Pre-sliding of the femoral neck system to prevent postoperative shortening of femoral neck fractures.

Objective: The purpose of this study is to evaluate the effect of pre-sliding of the femoral neck system (FNS) in the prevention of postoperative femoral neck shortening in femoral neck fractures. Method: This study was designed to retrospectively analyze data from 109 patients with femoral neck fractures who were admitted to a Level I trauma center between April 2020 and June 2022. Of these patients, 90 were followed up for more than 12 months. The study included 52 males and 38 females, with 35 cases of Garden I and II fractures and 55 cases of Garden III and IV fractures. The Harris Hip Score at 12 months postoperatively were recorded. The patients were divided into two groups based on their surgical records and postoperative radiography: the Pre-sliding group and the No-pre-sliding group. The purpose of this study is to analyze the role of pre-sliding in preventing femoral neck shortening, fracture healing time, degree of postoperative shortening, complications, and Harris Hip Score, and to make a comparison between the two groups. Results: All 90 patients were followed up for over one year after surgery. A statistically significant difference was observed in the preoperative Garden classification (P < 0.05). At 1 year after the operation, the shortening distance was 6.5 ± 6.4 mm in the No-pre-sliding group and 3.9 ± 3.4 mm in the Pre-sliding group. The Harris Hip Score were 88.7 (79.8, 93.5) in the No-pre-sliding group and 94.8 (87.7, 96.9) in the Pre-sliding group, with a statistically significant difference between the two groups (P < 0.05). Shortening was concentrated at 3 months postoperatively and reached a stable state within 6 months, with less persistent shortening occurring after 6 months. There was no statistically significant difference in the preoperative baseline data. Conclusion: Pre-sliding of the FNS prevents postoperative shortening of the femoral neck and improves hip function as measured by the Harris Hip Score.

Pre-sliding technique to improve femoral neck system against the shortening: a retrospective cohort study.

OBJECTIVE: To investigate the efficacy of using pre-sliding technique to prevent postoperative shortening of displaced femoral neck fracture fixed with femoral neck system (FNS). METHODS: Retrospective analysis of 110 cases of displaced femoral neck fracture treated with femoral neck system from September 2019 to November 2022 in our center, which were divided into 56 cases in the pre-sliding group and 54 cases in the traditional group. The baseline data such as gender, age, side, mechanism of injury, fracture type, operation time, intraoperative bleeding were recorded and compared between the two groups, and the quality of fracture reduction, shortening distance, Tip Apex Distance (TAD), union time, Harris score of the hip were also compared between the two groups. RESULTS: The TAD value of the pre-sliding group was smaller than that of the traditional group, and the difference was statistically significant (P < 0.001). The shortening distance in both groups on postoperative day 1 was smaller in the pre-sliding group than in the traditional group, but the difference was not statistically significant (P = 0.07), and the shortening distance was smaller than in the traditional group at 1, 3, 6, and 12 months postoperatively, and the difference was statistically significant (all P < 0.001). Of the 110 cases, 34 (30.9%) had moderate or severe shortening, of which 24 (44.4%) were in the traditional group and 10 (17.9%) in the pre-sliding group, and the difference was statistically significant (P < 0.001), and the Harris score at 1 year, which was higher in the pre-sliding group than in the traditional group, and the difference between the two groups was statistically significant (P < 0.001). There was no statistically significant difference in the comparison of baseline data such as gender, age, side, mechanism of injury, fracture type, operation time, intraoperative bleeding, and quality of reduction between the two groups (all P > 0.05), and no statistically significant difference in fracture healing time between the two groups (P = 0.113). CONCLUSION: The use of the pre-sliding technique of displaced femoral neck fracture fixed with FNS reduces the incidence of moderate and severe shortening, improves the postoperative TAD value, and improves the hip function scores, with a satisfactory midterm efficacy.

Comparison of femoral neck shortening after femoral neck system and cannulated cancellous screw fixation for displaced femoral neck fractures in young adults.

