T1Gd is reduced in bone marrow lesions overlying cartilage in the hip.

OBJECTIVE: Bone Marrow Lesions (BMLs) are areas in bone with high fluid signal on MRI associated with painful and progressive OA. While cartilage near BMLs in the knee has been shown to be degenerated, this relationship has not been investigated in the hip. RESEARCH QUESTION: is T1Gd lower in areas of cartilage overlying BMLs in the hip? DESIGN: 128 participants were recruited from a population-based study of hip pain in 20-49-year-olds. Proton-density weighted fat-suppressed and delayed Gadolinium Enhanced MR Imaging of Cartilage (dGEMRIC) images were acquired to locate BMLs and quantify hip cartilage health. BML and cartilage images were registered and cartilage was separated into BML overlying and surrounding regions. Mean T1Gd was measured in 32 participants with BMLs in both cartilage regions and in matched regions in 32 age- and sex-matched controls. Mean T1Gd in the overlying cartilage was compared using linear mixed-effects models between BML and control groups for acetabular and femoral BMLs, and between cystic and non-cystic BML groups. RESULTS: Mean T1Gd of overlying cartilage was lower in the BML group compared to the control group (acetabular: -105 ms; 95% CI: -175, -35; femoral: -8 ms; 95% CI: -141, 124). Mean T1Gd in overlying cartilage was lower in cystic compared to non-cystic BML subjects, but the confidence interval is too large to provide certainty in this difference (-3 [95% CI: -126, 121]). CONCLUSIONS: T1Gd is reduced in overlying cartilage in hips from a population-based sample of adults aged 20-49, which suggests BMLs are associated with local cartilage degeneration in hips.

Small tube-nosed seabirds fledge on the full moon and throughout the lunar cycle.

Many seabirds are attracted to anthropogenic light, and the risk is greater for recent fledglings. Moon phase predicts the probability of stranding (fewer birds strand on the full moon), but it remains uncertain whether moon phase is associated with when young seabirds fledge. Fledging behaviour of nocturnal, burrowing seabirds can be difficult to monitor using traditional methods but can provide insight into environmental factors that influence the risk of stranding. We used passive integrated transponder tags to monitor the fledging dates and times of Leach's storm-petrel (Hydrobates leucorhous) chicks across four breeding seasons (2017, 2018, 2021, 2022) at a major colony in Newfoundland and Labrador, Canada. We also assessed whether moon phase and incident illumination related to fledging date and time. The median fledge time was 1.6 h after sunset (0.6-11.7 h). The median fledge date was 10 October, and fledging dates ranged from 13 September to 13 November. Most importantly, moon phase was not associated with the time and date that Leach's storm-petrel chicks fledged. These results suggest that recently fledged storm-petrels are less attracted to anthropogenic light during high levels of natural illumination, which could indicate periods of higher stranding risk and help concentrate conservation efforts.

In situ genetic engineering of tumors for long-lasting and systemic immunotherapy.

Cancer immunotherapy has been the subject of extensive research, but highly effective and broadly applicable methods remain elusive. Moreover, a general approach to engender endogenous patient-specific cellular therapy, without the need for a priori knowledge of tumor antigen, ex vivo cellular manipulation, or cellular manufacture, could dramatically reduce costs and broaden accessibility. Here, we describe a biotechnology based on synthetic, biodegradable nanoparticles that can genetically reprogram cancer cells and their microenvironment in situ so that the cancer cells can act as tumor-associated antigen-presenting cells (tAPCs) by inducing coexpression of a costimulatory molecule (4-1BBL) and immunostimulatory cytokine (IL-12). In B16-F10 melanoma and MC38 colorectal carcinoma mouse models, reprogramming nanoparticles in combination with checkpoint blockade significantly reduced tumor growth over time and, in some cases, cleared the tumor, leading to long-term survivors that were then resistant to the formation of new tumors upon rechallenge at a distant site. In vitro and in vivo analyses confirmed that locally delivered tAPC-reprogramming nanoparticles led to a significant cell-mediated cytotoxic immune response with systemic effects. The systemic tumor-specific and cell-mediated immunotherapy response was achieved without requiring a priori knowledge of tumor-expressed antigens and reflects the translational potential of this nanomedicine.

