Genome-wide Analysis Identifies Nuclear Factor 1C as a Novel Transcription Factor and Potential Therapeutic Target in Small Cell Lung Cancer.

BACKGROUND: Recent insights regarding mechanisms mediating stemness, heterogeneity, and metastatic potential of lung cancers have yet to be fully translated to effective regimens for the treatment of these malignancies. This study sought to identify novel targets for lung cancer therapy. METHODS: Transcriptomes and DNA methylomes of 14 SCLC and 10 NSCLC lines were compared to normal human small airway epithelial cells (SAEC) and induced pluripotent stem cell (iPSC) clones derived from SAEC. SCLC lines, lung iPSC (Lu-iPSC), and SAEC were further evaluated by DNase I hypersensitivity (DHS-seq). Changes in chromatin accessibility and depths of transcription factor (TF) footprints were quantified using Bivariate analysis of Genomic Footprint. Standard techniques were used to examine growth and tumorigenencity as well as changes in transcriptomes and glucose metabolism of SCLC cells following Nuclear Factor 1C (NFIC) knockdown, and to examine NFIC expression in SCLC cells following exposure to BET inhibitors. RESULTS: Significant commonality of transcriptomes and DNA methylomes was observed between Lu-iPSC and SCLC; however, this analysis was uninformative regarding pathways unique to lung cancer. Linking results of DNase-seq to RNA-seq enabled identification of networks not previously associated with SCLC. When combined with footprint depth, NFIC, a transcription factor not previously associated with SCLC, had the highest score of occupancy at open chromatin sites. Knockdown of NFIC impaired glucose metabolism, decreased stemness, and inhibited growth of SCLC cells in-vitro and in-vivo. ChIP-seq analysis identified numerous sites occupied by Bromodomain-containing protein 4 (BRD4) in the NFIC promoter region. Knock-down of BRD4 or treatment with Bromodomain and extra-terminal domain (BET) inhibitors (BETi) markedly reduced NFIC expression in SCLC cells and SCLC PDX models. Approximately 8% of genes downregulated by BETi treatment were repressed by NFIC knockdown in SCLC, while 34% of genes repressed following NFIC knockdown were also downregulated in SCLC cells following BETi treatment. CONCLUSIONS: NFIC is a key TF and possible mediator of transcriptional regulation by BET family proteins in SCLC. Our findings highlight the potential of genome-wide chromatin accessibility analysis for elucidating mechanisms of pulmonary carcinogenesis and identifying novel targets for lung cancer therapy.

Synthesis and biological evaluation of folic acid-rotenol conjugate as a potent targeted anticancer prodrug.

Rotenone, a plant-based agricultural insecticide, has been shown to have anti-tumor activity through targeting mitochondrial complex I in cancer cells. However, off-target toxic side effect on nervous systems have greatly restricted the application of rotenone as anticancer drugs. Here, a folic acid-rotenol (FA-rotenol) conjugate was prepared by covalent coupling of the tumor-targeting ligand folic acid with rotenone derivative-rotenol to enhance its accumulation at tumor site. FA-rotenol conjugates present high in vitro cytotoxicties against several cell lines by inducing mitochondrial membrane potential depolarization and increasing the level of intracellular reactive oxygen species (ROS) to activate the mitochondrial pathway of apoptosis and enhance the G2/M cell cycle arrest. Because of the high affinity with over-expressed folate receptors, FA-rotenol conjugate demonstrated more effective in vivo therapeutic outcomes in 4T1 tumor-bearing mice than rotenone and rotenol. In addition, FA-rotenol conjugate can markedly inhibit the cell migration and invasion of HepG-2 cells. These studies confirm the feasibility of tumor-targeted ligand conjugated rotenone derivatives for targeted antitumor therapy; likewise, they lay the foundations for the development of other rotenol-conjugates with antitumor potential.

Ratiometric fluorescence sensing NADH using AIE-dots transducers at the point of care.

