Immune cell-derived exosomes as promising tools for cancer therapy.

Exosomes are nanoscale vesicles with a size of 30-150 nm secreted by living cells. They are vital players in cellular communication as they can transport proteins, nucleic acids, lipids, and etc. Immune cell-derived exosomes (imEXOs) have great potential for tumor therapy because they have many of the same functions as their parent cells. Especially, imEXOs display unique constitutive characteristics that are directly involved in tumor therapy. Herein, we begin by the biogenesis, preparation, characterization and cargo loading strategies of imEXOs. Next, we focus on therapeutic potentials of imEXOs from different kinds of immune cells against cancer from preclinical and clinical studies. Finally, we discuss advantages of engineered imEXOs and potential risks of imEXOs in cancer treatment. The advantages of engineered imEXOs are highlighted, including selective killing effect, effective tumor targeting, effective lymph node targeting, immune activation and regulation, and good biosafety.

Synthetic High-Density Lipoprotein-Based Nanomedicine to Silence SOCS1 in Tumor Microenvironment and Trigger Antitumor Immunity against Glioma.

Immunotherapies have shed light on the treatment of many cancers, but have not improved the outcomes of glioma (GBM). Here, we demonstrated that suppressor of cytokine signaling 1 (SOCS1) was associated with the GBM-associated immunosuppression and developed a multifunctional nanomedicine, which silenced SOCS1 in the tumor microenvironment (TME) of GBM and triggered strong antitumor immunity against GBM. Synthetic high-density lipoprotein (sHDL) was selected as the nanocarrier and a peptide was used to facilitate the blood-brain-barrier (BBB) penetration. The nanocarrier was loaded with a small interfering RNA (siRNA), a peptide, and an adjuvant to trigger antitumor immunity. The nanomedicine concentrated on the TME in vivo, further promoting dendritic cell maturation and T cell proliferation, triggering strong cytotoxic T lymphocyte responses, and inhibiting tumor growth. Our work provides an alternative strategy to simultaneously target and modulate the TME in GBM patients and points to an avenue for enhancing the efficacy of immunotherapeutics.

Suppression of cytokine release syndrome during CAR-T-cell therapy via a subcutaneously injected interleukin-6-adsorbing hydrogel.

The infusion of chimaeric antigen receptor (CAR) T cells can trigger the release of life-threatening supraphysiological levels of pro-inflammatory cytokines. However, uncertainty regarding the timing and severity of such cytokine release syndrome (CRS) demands careful monitoring of the conditions required for the administration of neutralizing antibodies. Here we show that a temperature-sensitive hydrogel conjugated with antibodies for the pro-inflammatory cytokine interleukin-6 (IL-6) and subcutaneously injected before the infusion of CAR-T cells substantially reduces the levels of IL-6 during CRS while maintaining the therapy's antitumour efficacy. In immunodeficient mice and in mice with transplanted human haematopoietic stem cells, the subcutaneous IL-6-adsorbing hydrogel largely suppressed CAR-T-cell-induced CRS, substantially improving the animals' survival and alleviating their levels of fever, hypotension and weight loss relative to the administration of free IL-6 antibodies. The implanted hydrogel, which can be easily removed with a syringe following a cooling-induced gel-sol transition, may allow for a shift in the management of CRS, from monitoring to prevention.

Radiotherapy-Triggered Proteolysis Targeting Chimera Prodrug Activation in Tumors.

Proteolysis targeting chimera (PROTAC) is an emerging protein degradation strategy, which shows excellent advantages in targeting those so-called "undruggable" proteins. However, the potential systemic toxicity of PROTACs caused by undesired off-tissue protein degradation may limit the application of PROTACs in clinical practice. Here we reported a radiotherapy-triggered PROTAC prodrug (RT-PROTAC) activation strategy to precisely and spatiotemporally control protein degradation through X-ray radiation. We demonstrated this concept by incorporating an X-ray inducible phenyl azide-cage to a bromodomain (BRD)-targeting PROTAC to form the first RT-PROTAC. The RT-PROTAC prodrug exhibits little activity but can be activated by X-ray radiation in vitro and in vivo. Activated RT-PROTAC degrades BRD4 and BRD2 with a comparable effect to the PROTAC degrader and shows a synergistic antitumor potency with radiotherapy in the MCF-7 xenograft model. Our work provides an alternative strategy to spatiotemporally control protein degradation in vivo and points to an avenue for reducing the undesired systemic toxicity of PROTACs.

High-grade pivot-shift phenomenon after anterior cruciate ligament injury is associated with asymmetry of lateral and medial compartment anterior tibial translation and lateral meniscus posterior horn tears.

