Anteromedial Cortical Support in Reduction of Trochanteric Hip Fractures: From Definition to Application.

➤ The concept of anteromedial cortical support (AMCS) serves as valuable guidance for the intraoperative reduction of trochanteric hip fractures.➤ Positive medial cortical support (MCS) and positive or neutral anterior cortical support (ACS) are desirable. Some evidence has suggested that positive MCS is potentially superior to neutral MCS.➤ Experimental studies underscore the vital importance of the anteromedial wall and reveal why positive MCS potentially outperforms neutral MCS.➤ Incorporating the AMCS concept, the Chang reduction quality criteria (CRQC) are a reliable alternative approach to evaluate the reduction quality of trochanteric hip fractures.

Cell surface patching via CXCR4-targeted nanothreads for cancer metastasis inhibition.

The binding of therapeutic antagonists to their receptors often fail to translate into adequate manipulation of downstream pathways. To fix this 'bug', here we report a strategy that stitches cell surface 'patches' to promote receptor clustering, thereby synchronizing subsequent mechano-transduction. The "patches" are sewn with two interactable nanothreads. In sequence, Nanothread-1 strings together adjacent receptors while presenting decoy receptors. Nanothread-2 then targets these decoys multivalently, intertwining with Nanothread-1 into a coiled-coil supramolecular network. This stepwise actuation clusters an extensive vicinity of receptors, integrating mechano-transduction to disrupt signal transmission. When applied to antagonize chemokine receptors CXCR4 expressed in metastatic breast cancer of female mice, this strategy elicits and consolidates multiple events, including interception of metastatic cascade, reversal of immunosuppression, and potentiation of photodynamic immunotherapy, reducing the metastatic burden. Collectively, our work provides a generalizable tool to spatially rearrange cell-surface receptors to improve therapeutic outcomes.

Importance of the Posterior Plate in Three-Column Tibial Plateau Fractures: A Finite Element Analysis and Clinical Validation.

OBJECTIVE: Dual-plate fixation was thought to be the gold standard for treating complicated bicondylar tibial plateau fractures, yet it was found to be hard to accommodate the posterior column in three-column fractures. Currently, column-specific fixation is becoming more and more recognized, but no comprehensive investigation has been performed to back it up. Therefore, the objective of this study was to validate the importance of posterior column fixation in the three-column tibial fractures by a finite element (FE) analysis and clinical study. METHODS: In FE analysis, three models were developed: the longitudinal triple-plate group (LTPG), the oblique triple-plate group (OTPG), and the dual-plate group (DPG). Three loading scenarios were simulated. The distribution of the displacement and the equivalent von Mises stress (VMS) in each structure was calculated. The comparative measurements including the maximum posterior column collapse (MPCC), the maximum total displacement of the model (MTD), the maximum VMS of cortical posterior column (MPC-VMS), and the maximum VMS located on each group of plates and screws (MPS-VMS). The clinical study evaluated the indicators between the groups with or without the posterior plate, including operation time, blood loss volume, full-weight bearing period, Hospital for Special Surgery Knee Scoring system (HSS), Rasmussen score, and common postoperative complications. RESULTS: In the FE analysis, the MPCC, the MPC-VMS, and the MTD were detected in much lower amounts in LTPG and OTPG than in DPG. In comparison with DPG, the LTPG and OTPG had larger MPS-VMS. In the clinical study, 35 cases were included. In the triple-plate (14) and dual-plate (21) groups, the operation took 115.6 min and 100.5 min (p < 0.05), respectively. Blood loss in both groups was 287.0 mL and 206.6 mL (p < 0.05), and the full-weight bearing period was 14.5 weeks and 16.2 weeks (p < 0.05). At the final follow-up, the HSS score was 85.0 in the triple-plate group and 77.5 in the dual-plate (p < 0.05), the Rasmussen score was 24.1 and 21.6 (p < 0.05), there were two cases with reduction loss (9.5%) in the dual-plate group and one case of superficial incision infection found in the triple-plate group. CONCLUSION: The posterior implant was beneficial in optimizing the biomechanical stability and functional outcomes in the three-column tibial plateau fractures.

Allogeneic "Zombie Cell" as Off-The-Shelf Vaccine for Postsurgical Cancer Immunotherapy.

Allogeneic tumor cell vaccines provide off-the-shelf convenience but lack patient specificity due to heterogeneity in tumor antigens. Here, allogeneic tumor cell corpses are converted into "zombie cells" capable of assimilating heterogeneous tumor by seizing cancer cells and spreading adjuvant infection. This causes pseudo-oncolysis of tumors, transforming them into immunogenic targets for enhanced phagocytosis. It is shown that in postoperative tumor models, localized delivery of premade "zombie cells" through stepwise gelation in resection cavity consolidates tumor surgery. Compared to analogous vaccines lacking "seizing" or "assimilating" capability, "zombie cell" platform effectively mobilizes T cell response against residual tumors, and establishes immunological memory against tumor re-challenge, showing less susceptibility to immune evasion. Despite using allogeneic sources, "zombie cell" platform functions as generalizable framework to produce long-term antitumor immunity in different tumor models, showing comparable effect to autologous vaccine. Together, with the potential of off-the-shelf availability and personalized relevance to heterogenous tumor antigens, this study suggests an alternative strategy for timely therapy after tumor surgery.

