Magnetic Resonance Imaging Features of Anterolateral Ligament in Young Adults without Anterior Cruciate Ligament Injury: Preliminary Evaluation.

This study aimed to characterize the Magnetic Resonance Imaging (MRI) features of the Anterolateral Ligament (ALL) in young adults without Anterior Cruciate Ligament (ACL) injury and evaluate its visibility using MRI. In this retrospective analysis, MRI scans of 66 young adults without ACL injuries were assessed by two radiologists. The ALL was examined from its bone-to-bone attachment between the lateral femoral epicondyle and the lateral tibia. The visibility of the ALL was classified as normal, probably normal, abnormal, or non-visualized, based on ligament continuity and thickness relative to the Meniscotibial Ligament (MTL). A continuous structure with thickness equal to or greater than the MTL was considered normal; continuous but wavy and thin features were categorized as probably normal; discontinuity and angulation were deemed abnormal. The proximal attachment of the ALL was categorized as anterior, central, or posterior to the Fibular Collateral Ligament (FCL), while the distal attachment was noted as either at the same location or distal to the MTL. The ALL was identified in 87.9-95.5% of knees and was non-visualized in 4.5-12.1% of cases. Continuous ligamentous structures were observed in 63.7-71.2% of knees (normal in 30.3-37.9%; probably normal in 27.3-40.9%), whereas 19.7-30.3% exhibited abnormal features. Inter-observer agreement was moderate to substantial (κ = 0.66, 0.56), and intra-observer agreement was substantial to excellent (κ = 0.82, 0.66). Among the 58 visible ALLs, proximal attachments were predominantly anterior (63.8%) or central (32.8%) to the FCL, with a minority posterior (1.7%). In total, 4 of the 19 central insertions were incorporated into the FCL mid-substance, and one case was blended into the meniscofemoral ligament. Distal attachments were equally distributed between the same location (50%) and distal to the MTL (50%) (mean 3.7 mm distal). In conclusion, MRI was feasible for detecting the ALL in most young adults without ACL injury, revealing continuous ligament structures in about two-thirds of cases. Approximately 40% of cases exhibited a thickness equal to or greater than the MTL, with the majority of proximal attachments located anterior to the FCL and distal attachments evenly divided between the same insertion and distal to the MTL.

Optimizing long-term stability of siRNA using thermoassemble ionizable reverse pluronic-Bcl2 micelleplexes.

Thermosassemble Ionizable Reverse Pluronic (TIRP) platform stands out for its distinctive combination of thermoassemble and ionizable features, effectively overcoming challenges in previous siRNA delivery systems. This study opens up a formation for long-term stabilization, and high loading of siRNA, specifically crafted for targeting oncogenic pathways. TIRP-Bcl2 self-assembles into a unique micelle structure with a nanodiameter of 75.8 ± 5.7 nm, efficiently encapsulating Bcl2 siRNA while maintaining exceptional colloidal stability at 4 °C for 8 months, along with controlled release profiles lasting 180 h. The dual ionizable headgroup enhance the siRNA loading and the revers pluronic unique structural orientation enhance the stability of the siRNA. The thermoassemble of TIRP-Bcl2 facilitates flexi-rigid response to mild hyperthermia, enhancing deep tissue penetration and siRNA release in the tumor microenvironment. This responsive behavior improves intracellular uptake and gene silencing efficacy in cancer cells. TIRP, with its smaller particle size and reverse pluronic nature, efficiently transports siRNA across the blood-brain barrier, holding promise for revolutionizing glioblastoma (GBM) treatment. TIRP-Bcl2 shows significant potential for precise, personalized therapies, promising prolonged siRNA delivery and in vitro/in vivo stability. This research opens avenues for further exploration and clinical translation of this innovative nanocarrier system across different cancers.

Automated Detection and Segmentation of Bone Metastases on Spine MRI Using U-Net: A Multicenter Study.

