Granzyme D Is a Novel Murine Mast Cell Protease That Is Highly Induced by Multiple Pathways of Mast Cell Activation

Granzymes are serine proteases known mostly for their role in the induction of apoptosis. Granzymes A and B have been extensively studied, but relatively little is known about granzymes C to G and K to M. T cells, lymphohematopoietic stromal cells, and granulated metrial gland cells express granzyme D, but the function of granzyme D is unknown. Here we show that granzyme D is expressed by murine mast cells and that its level of expression correlates positively with the extent of mast cell maturation. Coculture of mast cells with live, Gram-positive bacteria caused a profound, Toll-like receptor 2 (TLR2)-dependent induction of granzyme D expression. Granzyme D expression was also induced by isolated bacterial cell wall components, including lipopolysaccharide (LPS) and peptidoglycan, and by stem cell factor, IgE receptor cross-linking, and calcium ionophore stimulation. Granzyme D was released into the medium in response to mast cell activation. Granzyme D induction was dependent on protein kinase C and nuclear factor of activated T cells (NFAT). Together, these findings identify granzyme D as a novel murine mast cell protease and implicate granzyme D in settings where mast cells are activated, such as bacterial infection and allergy.     

Cerebrospinal fluid cathepsin B and S

Cathepsins are increased in the brain of elderly animals. We investigate the presence of cathepsin B and S in human cerebrospinal fluid (CSF) plasma and the associations with cystatin C, age and sex. We measured cathepsin B and S concentrations in CSFs from 118 persons, undergoing elective surgical procedures, with ELISA. Both cathepsin B and cathepsin S were positively correlated with age. No correlation was observed between cathepsin B or S and length, height or body mass index. Both cathepsin B and S were positively correlated to the cystatin C concentration in CSF. Calculated reference intervals were 4,893–17,636 pg/mL for cathepsin B and 2,681–11,459 pg/mL for cathepsin S. Elderly individuals had significantly higher levels of both cathepsin B (r _s = 0.38, p = 0.00002) and cathepsin S (r _s = 0.35, p = 0.0001) in CSF.     

Advanced Imaging Modalities in Early Stage Breast Cancer: Preoperative Use in the United States Medicare Population

Background

Guidelines for breast cancer staging exist, but adherence remains unknown. This study evaluates patterns of imaging in early stage breast cancer usually reserved for advanced disease.

Methods

Surveillance Epidemiology, and End Results data linked to Medicare claims from 1992–2005 were reviewed for stage I/II breast cancer patients. Claims were searched for preoperative performance of computed tomography (CT), positron emission tomography (PET), bone scans, and brain magnetic resonance imaging (MRI) (“advanced imaging”).

Results

There were 67,874 stage I/II breast cancer patients; 18.8 % (n = 12,740) had preoperative advanced imaging. The proportion of patients having CT scans, PET scans, and brain MRI increased from 5.7 % to 12.4 % (P < 0.0001), 0.8 % to 3.4 % (P < 0.0001) and 0.2 % to 1.1 % (P = 0.008), respectively, from 1992 to 2005. Bone scans declined from 20.1 % to 10.7 % (P < 0.0001). “Breast cancer” (174.x) was the only diagnosis code associated with 62.1 % of PET scans, 37.7 % of bone scans, 24.2 % of CT, and 5.1 % of brain MRI. One or more symptoms or metastatic site was suggested for 19.6 % of bone scans, 13.0 % of CT, 13.0 % of PET, and 6.2 % of brain MRI. Factors associated (P < 0.05) with use of all modalities were urban setting, breast MRI and ultrasound. Breast MRI was the strongest predictor (P < 0.0001) of bone scan (odds ratio [OR] 1.63, 95 % confidence interval [CI] 1.44–1.86), Brain MRI (OR 1.74, 95 % CI 1.15–2.63), CT (OR 2.42, 95 % CI 2.12–2.76), and PET (OR 5.71, 95 % CI 4.52–7.22).

Conclusions

Aside from bone scans, performance of advanced imaging is increasing in early stage Medicare breast cancer patients, with limited rationale provided by coded diagnoses. In light of existing guidelines and increasing scrutiny about health care costs, greater reinforcement of current indications is warranted.