Are Red Blood Cell Distribution Width and Platelet Count Useful for Diagnosing Periprosthetic Joint Infection in Patients Undergoing Re-Revision Arthroplasty.

OBJECTIVE: Accurate and prompt identification of periprosthetic joint infections (PJIs) is critical prior to re-revision arthroplasty to ensure optimal surgical outcomes. Among routinely measured blood indices, red blood cell distribution width (RDW) and platelet count (PLT) have shown strong correlations with infection presence. This study aimed to assess the utility of RDW and PLT for diagnosing PJI in patients scheduled for re-revision arthroplasty. METHODS: This retrospective research encompassed all patients who underwent re-revision hip or knee arthroplasty at our institution from 2008 to 2022. Participants were categorized into either the PJI (n = 41) or the non-PJI (n = 47) group following the guidelines established in the 2013 International Consensus Meeting on PJI. In this analysis, RDW and PLT counts were evaluated alongside conventional inflammatory markers, including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). The efficacy of these diagnostics was evaluated by the area under the receiver operating characteristic (ROC) curve ([area under the curve AUC]). RESULTS: RDW demonstrated a modest AUC of 0.678 with sensitivity at 61.0% and specificity at 71.7%, using a threshold of 14.5%. PLT was on par with ESR, showing an AUC of 0.773, and both sensitivity and specificity around 73% at a threshold of 201 × 109/L. CRP presented the highest diagnostic accuracy with an AUC of 0.815, achieving a sensitivity of 82.9% and specificity of 73.9% at a 6.9 mg/L threshold, surpassing ESR's AUC of 0.754. None of the biomarkers, individually or combined, outperformed CRP alone (p > 0.05). CONCLUSIONS: In the context of re-revision arthroplasty, RDW and PLT demonstrate limited efficacy as diagnostic biomarkers for PJI. However, CRP retains its reliability as a biomarker when the diagnostic threshold is appropriately recalibrated.

Effects of minimum monitor unit per dynamic control point on intensity-modulated radiotherapy planning for nasopharyngeal carcinoma: A retrospective study.

The present study aimed to improve the dose distribution of radiotherapy planning for nasopharyngeal carcinoma (NPC) by comparing the effects of various minimum monitor units (MUs) per dynamic control point (MMCP) values on the quality and execution efficiency of dynamic intensity-modulated radiotherapy (IMRT) planning. Thirty-four clinically implemented dynamic IMRT plans for patients with NPC were retrospectively selected. In total, 170 plans were obtained by modifying only the MMCP values (set as 1, 3, 5, 7, and 9) in the treatment planning system's (TPS) optimization parameters. These plans were divided into 5 groups. Analyzing the effects of MMCP on the target and organ dose at risk (OAR), also the execution efficiency of the treatment plan in each group and using a quality score system, we conducted an objective quantitative study of the dose distribution and execution efficiency. The target dose evaluation indicators (target coverage (TC), homogeneity index (HI), and conformity index (CI)) of all IMRT plans showed a trend of variation with an increase in MMCP values, and the difference was statistically significant when MMCP values were 5, 7, 9, and 1 (p < 0.05). With an increase in MMCP, the dose to OAR slightly increased, but the difference was not statistically significant (p > 0.05). With an increase in MMCP, the average number of MUs per segment significantly increased (p < 0.01). The groups based on MMCP values of 1, 3, 5, 7, and 9 received quality score system of 1.188, 1.180, 1.171, 0.987, and 1.184, respectively, with the MMCP7 group achieving the lowest score, indicating that this plan had the highest overall quality. The MMCP value for dynamic IMRT planning in the Monaco TPS for patients with NPC should be set to 7 to achieve fewer segments, the best execution efficiency without significantly deteriorating the target and OAR dose.

Ultrasound-Activated Probiotics Vesicles Coating for Titanium Implant Infections Through Bacterial Cuproptosis-Like Death and Immunoregulation.

