Surgeon Specialty Influences Referral Rate for Osteoporosis Management Following Vertebral Compression Fractures

Study Design Retrospective chart review. Objective To evaluate the referral rate for long-term osteoporosis management following vertebral compression fracture treated by different specialties at a single academic institution. Methods Patients undergoing vertebral cement augmentation for painful osteoporotic compression fractures from 2009 to 2014 were identified. Medical records were reviewed to determine if the treating surgeon discussed and/or referred the patient for long-term osteoporosis management. Any referral for or mention of medical long-term osteoporosis management was counted as a positive response. Results were statistically analyzed with chi-square test. Results Two hundred fourteen patients underwent vertebral cement augmentation; 150 met inclusion criteria. Orthopedic surgeons treated 88 patients, neurosurgeons treated 39, and interventional radiology or pain management physicians treated 23. Orthopedic surgeons referred 82% of patients for osteoporosis management, neurosurgeons referred 36%, and interventional radiology/pain management referred 17%. The referral rate was significantly higher for orthopedic surgeons compared with either of the other two groups; there was no significant difference between neurosurgery and interventional radiology/pain management. Conclusions Among physicians who treat osteoporotic vertebral compression fractures, orthopedic surgeons more frequently address osteoporosis or refer patients for osteoporosis management compared with neurosurgeons and interventional radiologists or pain management physicians. The results of this study shed light on the disparity in how different specialties approach treatment of osteoporosis in patients with fractures painful enough to require surgery and highlight potential areas for improvement in osteoporosis awareness training

Novel rat tail discitis model using bioluminescent Staphylococcus aureus

Management of spondylodiscitis is a challenging clinical problem requiring medical and surgical treatment strategies. The purpose of this study was to establish a rat model of spondylodiscitis that utilizes bioluminescent Staphylococcus aureus, thus permitting in-vivo surveillance of infection intensity. Inocula of the bioluminescent S. aureus strain XEN36 were created in concentrations of 102 CFU/0.1 mL, 104 CFU/0.1 mL, and 106 CFU/0.1 mL. Three groups of rats were injected with the bacteria in the most proximal intervertebral tail segment. The third most proximal tail segment was injected with saline as a control. Bioluminescence was measured at baseline, 3 days, and weekly for a total of 6 weeks. Detected bioluminescence for each group peaked at day three and returned to baseline at 21 days. The average intensity was highest for the experimental group injected with the most concentrated bacterial solution (106 CFU/0.1 mL). Radiographic analysis revealed loss of intervertebral disc space and evidence of osseous bridging. Saline injected spaces exhibited no decrease in intervertebral spacing as compared to distal sites. Histologic analysis revealed neutrophilic infiltrates, destruction of the annulus fibrosus and nucleus pulposus, destruction of vertebral endplates, and osseous bridging. Saline injected discs exhibited preserved annulus fibrosus and nucleus pulposus on histology. This study demonstrates that injection of bioluminescent S. aureus into the intervertebral disc of a rat tail is a viable animal model for spondylodiscitis research. This model allows for real-time, in-vivo quantification of infection intensity, which may decrease the number of animals required for infection studies of the intervertebral disc

Impact of the SPOP Mutant Subtype on the Interpretation of Clinical Parameters in Prostate Cancer.

Purpose: Molecular characterization of prostate cancer, including The Cancer Genome Atlas, has revealed distinct subtypes with underlying genomic alterations. One of these core subtypes, SPOP (speckle-type POZ protein) mutant prostate cancer, has previously only been identifiable via DNA sequencing, which has made the impact on prognosis and routinely used risk stratification parameters unclear. Methods: We have developed a novel gene expression signature, classifier (Subclass Predictor Based on Transcriptional Data), and decision tree to predict the SPOP mutant subclass from RNA gene expression data and classify common prostate cancer molecular subtypes. We then validated and further interrogated the association of prostate cancer molecular subtypes with pathologic and clinical outcomes in retrospective and prospective cohorts of 8,158 patients. Results: The subclass predictor based on transcriptional data model showed high sensitivity and specificity in multiple cohorts across both RNA sequencing and microarray gene expression platforms. We predicted approximately 8% to 9% of cases to be SPOP mutant from both retrospective and prospective cohorts. We found that the SPOP mutant subclass was associated with lower frequency of positive margins, extraprostatic extension, and seminal vesicle invasion at prostatectomy; however, SPOP mutant cancers were associated with higher pretreatment serum prostate-specific antigen (PSA). The association between SPOP mutant status and higher PSA level was validated in three independent cohorts. Despite high pretreatment PSA, the SPOP mutant subtype was associated with a favorable prognosis with improved metastasis-free survival, particularly in patients with high-risk preoperative PSA levels. Conclusion: Using a novel gene expression model and a decision tree algorithm to define prostate cancer molecular subclasses, we found that the SPOP mutant subclass is associated with higher preoperative PSA, less adverse pathologic features, and favorable prognosis. These findings suggest a paradigm in which the interpretation of common risk stratification parameters, particularly PSA, may be influenced by the underlying molecular subtype of prostate cancer