In situ hydrogel enhances non-efferocytic phagocytosis for post-surgical tumor treatment.

Post-surgical efferocytosis of tumor associated macrophages (TAMs) originates an immunosuppressive tumor microenvironment and facilitates abscopal metastasis of residual tumor cells. Currently, few strategies could inhibit efferocytosis while recovering the tumor-eliminative phagocytosis of TAMs. Herein, we developed an in situ hydrogel that contains anti-CD47 antibody (aCD47) and apocynin (APO), an inhibitor of nicotinamide adenine dinucleotide phosphate oxidase. This hydrogel amplifies the non-efferocytic phagocytosis of TAMs by (1) blocking the extracellular "Don't eat me" signal of efferocytosis with aCD47, which enhances the receptor-mediated recognition and engulfment of tumor cells by TAMs in the post-surgical tumor bed, and (2) by utilizing APO to dispose of tumor debris in a non-efferocytic manner, which prevents acidification and maturation of efferosomes and allows for M1-polarization of TAMs, leading to improved antigen presentation ability. With the complementary intervention of extracellular and intracellular, this hydrogel reverses the immunosuppressive effects of efferocytosis, and induces a potent M1-associated Th1 immune response against tumor recurrence. In addition, the in situ detachment and distal colonization of metastatic tumor cells were efficiently restrained due to the intervention of efferocytosis. Collectively, the hydrogel potentiates surgery treatment of tumor by recovering the tumor-elimination ability of post-surgical TAMs.

Modulation of Autophagy Direction to Enhance Antitumor Effect of Endoplasmic-Reticulum-Targeted Therapy: Left or Right?

Strategies that induce dysfunction in the endoplasmic reticulum (ER) hold great promise for anticancer therapy, but remain unsatisfactory due to the compensatory autophagy induction after ER disruption. Moreover, as autophagy can either promote or suppress cell survival, which direction of autophagy better suits ER-targeting therapy remains controversial. Here, a targeted nanosystem is constructed, which efficiently escorts anticancer therapeutics into the ER, triggering substantial ER stress and autophagy. Concurrently, an autophagy enhancer or inhibitor is combined into the same nanoparticle, and their impacts on ER-related activities are compared. In the orthotopic breast cancer mouse model, the autophagy enhancer increases the antimetastasis effect of ER-targeting therapy and suppresses over 90% of cancer metastasis, while the autophagy inhibitor has a bare effect. Mechanism studies reveal that further enhancing autophagy accelerates central protein snail family transcriptional repressor 1 (SNAI1) degradation, suppressing downstream epithelial-mesenchymal transition, while inhibiting autophagy does the opposite. With the same trend, ER-targeting therapy combined with an autophagy enhancer provokes stronger immune response and tumor inhibition than the autophagy inhibitor. Mechanism studies reveal that the autophagy enhancer elevates Ca2+ release from the ER and functions as a cascade amplifier of ER dysfunction, which accelerates Ca2+ release, resulting in immunogenic cell death (ICD) induction and eventually triggering immune responses. Together, ER-targeting therapy benefits from the autophagy-enhancing strategy more than the autophagy-inhibiting strategy for antitumor and antimetastasis treatment.

[Finite element study of three novel internal fixation modes for bicondylar four-quadrant fractures of tibial plateau].