PURPOSE: To investigate whether the high-grade pivot-shift phenomenon is associated with asymmetry of the lateral and medial compartment anterior tibial translation (L-ATT and M-ATT) and lateral meniscus posterior horn (LMPH) tears in anterior cruciate ligament (ACL) injuries. METHODS: A retrospective analysis was performed on 192 consecutive patients who had complete ACL injuries between January 2019 and December 2020. Among these, 156 met the inclusion criteria. L-ATT and M-ATT were measured using preoperative weight-bearing magnetic resonance imaging (MRI), and the differences between L-ATT and M-ATT were calculated. Thirty-five patients who demonstrated excessive differences in L-ATT and M-ATT (> 6.0 mm) were regarded as asymmetric (study group), and 36 patients with minimal or no differences in L-ATT and M-ATT (< 3.0 mm) were allocated to the control group. Demographic data, grade of the pivot-shift test, integrality of LMPH, and medial meniscus posterior horn (MMPH) were compared between the groups. Moreover, predictors of high-grade pivot-shift phenomenon, including asymmetry of L-ATT and M-ATT, integrity of LMPH and MMPH, time from injury to surgery, sex, age, and body mass index (BMI) were assessed using multivariable logistic regression analysis. RESULTS: The difference between L-ATT and M-ATT in the study group was significantly higher than that in the control group (mean ± SD: 8.4 ± 2.1 mm vs. 1.5 ± 1.0 mm, P < 0.001). A higher proportion of patients with high-grade pivot-shift phenomenon (2 + and 3 +) and LMPH tears were identified in the study group (high-grade pivot-shift phenomenon: 25/35 vs. 13/36, P = 0.003; LMPH tears: 18/35 vs. 5/36, P = 0.001). Additionally, asymmetry of L-ATT, M-ATT (odds ratio 5.8; 95% CI 1.7-19.8; P = 0.005), and LMPH tears (odds ratio 3.8; 95% CI 1.3-11.6; P = 0.018) were found to be good predictors of the high-grade pivot-shift phenomenon after ACL injury, whereas MMPH tears, time from injury to surgery, sex, age, and BMI were not. CONCLUSION: In patients with ACL injury, the high-grade pivot-shift phenomenon is associated with asymmetry between L-ATT and M-ATT, and LMPH tears. LEVEL OF EVIDENCE: III.

Biomimetic Nanocarriers Guide Extracellular ATP Homeostasis to Remodel Energy Metabolism for Activating Innate and Adaptive Immunity System.

Metabolic interventions via targeting intratumoral dysregulated metabolism pathways have shown promise in reinvigorating antitumor immunity. However, approved small molecule immunomodulators often suffer from ineffective response rates and severe off-target toxicity. ATP occupies a crucial role in energy metabolism of components that form the tumor microenvironment (TME) and influences cancer immunosurveillance. Here, a nanocarrier-assisted immunometabolic therapy strategy that targets the ATP-adenosine axis for metabolic reprogramming of TME is reported. An ecto-enzyme (CD39) antagonist POM1 and AMP-activated protein kinase (AMPK) agonist metformin are both encapsulated into cancer cell-derived exosomes and used as nanocarriers for tumor targeting delivery. This method increases the level of pro-inflammatory extracellular ATP (eATP) while preventing the accumulation of immunosuppressive adenosine and alleviating hypoxia. Elevated eATP triggers the activation of P2X7-NLRP3-inflammasome to drive macrophage pyroptosis, potentiates the maturation and antigen capacity of dendritic cells (DCs) to enhance the cytotoxic function of T cells and natural killer (NK) cells. As a result, synergistic antitumor immune responses are initiated to suppress tumor progress, inhibit tumor distant metastases, provide long-term immune memory that offers protection against tumor recurrence and overcome anti-PD1 resistance. Overall, this study provides an innovative strategy to advance eATP-driven antitumor immunity in cancer therapy.

Biological enhancement methods may be a viable option for ACL arthroscopic primary repair - A systematic review.

