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1.  Evidence for Ongoing DNA Damage in Multiple Myeloma Cells as Revealed by Constitutive Phosphorylation of H2AX 
Leukemia  2011;25(8):1344-1353.
DNA double strand breaks (DSBs) are deleterious lesions that can lead to chromosomal anomalies, genomic instability and cancer. The histone protein H2AX plays an important role in the DNA damage response (DDR) and the presence of phospho-H2AX (γH2AX) nuclear foci is the hallmark of DSBs. We hypothesize that ongoing DNA damage provides a mechanism by which chromosomal abnormalities and intratumor heterogeneity are acquired in malignant plasma cells (PCs) in patients with multiple myeloma (MM). Therefore, we assessed PCs from patients with the premalignant condition, monoclonal gammopathy of undetermined significance (MGUS) and MM, as well as human MM cell lines (HMCLs) for evidence of DSBs. γH2AX foci were detected in 2/5 MGUS samples, 37/40 MM samples and 6/6 HMCLs. Notably, the DSB response protein 53BP1 colocalized with γH2AX in both MM patient samples and HMCLs. Treatment with wortmannin decreased phosphorylation of H2AX and suggests phosphoinositide (PI) 3-kinases and/or PI3-kinase like family members underlie the presence of γH2AX foci in MM cells. Taken together, these data imply that ongoing DNA damage intensifies across the disease spectrum of MGUS to MM and may provide a mechanism whereby clonal evolution occurs in the monoclonal gammopathies.
PMCID: PMC3940337  PMID: 21566653
Myeloma; H2AX; PI3-kinase; ATR; DNA damage
2.  Increased Expression of Extracellular Matrix Metalloproteinase Inducer (CD147) in Multiple Myeloma: Role in Regulation of Myeloma Cell Proliferation 
Leukemia  2012;26(10):2286-2296.
Multiple myeloma (MM) is preceded by the asymptomatic premalignant state, monoclonal gammopathy of undetermined significance (MGUS). Although MGUS patients may remain stable for years, they are at increased risk of progressing to MM. A better understanding of the relevant molecular changes underlying the transition from an asymptomatic to symptomatic disease state is urgently needed. Our studies show for the first time that the CD147 molecule (extracellular matrix metalloproteinase inducer) may be playing an important biological role in MM. We first demonstrate that CD147 is over-expressed in MM plasma cells (PCs) vs. normal and premalignant PCs. Next, functional studies revealed that the natural CD147 ligand, cyclophilin B, stimulates MM cell growth. Moreover, when MM patient PCs displaying bimodal CD147 expression were separated into CD147bright and CD147dim populations and analyzed for proliferation potential, we discovered that CD147bright PCs displayed significantly higher levels of cell proliferation than did CD147dim PCs. Lastly, CD147 silencing significantly attenuated MM cell proliferation. Taken together, these data suggest that the CD147 molecule plays a key role in MM cell proliferation and may serve as an attractive target for reducing the proliferative compartment of this disease.
PMCID: PMC3915875  PMID: 22460757
CD147; multiple myeloma; cyclophilin B; plasma cells
3.  Clinical Presentation and Outcome of Perioperative Myocardial Infarction in Very Elderly Following Hip Fracture Surgery 
Patterns of clinical symptoms and outcomes of Perioperative Myocardial Infarction (PMI) in elderly after hip fracture repair surgery are not well defined.
A retrospective 1:2 case-control study in a cohort of 1,212 elderly patients undergoing hip fracture surgery from 1988–2002 in Olmsted County, Minnesota.
The mean age was 85.3±7.4 with 76% of population being female. PMI occurred in 167 (13.8%) patients within 7 days, of which 153 (92%) occurred in first 48 hours; 75% of patients were asymptomatic. Among patients with PMI, in-hospital mortality was 14.4 %, 30-day mortality was 29 (17.4%), and one year mortality was 66 (39.5%). PMI was associated with a higher inpatient mortality rate (OR, 15.1; CI 4.6-48.8), 30-day mortality (HR, 4.3; CI, 2.1-8.9) and one-year mortality (HR, 1.9; CI, 1.4-2.7).
Elderly patients, after hip fracture surgery, have a higher incidence of PMI and mortality than what guidelines indicate. The majority of elderly patients with PMI did not experience ischemic symptoms and required cardiac biomarkers for diagnosis. The results of our study support the measurement of troponin in postoperative elderly patients for the diagnosis of PMI, in order to implement in-hospital preventive strategies to reduce PMI associated mortality.
PMCID: PMC3822042  PMID: 22956471
Elderly population; Perioperative myocardial infarction; Hip fracture surgery
4.  Myocardial Infarction Following Hip Fracture Repair: A Population-Based Study 
To quantify the occurrence of myocardial infarction (MI) occurring in the early postoperative period following surgical hip fracture repair and estimate the impact on one-year mortality.