Implant-associated infections (IAIs) are the main cause of prosthetic implant failure. Bacterial biofilms prevent antibiotic penetration, and the unique metabolic conditions in hypoxic biofilm microenvironment may limit the efficacy of conventional antibiotic treatment. Escaping survival bacteria may not be continually eradicated, resulting in the recurrence of IAIs. Herein, a sonosensitive metal-organic framework of Cu-TCPP (tetrakis(4-carboxyphenyl) porphyrin) nanosheets and tinidazole doped probiotic-derived membrane vesicles (OMVs) with high-penetration sonodynamic therapy (SDT), bacterial metabolic state interference, and bacterial cuproptosis-like death to eradicate IAIs is proposed. The Cu-TCPP can convert O2 to toxic 1O2 through SDT in the normoxic conditions, enhancing the hypoxic microenvironment and activating the antibacterial activity of tinidazole. The released Cu(II) under ultrasound can be converted to Cu(I) by exogenous poly(tannic acid) (pTA) and endogenous glutathione. The disruption of the bacterial membrane by SDT can enhance the Cu(I) transporter activity. Transcriptomics indicate that the SDT-enhanced Cu(I) overload and hypoxia-activated therapy hinder the tricarboxylic acid cycle (TCA), leading to bacterial cuproptosis-like death. Moreover, the OMVs-activated therapy can polarize macrophages to a M2-like phenotype and facilitate bone repair. The sonodynamic biofilm microenvironment modulation strategy, whereby the hypoxia-enhanced microenvironment is potentiated to synergize SDT with OMVs-activated therapy, provides an effective strategy for antibacterial and osteogenesis performance.

Chiral Iridium-Based TLD-1433 Analogues: Exploration of Enantiomer-Dependent Behavior in Photodynamic Cancer Therapy.

Metallodrug-based photodynamic therapy (PDT) agents have demonstrated significant superiority against cancers, while their different chirality-induced biological activities remain largely unexplored. In this work, we successfully developed a pair of enantiopure mononuclear Ir(III)-based TLD-1433 analogues, Δ-Ir-3T and Λ-Ir-3T, and their enantiomer-dependent anticancer behaviors were investigated. Photophysical measurements revealed that they display high photostability and chemical stability, strong absorption at 400 nm with high molar extinction coefficients (ε = 5.03 × 104 M-1 cm-1), and good 1O2 relative quantum yields (ΦΔ ≈ 47%). Δ- and Λ-Ir-3T showed potent efficacy against MCF-7 cancer cells, with a photocytotoxicity index of ≤44 238. This impressive result, to the best of our knowledge, represents the highest value among reported mononuclear Ir(III)-based PDT agents. Remarkably, Λ-Ir-3T tended to be more potent than Δ-Ir-3T when tested against SK-MEL-28, HepG2, and LO2 cells, with consistent results across multiple test repetitions.

Elucidation of genes enhancing natural product biosynthesis through co-evolution analysis.

Streptomyces has the largest repertoire of natural product biosynthetic gene clusters (BGCs), yet developing a universal engineering strategy for each Streptomyces species is challenging. Given that some Streptomyces species have larger BGC repertoires than others, we proposed that a set of genes co-evolved with BGCs to support biosynthetic proficiency must exist in those strains, and that their identification may provide universal strategies to improve the productivity of other strains. We show here that genes co-evolved with natural product BGCs in Streptomyces can be identified by phylogenomics analysis. Among the 597 genes that co-evolved with polyketide BGCs, 11 genes in the 'coenzyme' category have been examined, including a gene cluster encoding for the cofactor pyrroloquinoline quinone. When the pqq gene cluster was engineered into 11 Streptomyces strains, it enhanced production of 16,385 metabolites, including 36 known natural products with up to 40-fold improvement and several activated silent gene clusters. This study provides an innovative engineering strategy for improving polyketide production and finding previously unidentified BGCs.

Clinical Analysis of Microwave Ablation Combined with Decompression and Pedicle Screw Fixation in the Treatment of Spinal Metastases.

