CT-guided bone marrow aspirations and biopsies: retrospective study and comparison with blind procedures.

PURPOSE: To compare the pathology results of CT-guided and blind bone marrow aspirations and biopsies. METHODS: Ninety-eight consecutive CT-guided biopsies and 98 age- and gender-matched blind (non-CT-guided) posterior iliac crest bone marrow aspirations and biopsies performed in 2017 were reviewed for adequacy of core biopsies and aspirate smears. CT procedure images and CT abdomen/pelvis images were reviewed to evaluate anatomic features of the posterior ilium and soft tissues. Statistical analysis was performed using a T test, Fisher exact test, and Kruskal-Wallis test. RESULTS: There was no significant difference in the age and gender of the two groups (p > 0.05). However, the CT-guided group had a higher BMI (p = 0.0049) and posterior soft tissue thickness (p = 0.0016). More CT-guided biopsy samples (CT 93 (95%); blind 77 (79%); p = 0.0006) and aspirate smears (CT 90 (92%); blind 78 (80%); p = 0.042) were categorized as adequate. The CT-guided group had longer core lengths (CT 1.4 ± 0.6 (range 0.3-3.5) cm; blind 1.0 ± 0.60 (range 0-2.6) cm; p = 0.0001). Overall, 131/164 (80%) of the cases had at least one of the described features (slanted posterior ilium (angle > 30°), 30%; rounded posterior ilium, 20%; thick posterior ilium cortex, 13%; focal lesion in posterior ilium, 12%; prior procedure in posterior ilium, 5%; posterior soft tissue thickness > 3 cm, 40%). CONCLUSION: CT-guided bone marrow procedures were more likely to result in both adequate aspirate smears and biopsy samples and longer core lengths when compared with blind procedures.

Gene delivery to the spinal cord using MRI-guided focused ultrasound.

Non-invasive gene delivery across the blood-spinal cord barrier (BSCB) remains a challenge for treatment of spinal cord injury and disease. Here, we demonstrate the use of magnetic resonance image-guided focused ultrasound (MRIgFUS) to mediate non-surgical gene delivery to the spinal cord using self-complementary adeno-associated virus serotype 9 (scAAV9). scAAV9 encoding green fluorescent protein (GFP) was injected intravenously in rats at three dosages: 4 × 10(8), 2 × 10(9) and 7 × 10(9) vector genomes per gram (VG g(-1)). MRIgFUS allowed for transient, targeted permeabilization of the BSCB through the interaction of focused ultrasound (FUS) with systemically injected Definity lipid-shelled microbubbles. Viral delivery at 2 × 10(9) and 7 × 10(9) VG g(-1) leads to robust GFP expression in FUS-targeted regions of the spinal cord. At a dose of 2 × 10(9) VG g(-1), GFP expression was found in 36% of oligodendrocytes, and in 87% of neurons in FUS-treated areas. FUS applications to the spinal cord could address a long-term goal of gene therapy: delivering vectors from the circulation to diseased areas in a non-invasive manner.

Local treatment of mixed osteolytic/osteoblastic spinal metastases: is photodynamic therapy effective?

The widespread use of systemic and local therapies aimed at spinal metastatic lesions secondary to breast cancer has increased the incidence of mixed osteolytic/osteoblastic patterns of bony disease. The complex structure of these lesions requires novel therapeutic approaches to both reduce tumor burden and restore structural stability. In photodynamic therapy (PDT), a minimally invasive approach can be used to employ light to activate a photosensitizing agent that preferentially accumulates in tumor tissue, leading to cell toxicity and death. Previous work in an osteolytic rat model (MT-1) demonstrated that PDT effectively ablates tumor and improves vertebral structural properties. The aim of this study was to assess the efficacy of PDT in a rat model of mixed osteolytic/osteoblastic spinal metastases. Mixed spinal metastases were generated through intracardiac injection of Ace-1 canine prostate cancer cells into female athymic rats (day 0). A single PDT treatment was applied to lumbar vertebra L2 of tumor-bearing and healthy control rats (day 14). PDT-treated and untreated control rats were euthanized and excised spines imaged with µCT to assess bone quality (day 21). Spines were mechanically tested or histologically processed to assess mechanical integrity, tumor burden, and remodelling properties. Untreated tumor-bearing vertebrae showed large areas of osteolysis and areas of immature, new bone formation. The overall bone quality resulting from these lesions consisted of decreased structural properties but without a significant reduction in mechanical integrity. PDT was shown to significantly decrease tumor burden and osteoclastic activity, thereby improving vertebral bone structural properties. While non-tumor-bearing vertebrae exhibited significantly more new bone formation following PDT, the already heightened level of new bone formation in the mixed tumor-bearing vertebrae was not further increased. As such, the effect of PDT on mixed metastases may be more influenced by suppression of osteoclastic resorption as opposed to the triggering of new bone formation.