Neotropical Birds Respond Innately to Unfamiliar Acoustic Signals.

AbstractMany animals respond to heterospecific signals that indicate the presence of food or predators. Although the benefits of responding are clear, the behavioral and cognitive mechanisms underlying responses are not. Whether responses are learned, innate, or an epiphenomenon created by following other species as they respond to signals remains unknown because most studies have involved respondents that are sympatric with their heterospecific signalers and that have therefore had opportunities to learn their signals. In this study, we tested the mechanisms underlying avian responses to heterospecific chick-a-dee calls. All North American parids produce chick-a-dee calls in response to arousing stimuli, such as food and predators, and diverse species respond by approaching the caller and consuming the food or mobbing the predator. We broadcast chick-a-dee calls plus two control stimuli in Costa Rica, Colombia, and Brazil, where no parids ever occur. We conducted our trials in the winter, when Neotropical migrants that might be familiar with chick-a-dee calls were present, and in the temperate breeding season, when migrants were absent. Across 138 trials, 38 resident species from 14 families and four orders responded to chick-a-dee calls by approaching to within 5 m of the playback speaker. A phylogenetic logistic regression showed that whether a species responded was not significantly associated with the species' mean body mass or the structural similarity between its calls and chick-a-dee calls. Residents were significantly more likely to approach chick-a-dee calls than either control stimulus. This pattern was unaffected by the presence of migrants, thus demonstrating that the observed responses are innate. Our study shows that learning cannot fully explain responses to heterospecific chick-a-dee calls and that structural features distinguishing these calls from other vocalizations are important.

Size-Controlled and Shelf-Stable DNA Particles for Production of Lentiviral Vectors.

Polyelectrolyte complex particles assembled from plasmid DNA (pDNA) and poly(ethylenimine) (PEI) have been widely used to produce lentiviral vectors (LVVs) for gene therapy. The current batch-mode preparation for pDNA/PEI particles presents limited reproducibility in large-scale LVV manufacturing processes, leading to challenges in tightly controlling particle stability, transfection outcomes, and LVV production yield. Here we identified the size of pDNA/PEI particles as a key determinant for a high transfection efficiency with an optimal size of 400-500 nm, due to a cellular-uptake-related mechanism. We developed a kinetics-based approach to assemble size-controlled and shelf-stable particles using preassembled nanoparticles as building blocks and demonstrated production scalability on a scale of at least 100 mL. The preservation of colloidal stability and transfection efficiency was benchmarked against particles generated using an industry standard protocol. This particle manufacturing method effectively streamlines the viral manufacturing process and improves the production quality and consistency.

Photocrosslinked Bioreducible Polymeric Nanoparticles for Enhanced Systemic siRNA Delivery as Cancer Therapy.

Clinical translation of polymer-based nanocarriers for systemic delivery of RNA has been limited due to poor colloidal stability in the blood stream and intracellular delivery of the RNA to the cytosol. To address these limitations, this study reports a new strategy incorporating photocrosslinking of bioreducible nanoparticles for improved stability extracellularly and rapid release of RNA intracellularly. In this design, the polymeric nanocarriers contain ester bonds for hydrolytic degradation and disulfide bonds for environmentally triggered small interfering RNA (siRNA) release in the cytosol. These photocrosslinked bioreducible nanoparticles (XbNPs) have a shielded surface charge, reduced adsorption of serum proteins, and enable superior siRNA-mediated knockdown in both glioma and melanoma cells in high-serum conditions compared to non-crosslinked formulations. Mechanistically, XbNPs promote cellular uptake and the presence of secondary and tertiary amines enables efficient endosomal escape. Following systemic administration, XbNPs facilitate targeting of cancer cells and tissue-mediated siRNA delivery beyond the liver, unlike conventional nanoparticle-based delivery. These attributes of XbNPs facilitate robust siRNA-mediated knockdown in vivo in melanoma tumors colonized in the lungs following systemic administration. Thus, biodegradable polymeric nanoparticles, via photocrosslinking, demonstrate extended colloidal stability and efficient delivery of RNA therapeutics under physiological conditions, and thereby potentially advance systemic delivery technologies for nucleic acid-based therapeutics.