OBJECTIVES: There is still controversy over the choice of treatment for end-stage spinal metastases. With the continuous development of microwave technology in spinal tumors, related studies have reported that microwave combined with techniques such as pedicle screw fixation and percutaneous vertebroplasty can achieve the purpose of tumor ablation, relieving spinal cord compression, enhancing spinal stability, effectively relieving pain, and reducing recurrence rates. This study aimed to analyze the effectiveness of microwave ablation combined with decompression and pedicle screw fixation in the palliative management of spinal metastases with pathological fractures. METHODS: This retrospective study enrolled 82 patients with spinal metastases and pathological fractures treated between January 2016 and July 2020, with 44 patients undergoing pedicle screw fixation along with laminectomy (fixation group) and the remaining 38 receiving microwave ablation in addition to the treatment provided to group fixation (MWA group). Before surgery, all patients underwent pain assessment using the visual analogue scale (VAS) and evaluation of spinal cord injury using the Frankel classification. After surgery, the patients' prognoses were assessed using the Tomita score, modified Tokuhashi score system, and progression-free survival. Additionally, we compared operative time and blood loss between the two groups. Survival analysis utilized the Kaplan-Meier method with a log-rank test for group comparisons. Paired t-tests and the Mann-Whitney U test were applied to metric and non-normally distributed data, respectively. Neurological function improvement across groups was evaluated using the χ2 test. RESULTS: All patients were followed up for a median duration of 18 and 20 months in the fixation and MWA groups, respectively, with follow-up periods ranging from 6 to 36 months. Statistically significant reductions in postoperative VAS scores were observed in all patients compared with their preoperative scores. The MWA group exhibited reduced blood loss (t = 2.74, p = 0.01), lower VAS scores at the 1- and 3-month follow-ups (t = 2.34, P = 0.02; t = 2.83, p = 0.006), and longer progression-free survival than the fixation group (p = 0.03). Although the operation times in the MWA group were longer than those in the fixation group, this difference was not statistically significant (t = 6.06, p = 0.12). No statistically significant differences were found regarding improvements in spinal cord function between the two groups (p = 0.77). CONCLUSION: Compared with decompression and pedicle screw fixation for treating spinal metastases with pathological fractures, microwave ablation combined with decompression and pedicle screw fixation showed better outcomes in terms of pain control, longer progression-free survival, and lower blood loss without increasing operative time, which has favorable implications for clinical practice.

Simultaneous determination of BGT-002 and its acyl glucuronide metabolite ZM326E-M2 in human plasma by liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study.

BGT-002, a new type of ATP-citrate lyase inhibitor, is a promising therapeutic for treatment of hypercholesterolemia. After an oral administration of BGT-002 to subjects, it underwent extensive metabolism and an acyl monoglucuronide (ZM326E-M2) on 1- carboxylic acid group was the major circulating metabolite. In this study, an LC-MS/MS method was developed and validated for the simultaneous determination of BGT-002 and ZM326E-M2 in plasma and the evaluation of their pharmacokinetic characteristics in humans. After extraction from the plasma by acetonitrile-induced protein precipitation, the analytes were separated on a Waters ACQUITY UPLC® BEH C18 column using acetonitrile and 2 mM ammonium acetate containing 0.1% formic acid as the mobile phase for gradient elution. Negative electrospray ionization was performed using multiple reaction monitoring (MRM) of m/z 501.3→325.4 for ZM326E-M2 and m/z 507.3→331.2 for D6-ZM326E-M2, and pseudo-MRM of m/z 325.3→325.3 for BGT-002 and m/z 331.3→331.3 for D6-ZM326E, respectively. The method was validated with respect to accuracy, precision, linearity, stability, selectivity, matrix effect, and recovery. The analytical range in human plasma was linear over a concentration range of 0.0500-50.0 µg/mL for BGT-002 and 0.0100-10.0 µg/mL for ZM326E-M2. The pharmacokinetic results showed that after a single oral administration of 100 mg BGT-002, the parent drug was rapidly absorbed with a mean time to peak concentration (tmax) of 1.13 h, compared with BGT-002, the tmax (4.00 h) of ZM326E-M2 was significantly delayed. The peak concentration and plasma exposure of ZM326E-M2 were about 14.1% and 19.5% of the parent drug, suggesting that attention should be paid to the safety and efficacy of ZM326E-M2 in clinical research.