BACKGROUND: Bioactive factors combined with advanced anterior cruciate ligament (ACL) primary repair technology have been used to treat ACL repairs. The current review was conducted to identify whether biological enhancement could enable superior clinical outcome, including side-to-side difference, failure rate, reoperation rate and subjective scores. HYPOTHESIS: The implementation of ACL primary repair with biological enhancement will provide better clinical outcomes in terms of side-to-side differences, failure rate, reoperation rate and subjective scores than ACL primary repair alone. MATERIALS AND METHODS: A systematic literature review was performed following PRISMA guidelines by searching all studies reporting outcomes of arthroscopic primary repair with or without biological augmentation published until April 19, 2020, in Medline, PubMed, Embase and the Cochrane Library. Primary metrics were side-to-side differences, failure rate and reoperation rate, as well as measurements of patient-reported outcomes at the last follow-up. RESULTS: A total of 20 studies were finally included in this work, of which 3 were Grade I (15%), 3 studies were Grade III (15%), and 14 studies were Grade IV (70%) in terms of the level of evidence. There were 729 patients with a mean age of 30 (range: 8-68) years, and the mean follow-up period of which was 38 (range: 3-122) months. At the final follow-up, the postoperative side-to-side differences (the proportion of patients with a side-to-side difference less than 3mm) and patient-report outcomes were significantly better in the biological enhancement group. Nevertheless, there were no significant differences between the two groups in the rate of surgical failure, the rate of revision, or the positive Lachman test or pivot shift test. CONCLUSION: Biologically enhanced arthroscopic ACL primary repair was superior to ACL primary repair alone in terms of postoperative side-to-side differences (proportion of patients with a side-to-side difference less than 3mm) and patient-reported outcomes. Thus, biologically enhanced arthroscopic ACL primary repair can be preferentially recommended over ACL arthroscopic primary repair alone. LEVEL OF EVIDENCE: IV, systematic review.

Nanomaterials with changeable physicochemical property for boosting cancer immunotherapy.

The past decade has witnessed a great progress in cancer immunotherapy with the sequential approvals of therapeutic cancer vaccine, immune checkpoint inhibitor and chimeric antigen receptor (CAR) T cell therapy. However, some hurdles still remain to the wide implementation of cancer immunotherapy, including low immune response, complex tumor heterogeneity, off-target immunotoxicity, poor solid tumor infiltration, and immune evasion-induced treatment tolerance. Owing to changeable physicochemical properties in response to endogenous or exogenous stimuli, nanomaterials hold the remarkable potential in incorporation of multiple agents, efficient biological barrier penetration, precise immunomodulator delivery, and controllable content release for boosting cancer immunotherapy. Herein, we review the recent advances in nanomaterials with changeable physicochemical property (NCPP) to develop cancer vaccine, remold tumor microenvironment and evoke direct T cell activation. Besides, we provide our outlook on this emerging field at the intersection of NCPP design and cancer immunotherapy.

Posterior tibial slope measurements based on the full-length tibial anatomic axis are significantly increased compared to those based on the half-length tibial anatomic axis.

PURPOSE: This study aimed to compare the difference in posterior tibial slope (PTS) measurements based on the full-length and half-length tibial anatomic axes of the same group of patients. It was hypothesized that the obtained PTS values would be affected by the length of tibia chosen during the measurements. METHODS: Full-length true lateral tibia radiographs were obtained for each patient who underwent anterior cruciate ligament reconstruction (ACLR) in our department. PTS measurements were obtained by measuring the angle between the full-length or half-length tibial anatomic axis and an average of the lateral and medial tibial plateau. The anatomic axis was defined as the center of the tibial diaphysis. The PTS measurements from the full-length and half-length true lateral tibia radiographs were obtained and compared. Additionally, the absolute difference and the relationship between the two PTS measurements were calculated and analyzed. RESULTS: A total of 200 ACL-injured patients were included in this study. The average PTS values using the anatomic axis were 15.9 ± 3.7° and 14.1 ± 3.7° on full-length and half-length true lateral tibial radiographs. There was a significant difference between the measurements with the full-length and half-length tibial radiographs (P < 0.01). Additionally, 49.5% (n = 99) of patients had ≥ 2.0° differences between the full-length and half-length anatomic axis PTS measurement techniques; meanwhile, a strong and significant linear relationship (r = 0.95; P < 0.001) was identified between the two PTS measurements. CONCLUSION: There were significant differences and linear relationships between PTS measurements that measured the anatomic axis from full-length and half-length true lateral tibia radiographs. Therefore, the obtained PTS values were strongly associated with the length of tibia chosen during the measurements. Surgeons should pay more attention to the measurement techniques and the tibial length when considering the role of PTS in ACL injury and ACLR failure. Knowledge of the association is very important for calculating potential closing wedge proximal tibial osteotomies to correct excessive PTS in the setting of ACLR failures. LEVEL OF EVIDENCE: IV.

Derotational distal femoral osteotomy yields satisfactory clinical outcomes in pathological femoral rotation with failed medial patellofemoral ligament reconstruction.