Sympatry drives colour and song evolution in wood-warblers (Parulidae).

Closely related species often exhibit similarities in appearance and behaviour, yet when related species exist in sympatry, signals may diverge to enhance species recognition. Prior comparative studies provided mixed support for this hypothesis, but the relationship between sympatry and signal divergence is likely nonlinear. Constraints on signal diversity may limit signal divergence, especially when large numbers of species are sympatric. We tested the effect of sympatric overlap on plumage colour and song divergence in wood-warblers (Parulidae), a speciose group with diverse visual and vocal signals. We also tested how number of sympatric species influences signal divergence. Allopatric species pairs had overall greater plumage and song divergence compared to sympatric species pairs. However, among sympatric species pairs, plumage divergence positively related to the degree of sympatric overlap in males and females, while male song bandwidth and syllable rate divergence negatively related to sympatric overlap. In addition, as the number of species in sympatry increased, average signal divergence among sympatric species decreased, which is likely due to constraints on warbler perceptual space and signal diversity. Our findings reveal that sympatry influences signal evolution in warblers, though not always as predicted, and that number of sympatric species can limit sympatry's influence on signal evolution.

Omega-3 fatty acids accelerate fledging in an avian marine predator: a potential role of cognition.

Consuming omega-3 fatty acids (n-3 LCPUFAs) during development improves cognition in mammals, but the effect remains untested in other taxa. In aquatic ecosystems, n-3 LCPUFAs are produced by phytoplankton and bioaccumulate in the food web. Alarmingly, the warming and acidification of aquatic systems caused by climate change impair n-3 LCPUFA production, with an anticipated decrease of 80% by the year 2100. We tested whether n-3 LCPUFA consumption affects the physiology, morphology, behaviour and cognition of the chicks of a top marine predator, the ring-billed gull. Using a colony with little access to n-3 LCPUFAs, we supplemented siblings from 22 fenced nests with contrasting treatments from hatching until fledging; one sibling received n-3 LCPUFA-rich fish oil and the other, a control sucrose solution without n-3 LCPUFAs. Halfway through the nestling period, half the chicks receiving fish oil were switched to the sucrose solution to test whether n-3 LCPUFA intake remains crucial past the main growth phase (chronic versus transient treatments). Upon fledging, n-3 LCPUFAs were elevated in the blood and brains of chicks receiving the chronic treatment, but were comparable to control levels among those receiving the transient treatment. Across the entire sample, chicks with elevated n-3 LCPUFAs in their tissues fledged earlier despite their morphology and activity levels being unrelated to fledging age. Fledging required chicks to escape fences encircling their nest. We therefore interpret fledging age as a possible indicator of cognition, with chicks with improved cognition fledging earlier. These results provide insight into whether declining dietary n-3 LCPUFAs will compromise top predators' problem-solving skills, and thus their ability to survive in a rapidly changing world.

Open MRI validation of a hip model driven with subject-specific motion capture data in predicting anterior femoroacetabular clearance.