Comparison of outcomes after transplantation of peripheral blood stem cells versus bone marrow following an identical nonmyeloablative conditioning regimen.

This is the first study to examine the outcomes in 54 patients with hematologic malignancies who received an HLA-matched related donor bone marrow (BM, n = 42) or GCSF-mobilized peripheral blood stem cells (PBSC, n = 12) following identical nonmyeloablative conditioning with the intention of induction of mixed chimerism (MC) followed by prophylactic donor leukocyte infusion (pDLI) to convert MC to full donor chimerism (FDC) and capture a graft-versus-tumor effect without clinical graft-versus-host disease (GVHD). Neutrophil and platelet recovery were faster and transfusion requirement was less in PBSC recipients (P < 0.05). A total of 48% of BMT recipients achieved FDC with a median conversion time of 84 days, including 13 following pDLI. In contrast, 83% (P = 0.04) in the PBSC group had spontaneous FDC at a median of 14 days, precluding the administration of pDLI. There was no significant difference in the incidences of acute or chronic GVHD, though the rates of chronic GVHD were considerably higher in PBSC group than in the BM group (6/7, 86% vs 10/24, 42%). CD4 and CD8 T-cell recovery was faster in PBSC recipients. In PBSC recipients, a higher number of CD34+ cells was associated with increased rates of severe, grade III-IV acute GVHD.

Preclinical activity of CPI-0610, a novel small-molecule bromodomain and extra-terminal protein inhibitor in the therapy of multiple myeloma.

Inhibition of the bromodomain and extra-terminal (BET) proteins is a promising therapeutic strategy for various hematologic cancers. Previous studies suggest that BET inhibitors constrain tumor cell proliferation and survival mainly through the suppression of MYC transcription and activity. However, suppression of the transcription of additional genes also contributes to the antitumor activity of BET inhibitors but is less well understood. Here we examined the therapeutic potential of CPI-0610, a potent BET inhibitor currently undergoing phase I clinical testing, in multiple myeloma (MM). CPI-0610 displays potent cytotoxicity against MM cell lines and patient-derived MM cells through G1 cell cycle arrest and caspase-dependent apoptosis. CPI-0610-mediated BET inhibition overcomes the protective effects conferred by cytokines and bone marrow stromal cells. We also confirmed the in vivo efficacy of CPI-0610 in a MM xenograft mouse model. Our study found IKZF1 and IRF4 to be among the primary targets of CPI-0610, along with MYC. Given that immunomodulatory drugs (IMiDs) stabilize cereblon and facilitate Ikaros degradation in MM cells, we combined it with CPI-0610. Combination studies of CPI-0610 with IMiDs show in vitro synergism, in part due to concomitant suppression of IKZF1, IRF4 and MYC, providing a rationale for clinical testing of this drug combination in MM patients.

Foxo3 activity promoted by non-coding effects of circular RNA and Foxo3 pseudogene in the inhibition of tumor growth and angiogenesis.

