Petaloid Metal-Organic Frameworks for Resiquimod Delivery To Potentiate Antitumor Immunity.

The morphological features of materials significantly influence their interactions with cells, consequently affecting the cellular uptake of these materials. In this study, we examine the cellular uptake behavior of spherical metal-organic frameworks (MOFs) and petaloid MOFs, both possessing similar sizes and compositions. In comparison to spherical MOFs, dendritic cells (DCs) and macrophages exhibit superior phagocytic uptake of petaloid MOFs. Next, the results demonstrate that R848@petaloid MOFs more effectively promote the repolarization of tumor-associated macrophages (TAMs) from the M2 to M1 phenotype and the maturation of DCs. More importantly, the R848-loaded petaloid MOFs are found to significantly enhance the therapeutic effects of radiotherapy (RT) by eliciting antitumor responses. Furthermore, R848@petaloid MOFs combined with RT and αPD-L1 elicit a potent abscopal effect, effectively suppressing tumor metastasis. Therefore, this work proposes a new strategy to enhance the uptake of immunomodulators by immune cells through modulating the morphology of drug delivery carriers.

Reactive Oxygen Species-Triggered Curcumin Release from Hollow Mesoporous Silica Nanoparticles for PM2.5-Induced Acute Lung Injury Treatment.

Exposure to fine particulate matter with a diameter ≤2.5 µm (PM2.5) can result in serious inflammation and oxidative stress in lung tissue. However, there is presently very few effective treatments for PM2.5-induced many pulmonary diseases, such as acute lung injury (ALI). Herein, curcumin-loaded reactive oxygen species (ROS)-responsive hollow mesoporous silica nanoparticles (Cur@HMSN-BSA) are proposed for scavenging the intracellular ROS and suppressing inflammatory responses against PM2.5-induced ALI. The prepared nanoparticles were coated with bovine serum albumin (BSA) via an ROS-sensitive thioketal (TK)-containing linker, in which the TK-containing linker would be cleaved by the excessive amounts of ROS in inflammatory sites to induce the detachment of BSA from the nanoparticles surface and thus triggering release of loaded curcumin. The Cur@HMSN-BSA nanoparticles could be used as ROS scavengers because of their excellent ROS-responsiveness, which were able to efficiently consume high concentrations of intracellular ROS. Furthermore, it was also found that Cur@HMSN-BSA downregulated the secretion of several important pro-inflammatory cytokines and promoted the polarization from M1 phenotypic macrophages to M2 phenotypic macrophages for eliminating PM2.5-induced inflammatory activation. Therefore, this work provided a promising strategy to synergistically scavenge intracellular ROS and suppress the inflammation responses, which may serve as an ideal therapeutic platform for pneumonia treatment.

The Diagnostic Value of miR-124a Expression in Peripheral Blood and Synovial Fluid of Patients with Rheumatoid Arthritis.

INTRODUCTION: Rheumatoid arthritis (RA), a chronic autoimmune disorder, is currently a severe health threat. Previous studies have documented the altered expression of various miRNAs in RA patients. This study determined the expression of miR-124a in RA patients and estimated its diagnostic value for RA. METHODS: A total of 80 RA patients were enrolled as the study subjects, and 36 patients with osteoarthritis were included, with another 36 healthy people as the controls. miR-124a expression levels in peripheral blood plasma, peripheral blood mononuclear cells (PBMCs), and synovial fluid were measured using reverse transcription quantitative polymerase chain reaction, followed by Pearson correlation analysis. Additionally, the association between miR-124a and major clinical indicators was assessed, such as rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), and disease activity score of 28 joints (DAS28). The diagnostic efficacy of miR-124a expression in plasma, PBMCs, and synovial fluid for RA was evaluated by the receiver operating characteristic curve, and the difference in the area under the curve (AUC) was analyzed. RESULTS: miR-124a was downregulated in RA patients, and the expression levels of miR-124a in plasma, PBMCs, and synovial fluid showed a certain degree of positive correlation. miR-124a was inversely linked with RF, ESR, and DAS28. For the diagnosis of RA patients, the AUC of plasma miR-124a was 0.899 and the cut-off value was 0.800, with 68.75% sensitivity and 94.44% specificity; the AUC of miR-124a in PBMCs was 0.937 and the cut-off value was 0.805, with 82.50% sensitivity and 91.67% specificity; the AUC of miR-124a in plasma combined with PBMCs was 0.961, with a higher diagnostic value than independent plasma or PBMCs; the AUC of miR-124a in synovial fluid was 0.929 and the cut-off value was 0.835, with 80.00% sensitivity and 88.89% specificity. CONCLUSION: miR-124a expression is downregulated in the plasma, PBMCs, and synovial fluid of RA patients and has a high diagnostic value for RA.