Objective: To compare the biomechanical differences among the three novel internal fixation modes in treatment of bicondylar four-quadrant fractures of the tibial plateau through finite-element technique, and find an internal fixation modes which was the most consistent with mechanical principles. Methods: Based on the CT image data of the tibial plateau of a healthy male volunteer, a bicondylar four-quadrant fracture model of the tibial plateau and three experimental internal fixation modes were established by using finite element analysis software. The anterolateral tibial plateaus of groups A, B, and C were fixed with inverted L-shaped anatomic locking plates. In group A, the anteromedial and posteromedial plateaus were longitudinally fixed with reconstruction plates, and the posterolateral plateau was obliquely fixed with reconstruction plate. In groups B and C, the medial proximal tibia was fixed with T-shaped plate, and the posteromedial plateau was longitudinally fixed with the reconstruction plate or posterolateral plateau was obliquely fixed with the reconstruction plate, respectively. An axial load of 1 200 N was applied to the tibial plateau (a simulation of a 60 kg adult walking with physiological gait), and the maximum displacement of fracture and maximum Von-Mises stress of the tibia, implants, and fracture line were calculated in 3 groups. Results: Finite element analysis showed that the stress concentration area of tibia in each group was distributed at the intersection between the fracture line and screw thread, and the stress concentration area of the implant was distributed at the joint of screws and the fracture fragments. When axial load of 1 200 N was applied, the maximum displacement of fracture fragments in the 3 groups was similar, and group A had the largest displacement (0.74 mm) and group B had the smallest displacement (0.65 mm). The maximum Von-Mises stress of implant in group C was the smallest (95.49 MPa), while that in group B was the largest (177.96 MPa). The maximum Von-Mises stress of tibia in group C was the smallest (43.35 MPa), and that in group B was the largest (120.50 MPa). The maximum Von-Mises stress of fracture line in group A was the smallest (42.60 MPa), and that in group B was the largest (120.50 MPa). Conclusion: For the bicondylar four-quadrant fracture of the tibial plateau, a T-shaped plate fixed in medial tibial plateau has a stronger supporting effect than the use of two reconstruction plates fixed in the anteromedial and posteromedial plateaus, which should be served as the main plate. The reconstruction plate, which plays an auxiliary role, is easier to achieve anti-glide effect when it is longitudinally fixed in posteromedial plateau than obliquely fixed in posterolateral plateau, which contributes to the establishment of a more stable biomechanical structure.

[Progress in surgical treatment of inferior patellar pole fractures].

Objective: To summarize the surgical treatment methods and progress of inferior patellar pole fractures and provide reference for clinical application. Methods: The literature on surgical treatment of inferior patellar pole fractures was extensively reviewed, and the relevant research progress, advantages, and limitations were summarized. Results: The inferior pole of the patella is an important part of the knee extension device, which can strengthen the force arm of the quadriceps. Inferior patellar pole fractures are relatively rare and often comminuted, usually requiring surgical treatment. At present, there are various methods to treat inferior patellar pole fractures, including patellectomy of inferior pole, tension-band wiring technique, plate internal fixation, suture anchor fixation, claw-like shape memory alloy, separate vertical wiring technique. Different methods have their own characteristics, advantages, and disadvantages. The single internal fixation method has more complications and is easy to cause fixation failure. Therefore, the trend of combining various internal fixation methods is developing at present. Conclusion: When the main fragment of the inferior patellar pole fracture is large and mainly distributed transversely, the combination protocol based on tension-band wiring technique can be regarded as an ideal choice. When the fragments are severely damaged and small, the comprehensive protocol based on suture fixation can result in a better postoperative functional recovery.

Cascade Delivery to Golgi Apparatus and On-Site Formation of Subcellular Drug Reservoir for Cancer Metastasis Suppression.

As the foremost cause of cancer-related death, metastasis consists of three steps: invasion, circulation, and colonization. Only targeting one single phase of the metastasis cascade may be insufficient since there are many alternative routes for tumor cells to disseminate. Here, to target the whole cascade of metastasis, hybrid erythrocyte and tumor cell membrane-coated nanoparticle (Hyb-NP) is designed with dual functions of increasing circulation time and recognizing primary, circulating, and colonized tumors. After loading with monensin, a recently reported metastasis inhibitor, the delivery system profoundly reduces spontaneous metastasis in an orthotopic breast cancer model. Underlying mechanism studies reveal that Hyb-NP can deliver monensin to its action site in the Golgi apparatus, and in return, monensin can block the exocytosis of Hyb-NP from the Golgi apparatus, forming a reservoir-like subcellular structure. Notably, the Golgi apparatus reservoir displays three vital functions for suppressing metastasis initialization, including enhanced subcellular drug retention, metastasis-related cytokine release inhibition, and directional migration inhibition. Collectively, based on metastasis cascade targeting at the tissue level, further formation of the Golgi apparatus drug reservoir at the subcellular level provides a potential therapeutic strategy for cancer metastasis suppression.

Peritumoral scaffold neutralizes tumor pH for chemotherapy sensitization and metastasis inhibition.

The abnormal metabolism of rapidly growing tumors can create an acidic tumor microenvironment (TME) that renders cancer cells resistant to chemotherapy and further facilitates endothelial-to-mesenchymal transition (EMT) progress to promote metastasis. Here, we developed a combination strategy consisting of (1) peritumorally injected scaffold that alleviates TME acidosis, and (2) intravenously injected nanoparticles that delivers anti-cancer agents to tumor. Concurrent treatment with these two drug delivery systems profoundly delayed the growth of primary tumor and reduced the spontaneous metastasis to lung in an orthotopic breast cancer mouse model. Mechanism studies both in vitro and in vivo further revealed that neutralization of TME pH by the hydrogel scaffold sensitized cancer cells to nanoparticle-based chemotherapy, thereby strengthening the cytotoxicity against tumor growth; In parallel, reversal of tumor acidity downregulated various pro-metastatic proteins intratumorally to block the EMT progress, thereby reducing the metastatic potential of cancer cells. This work provided proof-of-concept demonstration that chemotherapy sensitization and EMT suppression could be synchronized by the modulation of TME pH, which may be potentially beneficial for simultaneous inhibition of tumor growth and cancer metastasis.