CB1R dysfunction of inhibitory synapses in the ACC drives chronic social isolation stress-induced social impairments in male mice.

Social isolation is a risk factor for multiple mood disorders. Specifically, social isolation can remodel the brain, causing behavioral abnormalities, including sociability impairments. Here, we investigated social behavior impairment in mice following chronic social isolation stress (CSIS) and conducted a screening of susceptible brain regions using functional readouts. CSIS enhanced synaptic inhibition in the anterior cingulate cortex (ACC), particularly at inhibitory synapses of cholecystokinin (CCK)-expressing interneurons. This enhanced synaptic inhibition in the ACC was characterized by CSIS-induced loss of presynaptic cannabinoid type-1 receptors (CB1Rs), resulting in excessive axonal calcium influx. Activation of CCK-expressing interneurons or conditional knockdown of CB1R expression in CCK-expressing interneurons specifically reproduced social impairment. In contrast, optogenetic activation of CB1R or administration of CB1R agonists restored sociability in CSIS mice. These results suggest that the CB1R may be an effective therapeutic target for preventing CSIS-induced social impairments by restoring synaptic inhibition in the ACC.

Targeting Mitochondrial Sirtuins in Age-Related Neurodegenerative Diseases and Fibrosis.

Aging is a natural and complex biological process that is associated with widespread functional declines in numerous physiological processes, terminally affecting multiple organs and tissues. Fibrosis and neurodegenerative diseases (NDs) often occur with aging, imposing large burdens on public health worldwide, and there are currently no effective treatment strategies for these diseases. Mitochondrial sirtuins (SIRT3-5), which are members of the sirtuin family of NAD+-dependent deacylases and ADP-ribosyltransferases, are capable of regulating mitochondrial function by modifying mitochondrial proteins that participate in the regulation of cell survival under various physiological and pathological conditions. A growing body of evidence has revealed that SIRT3-5 exert protective effects against fibrosis in multiple organs and tissues, including the heart, liver, and kidney. SIRT3-5 are also involved in multiple age-related NDs, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. Furthermore, SIRT3-5 have been noted as promising targets for antifibrotic therapies and the treatment of NDs. This review systematically highlights recent advances in knowledge regarding the role of SIRT3-5 in fibrosis and NDs and discusses SIRT3-5 as therapeutic targets for NDs and fibrosis.

GPR84 regulates pulmonary inflammation by modulating neutrophil functions.

Acute lung injury (ALI) is an acute, progressive hypoxic respiratory failure that could develop into acute respiratory distress syndrome (ARDS) with very high mortality rate. ALI is believed to be caused by uncontrolled inflammation, and multiple types of immune cells, especially neutrophils, are critically involved in the development of ALI. The treatment for ALI/ARDS is very limited, a better understanding of the pathogenesis and new therapies are urgently needed. Here we discover that GPR84, a medium chain fatty acid receptor, plays critical roles in ALI development by regulating neutrophil functions. GPR84 is highly upregulated in the cells isolated from the bronchoalveolar lavage fluid of LPS-induced ALI mice. GPR84 deficiency or blockage significantly ameliorated ALI mice lung inflammation by reducing neutrophils infiltration and oxidative stress. Further studies reveal that activation of GPR84 strongly induced reactive oxygen species production from neutrophils by stimulating Lyn, AKT and ERK1/2 activation and the assembly of the NADPH oxidase. These results reveal an important role of GPR84 in neutrophil functions and lung inflammation and strongly suggest that GPR84 is a potential drug target for ALI.

Development of the novel ACLY inhibitor 326E as a promising treatment for hypercholesterolemia.