It has recently been shown that the upregulation of a pseudogene specific to a protein-coding gene could function as a sponge to bind multiple potential targeting microRNAs (miRNAs), resulting in increased gene expression. Similarly, it was recently demonstrated that circular RNAs can function as sponges for miRNAs, and could upregulate expression of mRNAs containing an identical sequence. Furthermore, some mRNAs are now known to not only translate protein, but also function to sponge miRNA binding, facilitating gene expression. Collectively, these appear to be effective mechanisms to ensure gene expression and protein activity. Here we show that expression of a member of the forkhead family of transcription factors, Foxo3, is regulated by the Foxo3 pseudogene (Foxo3P), and Foxo3 circular RNA, both of which bind to eight miRNAs. We found that the ectopic expression of the Foxo3P, Foxo3 circular RNA and Foxo3 mRNA could all suppress tumor growth and cancer cell proliferation and survival. Our results showed that at least three mechanisms are used to ensure protein translation of Foxo3, which reflects an essential role of Foxo3 and its corresponding non-coding RNAs.

Exercises for mechanical neck disorders: A Cochrane review update.

BACKGROUND: Neck pain (NP) is disabling and costly. OBJECTIVES: To assess the effectiveness of exercise on pain, disability, function, patient satisfaction, quality of life (QoL) and global perceived effect (GPE) in adults with NP. METHODS: We searched computerised databases up to May 2014 for randomized controlled trials (RCTs) comparing exercise to a control in adults with NP with/without cervicogenic headache (CGH) or radiculopathy. Two reviewers independently conducted selection, data abstraction and assessed risk of bias. Meta-analyses were performed to establish pooled standardised mean differences (SMDp). The Grade of Recommendation, Assessment, Development and Evaluation (GRADE) was used to summarise the body of evidence. MAIN RESULTS: The following exercises (27 trials) were supported by 'Moderate GRADE' evidence: For chronic NP, 1) cervico-scapulothoracic and upper extremity (UE) strengthening for moderate to large pain reduction immediately post treatment (IP) and at short-term (ST) follow-up; 2) scapulothoracic and UE endurance training for a small pain reduction (IP/ST); 3) cervical, shoulder and scapulothoracic strengthening and stretching exercise for a small to large pain reduction in the long-term (LT) (SMDp -0.45 [95%CI: -0.72 to -0.18]) and function improvement; 4) cervico-scapulothoracic strengthening/stabilisation exercises for pain and function at intermediate-term (IT) (SMDp -14.90 [95%CI: -22.40 to -7.39]). 5) mindfulness exercises (Qigong) for minor improved function but not GPE (ST). For chronic CGH, cervico-scapulothoracic strengthening and endurance exercises including pressure biofeedback for small/moderate improvement of pain, function and GPE (IP/LT). AUTHORS' CONCLUSIONS: Specific strengthening exercises of the neck, scapulothoracic and shoulder for chronic NP and chronic CGH are beneficial. Future research should explore optimal dosage.

Increased fatty acid uptake and altered fatty acid metabolism in insulin-resistant muscle of obese Zucker rats.

Altered muscle fatty acid (FA) metabolism may contribute to the presence of muscle insulin resistance in the genetically obese Zucker rat. To determine whether FA uptake and disposal are altered in insulin-resistant muscle, we measured palmitate uptake, oxidation, and incorporation into di- and triglycerides in isolated rat hindquarters, as well as muscle plasma membrane fatty acid-binding protein (FABP(PM)) content of lean (n = 16, fa/+) and obese (n = 15, fa/fa) Zucker rats (12 weeks of age). Hindquarters were perfused with 7 mmol/l glucose, 1,000 micromol/l albumin-bound palmitate, and albumin-bound [1-(14)C]palmitate at rest (no insulin). Glucose uptake was 42% lower in the obese than in the lean rats and indicated the presence of muscle insulin resistance. Fractional and total rates of palmitate uptake were 42 and 74% higher in the obese than in the lean rats and were associated with higher muscle FABP(PM) content (r(2) = 0.69, P < 0.05). The percentage of palmitate oxidized was not significantly different between groups. FA disposal to storage was altered according to fiber type. When compared with lean rats, the rate of triglyceride synthesis in red muscle was 158% higher in obese rats, and the rate of palmitate incorporation into diglycerides in white muscle was 93% higher in obese rats. Pre- and postperfusion muscle triglyceride levels were higher in both red and white muscles of the obese rats. These results show that increased FA uptake and altered FA disposal to storage may contribute to the development of muscle insulin resistance in obese Zucker rats.