PURPOSE: The purpose of this study was to evaluate the clinical outcomes of de-rotational distal femoral osteotomy (DDFO) in patients who underwent primary medial patellofemoral ligament reconstruction (MPFLR) failure with increased femoral anteversion along with high-grade J sign. METHODS: Between 2011 and 2019, 14 patients underwent DDFO revision surgery due to failed MPFLR. The pre- and postoperative J sign grade, Caton-Deschamps index (CDI), tibial tuberosity-trochlear groove (TT-TG) distance, femoral anteversion angle (FAA), patellar lateral tilt angle (PLTA), MPFL graft laxity, and patient-reported outcomes (Kujala, Lysholm, Tegner, and International Knee Documentation Committee (IKDC) subjective scores) were collected. The anterior-posterior and proximal-distal distances between the actual point and the Schöttle point were also calculated. RESULTS: Fourteen patients underwent MPFLR revision by DDFO combined with MPFLR. The mean PLTA improved from 40.7° ± 11.9° to 20.5° ± 8.7° (P < 0.001). The mean FAA significantly decreased from 42.7° ± 12.0° to 14.1° ± 5.2° (P < 0.001). The mean patellar laxity index (PLI) decreased from 82.4% preoperatively to 15.1% postoperatively (P < 0.001). None of these patients experienced subluxation or re-dislocation during follow-up of 29.7 ± 5.0 months after revision surgery. Meanwhile, the Tegner score at the last follow-up ranged from 3 to 6, with a median of 5. The Kujala, Lysholm, and IKDC subjective scores showed significant improvements, from a mean of 51.0 ± 6.8 preoperatively to 75.4 ± 5.1 postoperatively (P < 0.001), 49.2 ± 7.9 to 75.2 ± 7.2 (P < 0.001), and 42.9 ± 6.2 to 76.8 ± 6.0 (P < 0.001), respectively. The proportion of patients with a high-grade J sign was significantly lower postoperatively than preoperatively (100% vs. 14%). Four out of 14 patients (29%) showed femoral tunnel mal-positioning. CONCLUSION: MPFLR revision by DDFO combined with MPFLR achieved favorable clinical outcomes in patients with increased femoral anteversion along with high-grade J sign. LEVEL OF EVIDENCE: IV.

An amphiphilic dendrimer as a light-activable immunological adjuvant for in situ cancer vaccination.

Immunological adjuvants are essential for successful cancer vaccination. However, traditional adjuvants have some limitations, such as lack of controllability and induction of systemic toxicity, which restrict their broad application. Here, we present a light-activable immunological adjuvant (LIA), which is composed of a hypoxia-responsive amphiphilic dendrimer nanoparticle loaded with chlorin e6. Under irradiation with near-infrared light, the LIA not only induces tumour cell lysis and tumour antigen release, but also promotes the structural transformation of 2-nitroimidazole containing dendrimer to 2-aminoimidazole containing dendrimer which can activate dendritic cells via the Toll-like receptor 7-mediated signaling pathway. The LIA efficiently inhibits both primary and abscopal tumour growth and induces strong antigen-specific immune memory effect to prevent tumour metastasis and recurrence in vivo. Furthermore, LIA localizes the immunological adjuvant effect at the tumour site. We demonstrate this light-activable immunological adjuvant offers a safe and potent platform for in situ cancer vaccination.

Increased Posterior Tibial Slope Is Associated With Greater Risk of Graft Roof Impingement After Anatomic Anterior Cruciate Ligament Reconstruction.