This study is a population-based, historical cohort study of patients who underwent surgical repair of a hip fracture. This studyutilized the computerized medical record linkage system of the Rochester Epidemiology Project.
Academic and community hospitals, outpatient offices and nursing homes in Olmsted County, Minnesota.
In the 15-year study period (1988–2002), 1116 elderly patients underwent surgical repair of a hip fracture.
At the end of the first seven days following hip fracture repair, patients were classified into one of three groups: clinically verified MIs (cv-MI), subclinical myocardial ischemia (sc-MI) and no myocardial ischemia. One-year mortality was compared between these groups. Multivariate models assessed risk factors for early postoperative cv-MI and one-year mortality, respectively.
Within the first seven days following hip fracture repair, 116 (10.4%) patients experienced cv-MIs and 41 (3.7%) had sc-MIs. Overall 1-year mortality rate was 22% and there was no difference between those with sc-MIs and those with nomyocardial ischemia. One-year mortality for those with cv-MI was significantly higher than the other two groups (35.8%). Occurrence of early postoperative cv-MI, male gender, and histories of heart failure or dementia were independently associated with increased one-year mortality; while, pre-fracture home residence and preoperative higher hemoglobin were protective.
Early postoperative, clinically verified, MIs following hip fracture repair exceeds rates following other major orthopedic surgeries and is independently associated with increased one-year mortality.
PMCID: PMC3593312  PMID: 23110362
Hip Fracture; Myocardial Infarction; Mortality; Geriatric; Postoperative Complications
5.  The Structure of the TNFRSF13C Promoter Enables Differential Expression of BAFF-R during B Cell Ontogeny and Terminal Differentiation 
The BAFF receptor (BAFF-R), encoded by the TNFRSF13C gene, is critically important for transitional B cell survival to maturity. Thus, ligation of BAFF-R by BAFF delivers a potent survival signal. Reports implicating the BAFF/BAFF-R signaling axis in the pathogenesis of autoimmune human diseases and B lineage malignancies have largely prompted studies focusing on BAFF expression; however, there is an equally critical need to better understand BAFF-R expression. Initial BAFF-R expression, although characterized in murine B cells, has not yet been reported in human B lymphopoiesis. In this study we first demonstrate that BAFF-R expression is absent from early precursors and is acquired by bone marrow B cells newly expressing the B cell receptor. We next focused on identifying the specific genomic region that controls BAFF-R expression in mature B cells, i.e., the TNFRSF13C promoter. To accomplish this, we used in silico tools examining interspecies genomic conservation in conjunction with reporter constructs transfected into malignant B and plasma cell lines. DNase protection assays using nuclear extracts from BAFF-R expressing cells suggested potential regulatory sites, which allowed the generation of EMSA probes that bound nuclear factors specific to BAFF-R-expressing cells. With a more stringent analysis of interspecies homology, these assays identified a site at which a single nucleotide substitution could distinctly impact promoter activity. Finally, ChIP assays revealed the in vivo binding of the specific transcription factor c-Rel to the most proximal genomic region, and c-Rel siRNA transfections in BAFF-R-expressing lines demonstrated a coincident knockdown of both c-Rel and BAFF-R mRNA.
PMCID: PMC3780588  PMID: 20554963
6.  Comprehensive Assessment of Potential Multiple Myeloma Immunoglobulin Heavy Chain V-D-J Intraclonal Variation Using Massively Parallel Pyrosequencing 
Oncotarget  2012;3(4):502-513.
Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells (PCs) in the bone marrow (BM). MM is viewed as a clonal disorder due to lack of verified intraclonal sequence diversity in the immunoglobulin heavy chain variable region gene (IGHV). However, this conclusion is based on analysis of a very limited number of IGHV subclones and the methodology employed did not permit simultaneous analysis of the IGHV repertoire of non-malignant PCs in the same samples. Here we generated genomic DNA and cDNA libraries from purified MM BMPCs and performed massively parallel pyrosequencing to determine the frequency of cells expressing identical IGHV sequences. This method provided an unprecedented opportunity to interrogate the presence of clonally related MM cells and evaluate the IGHV repertoire of non-MM PCs. Within the MM sample, 37 IGHV genes were expressed, with 98.9% of all immunoglobulin sequences using the same IGHV gene as the MM clone and 83.0% exhibiting exact nucleotide sequence identity in the IGHV and heavy chain complementarity determining region 3 (HCDR3). Of interest, we observed in both genomic DNA and cDNA libraries 48 sets of identical sequences with single point mutations in the MM clonal IGHV or HCDR3 regions. These nucleotide changes were suggestive of putative subclones and therefore were subjected to detailed analysis to interpret: 1) their legitimacy as true subclones; and 2) their significance in the context of MM. Finally, we report for the first time the IGHV repertoire of normal human BMPCs and our data demonstrate the extent of IGHV repertoire diversity as well as the frequency of clonally-related normal BMPCs. This study demonstrates the power and potential weaknesses of in-depth sequencing as a tool to thoroughly investigate the phylogeny of malignant PCs in MM and the IGHV repertoire of normal BMPCs.