Reduced nicotinamide adenine dinucleotide (NADH) has a strong impact on physiological metabolism, and its concentration is related to metabolic and neurodegenerative diseases. A more reliable and accurate detection method for NADH quantitation is needed for early disease diagnosis and point-of-care testing. Aggregation-induced emission (AIE) materials are widely used to improve the sensitivity in analytes assays due to their anti-aggregation-caused quenching property. Here we developed TPA-BQD-Py AIE-dots transducers and evaluated its performance in NADH detection. The NADH concentration-dependent ratiometric sensing was based on electron transfer from TPA-BQD-Py AIE-dots to NADH with variable fluorescence intensity at 584 nm and 470 nm, resulting in high sensitivity (limit of detection at 110 nM), photostability, selectivity, and a rapid and reversible response. We further developed the application of TPA-BQD-Py AIE-dots transducers in in vivo NADH imaging using a smartphone and digital camera, respectively, demonstrating the potential for NADH point-of-care testing.

Proteomics: A new dimension to decode small cell lung cancer.

Small cell lung cancer (SCLC) is a recalcitrant malignancy. Conquering it will require deep insight into its biology. In this issue of Cell, Liu and colleagues describe proteomic and phosphoproteomic landscapes of resected SCLC tumors and illustrate the potential of this knowledge to identify new SCLC vulnerabilities.

Determining the association of insurance coverage and survival outcomes in patients with olfactory neuroblastoma utilizing machine learning.

KEY POINTS: We use machine learning to examine health insurance and mortality in olfactory neuroblastoma. Private insurance significantly improved survival even after adjusting for confounders. The regression model also found no statistical difference between Medicare and no insurance.

Health Insurance Coverage and Survival Outcomes among Nasopharyngeal Carcinoma Patients: A SEER Retrospective Analysis.

Objectives Insurance coverage plays a critical role in head and neck cancer care. This retrospective study examines how insurance coverage affects nasopharyngeal carcinoma (NPC) survival in the United States using the Surveillance, Epidemiology, and End Results (SEER) program database. Design, Setting, and Participants A total of 2,278 patients aged 20 to 64 years according to the International Classification of Diseases for Oncology (ICD-O) codes C11.0-C11.9 and ICD-O histology codes 8070-8078 and 8080-8083 between 2007 and 2016 were included and grouped into privately insured, Medicaid, and uninsured groups. Log-rank test and multivariable Cox's proportional hazard model were performed. Main Outcome Measures Tumor stage, age, sex, race, marital status, disease stage, year of diagnosis, median household county income, and disease-specific survival outcomes including cause of death were analyzed. Results Across all tumor stages, privately insured patients had a 59.0% lower mortality risk than uninsured patients (hazard ratio [HR]: 0.410, 95% confidence interval [CI]: [0.320, 0.526], p < 0.01). Medicaid patients were also estimated to have 19.0% lower mortality than uninsured patients (HR: 0.810, 95% CI: [0.626, 1.048], p = 0.108). Privately insured patients with regional and distant NPC had significantly better survival outcomes compared with uninsured individuals. Localized tumors did not show any association between survival and type of insurance coverage. Conclusion Privately insured individuals had significantly better survival outcomes than uninsured or Medicaid patients, a trend that was preserved after accounting for tumor grade, demographic and clinicopathologic factors. These results underscore the difference in survival outcomes when comparing privately insured to Medicaid/uninsured populations and warrant further investigation in efforts for health care reform.

In vivo photothermal therapy monitored by multi-position calibrated photoacoustic thermometer.

With the ability of monitoring both temperature and photothermal agents, the photoacoustic (PA) imaging is a promising guiding tool for the photothermal therapy (PTT). The calibration line which depicts the relative variation of PA amplitude with the temperature should be obtained before using PA thermometer. In existing study, a calibration line was generated based on the data from one spatial position, and used in the whole region of interesting (ROI). However, the generalization of this calibration line in ROI was not verified, especially for ROI with heterogeneous tissues. Moreover, the relationship between the distributions of photothermal agents and effective treatment area is not clear, hindering using photothermal agents' distribution to optimize the administration-therapy interval. In this study, the distribution of effective photothermal agents and temperature in subcutaneously transplanted tumor mouse models were continuously monitored by 3D photoacoustic/ ultrasonic dual-modality imaging in 8 h after administration. With multiple micro-temperature probes in tumor and surrounding normal tissue, the PA thermometer was calibrated and evaluated at multiple spatial positions for the first time. The generalization in homologous tissue and tissue specificity in heterogeneous tissues of the PA thermometer calibration line were verified. Our study not only validated the effectivity of PA thermometer by proving the generalization of calibration line, but also removes a major obstacle that prevents applying the PA thermometer to a heterogeneous tissues ROI. The positive correlation between the proportion of effective treatment area and the proportion of effective photothermal agent area in the tumor was observed. Since the latter can be monitored with fast PA imaging, PA imaging can be employed as a convenient tool for seeking optimal administration-treatment interval.