Hepatic cholesterol accumulation is an important contributor to hypercholesterolemia, which results in atherosclerosis and cardiovascular disease (CVD). ATP-citrate lyase (ACLY) is a key lipogenic enzyme that converts cytosolic citrate derived from tricarboxylic acid cycle (TCA cycle) to acetyl-CoA in the cytoplasm. Therefore, ACLY represents a link between mitochondria oxidative phosphorylation and cytosolic de novo lipogenesis. In this study, we developed the small molecule 326E with an enedioic acid structural moiety as a novel ACLY inhibitor, and its CoA-conjugated form 326E-CoA inhibited ACLY activity with an IC50 = 5.31 ± 1.2 µmol/L in vitro. 326E treatment reduced de novo lipogenesis, and increased cholesterol efflux in vitro and in vivo. 326E was rapidly absorbed after oral administration, exhibited a higher blood exposure than that of the approved ACLY inhibitor bempedoic acid (BA) used for hypercholesterolemia. Chronic 326E treatment in hamsters and rhesus monkeys resulted in remarkable improvement of hyperlipidemia. Once daily oral administration of 326E for 24 weeks prevented the occurrence of atherosclerosis in ApoE-/- mice to a greater extent than that of BA treatment. Taken together, our data suggest that inhibition of ACLY by 326E represents a promising strategy for the treatment of hypercholesterolemia.

The brain structure and function abnormalities of migraineurs: A systematic review and neuroimaging meta-analysis.

Objectives: To quantitatively summarize the specific changes in brain structure and function in migraine patients. Methods: A literature screening of migraine was conducted from inception to Sept 1, 2022, in PubMed, Web of Science, Cochrane Library, and Medline databases using the keyword combination of "migraine and MRI." Activation likelihood estimation (ALE) was performed to assess the differentiation of functional connectivity (FC), regional homogeneity (ReHo), and gray matter volume (GMV) of migraine patients. Results: Eleven voxel-based morphometry (VBM) studies and 25 resting-state fMRI (rs-fMRI) studies (16 FC and 9 ReHo studies) were included in this study. ALE analysis revealed the ReHo increase in the brainstem and left thalamus, with no decreased area. Neither increased nor decreased regions were detected in FC and GMV of migraine patients. Conclusions: The left thalamus and brainstem were the significantly activated regions of migraine. It is a meaningful insights into the pathophysiology of migraine. The consistent alterated brain areas of morphometrical and functional in migraine patients were far from reached based on current studies.

The association between metabolic equivalent and visceral adiposity index among children and adolescents: Ten-cycle cross-sectional study on NHANES (1999-2018).

Metabolic disorder is globally prevalent in children and adolescents, and physical activity may have a protective role against metabolic disorder. However, the association between metabolic equivalent (MET) and visceral adiposity index (VAI) among children and adolescents remains unclear. This study aimed to address this concern. Data were retrieved from the National Health and Nutrition Examination Survey (NHANES), which used the Global Physical Activity Questionnaire to assess the physical activity levels. VAI was calculated according to body mass index (BMI), waist circumference (WC), triglyceride (TG), and high-density lipoprotein (HDL). Linear regression was adopted to assess the association between MET and VAI. Restricted cubic spline regression was used to further explore the nonlinear relationship, Interaction effect analysis was conducted to identify whether the sample characteristic could modify the effect of MET on VAI. After data cleansing, a total of 3402 participants aged <18 years were enrolled. In the fully adjusted linear regression model, the ß for VAI was 0.01 (95% confidence interval [CI]: -0.08, 0.09) for the second tertile and -0.11 (95% CI: -0.20, -0.03) for the third tertile. A linear downward trend was found in the restricted cubic spline regression (overall P < .05). Interaction effect analysis revealed no significant effects of age, gender, race, income poverty ratio, and insurance (all P for interaction >0.05). High physical activity intensity is associated with decreased VAI scores in children and adolescents.

Quercetin ameliorates memory impairment by inhibiting abnormal microglial activation in a mouse model of paradoxical sleep deprivation.