PMCID: PMC3380583  PMID: 22522905
IGHV; multiple myeloma; heterogeneity; massively parallel sequencing
7.  Body Mass Index and Risk of Adverse Cardiac Events in Elderly Hip Fracture Patients: A Population-Based Study 
Obesity is protective for the development of hip fractures yet a risk factor for cardiac disease. Whether obesity impacts cardiac complications following hip fracture repair is unknown.
A population-based, historical study using the Rochester Epidemiology Project
Olmsted County, Minnesota
All urgent hip fracture repairs between 1988–2002.
Body mass index (BMI) was categorized as underweight (<18.5kg/m2), normal (18.5–24.9kg/m2), overweight (25.0–29.9kg/m2) and obese (≥30kg/m2). Post-operative cardiac complications were defined as myocardial infarction, angina, congestive heart failure, or new-onset arrhythmias within one-year of surgery. Incidence rates were estimated for each outcome and overall cardiac complications were assessed using Cox proportional hazard models, adjusted for age, sex, year of surgery, use of beta-blockers and the Revised Cardiac Risk Index.
There were 184 (15.6%) underweight, 640 (54.2%) normal, 251 (21.3%) overweight, and 105 (8.9%) obese hip fracture repairs (mean age, 84.2±7.5 years; 80% female). Baseline American Society of Anesthesia status was similar among all groups (ASA I/II vs. III–V, p=0.14). Underweight patients had a significantly higher risk of developing myocardial infarction (odds ratio [OR] 1.44; 95%CI 1.0–2.1; p=0.05) and arrhythmias (OR 1.59; 95%CI:1.0–2.4;p=0.04) than normal BMI patients. Multivariate analysis demonstrated underweight patients had a higher risk of developing an adverse cardiac event of any type (OR 1.56; 95%CI:1.22–1.98; p<0.001). Overweight and obese hip fracture patients had no excess risk of any cardiac complication.
The obesity paradox and low functional reserve in underweight patients may influence the development of post-operative cardiac events in this elderly hip fracture population.
PMCID: PMC3039447  PMID: 19175436
obesity; hip fractures; cardiovascular disease; elderly; post-operative
8.  Predictors of Ischemic Stroke After Hip Operation: A Population-Based Study 
Hip operation (total hip arthroplasty [THA] or fracture repair) is the most common noncardiac surgical procedure performed in patients age 65 years and older.
To determine the predictors of ischemic stroke in patients who have undergone hip operation.
Population-based historical cohort study, in which postoperative ischemic strokes were identified from medical record review for stroke diagnostic codes and brain imaging results and were confirmed by physician review.
Tertiary care center in Olmsted County, Minnesota.
Residents of Olmsted County who underwent hip surgical procedure.
Incidence of ischemic stroke within 1 year of hip operation.
In total, 1606 patients underwent 1886 hip procedures from 1988 through 2002 and were observed for ischemic stroke for 1 year after their procedure. Sixty-seven ischemic strokes were identified. The rate of stroke at 1 year after hip operation was 3.9%. In univariate analysis, history of atrial fibrillation (hazard ratio [HR], 2.16; P = 0.005), hip fracture repair vs. total hip arthroplasty (HR, 3.80; P < 0.001), age 75 years or older (HR, 2.20; P = 0.02), aspirin use (HR, 1.8; P = 0.01), and history of previous stroke (HR, 4.18; P < 0.001) were significantly associated with increased risk of stroke. In multivariable analysis, history of stroke (HR, 3.27; P < 0.001) and hip fracture repair (HR, 2.74; P = 0.004) were strong predictors of postoperative stroke.
This population-based historical cohort of patients with hip operation had a 3.9% cumulative probability of ischemic stroke over the first postoperative year. Hip fracture repair and history of stroke were the strongest predictors of this complication.
PMCID: PMC2933135  PMID: 19484726
arthroplasty; hip; hip fracture; ischemia; stroke
9.  Body Mass Index and Risk of Non-Cardiac Post-Operative Medical Complications in Elderly Hip Fracture Patients: A Population-Based Study 
Obese patients are thought to be at higher risk of post-operative medical complications. We sought to determine whether body mass index (BMI) is associated with post-operative in-hospital non-cardiac complications following urgent hip fracture repair.
