ABSTRACT
INTRODUCTION: Calcium metabolism dysregulation in the setting of primary hyperparathyroidism (PHPT) mediated chondrocalcinosis is implicated in joint pain, a key element in the decision regarding arthroplasty for osteoarthritis. The relationship between hypercalcemia and joint pain, before and after arthroplasty, is unknown. This study investigates the association between preoperative hypercalcemia and postoperative outcomes following total knee (TKA) and total hip arthroplasty (THA). METHODS: A retrospective chart review was conducted on patients who underwent initial elective THA or TKA. Patients with a preoperative serum calcium >10.2 mg/dL were matched (1:2-1:4) with nearest neighbor to patients with normal serum calcium. THA and TKA functional outcomes were measured at baseline and 1-y postoperatively using patient-reported Hip Disability and Osteoarthritis Outcome Scores and Knee Injury and Osteoarthritis Outcome Scores surveys. Postoperative complications, readmissions, length of stay, and functional outcome scores were compared. RESULTS: Four hundred ninety-five patients (106 hypercalcemic cases, 389 matched controls) were included. Of these, 223 patients underwent THA (46 cases; 177 controls) and 272 patients underwent TKA (61 cases; 211 controls). There were no differences in Hip Disability and Osteoarthritis Outcome Scores and Knee Injury and Osteoarthritis Outcome Scores scores, postoperative complications, readmissions, or length of stay between cases and controls. Only 19/106 (18%) hypercalcemic patients had a parathyroid hormone (PTH); of these, 9 (47%) had possible PHPT (PTH > 40). CONCLUSIONS: Patients with hypercalcemia undergoing arthroplasty have similar functional and postoperative outcomes as normocalcemic patients. As PTH was obtained in <20% of hypercalcemic cases and 50% had possible PHPT, we recommend that hypercalcemic patients undergo PHPT workup. Additional investigation is needed to determine the effect of PHPT on arthroplasty outcomes.
ABSTRACT
The first metastable assembly intermediate of the eukaryotic ribosomal small subunit (SSU) is the SSU Processome, a large complex of RNA and protein factors that is thought to represent an early checkpoint in the assembly pathway. Transition of the SSU Processome towards continued maturation requires the removal of the U3 snoRNA and biogenesis factors as well as ribosomal RNA processing. While the factors that drive these events are largely known, how they do so is not. The methyltransferase Bud23 has a role during this transition, but its function, beyond the nonessential methylation of ribosomal RNA, is not characterized. Here, we have carried out a comprehensive genetic screen to understand Bud23 function. We identified 67 unique extragenic bud23Δ-suppressing mutations that mapped to genes encoding the SSU Processome factors DHR1, IMP4, UTP2 (NOP14), BMS1 and the SSU protein RPS28A. These factors form a physical interaction network that links the binding site of Bud23 to the U3 snoRNA and many of the amino acid substitutions weaken protein-protein and protein-RNA interactions. Importantly, this network links Bud23 to the essential GTPase Bms1, which acts late in the disassembly pathway, and the RNA helicase Dhr1, which catalyzes U3 snoRNA removal. Moreover, particles isolated from cells lacking Bud23 accumulated late SSU Processome factors and ribosomal RNA processing defects. We propose a model in which Bud23 dissociates factors surrounding its binding site to promote SSU Processome progression.
Subject(s)
Methyltransferases/metabolism , Ribosome Subunits, Small/metabolism , Saccharomyces cerevisiae Proteins/metabolism , DEAD-box RNA Helicases/genetics , DEAD-box RNA Helicases/metabolism , GTP-Binding Proteins/genetics , GTP-Binding Proteins/metabolism , Methyltransferases/genetics , Mutation , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Protein Binding , RNA, Small Nucleolar/metabolism , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Ribosomal Proteins/genetics , Ribosomal Proteins/metabolism , Saccharomyces cerevisiae , Saccharomyces cerevisiae Proteins/geneticsABSTRACT
BACKGROUND: Poor outcomes for patients with ovarian cancer relate to dormant, drug-resistant cancer cells that survive after primary surgery and chemotherapy. Ovarian cancer (OvCa) cells persist in poorly vascularized scars on the peritoneal surface and depend on autophagy to survive nutrient deprivation. The authors have sought drugs that target autophagic cancer cells selectively to eliminate residual disease. METHODS: By using unbiased small-interfering RNA (siRNA) screens, the authors observed that knockdown of anaplastic lymphoma kinase (ALK) reduced the survival of autophagic OvCa cells. Small-molecule ALK inhibitors were evaluated for their selective toxicity against autophagic OvCa cell lines and xenografts. Autophagy was induced by reexpression of GTP-binding protein Di-Ras3 (DIRAS3) or serum starvation and was evaluated with Western blot analysis, fluorescence imaging, and transmission electron microscopy. Signaling pathways required for crizotinib-induced apoptosis of autophagic cells were explored with flow cytometric analysis, Western blot analysis, short-hairpin RNA knockdown of autophagic proteins, and small-molecule inhibitors of STAT3 and BCL-2. RESULTS: Induction of autophagy by reexpression of DIRAS3 or serum starvation in multiple OvCa cell lines significantly reduced the 50% inhibitory concentration of crizotinib and other ALK inhibitors. In 2 human OvCa xenograft models, the DIRAS3-expressing tumors treated with crizotinib had significantly decreased tumor burden and long-term survival in 67% to 79% of mice. Crizotinib treatment of autophagic cancer cells further enhanced autophagy and induced autophagy-mediated apoptosis by decreasing phosphorylated STAT3 and BCL-2 signaling. CONCLUSIONS: Crizotinib may eliminate dormant, autophagic, drug-resistant OvCa cells that remain after conventional cytoreductive surgery and combination chemotherapy. A clinical trial of ALK inhibitors as maintenance therapy after second-look operations should be seriously considered.