Paradoxical sleep deprivation (PSD) is prevalent in modern society, and impaired memory is one of its serious consequences. The pathogenic mechanism is still unclear, and the therapeutic strategies for PSD are limited. Here, we found that quercetin treatment ameliorated memory impairments caused by PSD in a dose-dependent manner in an animal model. Quercetin could restore the dynamic changes of the gamma band while the animals performed novel object recognition (NOR) tasks as determined by electroencephalogram analysis. Morphological analysis showed that quercetin, by targeting the hippocampal CA1 region, strikingly ameliorated the overactivation of microglia induced by PSD. Mechanistically, quercetin inhibited the toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor kappa-b (NF-κB) cascade, which is critical for abnormal microglial activation following PSD stress. Our results provided experimental evidence for the therapeutic effects of quercetin on PSD-related memory impairments by suppressing TLR4/MyD88/NF-κB signaling that mediated abnormal microglia activation in the hippocampus.

Changes of brain function in patients with type 2 diabetes mellitus measured by different analysis methods: A new coordinate-based meta-analysis of neuroimaging.

Objective: Neuroimaging meta-analysis identified abnormal neural activity alterations in patients with type 2 diabetes mellitus (T2DM), but there was no consistency or heterogeneity analysis between different brain imaging processing strategies. The aim of this meta-analysis was to determine consistent changes of regional brain functions in T2DM via the indicators obtained by using different post-processing methods. Methods: Since the indicators obtained using varied post-processing methods reflect different neurophysiological and pathological characteristics, we further conducted a coordinate-based meta-analysis (CBMA) of the two categories of neuroimaging literature, which were grouped according to similar data processing methods: one group included regional homogeneity (ReHo), independent component analysis (ICA), and degree centrality (DC) studies, while the other group summarized the literature on amplitude of low-frequency fluctuation (ALFF) and cerebral blood flow (CBF). Results: The final meta-analysis included 23 eligible trials with 27 data sets. Compared with the healthy control group, when neuroimaging studies were combined with ReHo, ICA, and DC measurements, the brain activity of the right Rolandic operculum, right supramarginal gyrus, and right superior temporal gyrus in T2DM patients decreased significantly. When neuroimaging studies were combined with ALFF and CBF measurements, there was no clear evidence of differences in the brain function between T2DM and HCs. Conclusion: T2DM patients have a series of spontaneous abnormal brain activities, mainly involving brain regions related to learning, memory, and emotion, which provide early biomarkers for clarifying the mechanism of cognitive impairment and neuropsychiatric disorders in diabetes. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=247071, PROSPERO [CRD42021247071].

Disruption of adipocyte HIF-1α improves atherosclerosis through the inhibition of ceramide generation.

Atherosclerosis is a chronic multifactorial cardiovascular disease. Western diets have been reported to affect atherosclerosis through regulating adipose function. In high cholesterol diet-fed ApoE -/- mice, adipocyte HIF-1α deficiency or direct inhibition of HIF-1α by the selective pharmacological HIF-1α inhibitor PX-478 alleviates high cholesterol diet-induced atherosclerosis by reducing adipose ceramide generation, which lowers cholesterol levels and reduces inflammatory responses, resulting in improved dyslipidemia and atherogenesis. Smpd3, the gene encoding neutral sphingomyelinase, is identified as a new target gene directly regulated by HIF-1α that is involved in ceramide generation. Injection of lentivirus-SMPD3 in epididymal adipose tissue reverses the decrease in ceramides in adipocytes and eliminates the improvements on atherosclerosis in the adipocyte HIF-1α-deficient mice. Therefore, HIF-1α inhibition may constitute a novel approach to slow atherosclerotic progression.

Simple contextual cueing prevents retroactive interference in short-term perceptual training of orientation detection tasks.