BACKGROUND: Increased posterior tibial slope (PTS) has been reported to be associated with irreducible anterior tibial subluxation in extension after anatomic anterior cruciate ligament (ACL) reconstruction (ACLR), which raises concerns about the greater risk of graft roof impingement (GRI) although the tibial tunnel is positioned anatomically. HYPOTHESIS: Increased PTS would be associated with greater risk of GRI after anatomic ACLR. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Between January 2016 and December 2017, a total of 418 consecutive patients were diagnosed as having noncontact ACL injuries and underwent primary anatomic ACLR. Among them, 26 patients had ≥1 of the following features during the second-look arthroscopy: fractured/guillotined bundles at the tibial insertion or cyclops lesion. These patients were confirmed to have GRI and were allocated to the study group. They were also matched 1:2 to 52 control participants without GRI. PTS was measured on true lateral whole-leg radiographs. Intra-articular ACL graft signal intensity was evaluated on postoperative magnetic resonance imaging scans (mean, 32.8 months; range, 26-38 months) and divided into 3 grades (I, good; II, moderate; III, poor) based on degree of GRI. Moreover, anterior subluxation of the lateral compartment (ASLC) and medial compartment (ASMC) in extension relative to the femoral condyles were measured on postoperative magnetic resonance imaging scans and compared between the groups. In addition, predictors of GRI were evaluated using multivariate logistic regression analysis and included body mass index, PTS, pivot-shift test, KT-1000 side-to-side difference, and concomitant meniscal tears. RESULTS: PTS in the study group was significantly higher than that in control group (mean ± SD, 13.8°± 1.5° vs 9.5°± 1.8°; P < .05). In the study group (n = 26), patients with grade III (poor) graft signal intensity (n = 9) showed significantly higher PTS than those with grade II (moderate; n = 17) (16.4°± 1.7° vs 12.4°± 1.3°; P < .05). Moreover, the mean postoperative ASLC and ASMC in extension were significantly larger in the study group than the control group (ASLC, 4.1 ± 1.3 vs 0.8 ± 0.4 mm; ASMC, 4.3 ± 1.5 vs 0.9 ± 0.3 mm; P < .05). Furthermore, the abnormal degree of PTS (≥12°) was determined to be an independent risk factor associated with GRI after anatomic ACLR (odds ratio, 9.0 [95% CI, 3.7-30.2]; P < .001), whereas body mass index, grade of pivot-shift test, KT-1000 side-to-side difference, and concomitant meniscal tears were not. CONCLUSION: Increased PTS (≥12°) was associated with greater risk of GRI after anatomic ACLR. This may provide additional information for counseling patients with greater risk of GRI.

Clinical, Radiographic, and Arthroscopic Outcomes of Surgical Repair for Radial and Avulsed Lesions on the Lateral Meniscus Posterior Root During ACL Reconstruction: A Systematic Review.

BACKGROUND: Clinical outcomes of surgical repairs for tears of the lateral meniscus posterior root (LMPR) in patients undergoing anterior cruciate ligament (ACL) reconstruction (ACLR) have not been comprehensively investigated. PURPOSE: To systematically review the clinical, radiographic, and arthroscopic results of surgical repairs for tears of the LMPR in patients undergoing ACLR. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: A systematic electronic search of the PubMed and Embase databases was performed to identify studies reporting clinical, radiographic, or arthroscopic results of surgical repairs for tears of the LMPR in patients undergoing ACLR. Each included study was abstracted regarding study characteristics, patient characteristics, surgical technique, and outcome measures. The methodological quality of the included studies was analyzed according to the Methodological Index for Non-Randomized Studies (MINORS) criteria. RESULTS: Nine studies were included in this systematic review, representing a total of 215 knees in 215 patients. Overall, 123 side-to-side repairs and 89 pullout repairs were performed for tears of the LMPR during ACLR. After a mean follow-up of 33.9 months, significant improvements (P < .05) were found in the mean Lysholm score (from 58.3 to 91.4) as well as the mean International Knee Documentation Committee subjective score (from 61.1 to 87.2). Weightbearing anteroposterior radiographs of 41 patients showed no significant narrowing of lateral joint space width. On magnetic resonance imaging scans, 31 patients demonstrated no significant progression of chondral lesions, and no significant decreases in meniscal extrusion on coronal planes were reported in another 76 patients. The complete/partial healing was 93.6% on second-look arthroscopy after side-to-side repairs for radial tears of the LMPR. The MINORS value showed a high risk of bias for all 9 studies. CONCLUSION: Patients with tears of the LMPR associated with ACL injuries achieved favorable functional scores after ACLR and LMPR repairs, and the side-to-side repair for radial tears of the LMPR succeeded in a high meniscal healing rate of >90%. However, the authors of this review were unable to definitively conclude whether LMPR repairs fully restore the hoop stress of the lateral meniscus.

The presence of a preoperative high-grade J-sign and femoral tunnel malposition are associated with residual graft laxity after MPFL reconstruction.