We conducted a population-based study of Olmsted County, Minnesota residents operated for hip fracture in 1988–2002. BMI was categorized as underweight (<18.5kg/m2), normal (18.5–24.9kg/m2), overweight (25.0–29.9kg/m2) and obese (≥30kg/m2). Post-operative inpatient non-cardiac medical complications were assessed. Complication rates were estimated for each BMI category and overall complication rates were assessed using logistic regression models adjusted for age, sex, calendar year, and American Society of Anesthesia (ASA) class.
There were 184 (15.6%) underweight, 640 (54.2%) normal, 251 (21.3%) overweight, and 105 (8.9%) obese hip fracture repairs (mean age, 84.2±7.5 years; 80% female). No significant difference was found among the BMI categories for baseline ASA status (ASA III–IV vs. I–II; p=0.14). After adjustment, the risk of developing an inpatient non-cardiac complication for each BMI category, compared to normal BMI, was: underweight (OR 1.33; 95%CI: 0.95–1.88; p=0.10), overweight (OR 1.01;95%CI: 0.74–1.38; p=0.95), and obese (OR 1.28;95%CI: 0.82–1.98; p=0.27). Multivariate analysis using stepwise selection demonstrated that an ASA status of III–V vs. I–II(OR 1.84, 95%CI: 1.25–2.71; p=0.002), a history of chronic obstructive pulmonary disease or asthma (OR 1.58; 95%CI: 1.18–2.12; p=0.002), male sex (OR 1.49, 95%CI:1.10–2.02; p=0.01) and older age (OR 1.05;95%CI: 1.03–1.06; p<0.001), significantly contributed to an increased risk of developing a post-operative non-cardiac inpatient complication. Underweight patients had higher in-hospital mortality rates than normal BMI patients (9.3 vs. 4.4%; p=0.01).
BMI has no significant influence on post-operative non-cardiac medical complications in hip fracture patients. These results attenuate concerns that obese or frail underweight hip fracture patients may be at higher risk post-operatively for inpatient complications.
PMCID: PMC2780331  PMID: 19824100
Obesity; hip fractures; inpatient; medical complications; post-operative; elderly
10.  C-Reactive Protein, Erythrocyte Sedimentation Rate and Orthopedic Implant Infection 
PLoS ONE  2010;5(2):e9358.
C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) have been shown to be useful for diagnosis of prosthetic hip and knee infection. Little information is available on CRP and ESR in patients undergoing revision or resection of shoulder arthroplasties or spine implants.
We analyzed preoperative CRP and ESR in 636 subjects who underwent knee (n = 297), hip (n = 221) or shoulder (n = 64) arthroplasty, or spine implant (n = 54) removal. A standardized definition of orthopedic implant-associated infection was applied. Receiver operating curve analysis was used to determine ideal cutoff values for differentiating infected from non-infected cases. ESR was significantly different in subjects with aseptic failure infection of knee (median 11 and 53.5 mm/h, respectively, p = <0.0001) and hip (median 11 and 30 mm/h, respectively, p = <0.0001) arthroplasties and spine implants (median 10 and 48.5 mm/h, respectively, p = 0.0033), but not shoulder arthroplasties (median 10 and 9 mm/h, respectively, p = 0.9883). Optimized ESR cutoffs for knee, hip and shoulder arthroplasties and spine implants were 19, 13, 26, and 45 mm/h, respectively. Using these cutoffs, sensitivity and specificity to detect infection were 89 and 74% for knee, 82 and 60% for hip, and 32 and 93% for shoulder arthroplasties, and 57 and 90% for spine implants. CRP was significantly different in subjects with aseptic failure and infection of knee (median 4 and 51 mg/l, respectively, p<0.0001), hip (median 3 and 18 mg/l, respectively, p<0.0001), and shoulder (median 3 and 10 mg/l, respectively, p = 0.01) arthroplasties, and spine implants (median 3 and 20 mg/l, respectively, p = 0.0011). Optimized CRP cutoffs for knee, hip, and shoulder arthroplasties, and spine implants were 14.5, 10.3, 7, and 4.6 mg/l, respectively. Using these cutoffs, sensitivity and specificity to detect infection were 79 and 88% for knee, 74 and 79% for hip, and 63 and 73% for shoulder arthroplasties, and 79 and 68% for spine implants.
CRP and ESR have poor sensitivity for the diagnosis of shoulder implant infection. A CRP of 4.6 mg/l had a sensitivity of 79 and a specificity of 68% to detect infection of spine implants.
PMCID: PMC2825262  PMID: 20179760

Results 1-10 (10)