Comparison of Effectiveness and Safety in Treating Acute Acromioclavicular Joint Dislocation with Five Different Surgical Procedures: A Systematic Review and Network Meta-Analysis.

This network meta-analysis aims to evaluate the comparative effectiveness and safety of suture anchors (SA), tendon grafts (TG), hook plates (HP), Tight-Rope (TR), and EndoButton (EB) in the treatment of acute acromioclavicular joint (ACJ) dislocation. The Embase, PubMed, and Web of Science databases were searched from their inception date to June 3, 2022. Studies included all eligible randomized controlled trials (RCTs) and cohort studies with the comparison of five different fixation systems among SA, TG, HP, TR, and EB were identified. All studies were reviewed, performed data extraction, and assessed the risk of bias independently by two reviewers. The primary outcomes are Constant-Murley score (CMS) improvement for assessing clinical efficacy, and complications. The second outcomes are visual analog scale (VAS) for assessing pain relief and the coracoclavicular distance (CCD) for assessing postoperative joint reduction. Version 2 of the revised Cochrane risk of bias tool for randomized trials (RoB 2) and the risk of bias in nonrandomized studies of interventions (ROBINS-I) were used to assess the RCTs and non-randomized trials, respectively. The continuous outcomes were presented as mean differences (MD), and risk ratios (OR) were used for dichotomous outcomes, both with 95% confidence intervals (CI). Surface under the cumulative ranking curves (SUCRA) results were calculated to offer a ranking of each intervention. We identified 31 eligible trials, including 1687 patients in total. HP showed less CMS improvement than TR and EB in both the Network Meta-analysis (NMA) and pairwise meta-analysis. HP also showed less CMS improvement than SA in NMA. For pain relief, HP performed worse than TR both in pairwise meta-analysis and NMA. No significant differences were found for the measured value of CCD. Both TR and EB showed a lower incidence of complications than HP in pairwise meta-analysis. The rank of SUCRA for CMS improvement was as follows: SA, TR, EB, TG, and HP; for pain relief: TR, EB, TG, SA, and HP; for CCD: HP, TR, SA, EB, and TG. For complications, HP showed the highest rank, followed by TG, EB, TR, and SA. SA shows better clinical effectiveness and reliable safety in the treatment of acute ACJ dislocation. Although HP is the most widely used surgical option currently, it should be carefully taken into consideration for its high incidence of complications.

mTOR inhibition overcomes RSK3-mediated resistance to BET inhibitors in small cell lung cancer.

Small cell lung cancer (SCLC) is a recalcitrant malignancy with limited treatment options. Bromodomain and extraterminal domain inhibitors (BETis) have shown promising preclinical activity in SCLC, but the broad sensitivity spectrum limits their clinical prospects. Here, we performed unbiased high-throughput drug combination screens to identify therapeutics that could augment the antitumor activities of BETis in SCLC. We found that multiple drugs targeting the PI-3K-AKT-mTOR pathway synergize with BETis, among which mTOR inhibitors (mTORis) show the highest synergy. Using various molecular subtypes of the xenograft models derived from patients with SCLC, we confirmed that mTOR inhibition potentiates the antitumor activities of BETis in vivo without substantially increasing toxicity. Furthermore, BETis induce apoptosis in both in vitro and in vivo SCLC models, and this antitumor effect is further amplified by combining mTOR inhibition. Mechanistically, BETis induce apoptosis in SCLC by activating the intrinsic apoptotic pathway. However, BET inhibition leads to RSK3 upregulation, which promotes survival by activating the TSC2-mTOR-p70S6K1-BAD cascade. mTORis block this protective signaling and augment the apoptosis induced by BET inhibition. Our findings reveal a critical role of RSK3 induction in tumor survival upon BET inhibition and warrant further evaluation of the combination of mTORis and BETis in patients with SCLC.