Photodynamic therapy for the treatment of vertebral metastases in a rat model of human breast carcinoma.

The feasibility and efficacy of photodynamic therapy (PDT) for the treatment of vertebral metastases using a minimally invasive surgical technique adapted from vertebroplasty was evaluated in a rodent model. Initial validation included photosensitizer (benzoporphyrin-derivative monoacid-ring A) drug uptake studies and in vitro confirmation of PDT efficacy. Intracardiac injection of human MT-1 breast cancer cells was performed in athymic rats. In 63 rats that developed vertebral metastases 21 days post-inoculation, single treatment of PDT was performed using a parapedicular approach placing an optical fiber adjacent to targeted vertebrae. Two milligrams per kilogram of photosensitizer drug was administered intravenously followed by 150 mW of 690 nm light illumination at varying drug-light intervals and light energies. Histologic and immunohistochemical analysis was performed assessing treatment effect. Local tumor viability and growth was quantified by bioluminescence imaging pre and 48 h post-treatment. PDT demonstrated an ablative effect on vertebral metastases (light energies 25-150 J). The effect varied in proportion to light energy with the greatest anti-tumor effect observed at 150 J using a 3 h drug-light interval. 9/22 rodents in the 3 h drug-light interval developed hindlimb paralysis following treatment, consistent with drug uptake studies demonstrating an increase in spinal cord uptake 3h following drug administration. The observations of paralysis following treatment highlight the importance of closely defining the therapeutic window of treatment in safety and efficacy.

Calibration and validation of an air-displacement plethysmography method for estimating percentage body fat in an elderly population: a comparison among compartmental models.

BACKGROUND: The use of hydrostatic weighing (HW) to measure body composition in the elderly can be difficult and is based on the assumption of constancy of body compartments. OBJECTIVE: We calibrated and validated a new air-displacement plethysmography (AP) method for measuring body composition in the elderly. DESIGN: A 4-compartment equation for calculating percentage body fat (%BF) that used body density (D(b)), total body water, and bone mineral content was used as the criterion for evaluating %BF estimated by the 2- and 3-compartment models. D(b) was measured by HW [D(b(HW))] and by use of the AP instrument [D(b(AP))] in 30 elderly men and 28 elderly women aged 70-79 y. RESULTS: D(b(AP)) was not significantly different from D(b(HW)). However, analysis of variance showed a significant two-way interaction between sex and compartment model (P < 0.02), indicating that the comparisons between the sexes were different across all compartment models. The %BF calculated for the women was significantly higher than that calculated for the men by both HW and AP and for all compartment models. CONCLUSION: Our data indicate that D(b(AP)) was not significantly different from D(b(HW)). Although differences were seen in %BF between the sexes, we observed no significant differences among the compartment models within each sex for this group of older individuals.

Training-induced elevation in FABP(PM) is associated with increased palmitate use in contracting muscle.