OBJECTIVE: To develop and evaluate a deep learning model for automated segmentation and detection of bone metastasis on spinal MRI. MATERIALS AND METHODS: We included whole spine MRI scans of adult patients with bone metastasis: 662 MRI series from 302 patients (63.5 ± 11.5 years; male:female, 151:151) from three study centers obtained between January 2015 and August 2021 for training and internal testing (random split into 536 and 126 series, respectively) and 49 MRI series from 20 patients (65.9 ± 11.5 years; male:female, 11:9) from another center obtained between January 2018 and August 2020 for external testing. Three sagittal MRI sequences, including non-contrast T1-weighted image (T1), contrast-enhanced T1-weighted Dixon fat-only image (FO), and contrast-enhanced fat-suppressed T1-weighted image (CE), were used. Seven models trained using the 2D and 3D U-Nets were developed with different combinations (T1, FO, CE, T1 + FO, T1 + CE, FO + CE, and T1 + FO + CE). The segmentation performance was evaluated using Dice coefficient, pixel-wise recall, and pixel-wise precision. The detection performance was analyzed using per-lesion sensitivity and a free-response receiver operating characteristic curve. The performance of the model was compared with that of five radiologists using the external test set. RESULTS: The 2D U-Net T1 + CE model exhibited superior segmentation performance in the external test compared to the other models, with a Dice coefficient of 0.699 and pixel-wise recall of 0.653. The T1 + CE model achieved per-lesion sensitivities of 0.828 (497/600) and 0.857 (150/175) for metastases in the internal and external tests, respectively. The radiologists demonstrated a mean per-lesion sensitivity of 0.746 and a mean per-lesion positive predictive value of 0.701 in the external test. CONCLUSION: The deep learning models proposed for automated segmentation and detection of bone metastases on spinal MRI demonstrated high diagnostic performance.

Assessing visibility and bone changes of spinal metastases in CT scans: a comprehensive analysis across diverse cancer types.

OBJECTIVES: To analyze the characteristics of spinal metastasis in CT scans across diverse cancers for effective diagnosis and treatment, using MRI as the gold standard. METHODS: A retrospective study of 309 patients from four centers, who underwent concurrent CT and spinal MRI, revealing spinal metastasis, was conducted. Data on metastasis including total number, volume, visibility on CT (visible, indeterminate, or invisible), and type of bone change were collected. Through chi-square and Mann-Whitney U tests, we characterized the metastasis across diverse cancers and investigated the variation in the intra-individual ratio representing the percentage of lesions within each category for each patient. RESULTS: Out of 3333 spinal metastases from 309 patients, 55% were visible, 21% indeterminate, and 24% invisible. Sclerotic and lytic lesions made up 47% and 43% of the visible and indeterminate categories, respectively. Renal cell carcinoma (RCC), prostate cancer, and hepatocellular carcinoma (HCC) had the highest visibility at 86%, 73%, and 67% (p < 0.0001, p < 0.0001, and p = 0.003), while pancreatic cancer was lowest at 29% (p < 0.0001). RCC and HCC had significantly high lytic metastasis ratios (interquartile range (IQR) 0.96-1.0 and 0.31-1.0, p < 0.001 and p = 0.005). Prostate cancer exhibited a high sclerotic lesion ratio (IQR 0.52-0.97, p < 0.001). About 39% of individuals had invisible or indeterminate lesions, even with a single visible lesion on CT. The intra-individual ratio for indeterminate and invisible metastases surpassed 18%, regardless of the maximal size of the visible metastasis. CONCLUSIONS: This study highlights the variability in characteristics of spinal metastasis based on the primary cancer type through unique lesion-centric analysis.

Usefulness of 3-Dimensional Computed Tomography Assessment of Femoral Tunnel after Anterior Cruciate Ligament Reconstruction.

Positioning of the femoral tunnel during anterior cruciate ligament (ACL) reconstruction is the most crucial factor for successful procedure. Owing to the inter-individual variability in the intra-articular anatomy, it can be challenging to obtain precise tunnel placement and ensure consistent results. Currently, the three-dimensional (3D) reconstruction of computed tomography (CT) scans is considered the best method for determining whether femoral tunnels are positioned correctly. Postoperative 3D-CT feedback can improve the accuracy of femoral tunnel placement. Precise tunnel formation obtained through feedback has a positive effect on graft maturation, graft failure, and clinical outcomes after surgery. However, even if femoral tunnel placement on 3D CT is appropriate, we should recognize that acute graft bending negatively affects surgical results. This review aimed to discuss the implementation of 3D-CT evaluation for predicting postoperative outcomes following ACL re-construction. Reviewing research that has performed 3D CT evaluations after ACL reconstruction can provide clinically significant evidence of the formation of ideal tunnels following anatomic ACL reconstruction.

Brain endothelial cell-derived extracellular vesicles with a mitochondria-targeting photosensitizer effectively treat glioblastoma by hijacking the blood‒brain barrier.