Biomineralized MnO2 Nanoplatforms Mediated Delivery of Immune Checkpoint Inhibitors with STING Pathway Activation to Potentiate Cancer Radio-Immunotherapy.

Radiotherapy (RT), as one of the main methods in the clinical treatment of various malignant tumors, would induce systemic immunotherapeutic effects by triggering immunogenic cell death (ICD) of cancer cells. However, the antitumor immune responses produced by RT-induced ICD alone usually are not robust enough to eliminate distant tumors and thus ineffective against cancer metastases. Herein, a biomimetic mineralization method for facile synthesis of MnO2 nanoparticles with high anti-programmed death ligand 1 (αPDL1) encapsulation efficiency (αPDL1@MnO2) is proposed to reinforce RT-induced systemic antitumor immune responses. This therapeutic nanoplatforms-mediated RT can significantly improve the killing of tumor cells and effectively evoke ICD by overcoming hypoxia-induced radio-resistance and reprogramming the immunosuppressive tumor microenvironment (TME). Furthermore, the released Mn2+ ions from αPDL1@MnO2 under acidic tumor pH can activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and facilitate the dendritic cells (DCs) maturation. Meanwhile, αPDL1 released from αPDL1@MnO2 nanoparticles would further promote the intratumoral infiltration of cytotoxic T lymphocytes (CTLs) and trigger systemic antitumor responses, resulting in a strong abscopal effect to effectively inhibit tumor metastases. Overall, the biomineralized MnO2-based nanoplatforms offer a simple strategy for TME modulation and immune activation, which are promising for enhanced RT immunotherapy.

[Clinical therapeutic strategies of refracture after bone transport for tibial bone defect].

OBJECTIVE: To explore the clinical therapeutic strategies of refracture after Ilizarov bone transport technique in the treatment of tibial bone defect. METHODS: A retrospective study was performed on 19 patients with infected tibial bone defect treated by Ilizarov bone transport technique and then refracture from August 2010 to January 2020, including 18 males and 1 female with an average age of (37.7±13.0) years old ranging from 15 to 66 years old. Cause of injury invlved falling injury in 4 cases, crashing injury 1 case, crushing injury in 1 case and without obvious injury history in 13 cases. The ipsilateral distal femoral fracture in 2 cases occurred before the external fixator of tibia was removed, and the other 17 cases had a minimum of 1 day and a maximum of 30 months after the external fixator had been removed. The site of refracture was at regenerative zone in 8 cases, at docking site in 9 cases, at ipsilateral femoral shaft in 2 cases. According to the modified Simpson classification proposed by the author, the refracture was classified. The treatment of refracture include plaster splint, traction or external fixation. Bone healing and function were evaluated according to the standards of the Association for the Study and Application of the Method of Ilizarov(ASAMI). RESULTS: All patients were followed up, and the duration ranged from 9 to 17 months with an average of (12.3±3.2) months. According to the modified Simpson classification, there were 3 cases of type Ⅰa, 1 case of type Ⅰb, 3 cases of type Ⅰc, 1 case of type Ⅱ, 9 cases of type Ⅲ and 2 cases of type Ⅴ. All the refractures healed without infection or malunion. The fracture healing time of conservative treatment for 6 cases were 3, 5, 3, 2, 2, 2 months fespectively;and the healing time of fracture treated by surgery for 13 cases was 2 to 6 months, with an average of(4.4±1.4) months. According to ASAMI evaluation criteria, bony results showed all patients obtained excellent results, and functional results showed 6 patients got excellent results, 13 good beacause of ankle or knee stiffness. CONCLUSION: The modified Simpson classification could contain most clinical types of refracture after bone transport, and the external fixation is a simple and effective method for refracture.

