ABSTRACT
Ovarian cancer (OC) is the most deadly gynecological cancer and unlike most other neoplasms, survival rates for OC have not significantly improved in recent decades. We show that RAD6, an ubiquitin-conjugating enzyme, is significantly overexpressed in ovarian tumors and its expression increases in response to carboplatin chemotherapy. RAD6 expression correlated strongly with acquired chemoresistance and malignant behavior of OC cells, expression of stem cell genes and poor prognosis of OC patients, suggesting an important role for RAD6 in ovarian tumor progression. Upregulated RAD6 enhances DNA damage tolerance and repair efficiency of OC cells and promotes their survival. Increased RAD6 levels cause histone 2B ubiquitination-mediated epigenetic changes that stimulate transcription of stem cell genes, including ALDH1A1 and SOX2, leading to a cancer stem cell phenotype, which is implicated in disease recurrence and metastasis. Downregulation of RAD6 or its inhibition using a small molecule inhibitor attenuated DNA repair signaling and expression of cancer stem cells markers and sensitized chemoresistant OC cells to carboplatin. Together, these results suggest that RAD6 could be a therapeutic target to prevent and treat acquired chemoresistance and disease recurrence in OC and enhance the efficacy of standard chemotherapy.
Subject(s)
Neoplasms, Glandular and Epithelial/enzymology , Ovarian Neoplasms/enzymology , Ubiquitin-Conjugating Enzymes/physiology , Antineoplastic Agents/pharmacology , Carboplatin/pharmacology , Carcinoma, Ovarian Epithelial , Cell Line, Tumor , DNA Repair , DNA Replication , Disease-Free Survival , Drug Resistance, Neoplasm , Female , Humans , Neoplasms, Glandular and Epithelial/drug therapy , Neoplasms, Glandular and Epithelial/mortality , Neoplasms, Glandular and Epithelial/pathology , Neoplastic Stem Cells/enzymology , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/mortality , Ovarian Neoplasms/pathology , Prognosis , Signal TransductionABSTRACT
Sixteen patients scheduled for an uncemented total knee arthroplasty (TKA) were randomized to receive a tibial component either with (n = 8) or without (n = 8) hydroxyapatite (HA) coating. In 4 regions of interest, prospective measurements of bone mineral density (BMD) using dual-energy x-ray absorptiometry were performed in the proximal tibia. Two years after the operation, the only significant change in BMD was in the lateral tibial condyle, where BMD had increased by 6.1% (95% confidence interval: 2.3%-9.9%) in patients with tibial components without HA. The intragroup changes (0-24 months) in the uncoated group and HA-coated group were significantly different (P = .003) in these regions of interest. There was no significant effect of HA coating on bone remodeling pattern of the proximal tibia.
Subject(s)
Arthroplasty, Replacement, Knee , Bone Density , Durapatite , Tibia , Absorptiometry, Photon , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Prospective Studies , Prosthesis DesignSubject(s)
Granulomatosis with Polyangiitis/diagnosis , Granulomatosis with Polyangiitis/therapy , Heart Block/therapy , Antibodies, Antineutrophil Cytoplasmic/immunology , Antirheumatic Agents/therapeutic use , Electrocardiography , Granulomatosis with Polyangiitis/complications , Granulomatosis with Polyangiitis/immunology , Heart Block/diagnosis , Heart Block/etiology , Humans , Male , Middle Aged , Plasmapheresis , Treatment OutcomeABSTRACT
We evaluated the feasibility of DEXA (Norland XR-26 mark II) for quantitative measurements of bone mineral density (BMD) in the lateral plane of the distal femur after total knee arthroplasty (TKA). BMD was measured in 5-6 regions of interest (ROI) in close relation to the femoral component. In an in vitro study using 3 different distal femur phantoms, we found that the precision was affected by rotation of the distal femur. When BMD measurements were repeated within a range of motion of 40 degrees, 20 degrees, and 0 degrees, the coefficient of variation (CV) was approximately 15%, 10%, and 0.6%, respectively. We found that the use of bone cement for implant fixation had no effect on the level of BMD. Double measurements performed in 28 patients gave average CV values of 3.3%, 3.0%, and 2.6% for the uncemented Duracon, and Interax femoral components and the cemented AGC components, respectively. Our in vivo average CV measurements of BMD of the distal femur after TKA were on a level, suitable for repeated BMD measurements in prospective studies, which evaluate adaptive bone remodeling of the distal femur after cemented and uncemented TKA.
Subject(s)
Arthroplasty, Replacement, Knee , Bone Density , Absorptiometry, Photon , Adult , Aged , Aged, 80 and over , Feasibility Studies , Female , Femur/physiology , Humans , Male , Middle Aged , RotationABSTRACT
The effects of normal, low and high plasma concentrations of 1,25-(OH)2vitamin D (1,25-(OH)2D) combined with normal, low and high concentrations of plasma calcium on renal calbindin-D28k and intestinal calbindin-D9k were examined in rats. We found that the expression of renal calbindin-D28k was significantly (P<0.05) increased by high levels of 1,25-(OH)2D, but was not affected by a 50% reduction in 1,25-(OH)2D. In contrast the intestinal calbindin-D9k responded significantly (P<0.005) to both high and low 1,25-(OH)2D levels. The effect of 1,25-(OH)2D on intestinal calbindin-D9k was modulated by plasma calcium concentrations. Increased plasma calcium levels did not affect the renal calbindin-D28k concentrations, but suppressed intestinal calbindin-D9k (P<0.05). The effect of calcium was not mediated by calciotropic hormones. This suggests the existence of a calcium-sensing mechanism in the proximal duodenum. It is concluded that intestinal calbindin-D9k is more sensitive than renal calbindin-D28k to changes in 1,25-(OH)2D and that intestinal calbindin-D9k in contrast to renal calbindin-D28k is sensitive to changes in plasma calcium concentrations.