Cigarette Smoke Enhances the Malignant Phenotype of Esophageal Adenocarcinoma Cells by Disrupting a Repressive Regulatory Interaction Between miR-145 and LOXL2.

Although linked to esophageal carcinogenesis, the mechanisms by which cigarette smoke mediates initiation and progression of esophageal adenocarcinomas (EAC) have not been fully elucidated. In this study, immortalized esophageal epithelial cells and EAC cells (EACCs) were cultured with or without cigarette smoke condensate (CSC) under relevant exposure conditions. Endogenous levels of microRNA (miR)-145 and lysyl-likeoxidase 2 (LOXL2) were inversely correlated in EAC lines/tumors compared with that in immortalized cells/normal mucosa. The CSC repressed miR-145 and upregulated LOXL2 in immortalized esophageal epithelial cells and EACCs. Knockdown or constitutive overexpression of miR-145 activated or depleted LOXL2, respectively, which enhanced or reduced proliferation, invasion, and tumorigenicity of EACC, respectively. LOXL2 was identified as a novel target of miR-145 as well as a negative regulator of this miR in EAC lines/Barrett's epithelia. Mechanistically, CSC induced recruitment of SP1 to the LOXL2 promoter; LOXL2 upregulation coincided with LOXL2 enrichment and concomitant reduction of H3K4me3 levels within the promoter of miR143HG (host gene for miR-145). Mithramycin downregulated LOXL2 and restored miR-145 expression in EACC and abrogated LOXL2-mediated repression of miR-145 by CSC. These findings implicate cigarette smoke in the pathogenesis of EAC and demonstrate that oncogenic miR-145-LOXL2 axis dysregulation is potentially druggable for the treatment and possible prevention of these malignancies.

Semiconducting Polymer Dots for Point-of-Care Biosensing and In Vivo Bioimaging: A Concise Review.

In recent years, semiconducting polymer dots (Pdots) have attracted much attention due to their excellent photophysical properties and applicability, such as large absorption cross section, high brightness, tunable fluorescence emission, excellent photostability, good biocompatibility, facile modification and regulation. Therefore, Pdots have been widely used in various types of sensing and imaging in biological medicine. More importantly, the recent development of Pdots for point-of-care biosensing and in vivo imaging has emerged as a promising class of optical diagnostic technologies for clinical applications. In this review, we briefly outline strategies for the preparation and modification of Pdots and summarize the recent progress in the development of Pdots-based optical probes for analytical detection and biomedical imaging. Finally, challenges and future developments of Pdots for biomedical applications are given.

BET Inhibitors Target the SCLC-N Subtype of Small-Cell Lung Cancer by Blocking NEUROD1 Transactivation.

Small-cell lung cancer (SCLC) is a recalcitrant malignancy that urgently needs new therapies. Four master transcription factors (ASCL1, NEUROD1, POU2F3, and YAP1) have been identified in SCLC, and each defines the transcriptome landscape of one molecular subtype. However, these master transcription factors have not been found directly druggable. We hypothesized that blocking their transcriptional coactivator(s) could provide an alternative approach to target these master transcription factors. Here, we identify that BET proteins physically interact with NEUROD1 and function as transcriptional coactivators. Using CRISPR knockout and ChIP-seq, we demonstrate that NEUROD1 plays a critical role in defining the landscapes of BET proteins in the SCLC genome. Blocking BET proteins by inhibitors led to broad suppression of the NEUROD1-target genes, especially those associated with superenhancers, resulting in the inhibition of SCLC growth in vitro and in vivo. LSAMP, a membrane protein in the IgLON family, was identified as one of the NEUROD1-target genes mediating BET inhibitor sensitivity in SCLC. Altogether, our study reveals that BET proteins are essential in regulating NEUROD1 transactivation and are promising targets in SCLC-N subtype tumors. IMPLICATIONS: Our findings suggest that targeting transcriptional coactivators could be a novel approach to blocking the master transcription factors in SCLC for therapeutic purposes.

High-Precision Mapping of Membrane Proteins on Synaptic Vesicles using Spectrally Encoded Super-Resolution Imaging.