BACKGROUND: The purpose of this study was to compare the outcomes of femoral neck shortening between the femoral neck system (FNS) and the cannulated cancellous screws (CCS) for displaced femoral neck fractures in young adults PATIENTS AND METHODS: In this retrospective analysis, 225 patients aged 18-65 years with displaced femoral neck fracture were divided into two groups according to internal fixation: 135 patients in the FNS group and 90 patients in the CCS group. The length of hospital stay, duration of surgery, intraoperative blood loss, quality of reduction, extent of femoral neck shortening, incidence of femoral neck shortening, femoral neck shortening at each follow-up visit, Harris hip score (HHS), reoperation, and complications were compared between the two groups. RESULTS: The median follow-up time was 28.2 (26.0, 31.2) months in the FNS group and 30.2 (26.3, 34.7) months in the CCS group. The follow-up time, age, sex distribution, body mass index (BMI), mechanism of injury, injured side, length of hospital stay, time from injury to surgery, and fracture classification were similar between the groups. Duration of surgery was longer in the FNS group (65.0 (55.0, 87.0) min versus 55.0 (50.0, 65.0) min, P<0.001); intraoperative blood loss was greater in the FNS group (50.0 (20.0, 60.0) ml versus 20.0 (10.0, 35.0) ml, P<0.001). Femoral neck shortening was 2.4 (1.0, 4.5) mm in the FNS group versus 0.6 (0.0, 2.6) mm in the CCS group at 1 month postoperatively (P<0.001); 3.7 (1.8, 6.4) mm in the FNS group versus 1.2 (0.6, 3.8) mm in the CCS group at 3 months (P<0.001); 4.1(2.4, 7.7) mm in the FNS group versus 2.3 (1.1, 4.4) mm in the CCS group at 6 months (P<0.001); 4.2 (2.6, 7.7) mm in the FNS group versus 2.6 (1.3, 4.6) mm in the CCS group at 12 months (P<0.001); and 4.5 (2.8, 8.0) mm in the FNS group versus 2.8 (1.5, 4.8) mm in the CCS group at 18 months (P<0.001). The two groups showed no significant differences in HHS, reoperation, and reduction quality. CONCLUSION: Compared to CCS, FNS is deficient in preventing femoral neck shortening. Future research should focus on improving FNS in terms of preventing femoral neck shortening.

Brown Sequard syndrome in a patient with Klippel-Feil syndrome following minor trauma: a case report and literature review.

BACKGROUND: There are some cases of Klippel-Feil syndrome with spinal cord injury in clinical work. However, there is no literature report on Brown-Sequard syndrome after trauma. We report a case of Brown-Sequard syndrome following minor trauma in a patient with KFS type III. Her Brown-Sequard syndrome is caused by Klippel-Feil syndrome. CASE PRESENTATION: We found a 38-year-old female patient with KFS in our clinical work. She was unconscious on the spot following a minor traumatic episode. After treatment, her whole body was numb and limb activity was limited. Half an hour later, she felt numb and weak in the right limb and weak in the left limb. She had no previous hypertension, diabetes, or coronary heart disease. After one-month treatment of medication, hyperbaric oxygen, rehabilitation, and acupuncture in our hospital, her muscle strength partially recovered, but the treatment effect was still not satisfactory. Then, she underwent surgical treatment and postoperative comprehensive treatment, and rehabilitation training. She was able to take care of herself with assistance, and her condition improved from grade B to grade D according to the ASIA (ASIA Impairment Scale) classification. CONCLUSION: KFS, also known as short neck deformity, is a kind of congenital deformity characterized by impaired formation and faulty segmentation of the cervical spine, often associated with abnormalities of other organs. The cervical deformity in patients with KFS can alter the overall mechanical activity of the spine, as well as the compensatory properties of the spine for decelerating and rotatory forces, thus increasing the chance of spinal cord injury (SCI) following trauma. Many mechanisms can make patients more susceptible to injury. Increased range of motion of the segment adjacent to the fused vertebral body may lead to slippage of the adjacent vertebral body and altered disc stress, as well as cervical instability. SCI can result in complete or incomplete impairment of motor, sensory and autonomic nervous functions below the level of lesion. This woman presented with symptoms of BSS, a rare neurological disorder with incomplete SCI. Judging from the woman's symptoms, we concluded that previously she had KFS, which resulted in SCI without fracture and dislocation following minor trauma, with partial BSS. After the comprehensive treatment of surgery, hyperbaric oxygen, rehabilitation therapy, and neurotrophic drugs, two years later, we found her symptoms significantly improved, with ASIA Impairment Scale from grade B to grade D, and her ability to perform activities of daily living with aids.