To evaluate the effects of endurance training in rats on fatty acid metabolism, we measured the uptake and oxidation of palmitate in isolated rat hindquarters as well as the content of fatty acid-binding proteins in the plasma membranes (FABP(PM)) of red and white muscles from 16 trained (T) and 18 untrained (UT) rats. Hindquarters were perfused with 6 mM glucose, 1,800 microM palmitate, and [1-(14)C]palmitate at rest and during electrical stimulation (ES) for 25 min. FABP(PM) content was 43-226% higher in red than in white muscles and was increased by 55% in red muscles after training. A positive correlation was found to exist between succinate dehydrogenase activity and FABP(PM) content in muscle. Palmitate uptake increased by 64-73% from rest to ES in both T and UT and was 48-57% higher in T than UT both at rest (39.8 +/- 3.5 vs. 26.9 +/- 4. 4 nmol. min(-1). g(-1), T and UT, respectively) and during ES (69.0 +/- 6.1 vs. 43.9 +/- 4.4 nmol. min(-1). g(-1), T and UT, respectively). While the rats were resting, palmitate oxidation was not affected by training; palmitate oxidation during ES was higher in T than UT rats (14.8 +/- 1.3 vs. 9.3 +/- 1.9 nmol. min(-1). g(-1), T and UT, respectively). In conclusion, endurance training increases 1) plasma free fatty acid (FFA) uptake in resting and contracting perfused muscle, 2) plasma FFA oxidation in contracting perfused muscle, and 3) FABP(PM) content in red muscles. These results suggest that an increased number of these putative plasma membrane fatty acid transporters may be available in the trained muscle and may be implicated in the regulation of plasma FFA metabolism in skeletal muscle.

A rapid assay for detecting sulfonamides in tissues of slaughtered animals.

Governments regulate antimicrobial residues in slaughtered animals with surveillance programs for detecting drugs in food-producing animals. Although initial screening bioassay systems are recognized for their sensitivities to antimicrobial drug groups, none are sensitive to sulfonamides at or near the maximum residue levels (MRLs) in the Codex Alimentarious. We have developed a sulfonamide-sensitive rapid assay using Bacillus stearothermophilus inoculated PM indicator agar containing bromcresol purple and trimethoprim, where the end point is a combination of color change in the agar and zone of microbial growth inhibition around the sampling disk. Five sulfonamides, plus 16 other antimicrobial drugs were tested in standard concentrations in water, bovine kidney, and ground beef. Sulfonamides were detected at concentrations near the MRLs, and they were presumptively identified using para-aminobenzoic acid. The rapid assay was extremely sensitive to beta-lactams that were presumptively identified using penase. The system also was sensitive to tetracyclines, aminoglycosides, and macrolides, of which tetracyclines and gentamicin were identified using enzyme-linked immunosorbent assay (ELISA). In trials on slaughterhouse tissues submitted for testing in Ontario's meat surveillance program, the rapid assay identified twofold the number of positive kidneys and threefold the number of positive diaphragm samples compared to a standard microbiological inhibition test (MIT) currently approved. Fifty-three of 471 carcasses were sulfonamide positive with the rapid assay, while no sulfonamides were detected with the MIT. ELISA and thin-layer chromatography were used on selected samples to confirm the rapid assay sulfonamide presumptive results.

Antimicrobial drug residues in milk and meat: causes, concerns, prevalence, regulations, tests, and test performance.

This paper presents a historical review of antimicrobial use in food animals, the causes of residues in meat and milk, the types of residues found, their regulation in Canada, tests used for their detection, and test performance parameters, with an emphasis on immunoassay techniques. The development of residue detection methods began shortly after the introduction of antimicrobials to food animal production in the late 1940s. From initial technical concerns expressed by the dairy industry to the present public health and international trade implications, there has been an ongoing need for reliable, sensitive, and economical methods for the detection of antimicrobial residues in food animal products such as milk and meat. Initially there were microbial growth inhibition tests, followed by more sensitive and specific methods based on receptor binding, immunochemical, and chromatographic principle. An understanding of basic test performance parameters and their implications is essential when choosing an analytical strategy for residue testing. While each test format has its own attributes, none test will meet all the required analytical needs. Therefore the use of a tiered or integrated system employing assays designated for screening and confirmation is necessary to ensure that foods containing violative residues are not introduced into the food chain.

Characteristics of the LacTek test as applied to tissue samples: assessment of performance using incurred field samples.