PRN OPINION PAPER: Application of precision medicine across pharmacy specialty areas

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149551/1/jac51107_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149551/2/jac51107.pd

DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis.

Emerging evidence demonstrates that the DNA repair kinase DNA-PKcs exerts divergent roles in transcriptional regulation of unsolved consequence. Here, in vitro and in vivo interrogation demonstrate that DNA-PKcs functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppression of DNA-PKcs inhibits tumor metastases. Clinical assessment revealed that DNA-PKcs is significantly elevated in advanced disease and independently predicts for metastases, recurrence, and reduced overall survival. Further investigation demonstrated that DNA-PKcs in advanced tumors is highly activated, independent of DNA damage indicators. Combined, these findings reveal unexpected DNA-PKcs functions, identify DNA-PKcs as a potent driver of tumor progression and metastases, and nominate DNA-PKcs as a therapeutic target for advanced malignancies

Cyclooxygenase-2 overexpression is common in serrated and non-serrated colorectal adenoma, but uncommon in hyperplastic polyp and sessile serrated polyp/adenoma

<p>Abstract</p> <p>Background</p> <p>Cyclooxygenase-2 (COX-2, <it>PTGS2</it>) plays an important role in colorectal carcinogenesis. COX-2 overexpression in colorectal cancer is inversely associated with microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP). Evidence suggests that MSI/CIMP+ colorectal cancer may arise through the serrated tumorigenic pathway through various forms of serrated neoplasias. Therefore, we hypothesized that COX-2 may play a less important role in the serrated pathway.</p> <p>Methods</p> <p>By immunohistochemistry, we assessed COX-2 expression in 24 hyperplastic polyps, 7 sessile serrated polyp/adenomas (SSA), 5 mixed polyps with SSA and adenoma, 27 traditional serrated adenomas, 515 non-serrated adenomas (tubular adenoma, tubulovillous adenoma and villous adenoma), 33 adenomas with intramucosal carcinomas, 96 adenocarcinomas with serration (corkscrew gland) and 111 adenocarcinomas without serration.</p> <p>Results</p> <p>Strong (2+) COX-2 overexpression was more common in non-serrated adenomas (28% = 143/515) than in hyperplastic polyps (4.2% = 1/24, p = 0.008) and serrated polyps (7 SSAs and 5 mixed polyps) (0% = 0/12, p = 0.04). Furthermore, any (1+/2+) COX-2 overexpression was more frequent in non-serrated adenomas (60% = 307/515) than in hyperplastic polyps (13% = 3/24, p < 0.0001) and serrated polyps (SSAs and mixed polyps) (25% = 3/12, p = 0.03). Traditional serrated adenomas and non-serrated adenomas showed similar frequencies of COX-2 overexpression. Regardless of serration, COX-2 overexpression was frequent (~85%) in colorectal adenocarcinomas. Tumor location was not significantly correlated with COX-2 overexpression, although there was a trend towards higher frequencies of COX-2 overexpression in distal tumors (than proximal tumors) among hyperplastic polyps, SSAs, mixed polyps, traditional serrated adenomas and adenocarcinomas.</p> <p>Conclusion</p> <p>COX-2 overexpression is infrequent in hyperplastic polyp, SSA and mixed polyp with SSA and adenoma, compared to non-serrated and serrated adenoma. COX-2 overexpression becomes more frequent as tumors progress to higher grade neoplasias. Our observations suggest that COX-2 may play a less significant role in the serrated pathway of tumorigenesis; however, COX-2 may still play a role in later stage of the serrated pathway.</p