BACKGROUND: Cam and/or pincer morphologies (CPM) are potential precursors to hip osteoarthritis (OA) and important contributors to non-arthritic hip pain. However, only some CPM hips develop OA and/or pain, and it is not clear why. Anterior impingement between the femoral head/neck contour and acetabular rim during motion is a proposed pathomechanism. Understanding how activity and deformity combine to produce impingement may shed light on the causes of hip degeneration/pain. The objective of this study was to determine the accuracy of a subject-specific hip model driven by subject-specific motion data in predicting anterior impingement. METHODS: We recruited 22 participants with CPM (both with and without pain) and 11 controls. We collected subject-specific 3D kinematics during squatting and sitting flexion, adduction, and internal rotation (FADIR) (an active and a passive maneuver, respectively, proposed to provoke impingement). We then developed 3D subject-specific hip models from supine 3T hip MRI scans that predicted the beta angle (a measure of anterior femoroacetabular clearance) for each frame of acquired kinematics. To assess the accuracy of these predictions, we measured the beta angle directly in the final position of squatting and sitting FADIR using open MRI scans. We selected the frame of motion data matching the static imaged posture using the least-squares error in hip angles. Model accuracy for each subject was calculated as the absolute error between the open MRI measure of beta and the model prediction of beta at the matched time frame. To make the final model accuracy independent of goodness of match between open MRI position and motion data, a threshold was set for least-squares error in hip angles, and only participants that were below this threshold were considered in the final model accuracy calculation, yielding results from 10 participants for squatting and 7 participants for sitting FADIR. RESULTS: For squatting and sitting FADIR, we found an accuracy of 1.1°(0.8°) and 1.3°(mean (SD), and root mean squared error, respectively) and 0.5°(0.3°) and 0.6°, respectively. CONCLUSION: This subject-specific hip model predicts anterior femoroacetabular clearance with an accuracy of about 1°, making it useful to predict anterior impingement during activities measured with motion analysis.

Tibiofemoral Contact Measures During Standing in Toe-In and Toe-Out Postures.

Knee osteoarthritis is thought to result, in part, from excessive and unbalanced joint loading. Toe-in and toe-out gait modifications produce alterations in external knee joint moments, and some improvements in pain over the short- and long-term. The aim of this study was to probe mechanisms of altered joint loading through the assessment of tibiofemoral contact in standing with toe-in and toe-out positions using an open magnetic resonance scanner. In this study, 15 young, healthy participants underwent standing magnetic resonance imaging of one of their knees in 3 foot positions. Images were analyzed to determine contact in the tibiofemoral joint, with primary outcomes including centroid of contact and contact area for each compartment and overall. The centroid of contact shifted laterally in the lateral compartment with both toe-in and toe-out postures, compared with the neutral position (P < .01), while contact area in the medial and lateral compartments showed no statistical differences. Findings from this study indicate that changes in the loading anatomy are present in the tibiofemoral joint with toe-in and toe-out and that a small amount of lateralization of contact, especially in the lateral compartment, does occur with these altered lower limb orientations.

Alaska Native genomic research: perspectives from Alaska Native leaders, federal staff, and biomedical researchers.

Meaningful engagement of Alaska Native (AN) tribes and tribal health organizations is essential in the conduct of socially responsible and ethical research. As genomics becomes increasingly important to advancements in medicine, there is a risk that populations not meaningfully included in genomic research will not benefit from the outcomes of that research. AN people have historically been underrepresented in biomedical research; AN underrepresentation in genomics research is compounded by mistrust based on past abuses, concerns about privacy and data ownership, and cultural considerations specific to this type of research. Working together, the National Human Genome Research Institute and two Alaska Native health organizations, Southcentral Foundation and the Alaska Native Health Board, cosponsored a workshop in July 2018 to engage key stakeholders in discussion, strengthen relationships, and facilitate partnership and consideration of participation of AN people in community-driven biomedical and genomic research. AN priorities related to translation of genomics research to health and health care, return of genomic results, design of research studies, and data sharing were discussed. This report summarizes the perspectives that emerged from the dialogue and offers considerations for effective and socially responsible genomic research partnerships with AN communities.

The effect of posture on lumbar muscle morphometry from upright MRI.