The Lactek test, marketed for antimicrobial residue detection in milk, was validated for the detection of antimicrobial residues in tissues. A previous study found that the LacTek test could confidently identify tissue samples spiked with antimicrobial residues. However, the test could not reliably distinguish violative from nonviolative spiked samples relative to Canadian maximum residue limits (MRLs). The objectives of this study were to assess and compare the performance of the LacTek tests for beta-lactams, tetracyclines, gentamicin, and sulfamethazine on samples containing naturally incurred residues by running the test in parallel with the standard microbial inhibition test (MIT) presently used for the routine testing of tissues at our facility and to assess the agreement with high pressure liquid chromatographic (HPLC) determinative methods. Parallel testing with the official MIT found that the Lactek tests could be confidently used for testing tissue samples containing incurred residues. Among 1,008 MIT-positive samples, the LacTek test found that 90% contained beta-lactams and/or tetracyclines. A further 7.3% of violative residues could not be identified to an antimicrobial class. In addition, 9% of samples testing negative on the MIT were found to contain an antimicrobial residue by the LacTek tests. Comparative testing with HPLC methods found that there was very good agreement between the two tests and that most violations were due to penicillin G and oxytetracycline. Although the LacTek test cannot be used to distinguish violative from nonviolative residue levels, it does offer several advantages over the present MIT. These include speed, ease of use, the ability to identify residues to a specific class, and an improved sensitivity at the MRL level for the most commonly found antimicrobials in tissue.

Validation of the LacTek test applied to spiked extracts of tissue samples: determination of performance characteristics.

LacTek tests are competitive enzyme-linked immunosorbent assays intended for rapid detection of antimicrobial residues in bovine milk. In this study, the LacTek test protocol was modified for use with extracts of bovine tissue to detect beta-lactam, tetracycline, and sulfamethazine residues. Test performance characteristics--precision, accuracy, ruggedness, practicability, and analytical specificity and sensitivity--were investigated. Results suggest that LacTek tests can be easily adapted to detect antimicrobial residues in extracts of lean ground beef. However, positive samples may not contain residues at violative concentrations (i.e., Canadian maximum residue limits), and therefore, additional analysis would be required for final confirmation and quantitation (e.g., chromatography).

Determination of fluoroquinolone residues in animal tissues using Escherichia coli as indicator organism.

Three strains of Escherichia coli (ATCC 128, 10536, and 25922) and one strain of Bacillus subtilis (ATCC 3491) were compared as indicator microorganisms in microbial inhibition tests for their ability to detect fluoroquinolone residues. E. coli strains 128 and 10536 were most susceptible to fluoroquinolone residues, with detection limits of 35-50 micrograms/kg for enrofloxacin. Of the 2 strains, E. coli 10536 was slightly less susceptible. Ciprofloxacin was detected consistently by E. coli 128 at 30 micrograms/kg. Other fluoroquinolone drugs of veterinary interest detected by E. coli 128 were sarafloxacin and difloxacin at 100-250 micrograms/kg concentration. E. coli 25922 yielded 100% sensitivity in detection of enrofloxacin only at the 250 micrograms/kg concentration, and ciprofloxacin and sarafloxacin at 200 micrograms/kg. B. subtilis detected only enrofloxacin 100% of the time at 250 micrograms/kg. The E. coli strains tested were insensitive to other antibacterials commonly used in animals, with the exception of ceftiofur which was detected by E. coli 128 and 10536 at 500 micrograms/kg. The B. subtilis strain was not effective in detecting the fluoroquinolone drugs, whereas the E. coli strains were selective for the fluoroquinolones. E. coli 128 was 100% effective in detecting enrofloxacin and ciprofloxacin in spiked diaphragm homogenate samples at 50 micrograms/kg. Of the microorganisms tested, E. coli strain ATCC 128 was highly suitable as an indicator microorganism in a microbial inhibition assay for selective detection of fluoroquinolone antibacterial residues in animal tissues.

A novel Bruton's tyrosine kinase inhibitor CC-292 in combination with the proteasome inhibitor carfilzomib impacts the bone microenvironment in a multiple myeloma model with resultant antimyeloma activity.