PURPOSE: The purpose of this study was to analyse the risk factors associated with residual graft laxity after medial patellofemoral ligament reconstruction (MPFL-R) in patients with recurrent patellar dislocation (RPD). METHODS: A total of 312 consecutive patients (354 knees) with clinically diagnosed RPD who underwent MPFL-R from 2011 to 2015 were retrospectively analysed. Postoperative MPFL graft stability was assessed with patellofemoral stress radiography, and if the patellar central ridge surpassed the apex of the lateral femoral trochlea, the reconstructed MPFL was defined as having residual graft laxity. Finally, 15 patients who exhibited MPFL residual graft laxity (study group) were matched in a 1:2 fashion to 30 control participants (control group), who showed a normal postoperative patellar stability on stress radiography. Preoperative three-dimensional computed tomography (3D-CT) was used to identify patients with a high-grade J-sign. Femoral tunnel position was assessed using 3D-CT to identify cases with femoral tunnel malposition. Potential predictors of MPFL residual graft laxity, including age, sex, a preoperative high-grade J-sign, femoral tunnel malposition, and several radiological parameters, were assessed by logistic regression analysis. RESULTS: A preoperative high-grade J-sign was identified in 66.7% of the study group, which was significantly higher than that the 13.3% in the control group (P = 0.001). In addition, the presence of a preoperative high-grade J-sign (odds ratio, 11.9 [95% CI, 1.7-82.8]; P = 0.012) and femoral tunnel malposition (odds ratio, 8.2 [95% CI, 1.2-58.0]; P = 0.036) were determined to be independent risk factors associated with residual graft laxity after MPFL-R. CONCLUSION: The presence of a preoperative high-grade J-sign and femoral tunnel malposition are associated with residual graft laxity after MPFL-R in patients with RPD. These results may provide additional information for counselling patients on residual graft laxity after MPFL-R. LEVEL OF EVIDENCE: Level III.

Medial Patellofemoral Ligament Reconstruction With or Without Derotational Distal Femoral Osteotomy in Treating Recurrent Patellar Dislocation With Increased Femoral Anteversion: A Retrospective Comparative Study.

BACKGROUND: Controversy exists regarding the surgical treatment of recurrent patellar dislocation (RPD) with an increased femoral anteversion angle (FAA). Medial patellofemoral ligament reconstruction (MPFL-R) either alone or combined with derotational distal femoral osteotomy (DDFO) results in favorable clinical outcomes. PURPOSE: To compare the clinical outcomes of MPFL-R versus MPFL-R with DDFO in treating RPD with increased FAA (>30°). STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Between January 2014 and December 2017, 126 patients (135 knees) with RPD and increased FAA (>30°) were surgically treated using MPFL-R with or without DDFO and eligible for this retrospective study. These patients were allocated into 2 groups based on whether an additional DDFO was performed: the DDFO group (MPFL-R + DDFO with or without tibial tubercle transfer; n = 66) and the control group (MPFL-R with or without tibial tubercle transfer; n = 69). Pre- and postoperative patellar stability was measured using stress radiography. Patellar maltracking (J-sign) and patient-reported outcomes (Kujala, International Knee Documentation Committee, Lysholm, and Tegner scores) were evaluated and compared between the 2 groups. Subgroup analysis was performed by stratifying the results in terms of the severity of preoperative patellar maltracking (low-grade vs high-grade J-sign). RESULTS: A total of 135 knees (126 patients) with a mean follow-up time of 3.7 ± 1.2 years were evaluated in the present study. The rates of postoperative MPFL residual graft laxity and residual J-sign were significantly lower in the DDFO group than in the control group (6% vs 19%, P = .028; 33% vs 54%, P = .018). The DDFO group had significantly higher Kujala (82.3 vs 76.7; P = .001) and Lysholm (83.7 vs 77.7; P = .034) scores than the control group had postoperatively. For patients with a preoperative high-grade J-sign, further subgroup analysis demonstrated that the DDFO group had a significantly lower rate of MPFL residual graft laxity than the control group had (18% vs 57%; P = .029). CONCLUSION: In this retrospective study, treatment of RPD with increased femoral anteversion using MPFL-R with DDFO yielded more favorable subjective and objective outcomes than did MPFL-R without DDFO, and this circumstance was more remarkable when the patients had a preoperative high-grade J-sign.

Proton-driven transformable nanovaccine for cancer immunotherapy.

Cancer vaccines hold great promise for improved cancer treatment. However, endosomal trapping and low immunogenicity of tumour antigens usually limit the efficiency of vaccination strategies. Here, we present a proton-driven nanotransformer-based vaccine, comprising a polymer-peptide conjugate-based nanotransformer and loaded antigenic peptide. The nanotransformer-based vaccine induces a strong immune response without substantial systemic toxicity. In the acidic endosomal environment, the nanotransformer-based vaccine undergoes a dramatic morphological change from nanospheres (about 100 nanometres in diameter) into nanosheets (several micrometres in length or width), which mechanically disrupts the endosomal membrane and directly delivers the antigenic peptide into the cytoplasm. The re-assembled nanosheets also boost tumour immunity via activation of specific inflammation pathways. The nanotransformer-based vaccine effectively inhibits tumour growth in the B16F10-OVA and human papilloma virus-E6/E7 tumour models in mice. Moreover, combining the nanotransformer-based vaccine with anti-PD-L1 antibodies results in over 83 days of survival and in about half of the mice produces complete tumour regression in the B16F10 model. This proton-driven transformable nanovaccine offers a robust and safe strategy for cancer immunotherapy.