Clinical application of the sinus tarsi approach in the treatment of intra-articular calcaneal fracture.

To observe the clinical outcome of the sinus tarsi approach in the operative treatment of intra-articular calcaneal fractures.Forty-nine intra-articular calcaneal fractures in 45 patients were managed surgically with sinus tarsi approach. The anatomical plate and compression bolts were applied in 14 feet. The anatomical plate and screws were applied in 35 feet. Maryland foot score system was used to evaluate the function of the hindfoot at the followup.The reduction of the posterior facet was graded as nearly anatomical (less than 2 mm articular displacement) in 46 feet (93.9%). The width, height, and Böhler angle were significantly improved in all patients (P < .01). After a mean follow-up period of 18.7 months (14.5-29 months), the Maryland foot scores were: 34 feet scored 90-100 points (excellent), 6 feet scored 80-90 points (good), 6 feet scored 70-80 points (fair), and 3 feet scored 60-70 points (poor). Incision-edge necrosis occurred in 2 cases. One case suffered from incomplete medial plantar nerve injury. One case suffered from heel pad branch of the tibial nerve injury. Six cases suffered from sural nerve injury, and 4 cases sustained a lateral wound dehiscence due to a hematoma. No case suffered from lateral impingement syndrome. Up to now, no patient had to accept subtalar arthrodesis.Sinus tarsi approach provides good exposure to the subtalar joint. Open reduction and internal fixation of calcaneus fractures through a sinus tarsi approach allows adequate reduction with low risk of wound-healing complications.

Percutaneous Repair Technique for Acute Achilles Tendon Rupture with Assistance of Kirschner Wire.

The aim of this study is to introduce a self-designed, minimally invasive technique for repairing an acute Achilles tendon rupture percutaneously. Comparing with the traditional open repair, the new technique provides obvious advantages of minimized operation-related lesions, fewer wound complications as well as a higher healing rate. However, a percutaneous technique without direct vision may be criticized by its insufficient anastomosis of Achilles tendon and may also lead to the lengthening of the Achilles tendon and a reduction in the strength of the gastrocnemius. To address the potential problems, we have improved our technique using a percutaneous Kirschner wire leverage process before suturing, which can effectively recover the length of the Achilles tendon and ensure the broken ends are in tight contact. With this improvement in technique, we have great confidence that it will become the treatment of choice for acute Achilles tendon ruptures.

Management of traumatic hemipelvectomy: an institutional experience on four consecutive cases.

BACKGROUND AND OBJECTIVE: The incidence of traumatic hemipelvectomy is rare, but it is a devastating injury. Recently, an increasing number of patients with traumatic hemipelvectomy are admitted to trauma centers alive due to improvements of the pre-hospital care. Successful management requires prompt recognition of the nature of this injury and meticulous surgical technique. We present our successful experiences on four cases of traumatic hemipelvectomy in the past nine years. PATIENTS AND METHODS: Four cases with traumatic hemipelvectomy were admited to our hospital from June 21, 2002 to September 3, 2011. All injuries occurred due to vehicle accident and all patients were in a state of severe hypotension, with two of them having anal lacerations. These four cases were treated immediately with resuscitation, control of hemorrhage, early amputation, repeated debridement and closure of the wounds. An angiographic embolization was given to control hemorrhage in two of the cases preoperatively. One case underwent fecal diversion. Wound infection occurred in all of cases which was successfully controlled by repeated debridements, effective anti-biotic regimen, split-thickness skin grafts. RESULTS: All four cases were saved successfully with well-healed wounds during follow up from 1 to 7 years. They were able to walk by themself using crutches. CONCLUSION: Adhering to the surgery principles of damage control including appropriate resuscitation, hemorrhage control, coagulopathy correction and multiple debridements and closure of the wounds in reasonable period of time can save the life of cases suffering from severe pelvic ring injury.