Glioblastoma (GBM) is the most aggressive malignant brain tumor and has a high mortality rate. Photodynamic therapy (PDT) has emerged as a promising approach for the treatment of malignant brain tumors. However, the use of PDT for the treatment of GBM has been limited by its low blood‒brain barrier (BBB) permeability and lack of cancer-targeting ability. Herein, brain endothelial cell-derived extracellular vesicles (bEVs) were used as a biocompatible nanoplatform to transport photosensitizers into brain tumors across the BBB. To enhance PDT efficacy, the photosensitizer chlorin e6 (Ce6) was linked to mitochondria-targeting triphenylphosphonium (TPP) and entrapped into bEVs. TPP-conjugated Ce6 (TPP-Ce6) selectively accumulated in the mitochondria, which rendered brain tumor cells more susceptible to reactive oxygen species-induced apoptosis under light irradiation. Moreover, the encapsulation of TPP-Ce6 into bEVs markedly improved the aqueous stability and cellular internalization of TPP-Ce6, leading to significantly enhanced PDT efficacy in U87MG GBM cells. An in vivo biodistribution study using orthotopic GBM-xenografted mice showed that bEVs containing TPP-Ce6 [bEV(TPP-Ce6)] substantially accumulated in brain tumors after BBB penetration via transferrin receptor-mediated transcytosis. As such, bEV(TPP-Ce6)-mediated PDT considerably inhibited the growth of GBM without causing adverse systemic toxicity, suggesting that mitochondria are an effective target for photodynamic GBM therapy.

Bioreducible exosomes encapsulating glycolysis inhibitors potentiate mitochondria-targeted sonodynamic cancer therapy via cancer-targeted drug release and cellular energy depletion.

Nanocarrier-assisted sonodynamic therapy (SDT) has shown great potential for the effective and targeted treatment of deep-seated tumors by overcoming the critical limitations of sonosensitizers. However, in vivo SDT using nanocarriers is still constrained by their intrinsic toxicity and nonspecific cargo release. In this study, we developed bioreducible exosomes for the safe and tumor-specific delivery of mitochondria-targeting sonosensitizers [triphenylphosphonium-conjugated chlorin e6 (T-Ce6)] and glycolysis inhibitors (FX11). Redox-cleavable diselenide linker-bearing lipids were embedded into exosomes to trigger drug release in response to overexpressed glutathione in the tumor microenvironment. Bioreducible exosomes facilitate the cytoplasmic release of their payload in the reducing environment of tumor cells. They significantly enhance drug release and sonodynamic effects when irradiated with ultrasound (US). The mitochondria-targeted accumulation of T-Ce6 efficiently damaged the mitochondria of the cells under US irradiation, accelerating apoptotic cell death. FX11 substantially inhibited cellular energy metabolism, potentiating the antitumor efficacy of mitochondria-targeted SDT. Bioreducible exosomes effectively suppressed tumor growth in mice without significant systemic toxicity, via a combination of mitochondria-targeted SDT and energy metabolism-targeted therapy. This study offers new insights into the use of dual stimuli-responsive exosomes encapsulating sonosensitizers for safe and targeted sonodynamic cancer therapy.

Fluid-Attenuated Inversion Recovery Sequence with Fat Suppression for Assessment of Ankle Synovitis without Contrast Enhancement: Comparison with Contrast-Enhanced MRI.

The purpose of this study was to investigate the feasibility of the fluid-attenuated inversion recovery sequence with fat suppression (FLAIR-FS) for the assessment of ankle synovitis without contrast enhancement. FLAIR-FS and contrast-enhanced, T1-weighted sequences (CE-T1) of 94 ankles were retrospectively reviewed by two radiologists. Grading of synovial visibility (four-point scale) and semi-quantitative scoring of synovial thickness (three-point scale) were performed in four compartments of the ankle in both sequences. Synovial visibility and thickness in FLAIR-FS and CE-T1 images were compared, and agreement between both sequences was assessed. Synovial visibility grades and synovial thickness scores for FLAIR-FS images were lower than those for CE-T1 images (reader 1, p = 0.016, p < 0.001; reader 2, p = 0.009, p < 0.001). Dichotomized synovial visibility grades (partial vs. full visibility) were not significantly different between both sequences. The agreement in synovial thickness scores between the FLAIR-FS and CE-T1 images was moderate to substantial (κ = 0.41-0.65). The interobserver agreement between the two readers was fair for synovial visibility (κ = 0.27-0.32) and moderate to substantial for synovial thickness (κ = 0.54-0.74). In conclusion, FLAIR-FS is a feasible MRI sequence for the evaluation of ankle synovitis without contrast enhancement.