Dysregulation of iron homeostasis by TfR-1 renders EZH2 wild type diffuse large B-cell lymphoma resistance to EZH2 inhibition.

EZH2 has been regarded as an efficient target for diffuse large B-cell lymphoma (DLBCL), but the clinical benefits of EZH2 inhibitors (EZH2i) are limited. To date, only EPZ-6438 has been approved by FDA for the treatment of follicular lymphoma and epithelioid sarcoma. We have discovered a novel EZH1/2 inhibitor HH2853 with a better antitumor effect than EPZ-6438 in preclinical studies. In this study we explored the molecular mechanism underlying the primary resistance to EZH2 inhibitors and sought for combination therapy strategy to overcome it. By analyzing EPZ-6438 and HH2853 response profiling, we found that EZH2 inhibition increased intracellular iron through upregulation of transferrin receptor 1 (TfR-1), ultimately triggered resistance to EZH2i in DLBCL cells. We demonstrated that H3K27ac gain by EZH2i enhanced c-Myc transcription, which contributed to TfR-1 overexpression in insensitive U-2932 and WILL-2 cells. On the other hand, EZH2i impaired the occurrence of ferroptosis by upregulating the heat shock protein family A (Hsp70) member 5 (HSPA5) and stabilizing glutathione peroxidase 4 (GPX4), a ferroptosis suppressor; co-treatment with ferroptosis inducer erastin effectively overrode the resistance of DLBCL to EZH2i in vitro and in vivo. Altogether, this study reveals iron-dependent resistance evoked by EZH2i in DLBCL cells, and suggests that combination with ferroptosis inducer may be a promising therapeutic strategy.

Incidence and factors influencing neck shortening after screw fixation of femoral neck fractures with the femoral neck system.

OBJECTIVE: To investigate the effects of postoperative femoral neck shortening in patients with femoral neck fractures fixed with femoral neck system screws (FNS) and to explore the factors influencing femoral neck shortening. METHOD: To retrospectively analyze the data of 113 patients with femoral neck fractures admitted to the Second Hospital of Fuzhou City, affiliated with Xiamen University, between December 2019 and January 2022. Of these, 87 patients were followed up for more than 12 months, 49 men and 38 women: 36 cases of Garden I and II fractures and 51 cases of Garden III and IV fractures, to record the patient's hip Harris score at 12 months postoperatively. Patients were divided into femoral neck shortening group and femoral neck no shortening group according to their regular postoperative follow-up radiographic measurements. To count the incidence of femoral neck shortening, a comparison of postoperative complication rates and hip Harris scores between the two groups was made. Statistical comparison of the two groups and a multifactorial logistic regression analysis were also performed to analyze the factors affecting femoral neck shortening. RESULTS: All 87 patients were followed up for more than 12 months after surgery. In 34 of these cases, neck shortening occurred, and the incidence rate was 39.1%. 15 cases of severe shortening, incidence of 17.2%; fracture healing 84 cases, fracture healing rate of 96.5%. The hip Harris score was 83.99 (81.95, 89.20) in the neck shortening group at 12 months postoperatively, 90.87 (87.95, 94.80) for the group without neck shortening; the difference between the two groups was statistically significant (P < 0.01). 32 cases of fracture healing in the neck shortening group at 12 months after surgery, fracture healing rate of 94.1%; 52 cases healed without neck shortening group, fracture healing rate of 98.1%. The difference between the two groups was not statistically significant (P = 0.337). High incidence of neck shortening after FNS fixation of femoral neck fractures, cortical comminution of the severed end, fracture fractionation and quality of reduction were significantly correlated with neck shortening. CONCLUSION: High incidence of postoperative neck shortening after internal fixation of femoral neck fractures with the femoral neck system, the cortical comminution, the type of fracture, and the quality of fracture reduction are the influencing factors; femoral neck shortening can affect postoperative hip function, but does not affect fracture healing.