PURPOSE: To assess the effect of upright, seated, and supine postures on lumbar muscle morphometry at multiple spinal levels and for multiple muscles. METHODS: Six asymptomatic volunteers were imaged (0.5 T upright open MRI) in 7 postures (standing, standing holding 8 kg, standing 45° flexion, seated 45° flexion, seated upright, seated 45° extension, and supine), with scans at L3/L4, L4/L5, and L5/S1. Muscle cross-sectional area (CSA) and muscle position with respect to the vertebral body centroid (radius and angle) were measured for the multifidus/erector spinae combined and psoas major muscles. RESULTS: Posture significantly affected the multifidus/erector spinae CSA with decreasing CSA from straight postures (standing and supine) to seated and flexed postures (up to 19%). Psoas major CSA significantly varied with vertebral level with opposite trends due to posture at L3/L4 (increasing CSA, up to 36%) and L5/S1 (decreasing CSA, up to 40%) with sitting/flexion. For both muscle groups, radius and angle followed similar trends with decreasing radius (up to 5%) and increasing angle (up to 12%) with seated/flexed postures. CSA and lumbar lordosis had some correlation (multifidus/erector spinae L4/L5 and L5/S1, r = 0.37-0.45; PS L3/L4 left, r = - 0.51). There was generally good repeatability (average ICC(3, 1): posture = 0.81, intra = 0.89, inter = 0.82). CONCLUSION: Changes in multifidus/erector spinae muscle CSA likely represent muscles stretching between upright and seated/flexed postures. For the psoas major, the differential level effect suggests that changing three-dimensional muscle morphometry with flexion is not uniform along the muscle length. The muscle and spinal level-dependent effects of posture and spinal curvature correlation, including muscle CSA and position, highlight considering measured muscle morphometry from different postures in spine models.

Nonviral polymeric nanoparticles for gene therapy in pediatric CNS malignancies.

Together, medulloblastoma (MB) and atypical teratoid/rhabdoid tumors (AT/RT) represent two of the most prevalent pediatric brain malignancies. Current treatment involves radiation, which has high risks of developmental sequelae for patients under the age of three. New safer and more effective treatment modalities are needed. Cancer gene therapy is a promising alternative, but there are challenges with using viruses in pediatric patients. We developed a library of poly(beta-amino ester) (PBAE) nanoparticles and evaluated their efficacy for plasmid delivery of a suicide gene therapy to pediatric brain cancer models-specifically herpes simplex virus type I thymidine kinase (HSVtk), which results in controlled apoptosis of transfected cells. In vivo, PBAE-HSVtk treated groups had a greater median overall survival in mice implanted with AT/RT (P = 0.0083 vs. control) and MB (P < 0.0001 vs. control). Our data provide proof of principle for using biodegradable PBAE nanoparticles as a safe and effective nanomedicine for treating pediatric CNS malignancies.

Reliability of tibiofemoral contact area and centroid location in upright, open MRI.

BACKGROUND: Imaging cannot be performed during natural weightbearing in biomechanical studies using conventional closed-bore MRI, which has necessitated simulating weightbearing load on the joint. Upright, open MRI (UO-MRI) allows for joint imaging during natural weightbearing and may have the potential to better characterize the biomechanical effect of tibiofemoral pathology involving soft tissues. However open MRI scanners have lower field strengths than closed-bore scanners, which limits the image quality that can be obtained. Thus, there is a need to establish the reliability of measurements in upright weightbearing postures obtained using UO-MRI. METHODS: Knees of five participants with prior anterior cruciate ligament (ACL) rupture were scanned standing in a 0.5 T upright open MRI scanner using a 3D DESS sequence. Manual segmentation of cartilage regions in contact was performed and centroids of these contact areas were automatically determined for the medial and lateral tibiofemoral compartments. Inter-rater, test-retest, and intra-rater reliability were determined and quantified using intra-class correlation (ICC3,1), standard error of measurement (SEM), and smallest detectable change with 95% confidence (SDC95). Accuracy was assessed by using a high-resolution 7 T MRI as a reference. RESULTS: Contact area and centroid location reliability (inter-rater, test-retest, and intra-rater) for sagittal scans in the medial compartment had ICC3,1 values from 0.95-0.99 and 0.98-0.99 respectively. In the lateral compartment, contact area and centroid location reliability ICC3,1 values ranged from 0.83-0.91 and 0.95-1.00 respectively. The smallest detectable change in contact area was 1.28% in the medial compartment and 0.95% in the lateral compartment. Contact area and centroid location reliability for coronal scans in the medial compartment had ICC3,1 values from 0.90-0.98 and 0.98-1.00 respectively, and in the lateral compartment ICC3,1 ranged from 0.76-0.94 and 0.93-1.00 respectively. The smallest detectable change in contact area was 0.65% in the medial compartment and 1.41% in the lateral compartment. Contact area was accurate to within a mean absolute error of 11.0 mm2. CONCLUSIONS: Knee contact area and contact centroid location can be assessed in upright weightbearing MRI with good to excellent reliability. The lower field strength used in upright, weightbearing MRI does not compromise the reliability of tibiofemoral contact area and centroid location measures.