Preoperative Complete Patellofemoral Dislocation in Extension Predicts an Inferior Clinical Outcome After Medial Patellofemoral Ligament Reconstruction in Patients With Recurrent Patellar Dislocation.

BACKGROUND: Habitual patellar dislocation in extension (HPD-E) is a distinctive subtype of recurrent patellar dislocation (RPD); HPD-E represents the most severe type of patellar maltracking in RPD. It has been reported that the presence of preoperative patellar maltracking is associated with a worse clinical outcome after medial patellofemoral ligament (MPFL) reconstruction (MPFL-R). PURPOSE: To describe the radiological characteristics of HPD-E and to compare clinical outcomes after MPFL-R among patients with and without preoperative HPD-E. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: From January 2012 to December 2015, a total of 230 consecutive patients (246 knees) with RPD were treated with MPFL-R alone or combined with tibial tubercle osteotomy. Among them, 28 patients diagnosed with HPD-E by preoperative 3-dimensional computed tomography (CT; HPD-E group) were matched in a 1:1 fashion to 28 control participants who did not show HPD-E (control group). Routine radiography and CT were performed to evaluate patellar height, trochlear dysplasia, tibial tubercle-trochlear groove distance, and torsional deformities. The mean patellar laxity index and lateral patellar translation assessed with stress radiography were measured preoperatively and postoperatively to quantify MPFL laxity. At minimum 2-year follow-up, patient-reported outcomes (Kujala, Lysholm, and Tegner scores), patellar maltracking, and redislocation rates were compared between the HPD-E and control groups. RESULTS: The radiological characteristics of the HPD-E group were as follows: 89% (25/28) of patients had severe trochlear dysplasia (Dejour type B or D), and the mean femoral anteversion angle was 35.5° ± 4.7°. At the final follow-up, the HPD-E group had a significantly lower Kujala score (76.2 vs 84.5, respectively; P = .001), Lysholm score (75.4 vs 86.6, respectively; P < .001), and Tegner score (4.1 vs 5.8, respectively; P = .021) compared with the control group. The postoperative patellar laxity index (43% vs 19%, respectively; P < .001) and redislocation rate (25% vs 0%, respectively; P = .01) were significantly higher in the HPD-E group than in the control group. CONCLUSION: Preoperative 3-dimensional CT is a reliable method of identfying patients with HPD-E. Treatment of HPD-E by MPFL-R alone or combined with tibial tubercle osteotomy resulted in a higher redislocation rate, more severe MPFL residual laxity, and lower patient-reported outcome scores compared with patients without HPD-E who underwent MPFL-R.

Superhydrophilic fluorinated polymer and nanogel for high-performance 19F magnetic resonance imaging.

19F magnetic resonance imaging (19F MRI), a kind of non-invasive and non-radioactive diagnostic technique with no endogenous background signals, opens up new research avenues for accurate molecular imaging studies. However, 19F MRI is manily limited by the performance of contrast agents. Here, for the first time, we presented the zwitterionic fluorinated polymer and nanogel as new types of superhydrophilic, sensitive and ultra-stable 19F MRI contrast agents. The superhydrophilicity of carboxybetaine zwitterionic structure completely overcame the hydrophobic aggregation-induced signal attenuation associated with amphiphilic fluorinated polymer-based nanoprobes. In addition, the superhydrophilic contrast agent exhibited distinct advantages, including high 19F-content (19.1 wt%), superior resistance to protein adsorption, constant MR properties and 19F MRS-based quantitative determination in complex biological fluids, and intense 19F MRI signals in the whole-body images after intravenous injection. In combination with angiogenesis targeting ligand, the superhydrophilic contrast agent was applied for the unambiguous detection of tumor. Importantly, computational algorithm was established for the directly quantitative determination of bioavailability and tumor-to-whole body ratio (TBR) from the in vivo19F MRI dataset, providing real-time information with non-invasive manner. Finally, crosslinked nanogels were developed with significantly prolonged systemic circulation, of which intense 19F MRI signals nonspecifically distributed in the aortaventralis and blood-rich organs, instead of being trapped steadily in liver as with the state-of-the-art superhydrophobic perfluocarbon nanoemulsions. Overall, this kind of superhydrophilic, zwitterionic fluorinated polymer and nanogel could be defined as a new generation of high-performance 19F MRI contrast agents, which hold great potential for image-based unambiguous disease detection and computational quantification.