Perceptual training of multiple tasks suffers from interference between the trained tasks. Here, we conducted five psychophysical experiments with separate groups of participants to investigate the possibility of preventing the interference in short-term perceptual training. We trained the participants to detect two orientations of Gabor stimuli in two adjacent days at the same retinal location and examined the interference of training effects between the two orientations. The results showed significant retroactive interference from the second orientation to the first orientation (Experiment 1 and Experiment 2). Introducing a 6-h interval between the pre-test and training of the second orientation did not eliminate the interference effect, excluding the interpretation of disrupted reconsolidation as the pre-test of the second orientation may reactivate and destabilize the representation of the first orientation (Experiment 3). Finally, the training of the two orientations was accompanied by fixations in two colors, each serving as a contextual cue for one orientation. The results showed that the retroactive interference was not evident if the participants passively perceived contextual cues during the training and test sessions (Experiment 4). Importantly, this facilitation effect could be observed if the contextual cues appeared only during the training, demonstrating the robustness of the effect (Experiment 5). Our findings suggest that the retroactive interference effect in short-term perceptual training of orientation detection tasks was likely the result of higher-level factors such as shared contextual cues embedded in the tasks. The efficiency of multiple perceptual trainings could be facilitated by associating the trained tasks with different contextual cues.

Clinical Outcome of Free Vascularized Fibula Graft for Nonunion of Garden IV Femoral Neck Fracture of 13 Years Duration: A Case Report.

BACKGROUND: Femoral neck fractures in young patients are mostly caused by high-energy trauma and demonstrate more displacement and vertical fracture surfaces, which increase nonunion and osteonecrosis risks. Free vascularized fibula graft (FVFG) is effective in treating old femoral neck fractures and nonunion; however, available data are limited to patients within 2 years after injury or revision surgery. We present the case of a patient who was diagnosed with femoral neck fracture at the age 9 and treated with FVFG 13 years later. CASE PRESENTATION: A 9-year-old Asian girl who experienced left hip pain after an injury was diagnosed with Garden IV left femoral neck fracture, which was treated through manipulation reduction and fixed with splints. At age 16, the pain worsened after another injury and was considered to be in the physical development stage. She refused surgical treatment; hence, the fracture was fixed externally with splints. At age 22, she was hospitalized owing to a 12-day left hip pain with restricted movement caused by a fall. She was diagnosed with old Garden IV femoral neck fracture nonunion and treated with FVFG. Seven years postoperatively, imaging showed that the left femoral neck was internally fixed, the fracture had healed, and the Harris score was 90 points. The 36-Item Short Form Health Survey responses revealed that the patient's physiological functioning, emotional well-being, energy, and mental health were normal. She achieved satisfactory functional results and resumed her normal daily life. CONCLUSION: FVFG could provide satisfactory outcomes for long-term old femoral neck fractures.

The HDAC inhibitor GCJ-490A suppresses c-Met expression through IKKα and overcomes gefitinib resistance in non-small cell lung cancer.

OBJECTIVE: The novel compound GCJ-490A has been discovered as a pan-histone deacetylase (HDAC) inhibitor that exerts potent inhibitory activity against HDAC1, HDAC3, and HDAC6. Because of the important roles of HDACs in lung cancer development and the high distribution of GCJ-490A in lung tissue, we explored the anti-tumor potency of GCJ-490A against non-small cell lung cancer (NSCLC) in vitro and in vivo in this study. METHODS: The in vitro effects of GCJ-490A alone or combined with the EGFR inhibitor gefitinib against NSCLC were measured with proliferation, apoptosis, and colony formation assays. NSCLC xenograft models were used to investigate the efficacy of GCJ-490A combined with gefitinib for the treatment of NSCLC in vivo. Western blot assays, luciferase reporter assays, chromatin immunoprecipitation assays, quantitative real time-PCR, immunohistochemistry, and transcription factor activity assays were used to elucidate possible mechanisms. RESULTS: GCJ-490A effectively inhibited NSCLC cell proliferation and induced apoptosis in vitro and in vivo. Interestingly, inhibition of HDAC1 and HDAC6 by GCJ-490A increased histone acetylation at the IKKα promoter and enhanced IKKα transcription, thus decreasing c-Met. Moreover, this c-Met downregulation was found to be essential for the synergistic anti-tumor activity of GCJ-490A and gefitinib. CONCLUSIONS: These findings highlight the promising potential of HDAC inhibitors in NSCLC treatment and provide a rational basis for the application of HDAC inhibitors in combination with EGFR inhibitors in clinical trials.