Selective degradation of cellular BRD3 and BRD4-L promoted by PROTAC molecules in six cancer cell lines.

Targeted degradation of BET family proteins BRD2/3/4 or only BRD4 with PROTAC molecules has been a promising strategy for the treatment of human cancer. Meanwhile, selective degradation of cellular BRD3 and BRD4-L remains a challenging task. We report herein a novel PROTAC molecule 24 that promoted selective degradation of cellular BRD3 and BRD4-L, but not BRD2 or BRD4-S, in a panel of six cancer cell lines. The observed target selectivity was partially attributed to differences in protein degradation kinetics and in types of cell lines. In a MM.1S mouse xenograft model, an optimized lead compound 28 promoted selective degradation of BRD3 and BRD4-L in vivo and exhibited robust antitumor activity. In summary, we have demonstrated that selective degradation of BRD3 and BRD4-L over BRD2 and BRD4-S is a feasible and robust approach in multiple cancer cell lines and an animal model, which could be helpful for further investigations on BRD3 and BRD4-L that ultimately benefitting cancer research and therapeutics.

Discovery of 10H-Benzo[b]pyrido[2,3-e][1,4]oxazine AXL Inhibitors via Structure-Based Drug Design Targeting c-Met Kinase.

Receptor tyrosine kinase AXL exerts pivotal roles in cancer cell survival, metastasis, and drug resistance. Pharmacologic or genetic targeting of the aberrant AXL signaling has proven preferable antitumor efficacies in both preclinical and clinical studies, which highlights AXL as an attractive antitumor drug target. By conformational restriction of the anilinopyrimidine 10e and systematic structure-activity relationship (SAR) exploration, we discovered 10H-benzo[b]pyrido[2,3-e][1,4]oxazine 16j as a potent and orally bioavailable AXL inhibitor. As a type II AXL inhibitor, compound 16j displayed about 15-fold selectivity for AXL over its highly homologous kinase c-Met. And it significantly blocked cellular AXL signaling, inhibited AXL-mediated cell proliferation, and impaired growth arrest-specific protein 6 (Gas6)/AXL-stimulated cell migration and invasion. Moreover, 16j exhibited significant antitumor efficacy in AXL-driven xenograft model at a well-tolerant dosage, causing tumor stasis or regression.

18F-FDG PET as an imaging biomarker for the response to FGFR-targeted therapy of cancer cells via FGFR-initiated mTOR/HK2 axis.

Rationale: The overall clinical response to FGFR inhibitor (FGFRi) is far from satisfactory in cancer patients stratified by FGFR aberration, the current biomarker in clinical practice. A novel biomarker to evaluate the therapeutic response to FGFRi in a non-invasive and dynamic manner is thus greatly desired. Methods: Six FGFR-aberrant cancer cell lines were used, including four FGFRi-sensitive ones (NCI-H1581, NCI-H716, RT112 and Hep3B) and two FGFRi-resistant ones (primary for NCI-H2444 and acquired for NCI-H1581/AR). Cell viability and tumor xenograft growth analyses were performed to evaluate FGFRi sensitivities, accompanied by corresponding 18F-fluorodeoxyglucose (18F-FDG) uptake assay. mTOR/PLCγ/MEK-ERK signaling blockade by specific inhibitors or siRNAs was applied to determine the regulation mechanism. Results: FGFR inhibition decreased the in vitro accumulation of 18F-FDG only in four FGFRi-sensitive cell lines, but in neither of FGFRi-resistant ones. We then demonstrated that FGFRi-induced transcriptional downregulation of hexokinase 2 (HK2), a key factor of glucose metabolism and FDG trapping, via mTOR pathway leading to this decrease. Moreover, 18F-FDG PET imaging successfully differentiated the FGFRi-sensitive tumor xenografts from primary or acquired resistant ones by the tumor 18F-FDG accumulation change upon FGFRi treatment. Of note, both 18F-FDG tumor accumulation and HK2 expression could respond the administration/withdrawal of FGFRi in NCI-H1581 xenografts correspondingly. Conclusion: The novel association between the molecular mechanism (FGFR/mTOR/HK2 axis) and radiological phenotype (18F-FDG PET uptake) of FGFR-targeted therapy was demonstrated in multiple preclinical models. The adoption of 18F-FDG PET biomarker-based imaging strategy to assess response/resistance to FGFR inhibition may benefit treatment selection for cancer patients.