Split bullets loaded nanoparticles for amplified immunotherapy.

Dendritic cells (DCs) play central role in adaptive antitumor immunity, while their function is often hampered by low immunogenicity of tumor tissues and surrounding hostile microenvironment. Herein, a "split bullets" loaded nanoplatform that can bidirectionally injure mitochondria (MT) and endoplasmic reticulum (ER) of tumor cells is developed. After cellular uptake, the released "split bullets" separately target to different subcellular destinations and exert distinct effects on DCs: (1) MT-targeted "bullet" recruits peripheral DCs into tumor sites, due to its capability to trigger adenosine triphosphate release from tumor cells; (2) ER-targeted "bullet" activates tumor-infiltrating DCs, which is attributed to its ability to evoke calreticulin exposure on tumor cells. These effects collectively improve the tropism and reactivity of DCs to tumor-specific antigen in a two-pronged way. As a result of enhanced function of DCs in antigen capture, treatment of the "split bullets" loaded nanoplatform ignites robust immune response to suppress primary melanoma, and establishes systemic immune memory against post-surgical tumor recurrence. Overall, this nanoplatform offers a generalizable approach to boost DCs and augment immunotherapy.

Trauma-Responsive Scaffold Synchronizing Oncolysis Immunization and Inflammation Alleviation for Post-Operative Suppression of Cancer Metastasis.

Tumor surgery can create an inflammatory trauma to aggravate residual tumor "seed" to colonize pre-metastatic niches (PMNs) "soil" at secondary sites, thereby promoting post-operative metastasis. However, two-pronged strategies for post-surgical elimination of asynchronous "seeds" and "soil" at different regions are currently lacking. Here, we have designed a hydrogel that can be injected into a resection cavity, where it immediately forms a scaffold and gradually degrades responding to enriched reactive oxygen species at adjacent trauma for local delivery and on-demand release of autologous cancer cells succumbing to oncolysis (ACCO) and anti-inflammatory agent. The autologous cell source self-provides a whole array of tumor-associated antigens, and the oncolysis orchestration of a subcellular cascade confers a self-adjuvanting property, together guaranteeing high immunogenicity of the ACCO vaccine that enables specific antitumor immunization. In parallel, inflammation alleviation exerted bidirectional functions to reshape the local immune landscape and resuscitate ACCO, leading to the eradication of residual tumor "seeds" while simultaneously intercepting the "seed-soil" crosstalk to normalize distant lung leading to regression of pre-existing PMN "soil". As a result, regional and metastatic recurrence were completely thwarted. Together, this framework synchronizing oncolysis immunization and inflammation alleviation provides an effective option for post-operative suppression of metastasis.

Redirecting Chemotherapeutics to the Endoplasmic Reticulum Increases Tumor Immunogenicity and Potentiates Anti-PD-L1 Therapy.

The endoplasmic reticulum (ER) in cancer cells has been considered as a pharmacological target. Still, the effects of a ER-targeted system remain less investigated, due to the fact that most chemo-drugs take actions in the nucleus. Here, it is demonstrated that ER-targeted delivery of doxorubicin (DOX), a typically nucleus-tropic-and-acting agent, attenuates its original effect on cytotoxicity while generating new functions favorable for immune activation. First, a library of DOX derivatives with variable ER-targeting abilities is synthesized. The results reveal that higher ER-targeting efficiency correlates with greater ER stress. As compared with naïve drug, ER-targeted DOX considerably alters the mode of action from nuclear DNA damage-associated cytotoxicity to ER stress-mediated calreticulin exposure. Consequently, ER-targeted DOX decreases cytotoxicity but increases the capability to induce immunogenic cell death (ICD). Therefore, a platform combining naïve and ER-targeted DOX is constructed for in vivo application. Conventional polymer-DOX conjugate inhibits tumor growth by exerting a direct killing effect, and ER-targeted polymer-DOX conjugate suppresses residual tumors by eliciting ICD-associated immunity, together resulting in considerable tumor regression. In addition, simultaneous inhibition of adaptive PD-L1 enrichment (due to negative-feedback to ICD induction) further leads to greater therapeutic outcome. Collectively, ER-targeted therapy can enhance anticancer efficacy by promoting ICD-associated immunotherapy, and potentiating chemotherapy and checkpoint blockade therapy.