The spatial resolution of single-molecule localization microscopy is limited by the photon number of a single switching event because of the difficulty of correlating switching events dispersed in time. Here we overcome this limitation by developing a new class of photoswitching semiconducting polymer dots (Pdots) with structured and highly dispersed single-particle spectra. We imaged the Pdots at the first and the second vibronic emission peaks and used the ratio of peak intensities as a spectral coding. By correlating switching events using the spectral coding and performing 4-9 frame binning, we achieved a 2-3 fold experimental resolution improvement versus conventional superresolution imaging. We applied this method to count and map SV2 and proton ATPase proteins on synaptic vesicles (SVs). The results reveal that these proteins are trafficked and organized with high precision, showing unprecedented level of detail about the composition and structure of SVs.

Improved stacking ensemble learning based on feature selection to accurately predict warfarin dose.

Background: With the rapid development of artificial intelligence, prediction of warfarin dose via machine learning has received more and more attention. Since the dose prediction involve both linear and nonlinear problems, traditional machine learning algorithms are ineffective to solve such problems at one time. Objective: Based on the characteristics of clinical data of Chinese warfarin patients, an improved stacking ensemble learning can achieve higher prediction accuracy. Methods: Information of 641 patients from southern China who had reached a steady state on warfarin was collected, including demographic information, medical history, genotype, and co-medication status. The dataset was randomly divided into a training set (90%) and a test set (10%). The predictive capability is evaluated on a new test set generated by stacking ensemble learning. Additional factors associated with warfarin dose were discovered by feature selection methods. Results: A newly proposed heuristic-stacking ensemble learning performs better than traditional-stacking ensemble learning in key metrics such as accuracy of ideal dose (73.44%, 71.88%), mean absolute errors (0.11 mg/day, 0.13 mg/day), root mean square errors (0.18 mg/day, 0.20 mg/day) and R2 (0.87, 0.82). Conclusions: The developed heuristic-stacking ensemble learning can satisfactorily predict warfarin dose with high accuracy. A relationship between hypertension, a history of severe preoperative embolism, and warfarin dose is found, which provides a useful reference for the warfarin dose administration in the future.

A combined anterior cruciate ligament/Meniscal injury alters the patellofemoral joint kinematics of anterior cruciate ligament-deficient knees during a single-leg lunge exercise: A cross-sectional study.

Anterior cruciate ligament deficiency (ACLD) is often accompanied by concomitant meniscal tears. The study aimed to assess the kinematic alterations of patellofemoral joint (PFJ) in anterior cruciate ligament deficiency knees with or without meniscal tears during a single-leg lunge. Sixty unilateral anterior cruciate ligament deficiency patients were recruited for the study, including 15 isolated anterior cruciate ligament deficiency patients (group 1), 15 anterior cruciate ligament deficiency patients with medial meniscal tears (group 2), 15 patients with lateral meniscal tears (group 3) and 15 patients with combined medial/lateral meniscal tears (group 4). The patellofemoral joint kinematics were determined by a single fluoroscopic image system. Patellofemoral joint kinematics of contralateral anterior cruciate ligament-intact (ACLI) and anterior cruciate ligament deficiency knees were compared. With or without meniscal tears, anterior cruciate ligament deficiency knees had significantly smaller patellar flexion than the anterior cruciate ligament-intact knees (∼5°-10°; p < 0.05). anterior cruciate ligament deficiency knees had more patellar lateral tilting by approximately 1°-2° than the anterior cruciate ligament-intact knees (p < 0.05) in groups 2, 3, and 4. anterior cruciate ligament deficiency groups with medial meniscal deficiencies showed consistent increased lateral patellar translations (2-4 mm) compared to the anterior cruciate ligament-intact group during a single-leg lunge. The results indicate that meniscal tears alter anterior cruciate ligament deficiency patients' patellofemoral joint kinematics and the types of the meniscal injuries also affect the patellofemoral joint kinematics. Considering the varying effects of meniscal tears on the patellofemoral joint kinematics, specific treatments for anterior cruciate ligament deficiency patients with meniscal tears should be proposed in some closed kinetic chain (CKC) exercise programs, such as single-leg lunge.