PI3K-C2α knockdown decreases autophagy and maturation of endocytic vesicles

<div><p>Phosphoinositide 3-kinase (PI3K) family members are involved in diverse cellular fates including cell growth, proliferation, and survival. While many molecular details are known about the Class I and III PI3Ks, less is known about the Class II PI3Ks. To explore the function of all eight PI3K isoforms in autophagy, we knock down each gene individually and measure autophagy. We find a significant decrease in autophagy following siRNA-mediated <i>PIK3C2A</i> (encoding the Class 2 PI3K, PI3K-C2α) knockdown. This defective autophagy is rescued by exogenous PI3K-C2α, but not kinase-dead PI3K-C2α. Using confocal microscopy, we probe for markers of endocytosis and autophagy, revealing that PI3K-C2α colocalizes with markers of endocytosis. Though endocytic uptake is intact, as demonstrated by transferrin labeling, <i>PIK3C2A</i> knockdown results in vesicle accumulation at the recycling endosome. We isolate distinct membrane sources and observe that PI3K-C2α interacts with markers of endocytosis and autophagy, notably ATG9. Knockdown of either <i>PIK3C2A</i> or <i>ATG9A/B</i>, but not <i>PI3KC3</i>, results in an accumulation of transferrin-positive clathrin coated vesicles and RAB11-positive vesicles at the recycling endosome. Taken together, these results support a role for PI3K-C2α in the proper maturation of endosomes, and suggest that PI3K-C2α may be a critical node connecting the endocytic and autophagic pathways.</p></div

Comparison of HLA allelic imputation programs.

Imputation of human leukocyte antigen (HLA) alleles from SNP-level data is attractive due to importance of HLA alleles in human disease, widespread availability of genome-wide association study (GWAS) data, and expertise required for HLA sequencing. However, comprehensive evaluations of HLA imputations programs are limited. We compared HLA imputation results of HIBAG, SNP2HLA, and HLA*IMP:02 to sequenced HLA alleles in 3,265 samples from BioVU, a de-identified electronic health record database coupled to a DNA biorepository. We performed four-digit HLA sequencing for HLA-A, -B, -C, -DRB1, -DPB1, and -DQB1 using long-read 454 FLX sequencing. All samples were genotyped using both the Illumina HumanExome BeadChip platform and a GWAS platform. Call rates and concordance rates were compared by platform, frequency of allele, and race/ethnicity. Overall concordance rates were similar between programs in European Americans (EA) (0.975 [SNP2HLA]; 0.939 [HLA*IMP:02]; 0.976 [HIBAG]). SNP2HLA provided a significant advantage in terms of call rate and the number of alleles imputed. Concordance rates were lower overall for African Americans (AAs). These observations were consistent when accuracy was compared across HLA loci. All imputation programs performed similarly for low frequency HLA alleles. Higher concordance rates were observed when HLA alleles were imputed from GWAS platforms versus the HumanExome BeadChip, suggesting that high genomic coverage is preferred as input for HLA allelic imputation. These findings provide guidance on the best use of HLA imputation methods and elucidate their limitations

PI3K-C2α knockdown decreases autophagy.

<p>(A-E) U2OS cells stably expressing ptfLC3B were transfected with siRNAs directed against each of the eight PI3K isoforms for 48 hours. Cells were imaged with a 60× oil objective by fluorescent microscopy. Scale bars represent 10 μm. (A) Using a control siRNA, cells were treated with either vehicle or rapamycin for 6 hours to induce autophagy. (B-D) siRNA directed against each of the Class I PI3K isoforms <i>PIK3CA</i>, <i>PIK3CB</i>, <i>PIK3CG</i>, <i>PIK3CD</i> (B), <i>PIK3C2B</i> or <i>PIK3C2G</i> (C), and <i>PIK3C2A</i> or <i>PIK3C3</i> (D) and rapamycin treated for 6 hours. (E) Quantification of the number of autophagic puncta per cell in (A-D). Data represent means of n ≥ 25 cells with standard error of the mean. Unpaired <i>t</i> test, comparing experimental to rapamycin control. *denotes p < 0.05, ***denotes p < 0.001.</p