Femoral Tunnel Geometry and Graft Inclination Angles in Anterior Cruciate Ligament Reconstruction Using a Flexible Reamer System.

Background and Objectives: The aim of this study is to investigate the femoral tunnel geometry (femoral tunsnel location, femoral graft bending angle, and femoral tunnel length) on three-dimensional (3D) computed tomography (CT) and graft inclination on magnetic resonance imaging (MRI) after anatomic anterior cruciate ligament (ACL) reconstruction using a flexible reamer system. Materials and Methods: A total of 60 patients who underwent anatomical ACL reconstruction (ACLR) using a flexible reamer system were retrospectively reviewed. One day after the ACLR procedure was performed, all patients underwent three-dimensional computed tomography (3D-CT) and magnetic resonance imaging (MRI). The femoral tunnel location, femoral graft bending angle, femoral tunnel length, and graft inclination were assessed. Results: In the 3D-CTs, the femoral tunnel was located at 29.7 ± 4.4% in the posterior to anterior (deep to shallow) direction and at 24.1 ± 5.9% in the proximal to distal (high to low) direction. The mean femoral graft bending angle was 113.9 ± 5.7°, and the mean femoral tunnel length was 35.2 ± 3.1 mm. Posterior wall breakage was observed in five patients (8.3%). In the MRIs, the mean coronal graft inclination was 69.2 ± 4.7°, and the mean sagittal graft inclination was 52.4 ± 4.6°. The results of this study demonstrated that a comparable femoral graft bending angle and longer femoral tunnel length were observed compared with the reported outcomes from previous studies that used the rigid reamer system. Conclusions: ACLR using a flexible reamer system allowed for an anatomic femoral tunnel location and a comparable graft inclination to that of the native ACL. In addition, it achieved a tolerable femoral graft bending angle and femoral tunnel length.

Intraosseous administration into the skull: Potential blood-brain barrier bypassing route for brain drug delivery.

Progress in treating central nervous system (CNS) disorders is retarded owing to a limited understanding of brain disease pathology. Additionally, the blood-brain barrier (BBB) limits molecular entry into the brain. Many approaches for brain drug delivery to overcome the BBB, such as BBB permeability enhancement, transient BBB disruption, and direct surgical administration have been explored with limited success. Recent research has shown that direct vascular channels exist between the skull bone marrow and the meninges, allowing myeloid and lymphoid cells to migrate. We hypothesized that these direct channels may also allow brain drug delivery from the skull bone marrow to the brain. In this study, for the first time we propose intraosseous administration of drugs into the skull (intracalvariosseous [ICO]) as a novel approach for brain drug delivery via BBB bypassing routes. We tested the feasibility of the approach by applying nine representative compounds over thinned mouse skulls to simulate ICO and measuring the compound entry level in the brain compared to that after systemic administration. Surprisingly, we found that the skull is not completely impermeable to drug penetration into the brain and the tested compounds reached the brain tissue several tens-to-hundred times higher by ICO than systemic application. These findings suggest a role for the BBB bypassing route from skull to brain, apart from the systemic route, in the drug entry into the brain after ICO. This approach should be applicable to other CNS drugs and even BBB impermeable drugs. Overall ICO provides an innovative and advantageous pathway for effective treatment of brain diseases.

WZB117 Decorated Metformin-Carboxymethyl Chitosan Nanoparticles for Targeting Breast Cancer Metabolism.

The "Warburg effect" provides a novel method for treating cancer cell metabolism. Overexpression of glucose transporter 1 (GLUT1), activation of AMP-activated protein kinase (AMPK), and downregulation of mammalian target of rapamycin (mTOR) have been identified as biomarkers of abnormal cancer cell metabolism. Metformin (MET) is an effective therapy for breast cancer (BC), but its efficacy is largely reliant on the concentration of glucose at the tumor site. We propose a WZB117 (a GLUT1 inhibitor)-OCMC (O-carboxymethyl-chitosan)-MET combo strategy for simultaneous GLUT1 and mTOR targeting for alteration of BC metabolism. WZB117 conjugated polymeric nanoparticles were 225.67 ± 11.5 nm in size, with a PDI of 0.113 ± 0.16, and an encapsulation of 72.78 6.4%. OCMC pH-dependently and selectively releases MET at the tumor site. MET targets the mTOR pathway in cancer cells, and WZB117 targets BCL2 to alter GLUT1 at the cancer site. WZB117-OCMC-MET overcomes the limitations of MET monotherapy by targeting mTOR and BCL2 synergistically. WZB117-OCMC-MET activates AMPK and suppresses mTOR in a Western blot experiment, indicating growth-inhibitory and apoptotic characteristics. AO/EB and the cell cycle enhance cellular internalization as compared to MET alone. WZB117-OCMC-MET affects cancer cells' metabolism and is a promising BC therapeutic strategy.