Synthesis and in vitro cytotoxicity study of three di-organotin(IV) Schiff base di-acylhydrazone complexes.

Three di-organotin(IV) complexes have been synthesized by the reaction of Schiff base di-acylhydrazone ligands bis(5-chlorosalicylaldehyde) adipoylhydrazone and R2SnCl2 [R = Me (1), Ph (2), n-Bu (3)]. Structures of all complexes were characterized by 1H, 13C, 119Sn NMR, elemental analysis, IR and mass spectrometry. Experimental results showed that the symmetric diacylhydrazone ligands coordinate the tin atom in a hexadentate form, where the tin atom shows a penta-coordination, in a distorted triangular bipyramid geometry. Using MTT method, in vitro cytotoxicity of three complexes was determined against three cancer cell lines (A549, HeLa, HepG-2). Studies reveal that complex 3 showed the strongest cytotoxic activity among the three complexes, which may be correlated with the generation of intracellular reactive oxygen species. Uptake of complex 3 into cells and promotion of reactive oxygen species were visualized by confocal fluorescence imaging.

Knee Kinematic Patterns and Early Cartilage Lesion Characteristics in Patients with Anterior Cruciate Ligament Reconstruction.

Specific knee kinematic alterations have been theorized to correlate with the progression of cartilage degeneration, and therefore, post-traumatic osteoarthritis in patients with anterior cruciate ligament reconstruction (ACLR). However, how specific knee kinematic alterations contribute to knee joint cartilage degenerations remains to be unclear. To solve this problem, we hypothesized that there are specific cartilage-degenerating kinematic gait patterns that could be supported by the specific areas of cartilage lesions in ACLR knees. Thirty patients with unilateral ACLR knees and 30 healthy controls were recruited for the study. The kinematic differences between the ACLR knees and the healthy control knees during the stance phase were calculated to identify the kinematic patterns. Cartilage lesion distribution characteristics were acquired for patients with ACLR knees to validate the kinematic patterns using magnetic resonance images. Two kinematic patterns were modeled, i.e., sagittal (increased flexion angle and posterior tibial translation) and coronal (increased lateral tibial translation and abduction angle) kinematic patterns. For the sagittal pattern, the cartilage lesion distributions showed that there were more cartilage lesions (CLs) in the superoposterior regions than the posterior regions in the femoral condyles (p = 0.001), and more CLs in the posterior regions than the middle regions in the tibial plateau (p < 0.001). For the coronal pattern, the cartilage lesion distributions showed that there were more CLs in the lateral compartments near the tibial spine than the medial compartments near the tibial spine (tibial sides, p = 0.005 and femoral sides, p = 0.290). To conclude, the cartilage degeneration distribution evidence largely supports that the two kinematic patterns may contribute to cartilage degeneration in ACLR knees. These findings may provide a potential strategy of delaying early cartilage degeneration in ACLR knees by using motion (kinematic) pattern modification or training. However, investigations should be conducted on the actual effects of this potential strategy.

Kinematic alterations of the ankle in subjects with generalized joint hypermobility compared with the controls: A cross-sectional study.