Constructing identities: the implications of DTC ancestry testing for tribal communities.

PURPOSE: Direct-to-consumer (DTC) genetic ancestry companies have rapidly increased in popularity, with top testing services maintaining genetic databases of several million consumers. While genetic ancestry tests are often characterized as recreational, companies invoke deeply personal concepts of individual identity, group membership, and kinship when marketing their services. In particular, many companies claim to be able to determine Native American heritage, claims that are not supported by the state of the science and may have significant cultural and political consequences for US tribal communities. This study aims to fill the gaps in empirical work on this issue and characterize how genetic ancestry companies articulate indigenous identity through their marketing strategies. METHODS: We conducted a qualitative content analysis of the public facing websites for 25 DTC genetic ancestry companies that offer services measuring Native American ancestry. RESULTS: Our findings describe how genetic ancestry companies promote a causal relationship between genetics and self-identity through marketing language such as "Discover Yourself" and "Are you Native American?" and how this may affect US tribal communities. CONCLUSION: Genetic ancestry company claims regarding genetic ancestry, personal identity, and cultural membership are problematic and challenge how US tribal nations currently identify and create potential obstacles for tribal sovereignty.

The role of assembly parameters on polyplex poly(beta-amino ester) nanoparticle transfections.

Intracellular delivery of nucleic acids to mammalian cells using polyplex nanoparticles (NPs) remains a challenge both in vitro and in vivo, with transfections often suffering from variable efficacy. To improve reproducibility and efficacy of transfections in vitro using a next-generation polyplex transfection material poly(beta-amino ester)s (PBAEs), the influence of multiple variables in the preparation of these NPs on their transfection efficacy was explored. The results indicate that even though PBAE/pDNA polyplex NPs are formed by the self-assembly of polyelectrolytes, their transfection is not affected by the manner in which the components are mixed, facilitating self-assembly in a single step, but timing for self-assembly of 5-20 min is optimal. In addition, even though the biomaterials are biodegradable in water, their efficacy is not affected by up to eight freeze-thaw cycles of the polymer. It was found that there is a greater stability of nucleic acid-complexed polymer as a polyplex nanoparticle compared with free polymer. Finally, by exploring multiple buffer systems, it was identified that utilization of divalent cation magnesium or calcium acetate buffers at pH 5.0 is optimal for transfection using these polymeric materials, boosting transfection several folds compared with monovalent cations. Together, these results can improve the reproducibility and efficacy of PBAE and similar polyplex nanoparticle transfections and improve the robustness of using these biomaterials for bioengineering and biotechnology applications.

Differentially Branched Ester Amine Quadpolymers with Amphiphilic and pH-Sensitive Properties for Efficient Plasmid DNA Delivery.