Bruton's tyrosine kinase (Btk) modulates B-cell development and activation and has an important role in antibody production. Interestingly, Btk may also affect human osteoclast (OC) function; however, the mechanism was unknown. Here we studied a potent and specific Btk inhibitor, CC-292, in multiple myeloma (MM). In this report, we demonstrate that, although CC-292 increased OC differentiation, it inhibited OC function via inhibition of c-Src, Pyk2 and cortactin, all involved in OC-sealing zone formation. As CC-292 did not show potent in vitro anti-MM activity, we next evaluated it in combination with the proteasome inhibitor, carfilzomib. We first studied the effect of carfilzomib on OC. Carfilzomib did not have an impact on OC-sealing zone formation but significantly inhibited OC differentiation. CC-292 combined with carfilzomib inhibited both sealing zone formation and OC differentiation, resulting in more profound inhibition of OC function than carfilzomib alone. Moreover, the combination treatment in an in vivo MM mouse model inhibited tumor burden compared with CC-292 alone; it also increased bone volume compared with carfilzomib alone. These results suggest that CC-292 combined with carfilzomib augments the inhibitory effects against OC within the bone microenvironment and has promising therapeutic potential for the treatment of MM and related bone disease.

MicroRNA miR-93 promotes tumor growth and angiogenesis by targeting integrin-ß8.

It has been reported that the miR-106b∼25 cluster, a paralog of the miR-17∼92 cluster, possesses oncogenic activities. However, the precise role of each microRNA (miRNA) in the miR-106b∼25 cluster is not yet known. In this study, we examined the function of miR-93, one of the microRNAs within the miR-106b∼25 cluster, in angiogenesis and tumor formation. We found that miR-93 enhanced cell survival, promoted sphere formation and augmented tumor growth. Most strikingly, when miR-93-overexpressing U87 cells were co-cultured with endothelial cells, they supported endothelial cell spreading, growth, migration and tube formation. In vivo studies revealed that miR-93-expressing cells induced blood vessel formation, allowing blood vessels to extend to tumor tissues in high densities. Angiogenesis promoted by miR-93 in return facilitated cell survival, resulting in enhanced tumor growth. We further showed that integrin-ß8 is a target of miR-93. Higher levels of integrin-ß8 are associated with cell death in tumor mass and in human glioblastoma. Silencing of integrin-ß8 expression using small interfering RNA promoted cell proliferation, whereas ectopic expression of integrin-ß8 decreased cell growth. These findings showed that miR-93 promotes tumor growth and angiogenesis by suppressing, at least in part, integrin-ß8 expression. Our results suggest that inhibition of miR-93 function may be a feasible approach to suppress angiogenesis and tumor growth.

Image registration demonstrates the growth plate has a variable affect on vertebral strain.

Characterizing the biomechanical behavior of the vertebrae is important in understanding the impact of structural and material changes on spinal growth and fracture risk. The growth plate is critical for the normal development of the skeleton, with abnormalities leading to uneven maturation. Little is known about how growth plates affect the stress and strain experienced by the surrounding bone. Concentrated strain within the growth plate may influence mechanical cell signaling during development, lead to increased fracture risk at this site and may influence average bone strain measures. It is hypothesized that the growth plates and adjacent bony areas will take up a large amount of the strain within rat-tail vertebrae under axial compressive loading, leading to increased average bone strain measures. The sixth caudal vertebrae of 8 rnu/rnu rats were muCT scanned in both loaded (20-32 N axial compression) and unloaded configurations. Image registration was used to calculate strain in the bone due to the applied load by finding a spatial mapping between the two scans. In seven of the eight rats, the majority of the strain measured within their vertebrae was concentrated in the growth plates. Five of the specimens had growth plates that demonstrated rigid behavior in contrast to compliant growth plate behavior seen in the other three rats. The presence of a compliant growth plate led to higher average (-0.03 vs. -0.01) and maximum (-0.13 vs. -0.02) strains. The strain within the growth plate is important to consider when interpreting apparent tissue level biomechanical data commonly reported in the literature as this study suggests strains are not uniformly distributed with high concentrations in and around the growth plate. This strain distribution may provide insight into the mechanical signals that cells experience during the formation of new bone, with the higher strains near the growth plate signaling cells to lay down more bone, while also leading to increased risk of fracture in this region.