INTRODUCTION: Generalized joint hypermobility (GJH) is a hereditary connective tissue disease in which the range of motion (ROM) of multiple joints exceeds the normal range, and the ROM varies with age, gender, and ethnicity. At present, the six-degree-of-freedom (6-DOF) of ankle kinematics among people with GJH have not been studied. To investigate the kinematic characteristics in the ankle during treadmill gait of university students with generalized joint hypermobility compared to normal participants. We hypothesized that compared to the participants in the control group, those with GJH would exhibit kinematic characteristics of poorer active motion stability in the ankle during treadmill gait. METHODS: Healthy university student volunteers aged 18-24 (excluding those with a history of ankle trauma, etc.) were recruited and divided into a control group (50 volunteers) and a GJH group (Beighton score ≥4, 50 volunteers). Data of the 6-DOF kinematics of ankle was collected using a 3D gait analysis system. Variables were evaluated using independent t-tests and Wilcoxon signed-rank tests. RESULTS: In the proximal/distal parameter, proximal displacement was significantly increased in the GJH group compared with the control group during 4-9% and 96-97% of the gait phase (loading response and terminal swing phase), with an increase of (0.1-0.2 cm, p < .05). Regarding the proximal/distal, internal/external, plantarflexion/dorsiflexion, and anterior/posterior parameters, the participants with GJH exhibited greater ROM than those in the control group throughout the gait cycle (0.24 ± 0.22 cm vs. 0.19 ± 0.15 cm, p = 0.047, 5.56 ± 2.90° vs. 4.48 ± 3.30°, p = .020, 23.05 ± 5.75° vs. 20.36 ± 4.91°, p < .001, 0.65 ± 0.30 cm vs. 0.55 ± 0.27 cm, p = .018). However, ROM of inversion/eversion translation was found to be decreased in the GJH group compared to the control group (8.92 ± 1.59° vs. 9.47 ± 1.37°, p = .009). In addition, there was no statistical difference between the GJH group and the control group in ROM of medial/lateral translation (0.05 ± 0.06 cm vs. 0.04 ± 0.05 cm, p = .131). CONCLUSION: Our results confirm that our hypothesis is not valid. Although there were a few differences in each gait parameter of the ankle between the GJH group and the control group, the difference was not significant. These results indicate that the presence of GJH has less effect on ankle kinematics and enhance our knowledge of the relationship between GJH and 6-DOF of ankle kinematics.

Biomimetic semiconducting polymer dots for highly specific NIR-II fluorescence imaging of glioma.

Glioma with very short medium survival time consists of 80% of primary malignant types of brain tumors. The unique microenvironment such as the existence of the blood-brain barrier (BBB) makes the glioma theranostics exhibit low sensitivity in diagnosis, a poor prognosis and low treatment efficacy. Therefore, the development of multifunctional nanoplatform that can cross BBB and target the glioma is essential for the high-sensitivity detection and ablation of cancer cells. In this study, C6 cell membrane-coated conjugated polymer dots (Pdots-C6) were constructed for targeted glioma tumor detection. As a new kind of biomimetic and biocompatible nanoprobes, Pdots-C6 preserve the complex biological functions of natural cell membranes while possessing physicochemical properties for NIR-II fluorescence imaging of glioma. After encapsulating C6 cell membrane on the surface of conjugated Pdots, Pdots-C6 exhibited the most favorable specific targeting capabilities in vitro and in vivo. In particular, this pilot study demonstrates that biomimetic nanoparticles offer a potential tool to enhance specific targeting to the brain, hence improving glioma tumor detection accuracy.

The effect of insulin and kruppel like factor 10 on osteoblasts in the dental implant osseointegration in diabetes mellitus patients.

Diabetes mellitus, metabolic disease, is characterized by chronic hyperglycemia. Patients with diabetes mellitus are susceptible to infection and therefore have a higher prevalence and progression rate of periodontal disease. We aimed to study the effect of insulin and kruppel like factor 10 (KLF10) on osteoblasts proliferation and differentiation, and expression of bone metabolism-related molecules and related signaling pathway molecules of AKT serine/threonine kinase 1 (AKT) and nuclear factor kappa B subunit 1 (NF-κB) through in vitro experiments, which can provide theoretical basis for the dental implant osseointegration in diabetic patients. The osteoblasts (hFOB 1.19 cells) were subdivided into KLF10 gene over expression group, KLF10 gene knockdown group, and KLF10 gene knockdown + insulin treatment group. CCK-8 and ELISA were, respectively, used for analysis of cell proliferation and differentiation. In vitro experiments were applied to detect the mRNA and protein expression of bone metabolism-related molecules, respectively. GSE178351 dataset and GSE156993 dataset were utilized to explore the expression of KLF10 in periodontitis. In osteoblasts, insulin treatment increased the expression of KLF10. Insulin and KLF10 could reduce the proliferation and differentiation of osteoblasts. Knockdown of KLF10 could increase the expression of bone metabolism-related molecules and activate AKT and NF-κB pathways, whereas insulin reversed this effect. KLF10 was up-regulated in both patients with periodontitis and type 2 diabetes mellitus with periodontitis. It is assumed that knockdown of KLF10 in insulin resistance may promote osteoblasts differentiation and dental implant osseointegration in diabetic patients.