CD44 is a multifunctional protein involved in cell adhesion and signaling. The role of CD44 in prostate cancer (PCa) development and progression is controversial with studies showing both tumor-promoting and tumor-inhibiting effects. Most of these studies have used bulk-cultured PCa cells or PCa tissues to carry out correlative or overexpression experiments. The key experiment using prospectively purified cells has not been carried out. Here we use FACS to obtain homogeneous CD44 þ and CD44 À tumor cell populations from multiple PCa cell cultures as well as four xenograft tumors to compare their in vitro and in vivo tumor-associated properties. Our results reveal that the CD44 þ PCa cells are more proliferative, clonogenic, tumorigenic, and metastatic than the isogenic CD44 À PCa cells. Subsequent molecular studies demonstrate that the CD44 þ PCa cells possess certain intrinsic properties of progenitor cells. First, BrdU pulse-chase experiments reveal that CD44 þ cells colocalize with a population of intermediate label-retaining cells. Second, CD44 þ PCa cells express higher mRNA levels of several 'stemness' genes including Oct-3/4, Bmi, b-catenin, and SMO. Third, CD44 þ PCa cells can generate CD44 À cells in vitro and in vivo. Fourth, CD44 þ PCa cells, which are AR À , can differentiate into AR þ tumor cells. Finally, a very small percentage of CD44 þ PCa cells appear to undergo asymmetric cell division in clonal analyses. Altogether, our results suggest that the CD44 þ PCa cell population is enriched in tumorigenic and metastatic progenitor cells.

Chemoresistance is the major obstacle in multiple myeloma (MM) management. We previously showed that macrophages protect myeloma cells, on a cell contact basis, from melphalan or dexamethasone-induced apoptosis in vitro. In this study, we found that macrophage-mediated myeloma drug resistance was also seen with purified macrophages from myeloma patients’ bone marrow (BM) in vitro and was confirmed in vivo using the human myeloma-SCID (severe combined immunodeficient) mouse model. By profiling differentially regulated and paired plasma membrane protein genes, we showed that PSGL-1 (P-selectin glycoprotein ligand-1)/selectins and ICAM-1/CD18 played an important role in macrophage-mediated myeloma cell drug resistance, as blocking antibodies against these molecules or genetic knockdown of PSGL-1 or ICAM-1 in myeloma cells repressed macrophages’ ability to protect myeloma cells. Interaction of macrophages and myeloma cells via these molecules activated Src and Erk1/2 kinases and c-myc pathways and suppressed caspase activation induced by chemotherapy drugs. Thus, our study sheds new light on the mechanism of drug resistance in MM and provides novel targets for improving the efficacy of chemotherapy in patients.

Constraints on deliverable MU for each spot could create a significant distortion from the ideally optimized dose distributions for IMPT fields using SFO. To eliminate this problem, the treatment planning system should incorporate the MU constraints in the optimization process and the delivery system should reliably delivery smaller minimum MUs.

No abstract

RTOG 0915 was open, and closed on April 15; 2015 after accruing a total of 98 patients. All patients received planned SBRT treatment. Median follow-up was 27 months. In follow-up; 10 patients were lost to follow-up; 1 was in arm 1 and 9 in arm 2. Baseline patient and tumor characteristics were balanced between both arms. Thirteen (27%) patients on arm 1 and 16 (33%) patients on arm 2 experienced RTOG grade 3 AEs; there were no grade 4 AEs. Thoracic grade 3 AEs were experienced by 8 (16%) patients on arm 1 and 6 (12%) patients on arm 2. There were no differences in OS or PFS survival, log-rank PZ.44 and .99, respectively. OS at 2 years was 71% (95% CI; 55-82%) for arm 1 and 61% (95% CI; 44-78%) for arm 2. PFS at 2 years was 63% (95% CI; 46-75%) for arm 1 and 51% (95% CI; 34-65%) for arm 2. Conclusion: This randomized phase 2 study demonstrated that 30 Gy in one fraction was equivalent to 60 Gy in three fractions in terms of toxicity, progression-free survival, and overall survival.