Diagnostic Value of the Blood Neutrophil-to-Lymphocyte Ratio and Monocyte-to-Lymphocyte Ratio in Tibia Fracture-Related Infection.

Objective: The diagnostic value of neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) in predicting fracture-related infection (FRI) in tibia fracture patients remains to be explored. Methods: A retrospective controlled study was carried out with 170 tibia FRI patients and 162 control subjects. The following information was evaluated at admission: age, gender, clinical features, number of white blood cells (WBCs), neutrophils, lymphocytes, monocytes, red blood cells (RBCs), platelets, level of hemoglobin, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR), as well as NLR, MLR, and PLR. Results: The number of lymphocytes, RBCs, and platelets in the FRI group was higher than those in the control group, while the number of neutrophils and ESR level was lower (P < 0.05). The level of NLR and MLR was significantly lower in patients with tibia FRI than in control subjects (P < 0.05). Both indicators were positively correlated with WBCs, CRP level, and ESR level (P < 0.001). The results of logistic regression analysis showed that five variables including NLR, MLR, platelets, fracture pattern (closed or open fracture), and site pattern (single or multiple site) were used to construct the FRI risk predictor. The ROC curve analysis result showed that FRI risk predictor yielded the highest AUC, with a sensitivity of 91.2% and a specificity of 90.1%, and made the distinction efficiently between tibia FRI patients and non-FRI patients. Conclusion: NLR and MLR were decreased in tibia FRI patients compared to non-FRI patients. Both indicators had a positive correlation with WBCs, CRP level, and ESR level. FRI risk predictor constructed based on five variables including NLR and MLR had a high diagnostic value for tibia FRI.

SAF-248, a novel PI3Kδ-selective inhibitor, potently suppresses the growth of diffuse large B-cell lymphoma.

PI3Kδ is expressed predominately in leukocytes and overexpressed in B-cell-related malignances. PI3Kδ has been validated as a promising target for cancer therapy, and specific PI3Kδ inhibitors were approved for clinical practice. However, the substantial toxicity and relatively low efficacy as a monotherapy in diffuse large B-cell lymphoma (DLBCL) limit their clinical use. In this study, we described a novel PI3Kδ inhibitor SAF-248, which exhibited high selectivity for PI3Kδ (IC50 = 30.6 nM) over other PI3K isoforms at both molecular and cellular levels, while sparing most of the other human protein kinases in the kinome profiling. SAF-248 exhibited superior antiproliferative activity against 27 human lymphoma and leukemia cell lines compared with the approved PI3Kδ inhibitor idelalisib. In particular, SAF-248 potently inhibited the proliferation of a panel of seven DLBCL cell lines (with GI50 values < 1 µM in 5 DLBCL cell lines). We demonstrated that SAF-248 concentration-dependently blocked PI3K signaling followed by inducing G1 phase arrest and apoptosis in DLBCL KARPAS-422, Pfeiffer and TMD8 cells. Its activity against the DLBCL cells was negatively correlated to the protein level of PI3Kα. Oral administration of SAF-248 dose-dependently inhibited the growth of xenografts derived from Pfeiffer and TMD8 cells. Activation of mTORC1, MYC and JAK/STAT signaling was observed upon prolonged treatment and co-targeting these pathways would potentiate the activity of SAF-248. Taken together, SAF-248 is a promising selective PI3Kδ inhibitor for the treatment of DLBCL and rational drug combination would further improve its efficacy.