Piezocatalytic 2D WS2 Nanosheets for Ultrasound-Triggered and Mitochondria-Targeted Piezodynamic Cancer Therapy Synergized with Energy Metabolism-Targeted Chemotherapy.

Piezoelectric nanomaterials that can generate reactive oxygen species (ROS) by piezoelectric polarization under an external mechanical force have emerged as an effective platform for cancer therapy. In this study, piezoelectric 2D WS2 nanosheets are functionalized with mitochondria-targeting triphenylphosphonium (TPP) for ultrasound (US)-triggered, mitochondria-targeted piezodynamic cancer therapy. In addition, a glycolysis inhibitor (FX11) that can inhibit cellular energy metabolism is loaded into TPP- and poly(ethylene glycol) (PEG)-conjugated WS2 nanosheet (TPEG-WS2 ) to potentiate its therapeutic efficacy. Upon US irradiation, the sono-excited electrons and holes generated in the WS2 are efficiently separated by piezoelectric polarization, which subsequently promotes the production of ROS. FX11-loaded TPEG-WS2 (FX11@TPEG-WS2 ) selectively accumulates in the mitochondria of human breast cancer cells. In addition, FX11@TPEG-WS2 effectively inhibits the production of adenosine triphosphate . Thus, FX11@TPEG-WS2 exhibits outstanding anticancer effects under US irradiation. An in vivo study using tumor-xenograft mice demonstrates that FX11@TPEG-WS2 effectively accumulated in the tumors. Its tumor accumulation is visualized using in vivo computed tomography . Notably, FX11@TPEG-WS2 with US irradiation remarkably suppresses the tumor growth of mice without systemic toxicity. This study demonstrates that the combination of piezodynamic therapy and energy metabolism-targeted chemotherapy using mitochondria-targeting 2D WS2 is a novel strategy for the selective and effective treatment of tumors.

Novel aggregation-induced emission-photosensitizers with built-in capability of mitochondria targeting and glutathione depletion for efficient photodynamic therapy.

Owing to its non-invasive feature and excellent therapeutic effect, photodynamic therapy has received considerable interest in cancer therapy. However, the therapeutic efficacy of photodynamic therapy is limited by some intrinsic drawbacks of photosensitizers such as aggregation-caused quenching and non-specificity towards cellular organelles. Moreover, the overexpressed glutathione in tumour cells which exhibits a potent scavenging effect on reactive oxygen species generated during the photodynamic therapy process also reduces the efficacy of photodynamic therapy. Therefore, the synthesis of aggregation-induced emission based photosensitizers with cellular organelle targeting and glutathione-depletion capability is highly desirable in photodynamic therapy. Here, two new aggregation-induced emission based photosensitizers namely tetraphenylethylene-1-phenyvinyl-pyridine-phenylboronic acid (TPEPy-BA) and tetraphenylethylene-1-phenyvinyl-pyridine-phenylboronic acid pinacol ester (TPEPy-BE) were synthesized which easily aggregated under aqueous conditions and showed bright emission in the near infra-red region. Furthermore, these photosensitizers were encapsulated into an amphiphilic block copolymer (DSPE-PEG) to improve the aqueous stability and cellular internalization of photosensitizers. The developed photosensitizer nanoparticles showed high reactive oxygen species generation efficacy, mitochondria-targeting and glutathione-depletion capability. The results showed that tetraphenylethylene-1-phenyvinyl-pyridine-phenylboronic acid pinacol ester nanoparticles exhibited a highly efficient photodynamic ablation of MCF-7 cells compared to tetraphenylethylene-1-phenyvinyl-pyridine-phenylboronic acid nanoparticles, upon white light irradiation, due to its high intracellular reactive oxygen species generation efficiency and mitochondria-dysfunction ability. Moreover, tetraphenylethylene-1-phenyvinyl-pyridine-phenylboronic acid pinacol ester nanoparticles produced a glutathione-depleting adjuvant, quinone methide, which greatly reduced the glutathione level in cancer cells, thus enhancing the efficacy of photodynamic therapy. This study provides a new strategy for the synthesis of aggregation-induced emission based photosensitizers with combined mitochondria-targeting and glutathione-depletion capability for efficacious photodynamic therapy.

