast Carcinoma: A Probable Therapeutic Target

Background: Breast cancer is the most commonly diagnosed female cancer and is a major cause of cancer-related deaths in women. Triple-negative breast cancer (TNBC) is defined as ER, PR and HER2 negative, which are characterized by rapid progression with low survival rates with limited therapeutic choices. Polo-like kinase 1 protein acts as a cell division regulator which is highly expressed in many tumors making it a potentially valuable target for antiproliferative therapies. In this study we tried to evaluate the value of this marker as a possible therapeutic target in TNBC. Methods: This research studied the immunohistochemical expression of PLK1 done on 49 paraffin blocks of TNBC female patients and then correlated with the different clinicopathological parameters. Results: Our results showed high PLK1 expression in 91.9% of cases. Most of the high grade tumors showed high PLK1 high score (76.9%). All cases showing lymph node metastasis showed high PLK1 expression, implying a statistically significant correlation between PLK1 expression and tumor grade as well as N stage. Conclusion: PLK1, although a negative prognostic factor, but is a promising therapeutic target for treating TNBC patients.     

A llama single domain anti-idiotypic antibody mimicking HER2 as a vaccine: Immunogenicity and efficacy

HER2 over-expression in breast cancer correlates with reduced survival. Anti-idiotypic antibodies (Abs) that closely mimic HER2 could play a crucial role in the development of effective therapeutic vaccines. Here, we show that an anti-idiotypic single domain antibody (sdAb) 1HE isolated from a library generated from a Trastuzumab F(ab′)₂-immunized llama, closely mimics HER2. SdAb 1HE shows high affinity for Trastuzumab F(ab′)₂, selectively inhibits HER2 binding to Trastuzumab F(ab′)₂, and sera from sdAb 1HE-immunized BALB/c mice contain anti-HER2 antibodies that inhibit viability of HER2-positive cells. These results indicate that sdAb 1HE could be used as an anti-idiotype-based vaccine to boost immunity in patients bearing HER2-positive tumours.     

Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy

Autophagy is an intracellular bulk degradation process for proteins and organelles. In the heart, autophagy is stimulated by myocardial ischemia. However, the causative role of autophagy in the survival of cardiac myocytes and the underlying signaling mechanisms are poorly understood. Glucose deprivation (GD), which mimics myocardial ischemia, induces autophagy in cultured cardiac myocytes. Survival of cardiac myocytes was decreased by 3-methyladenine, an inhibitor of autophagy, suggesting that autophagy is protective against GD in cardiac myocytes. GD-induced autophagy coincided with activation of AMP-activated protein kinase (AMPK) and inactivation of mTOR (mammalian target of rapamycin). Inhibition of AMPK by adenine 9-beta-d-arabinofuranoside or dominant negative AMPK significantly reduced GD-induced autophagy, whereas stimulation of autophagy by rapamycin failed to cause an additive effect on GD-induced autophagy, suggesting that activation of AMPK and inhibition of mTOR mediate GD-induced autophagy. Autophagy was also induced by ischemia and further enhanced by reperfusion in the mouse heart, in vivo. Autophagy resulting from ischemia was accompanied by activation of AMPK and was inhibited by dominant negative AMPK. In contrast, autophagy during reperfusion was accompanied by upregulation of Beclin 1 but not by activation of AMPK. Induction of autophagy and cardiac injury during the reperfusion phase was significantly attenuated in beclin 1(+/-) mice. These results suggest that, in the heart, ischemia stimulates autophagy through an AMPK-dependent mechanism, whereas ischemia/reperfusion stimulates autophagy through a Beclin 1-dependent but AMPK-independent mechanism. Furthermore, autophagy plays distinct roles during ischemia and reperfusion: autophagy may be protective during ischemia, whereas it may be detrimental during reperfusion.     

Catheter-related Staphylococcus aureus bacteremia in cancer patients: high rate of complications with therapeutic implications

Risk factors for complications of catheter-related Staphylococcus aureus bacteremia (CRSAB) have been studied in the general patient population but have not been well defined in cancer patients. We investigated potential risk factors for intravascular and extravascular complications in these patients. We retrospectively reviewed the records of patients with CRSAB hospitalized at our institution between January 2001 and December 2004. Demographic, clinical, laboratory, and microbiologic characteristics were extracted for the period of hospitalization and up to 3 months thereafter. Intravascular complications were defined as infective endocarditis and/or septic thrombosis. Extravascular complications included septic arthritis, deep tissue abscess, osteomyelitis, septic pulmonary emboli, septic shock, and CRSAB-related death. Ninety-one patients were included in the current study; 63% had solid tumors and the remainder had hematologic malignancies. The incidence of overall complications was 40% (n = 36); 19% (n = 17) were intravascular. On multivariate analysis, renal failure was associated with an increased risk of overall complications (odds ratio [OR], 12.78; 95% confidence interval [CI], 1.43-114.29; p = 0.0226). Patients with solid tumors were more likely to have intravascular complications (OR, 5.47; 95% CI, 1.11-27.01; p = 0.04369). Risk factors for extravascular complications included hematologic malignancy (OR, 9.56; 95% CI, 2.36-38.77; p = 0.0016) and female sex (OR, 5.25; 95% CI, 1.2-22.99; p = 0.0279). Renal failure is a risk factor for CRSAB complications in patients with cancer. Patients with solid tumors and CRSAB tend to develop intravascular complications, while patients with hematologic malignancies are prone to develop extravascular complications. Hence consideration should be given to extending the duration of therapy beyond 2 weeks.