Minimally invasive treatment of calcaneal fracture by percutaneous leverage, anatomical plate, and compression bolts--the clinical evaluation of cohort of 156 patients.

OBJECTIVE: To introduce a minimally invasive procedure and investigate its clinical significance in the treatment of displaced intra-articular calcaneal fractures. This minimally invasive procedure consists of percutaneous leverage, manual compression, and fixation with anatomic plates and compression bolts through small lateral incisions. METHODS: Two hundred ten feet with calcaneal fractures from 156 patients were managed by this minimally invasive procedure. According to Sanders classification, the fracture patterns in our study include 132 type II, 60 type III, and 18 type IV fractures. The Böhler's and Gissan's angle as well as the width, height, and length of the calcaneum were measured on pre- and postoperative radiographs. The anatomic plates were removed from 3 months to 12 months after operation for all patients. The Maryland hindfoot score system was applied to evaluate the postoperative function of the hindfoot. RESULTS: All patients were followed up for an average of 9.7 months (range, 4.5-12 months). The reduction of the posterior articular facet was graded as nearly anatomic with articular displacement of < 3 mm in 159 fractures (75.7%). The reduction was measured radiologically by the change in the width, height, length of the calcaneum, and Böhler's and Gissan's angle, which have seen significant improvement in all patients. Based on the Maryland hindfoot score, 90 (43%) fractures was assessed as excellent, 90 (43%) good, 18 (8%) fair, and 12 (6%) poor. One hundred thirty-two patients (84.6%) were able to return to their original occupation at a mean time of 5.2 months (4.0-10.6 months) after operation. No patient sustained lateral impingement syndrome or soft tissue complications. Up to date, 20 patients (9.5%) sustained mild-to-moderate subtalar osteoarthritis, evidented radiologically as the narrowing of the joint space and subchondral sclerosis, but pain in the subtalar joint was present only in four patients (1.9%). No subtalar arthrodesis has been performed because of patients' unwillingness to undergo second procedure to relieve the pain that is well tolerable. CONCLUSION: This minimal invasive procedure featured percutaneous leverage, manual compression, and the application of the anatomic plates and compression bolts through lateral approach is proved to be an effective treatment for displaced intra-articular calcaneal fracture, offering the combination of fewer soft tissue complications and good reduction. With < 3-mm displacement of the posterior facet after reduction, the restoration of the calcaneal width and height can be very important to achieve satisfactory radiologic and functional outcomes.

Bioavailability of mifepristone in capsule versus tablet form in healthy nonpregnant women.

BACKGROUND: The study was conducted to assess the bioavailability of two formulations of mifepristone in capsule and tablet forms at a single dose of 75 mg (half the registered dose in China). STUDY DESIGN: A randomized two-way crossover study was conducted in 18 healthy nonpregnant women. Each subject was orally given a single dose of mifepristone at 75 mg in capsule or tablet form on an alternate basis. Serial blood samples were collected over a period of 96 h and assayed for the plasma concentration of mifepristone by high-performance liquid chromatography. Paired t tests were used to compare the capsule and tablet forms in terms of maximum concentration (C(max)), time to maximum concentration (T(max)) and area under the curve over 96 h (AUC(0-96 h)). Relative bioavailability (capsule/tablet) was derived from AUC(0-96 h). Bioequivalability was analyzed by two one-sided t tests. RESULTS: The major pharmacokinetic parameters were as follows: C(max) values were 1.26+/-0.38 and 1.25+/-0.40 mcg/mL, T(max) values were 0.94+/-0.34 and 0.89+/-0.47 h, T(1/2Ke) values were 36.2+/-21.0 and 33.4+/-12.3 h and AUC((0-96 h)) values were 19.7+/-6.4 and 19.6+/-9.9 mcg.h/mL for mifepristone in capsule and tablet forms, respectively. No significant difference was observed among these parameters. The relative bioavailability was 109.4+/-34.8%. CONCLUSION: This study suggests that the two formulations of mifepristone are bioequivalent, which provides pharmacokinetic evidence for further reducing the dosage of mifepristone in clinical use.