Mitochondria-targeting sonosensitizer-loaded extracellular vesicles for chemo-sonodynamic therapy.

Sonodynamic therapy (SDT) has emerged as an effective therapeutic modality as it employs ultrasound (US) to eradicate deep-seated tumors noninvasively. However, the therapeutic efficacy of SDT in clinical settings remains limited owing to the low aqueous stability and poor pharmacokinetic properties of sonosensitizers. In this study, extracellular vesicles (EVs), which have low systemic toxicity, were used as clinically available nanocarriers to effectively transfer a sonosensitizer to cancer cells. Chlorin e6 (Ce6), a sonosensitizer, was conjugated to a mitochondria-targeting triphenylphosphonium (TPP) moiety and loaded into EVs to enhance the efficacy of SDT, because mitochondria are critical subcellular organelles that regulate cell survival and death. Additionally, piperlongumine (PL), a pro-oxidant and cancer-specific chemotherapeutic agent, was co-encapsulated into EVs to achieve efficient and selective anticancer activity. The EVs substantially amplified the cellular internalization of TPP-conjugated Ce6 (TPP-Ce6), resulting in the enhanced generation of intracellular reactive oxygen species (ROS) in MCF-7 human breast cancer cells upon US exposure. Importantly, EVs encapsulating TPP-Ce6 effectively destroyed the mitochondria under irradiation with US, leading to efficient anticancer activity. The co-encapsulation of pro-oxidant PL into EVs significantly enhanced the SDT efficacy in MCF-7 cells through the excessive generation of ROS. Moreover, the EV co-encapsulating TPP-Ce6 and PL [EV(TPP-Ce6/PL)] exhibited cancer-specific cell death owing to the cancer-selective apoptosis triggered by PL. In vivo study using MCF-7 tumor-xenograft mice revealed that EV(TPP-Ce6/PL) effectively accumulated in tumors after intravenous injection. Notably, treatment with EV(TPP-Ce6/PL) and US inhibited tumor growth significantly without causing systemic toxicity. This study demonstrated the feasibility of using EV(TPP-Ce6/PL) for biocompatible and cancer-specific chemo-SDT.

Ensemble deep learning model for predicting anterior cruciate ligament tear from lateral knee radiograph.

OBJECTIVE: To develop an ensemble deep learning model (DLM) predicting anterior cruciate ligament (ACL) tears from lateral knee radiographs and to evaluate its diagnostic performance. MATERIALS AND METHODS: In this study, 1433 lateral knee radiographs (661 with ACL tear confirmed on MRI, 772 normal) from two medical centers were split into training (n = 1146) and test sets (n = 287). Three single DLMs respectively classifying radiographs with ACL tears, abnormal lateral femoral notches, and joint effusion were developed. An ensemble DLM predicting ACL tears was developed by combining the three DLMs via stacking method. The sensitivities, specificities, and area under the receiver operating characteristic curves (AUCs) of the DLMs and three radiologists were compared using McNemar test and Delong test. Subgroup analysis was performed to identify the radiologic features associated with the sensitivity. RESULTS: The sensitivity, specificity, and AUC of the ensemble DLM were 86.8% (95% confidence interval [CI], 79.9-92.0%), 89.4% (95% CI, 83.4-93.8%), and 0.927 (95% CI, 0.891-0.954), achieving diagnostic performance comparable with that of a musculoskeletal radiologist (P = 0.193, McNemar test; P = 0.131, Delong test). The AUC of the ensemble DLM was significantly higher than those of non-musculoskeletal radiologists (P = 0.043, P < 0.001). The sensitivity of the DLM was higher than that of the radiologists in the absence of an abnormal lateral femoral notch or joint effusion. CONCLUSION: The diagnostic performance of the ensemble DLM in predicting lateral knee radiographs with ACL tears was comparable to that of a musculoskeletal radiologist.

Comparative Analysis of Subtalar Ligaments Between Patients With Talocalcaneal Coalition and Control Subjects Using 3-Dimensional Magnetic Resonance Imaging.

