Matrix detachment and proteasomal inhibitors diminish Sulf-2 expression in breast cancer cell lines and mouse xenografts

Sulfatase 2 (Sulf-2) has been previously shown to be upregulated in breast cancer. Sulf-2 removes sulfate moieties on heparan sulfate proteoglycans which in turn modulate heparin binding growth factor signaling. Here we report that matrix detachment resulted in decreased Sulf-2 expression in breast cancer cells and increased cleavage of poly ADP-ribose polymerase. Silencing of Sulf-2 promotes matrix detachment induced cell death in MCF10DCIS cells. In an attempt to identify Sulf-2 specific inhibitor, we found that proteasomal inhibitors such as MG132, Lactacystin and Bortezomib treatment abolished Sulf-2 expression in multiple breast cancer cell lines. Additionally, we show that Bortezomib treatment of MCF10DCIS cell xenografts in mouse mammary fat pads significantly reduced tumor size, caused massive apoptosis and more importantly reduced Sulf-2 levels in vivo. Finally, our immunohistochemistry analysis of Sulf-2 expression in cohort of patient derived breast tumors indicates that Sulf-2 is significantly upregulated in autologous metastatic lesions compared to primary tumors (p < 0.037, Pearson correlation, Chi-Square analysis). In all, our data suggest that Sulf-2 might play an important role in breast cancer progression from ductal carcinoma in situ into an invasive ductal carcinoma potentially by resisting cell death.     

Does Race Affect Outcomes in Total Joint Arthroplasty?

Background

Several studies suggest worse surgical outcomes among racial/ethnic minorities. There is a paucity of research on preoperative and postoperative pain, general health, and disease-specific measures in which race is the main subject of investigation; furthermore, the results are not conclusive.

Questions/purposes

(1) Do black patients have more severe or more frequent preoperative pain, well-being, general health, and disease-specific scores when compared with white patients? (2) Are there differences between black patients and white patients after hip or knee arthroplasty on those same measures?

Methods

In this retrospective study, we used an institutional arthroplasty registry to analyze data on 2010 primary arthroplasties (1446 knees and 564 hips) performed by one surgeon at a single institution. Cases from patients self-identifying as black (n = 105) and white (n = 1905) were compared (controlling for confounders, including age and ethnicity) on the following preoperative and postoperative patient-oriented outcomes: pain intensity/frequency as measured by a visual analog scale (VAS), Quality of Well-Being (QWB-7), SF-36, and WOMAC scores. T-tests, chi square, and multivariate analysis of covariance were used. Alpha was set at 0.05. Postoperative analysis was performed only on those cases that had a minimum followup of 1 year (mean, 3.5 years; range, 1–9 years). Of the 2010 arthroplasties, 37% (39 of 105) of those cases performed in black patients and 64% (1219 of 1905) of those performed in white patients were included in the final postoperative model (multivariate analysis of covariance).

Results

Black patients had more severe preoperative pain intensity (VAS: 8 ± 1.8 versus 8 ± 2.0, mean difference = 0.76 [95% confidence interval {CI}, 0.34–1.1], p < 0.001). Black patients also had worse well-being scores (QWB-7: 0.527 ± 0.04 versus 0.532 ± 0.05, mean difference = −0.01 [CI, −0.02 to 0.00], p = 0.037). Postoperatively, pain intensity (VAS: 1 ± 3.1 versus 1 ± 1.8, mean difference= 0.8 [CI, 0.19–1.4], p= 0.010) and (QWB-7: 0.579 ± 0.09 versus 0.607 ± 0.11, mean difference= −0.049 [CI, −0.08 to −0.01], p = 0.008) were different but without clinical significance.

Conclusions

Black patients underwent surgery earlier in life and with different preoperative diagnoses when compared with white patients. Black patients had worse preoperative baseline pain, well-being, general health, and disease-specific scores as well as worse postoperative scores. However, these differences were very narrow and without clinical significance. Notwithstanding, the relations of race with outcomes remain complex. Further investigations to recognize disparities and minimize or address them are warranted.

Level of Evidence

Level III, prognostic study.     

A new strategy for label-free detection of lymphoma cancer cells

In this paper, a new strategy for highly selective and sensitive direct detection of lymphoma cells by exploiting the interaction between a peptide and its B-cell receptor, has been evaluated. In particular, an idiotype peptide, able to specifically bind the B-cell receptor of A20 cells in mice engrafted with A20 lymphoma, has been used as molecular probe. The new detection technique has been demonstrated on a planar crystalline silicon chip. Coverage of 85% of silicon surface and detection efficiency of 8.5 × 10⁻³ cells/μm² were obtained. The recognition strategy promises to extend its application in studying the interaction between ligands and their cell-surface receptors.OCIS codes: (000.1430) Biology and medicine, (280.1415) Biological sensing and sensors     

Paricalcitol for Secondary Hyperparathyroidism in Renal Transplantation

Secondary hyperparathyroidism contributes to post-transplant CKD mineral and bone disorder. Paricalcitol, a selective vitamin D receptor activator, decreased serum parathyroid hormone levels and proteinuria in patients with secondary hyperparathyroidism. This single-center, prospective, randomized, crossover, open-label study compared the effect of 6-month treatment with paricalcitol (1 μg/d for 3 months and then uptitrated to 2 µg/d if tolerated) or nonparicalcitol therapy on serum parathyroid hormone levels (primary outcome), mineral metabolism, and proteinuria in 43 consenting recipients of renal transplants with secondary hyperparathyroidism. Participants were randomized 1:1 according to a computer-generated sequence. Compared with baseline, median (interquartile range) serum parathyroid hormone levels significantly declined on paricalcitol from 115.6 (94.8–152.0) to 63.3 (52.0–79.7) pg/ml (P<0.001) but not on nonparicalcitol therapy. At 6 months, levels significantly differed between treatments (P<0.001 by analysis of covariance). Serum bone-specific alkaline phosphatase and osteocalcin decreased on paricalcitol therapy only and significantly differed between treatments at 6 months (P<0.001 for all comparisons). At 6 months, urinary deoxypyridinoline-to-creatinine ratio and 24-hour proteinuria level decreased only on paricalcitol (P<0.05). L3 and L4 vertebral mineral bone density, assessed by dual-energy x-ray absorption, significantly improved with paricalcitol at 6 months (P<0.05 for both densities). Paricalcitol was well tolerated. Overall, 6-month paricalcitol supplementation reduced parathyroid hormone levels and proteinuria, attenuated bone remodeling and mineral loss, and reduced eGFR in renal transplant recipients with secondary hyperparathyroidism. Long-term studies are needed to monitor directly measured GFR, ensure that the bone remodeling and mineral effects are sustained, and determine if the reduction in proteinuria improves renal and cardiovascular outcomes.