Development of highly effective nonviral gene delivery vectors for transfection of diverse cell populations remains a challenge despite utilization of both rational and combinatorial driven approaches to nanoparticle engineering. In this work, multifunctional polyesters are synthesized with well-defined branching structures via A2 + B2/B3 + C1 Michael addition reactions from small molecule acrylate and amine monomers and then end-capped with amine-containing small molecules to assess the influence of polymer branching structure on transfection. These Branched poly(Ester Amine) Quadpolymers (BEAQs) are highly effective for delivery of plasmid DNA to retinal pigment epithelial cells and demonstrate multiple improvements over previously reported leading linear poly(beta-amino ester)s, particularly for volume-limited applications where improved efficiency is required. BEAQs with moderate degrees of branching are demonstrated to be optimal for delivery under high serum conditions and low nanoparticle doses further relevant for therapeutic gene delivery applications. Defined structural properties of each polymer in the series, including tertiary amine content, correlated with cellular transfection efficacy and viability. Trends that can be applied to the rational design of future generations of biodegradable polymers are elucidated.

Knee osteoarthritis patients with more subchondral cysts have altered tibial subchondral bone mineral density.

BACKGROUND: Subchondral bone cysts are a widely observed, but poorly understood, feature in patients with knee osteoarthritis (OA). Clinical quantitative computed tomography (QCT) has the potential to characterize cysts in vivo but it is unclear which specific cyst parameters (e.g., number, size) are associated with clinical signs of OA, such as disease severity or pain. The objective of this study was to use QCT-based image-processing techniques to characterize subchondral tibial cysts in patients with knee OA and to explore relationships between proximal tibial subchondral cyst parameters and subchondral bone density as well as clinical characteristics of OA (alignment, joint space narrowing (JSN), OA severity, pain) in patients with knee OA. METHODS: The preoperative knee of 42 knee arthroplasty patients was scanned using QCT. Patient characteristics were obtained, including OA severity, knee pain, JSN, and alignment. We used 3D image processing techniques to obtain cyst parameters including: cyst number, cyst number per proximal tibial volume, cyst volume per proximal tibial volume, as well as maximum and average cyst volume across the proximal tibia, as well as regional bone mineral density (BMD) excluding cysts. We used Spearman's correlation coefficients to explore associations between patient characteristics and cyst parameters. RESULTS: At both the medial and lateral compartments of the proximal tibia, greater cyst number and volume were associated with higher BMD. At the lateral region, cyst number and volume were also associated with lateral OA severity, lateral JSN, alignment and sex. Pain was not associated with any cyst parameters at any region. CONCLUSION: Cyst number and volume were associated with BMD at both the medial and lateral compartments. Lateral cyst number and volume were also associated with joint alignment, OA severity, JSN and sex. This is the first study to use clinical QCT to explore subchondral tibial cysts in patients with knee OA and provides further evidence of the relationships between subchondral cysts and clinical OA characteristics.

Bioreducible Polymeric Nanoparticles Containing Multiplexed Cancer Stem Cell Regulating miRNAs Inhibit Glioblastoma Growth and Prolong Survival.

Despite our growing molecular-level understanding of glioblastoma (GBM), treatment modalities remain limited. Recent developments in the mechanisms of cell fate regulation and nanomedicine provide new avenues by which to treat and manage brain tumors via the delivery of molecular therapeutics. Here, we have developed bioreducible poly(ß-amino ester) nanoparticles that demonstrate high intracellular delivery efficacy, low cytotoxicity, escape from endosomes, and promotion of cytosol-targeted environmentally triggered cargo release for miRNA delivery to tumor-propagating human cancer stem cells. In this report, we combined this nanobiotechnology with newly discovered cancer stem cell inhibiting miRNAs to develop self-assembled miRNA-containing polymeric nanoparticles (nano-miRs) to treat gliomas. We show that these nano-miRs effectively intracellularly deliver single and combination miRNA mimics that inhibit the stem cell phenotype of human GBM cells in vitro. Following direct intratumoral infusion, these nano-miRs were found to distribute through the tumors, inhibit the growth of established orthotopic human GBM xenografts, and cooperatively enhance the response to standard-of-care γ radiation. Co-delivery of two miRNAs, miR-148a and miR-296-5p, within the bioreducible nano-miR particles enabled long-term survival from GBM in mice.