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.     

An ambulatory blood pressure monitoring study of the comparative antihypertensive efficacy of two angiotensin II receptor antagonists,irbesartan and valsartan

BACKGROUND: The primary objective of this study was to compare the change from baseline in mean diastolic ambulatory blood pressure (ABP) at 24 h post dose (trough measurement) after 8 weeks of treatment with irbesartan or valsartan in subjects with mild-to-moderate hypertension. Secondary objectives included comparing the mean changes from baseline in systolic ABP at trough; 24-h ABP; morning and night-time ABP; self-measured systolic blood pressure (SBP) and diastolic blood pressure (DBP); and office-measured SBP and DBP at trough. DESIGN: After a 3-week, single blind, placebo lead-in period, 426 subjects were randomized to receive either irbesartan 150 mg or valsartan 80 mg for 8 weeks. METHODS: Ambulatory blood pressure measurements were obtained at baseline and at week 8. Self-measured morning and evening DBP and SBP readings were obtained at home over a 7-day period at baseline and at week 8. Office-measured seated DBP and SBP measurements were obtained at trough, at baseline, and at week 8. RESULTS: Irbesartan demonstrated significantly greater reductions than valsartan for mean change from baseline in diastolic ABP at trough (-6.73 versus -4.84 mmHg, respectively; P = 0.035). Irbesartan produced significantly greater reductions than valsartan for mean systolic ABP at trough (-11.62 versus -7.5 mmHg, respectively; P < 0.01) and for mean 24-h diastolic ABP (-6.38 versus -4.82 mmHg, respectively; P = 0.023) and systolic ABP (-10.24 versus -7.76 mmHg; P < 0.01). Irbesartan also produced significantly greater reductions than valsartan for office-measured seated DBP (-10.46 versus 7.28 mmHg, respectively; P < 0.01) and SBP (-16.23 versus -9.96 mmHg, respectively; P < 0.01) and for self-measured morning DBP (-6.28 versus -3.75 mmHg, respectively; P < 0.01) and SBP (-10.21 versus -6.97 mmHg, respectively; P < 0.01). Both drugs were well tolerated. CONCLUSION: Irbesartan was more effective than valsartan in reducing DBP and SBP at trough and in providing greater overall 24-h blood pressure-lowering efficacy.     

Outcomes in splenic marginal zone lymphoma: analysis of 107 patients treated in British Columbia

Splenic marginal zone lymphoma (SMZL) accounts for less than 2% of all non‐Hodgkin lymphomas. We identified 107 cases diagnosed with SMZL between 1985 and 2012 from the British Columbia Cancer Agency Centre for Lymphoid Cancer and Lymphoma Pathology Databases. Patient characteristics were: median age 67 years (range 30–88), male 40%, stage IV 98%, splenomegaly 93%, bone marrow involvement 96%, peripheral blood involvement 87%. As initial treatment, 52 underwent splenectomy (10 with chemotherapy), 38 chemotherapy alone (21 chemoimmunotherapy containing rituximab, 1 rituximab alone), two antivirals for hepatitis C, and 15 were only observed. The 10‐year overall survival for first‐line splenectomy versus chemotherapy was 61% and 42%, respectively [Hazard Ratio (HR) 0·48, 95% confidence interval (CI) 0·26–0·88, P = 0·017]. The 10‐year failure‐free survival (FFS) after first‐line splenectomy vs chemotherapy was 39% and 14%, respectively (HR 0·48, 95% CI 0·28–0·80, P = 0·004). Among the 38 patients who received first‐line chemotherapy, FFS was similar between those receiving rituximab (n = 22) and those who did not (n = 16) (HR 0·64, 95% CI 0·31–1·34, P = 0·238). Fifteen patients transformed to aggressive lymphoma with median time to transformation of 3·5 years (range 6 months to 12 years) and the 10‐year transformation rate was 18%. In conclusion, splenectomy remains a reasonable treatment for patients with SMZL.