PURPOSE: The purpose of this study was to find the differences in the subtalar ligaments between patients with talocalcaneal (TC) coalition and control subjects using 3-dimensional isotropic magnetic resonance imaging. METHODS: Magnetic resonance imaging of 27 ankles with TC coalition and 27 age- and sex-matched controls were retrospectively reviewed. Absence of cervical ligament, anterior capsular ligament (ACL), interosseous TC ligament (ITCL), and partial or complete absence of 3 roots of the inferior extensor retinaculum was analyzed. Thickness and width of ACL and ITCL were measured when possible. RESULTS: Absence of ACL and ITCL was significantly more frequent in TC coalition patients than in controls (59.2% vs 7.4%, P < 0.0001; 44.4% vs 7.4%, P = 0.004). Absence of cervical ligament and 3 roots of the inferior extensor retinaculum did not differ between the 2 groups. Thickness and width of ACL were significantly smaller in TC coalition patients than in control subjects (0.81 ± 0.23 vs 1.27 ± 0.41 mm, P < 0.0001; 5.26 ± 1.17 vs 7.07 ± 1.46 mm, P = 0.001). Thickness and width of ITCL did not differ between the 2 groups. In the TC coalition group, the absence of ACL and ITCL did not differ according to coalition type, patient demographics, and magnetic resonance imaging units. CONCLUSIONS: Anterior capsular ligament and ITCL are frequently absent in TC coalition patients. Even when present, the ACL is attenuated in TC coalition patients compared with controls.

Extracellular vesicles with high dual drug loading for safe and efficient combination chemo-phototherapy.

Extracellular vesicles (EVs) have emerged as biocompatible nanocarriers for efficient delivery of various therapeutic agents, with intrinsic long-term blood circulatory capability and low immunogenicity. Here, indocyanine green (ICG)- and paclitaxel (PTX)-loaded EVs [EV(ICG/PTX)] were developed as a biocompatible nanoplatform for safe and efficient cancer treatment through near-infrared (NIR) light-triggered combination chemo/photothermal/photodynamic therapy. High dual drug encapsulation in EVs was achieved for both the hydrophilic ICG and hydrophobic PTX by simple incubation. The EVs substantially improved the photostability and cellular internalization of ICG, thereby augmenting the photothermal effects and reactive oxygen species production in breast cancer cells upon NIR light irradiation. Hence, ICG-loaded EVs activated by NIR light irradiation showed greater cytotoxic effects than free ICG. EV(ICG/PTX) showed the highest anticancer activity owing to the simultaneous chemo/photothermal/photodynamic therapy when compared with EV(ICG) and free ICG. In vivo study revealed that EV(ICG/PTX) had higher accumulation in tumors and improved pharmacokinetics compared to free ICG and PTX. In addition, a single intravenous administration of EV(ICG/PTX) exhibited a considerable inhibition of tumor proliferation with negligible systemic toxicity. Thus, this study demonstrates the potential of EV(ICG/PTX) for clinical translation of combination chemo-phototherapy.

Engineered extracellular vesicle-based sonotheranostics for dual stimuli-sensitive drug release and photoacoustic imaging-guided chemo-sonodynamic cancer therapy.

Sonodynamic therapy has shown promise as an effective alternative to conventional photodynamic therapy owing to its ability to treat deep-seated tumors. However, the development of stimuli-responsive sonosensitizers with high biocompatibility faces a significant challenge. Methods: In this study, we developed dual stimuli-responsive sonosensitizers with desirable biosafety using extracellular vesicles (EVs), a class of naturally occurring nanoparticles. Indocyanine green (ICG), which functions as both a sonosensitizer and photoacoustic (PA) imaging agent, was loaded into EVs, together with paclitaxel (PTX) and sodium bicarbonate (SBC), to achieve pH-responsive PA imaging-guided chemo-sonodynamic combination therapy. Results: The EVs significantly improved the cellular uptake of ICG, thus triggering enhanced sonodynamic effects in breast cancer cells. SBC-, ICG-, and PTX-loaded EV [SBC-EV(ICG/PTX)] efficiently released the PTX in response to acidic pH in the endo/lysosomes because CO2 bubbles generated from the SBC caused the EV membranes to burst. The drug release was further facilitated by ultrasound (US) treatment, demonstrating dual pH/US-responsive drug release. The ICG- and PTX-loaded EVs exhibited efficient anticancer activity against breast tumor cells owing to the combination of chemo-sonodynamic therapy. High-resolution PA imaging visualized the preferential tumor accumulation of SBC-EV(ICG/PTX) in tumor-bearing mice. Notably, a single intravenous injection of SBC-EV(ICG/PTX) with US irradiation significantly suppressed tumor growth in mice without systemic toxicity. Conclusions: Our findings demonstrate that dual stimuli-responsive SBC-EV(ICG/PTX) are promising sonotheranostic nanoplatforms for safe and efficient chemo-sonodynamic combination cancer therapy and photoacoustic imaging.