Metal-Based Nanocatalyst for Combined Cancer Therapeutics.

As a classical nanocatalyst-based therapeutic modality, chemodynamic therapy (CDT) has received more and more attention. To improve the therapeutic efficacy of CDT, various metal-based nanocatalysts have been designed and constructed to catalyze the Fenton or Fenton-like reaction in the past few years. However, the therapeutic efficacy of certain CDT is still restricted by the tumor microenvironment, such as limited concentration of intracellular H2O2, inappropriate pH condition, as well as overexpressed glutathione (GSH). Therefore, many other therapeutic modalities, such as photodynamic therapy (PDT), photothermal therapy (PTT), starvation therapy, chemotherapy, and gas therapy, have been utilized to combine with CDT for increasing the tumor treatment performance. In this review, we summarized the development of combinatory therapeutic modalities based on CDT in recent years.

A High-Grade J Sign Is More Likely to Yield Higher Postoperative Patellar Laxity and Residual Maltracking in Patients With Recurrent Patellar Dislocation Treated With Derotational Distal Femoral Osteotomy.

BACKGROUND: It has been speculated that the patellar J sign may have a negative effect on the clinical outcomes of patients with recurrent patellar dislocation (RPD). PURPOSE: To (1) evaluate clinical outcomes, postoperative patellar stability, and patellar maltracking correction in patients with RPD treated with derotational distal femoral osteotomy (DDFO) and combined procedures and (2) investigate the influence of J sign severity on the clinical outcomes. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Between January 2015 and December 2016, a total of 78 patients (81 knees) with RPD, a positive J sign, and an excessive femoral anteversion angle (FAA; ≥30°) were surgically treated with DDFO and combined procedures. J sign severity was graded according to a previously described classification system (grades 1-3). Routine radiography and computed tomography were performed on every patient to evaluate the patellar height, trochlear dysplasia, genu valgum, tibial tuberosity-trochlear groove distance, patellar lateral tilt angle, and patella-trochlear groove distance. The patellar lateral shift distance during stress radiography was measured preoperatively and postoperatively to quantify medial patellofemoral ligament (MPFL) graft laxity under anesthesia, and "MPFL residual graft laxity" was defined as the patellar ridge surpassing the apex of the lateral femoral trochlea. Patients were evaluated using the Kujala, International Knee Documentation Committee (IKDC), and Lysholm scores preoperatively and postoperatively. Patients were allocated into 3 subgroups in terms of the severity of the J sign: low-grade group 1 (grade 1; n = 19), low-grade group 2 (grade 2; n = 16), and high-grade group (grade 3; n = 12). Subgroup analyses were performed to investigate the influence of a high-grade J sign on the clinical outcomes. RESULTS: Among the 78 patients (81 knees), 47 patients (47 knees) met the inclusion criteria. The mean follow-up time was 26.1 ± 1.7 months. The mean preoperative and postoperative FAAs were 36.2°± 5.3° and 10.0°± 2.1°, respectively, with a mean correction angle of 26.2°± 5.9°. At the final follow-up, all patient-reported outcomes improved significantly, and subgroup analyses showed that the high-grade group had significantly lower Kujala scores (75.6 vs 85.3 for low-grade group 1 [P < .001] and 83.4 for low-grade group 2 [P = .001]), Lysholm scores (77.6 vs 84.6 for low-grade group 1 [P = .003]), and IKDC scores (78.6 vs 87.3 for low-grade group 1 [P = .001] and 84.3 for low-grade group 2 [P = .033]) than the low-grade groups. The total rate of MPFL residual graft laxity was 8.5% (4/47), and the prevalence of the postoperative residual J sign was 38.3% (18/47). Subgroup analyses showed significant differences between the high-grade group and the 2 low-grade groups with regard to the MPFL residual graft laxity rate (33.3% vs 0.0% for low-grade group 1 [P = .016] and 0.0% for low-grade group 2 [P = .024]), residual J sign rate (91.7% vs 15.8% for low-grade group 1 [P < .001] and 25.0% for low-grade group 2 [P < .001]), and patellar lateral shift distance (14.2 vs 8.1 mm for low-grade group 1 [P = .002] and 8.7 mm for low-grade group 2 [P = .007]). CONCLUSION: In a group of patients treated for RPD with a positive preoperative J sign and increased FAA (≥30°), patients with a preoperative high-grade J sign had inferior clinical outcomes, more MPFL residual graft laxity, and greater residual patellar maltracking.