Feasibility of MRI for the evaluation of interosseous ligament vertical segment via subtalar arthroscopy correlation: comparison of 2D and 3D MR images.

BACKGROUND: Interosseous ligament vertical segment (IOLV) and calcaneofibular ligament (CFL) have been reported to be important in stabilizing the subtalar joint. Unlike CFL, there is not much information regarding the comparison of MRI results with surgical evaluation of IOLV and the comparison between 2D and 3D MRI on IOLV evaluation. The feasibility of MRI in IOLV evaluation has yet to be reported. The purpose of this study was to evaluate the validity and reliability of MRI in IOLV tear detection via correlation with arthroscopic results. We also compared the diagnostic performance of 2D and 3D MR images. METHODS: In this retrospective study, 52 patients who underwent subtalar arthroscopy after ankle MRI were enrolled. Arthroscopic results confirmed IOLV tear in 25 cases and intact IOLV in 27 cases. Two radiologists independently evaluated the IOLV tears using only conventional 2D images, followed by isotropic 3D images, and comparison with arthroscopic results. RESULTS: Only the 2D sequences interpreted by two readers showed a sensitivity of 64.0-96.0%, a specificity of 29.6-44.4%, a positive predictive value of 51.6-56.4%, and a negative predictive value of 57.1-88.9%. Addition of isotropic 3D sequences changed the sensitivity to 60.0-80.0%, specificity to 63.0-77.8%, positive predictive value to 64.3-76.9%, and negative predictive value to 66.7-80.8%. The overall diagnostic performance of isotropic 3D sequences (AUC values: 0.679-0.816) was higher than that of 2D sequences (AUC values: 0.568-0.647). Inter-observer and intra-observer agreement between the two readers was moderate-to-good for both 2D and 3D sequences. The diagnostic accuracy in 19 patients with tarsal sinus fat obliteration tended to increase from 26.3-42.1% to 57.9-73.7% with isotropic 3D sequences compared with 2D sequences. CONCLUSIONS: Isotropic 3D MRI was feasible for the assessment of IOLV tear prior to subtalar arthroscopy. Additional 3D sequences showed higher diagnostic accuracy compared with conventional 2D sequences in IOLV evaluation. Isotropic 3D sequences may be more valuable in detecting IOLV tear in case of tarsal sinus fat obliteration.

Temperature and pH-responsive in situ hydrogels of gelatin derivatives to prevent the reoccurrence of brain tumor.

Glioblastoma multiforme (GBM) is a grade IV malignant brain tumor with a median survival time of approximately 12-16 months. Because of its highly aggressive and heterogeneous nature it is very difficult to remove by surgical resection. Herein we have reported dual stimuli-responsive and biodegradable in situ hydrogels of oligosulfamethazine-grafted gelatin and loaded with anticancer drug paclitaxel (PTX) for preventing the progress of Glioblastoma. The oligosulfamethazine (OSM) introduced to the gelatin backbone for the formation of definite and stable in situ hydrogel. The hydrogels transformed from a sol to a gel state upon changes in stimuli. pH and temperature and retained a distinct shape after subcutaneous administration in BALB/c mice. The viscosity of the sol state hydrogels was tuned by varying the feed molar ratio between gelatin and OSM. The porosity of the hydrogels was confirmed to be lower in higher degree OSM by SEM. Sustained release of PTX from hydrogels in physiological environments (pH 7.4) was further retarded up to 63% in 9th days in tumor environments (pH 6.5). While the empty hydrogels were non-toxic in cultured cells, the hydrogels loaded with PTX showed antitumor efficacy in orthotopic-GBM xenograft mice. Collectively, the gelatin-OSM formed porous hydrogels and released the cargo in a sustained manner in tumor environments efficiently suppressing the progress of GBM. Thus, gelatin-OSM hydrogels are a potential candidate for the direct delivery of therapeutics to the local areas in brain diseases.