Preclinical proof of principle for orally delivered Th17 antagonist miniproteins.

Interleukin (IL)-23 and IL-17 are well-validated therapeutic targets in autoinflammatory diseases. Antibodies targeting IL-23 and IL-17 have shown clinical efficacy but are limited by high costs, safety risks, lack of sustained efficacy, and poor patient convenience as they require parenteral administration. Here, we present designed miniproteins inhibiting IL-23R and IL-17 with antibody-like, low picomolar affinities at a fraction of the molecular size. The minibinders potently block cell signaling in vitro and are extremely stable, enabling oral administration and low-cost manufacturing. The orally administered IL-23R minibinder shows efficacy better than a clinical anti-IL-23 antibody in mouse colitis and has a favorable pharmacokinetics (PK) and biodistribution profile in rats. This work demonstrates that orally administered de novo-designed minibinders can reach a therapeutic target past the gut epithelial barrier. With high potency, gut stability, and straightforward manufacturability, de novo-designed minibinders are a promising modality for oral biologics.

Mechanistic computational modeling of monospecific and bispecific antibodies targeting interleukin-6/8 receptors.

The spread of cancer from organ to organ (metastasis) is responsible for the vast majority of cancer deaths; however, most current anti-cancer drugs are designed to arrest or reverse tumor growth without directly addressing disease spread. It was recently discovered that tumor cell-secreted interleukin-6 (IL-6) and interleukin-8 (IL-8) synergize to enhance cancer metastasis in a cell-density dependent manner, and blockade of the IL-6 and IL-8 receptors (IL-6R and IL-8R) with a novel bispecific antibody, BS1, significantly reduced metastatic burden in multiple preclinical mouse models of cancer. Bispecific antibodies (BsAbs), which combine two different antigen-binding sites into one molecule, are a promising modality for drug development due to their enhanced avidity and dual targeting effects. However, while BsAbs have tremendous therapeutic potential, elucidating the mechanisms underlying their binding and inhibition will be critical for maximizing the efficacy of new BsAb treatments. Here, we describe a quantitative, computational model of the BS1 BsAb, exhibiting how modeling multivalent binding provides key insights into antibody affinity and avidity effects and can guide therapeutic design. We present detailed simulations of the monovalent and bivalent binding interactions between different antibody constructs and the IL-6 and IL-8 receptors to establish how antibody properties and system conditions impact the formation of binary (antibody-receptor) and ternary (receptor-antibody-receptor) complexes. Model results demonstrate how the balance of these complex types drives receptor inhibition, providing important and generalizable predictions for effective therapeutic design.

Pan-histone deacetylase inhibitor vorinostat suppresses osteoclastic bone resorption through modulation of RANKL-evoked signaling and ameliorates ovariectomy-induced bone loss.

BACKGROUND: Estrogen deficiency-mediated hyperactive osteoclast represents the leading role during the onset of postmenopausal osteoporosis. The activation of a series of signaling cascades triggered by RANKL-RANK interaction is crucial mechanism underlying osteoclastogenesis. Vorinostat (SAHA) is a broad-spectrum pan-histone deacetylase inhibitor (HDACi) and its effect on osteoporosis remains elusive. METHODS: The effects of SAHA on osteoclast maturation and bone resorptive activity were evaluated using in vitro osteoclastogenesis assay. To investigate the effect of SAHA on the osteoclast gene networks during osteoclast differentiation, we performed high-throughput transcriptome sequencing. Molecular docking and the assessment of RANKL-induced signaling cascades were conducted to confirm the underlying regulatory mechanism of SAHA on the action of RANKL-activated osteoclasts. Finally, we took advantage of a mouse model of estrogen-deficient osteoporosis to explore the clinical potential of SAHA. RESULTS: We showed here that SAHA suppressed RANKL-induced osteoclast differentiation concentration-dependently and disrupted osteoclastic bone resorption in vitro. Mechanistically, SAHA specifically bound to the predicted binding site of RANKL and blunt the interaction between RANKL and RANK. Then, by interfering with downstream NF-κB and MAPK signaling pathway activation, SAHA negatively regulated the activity of NFATc1, thus resulting in a significant reduction of osteoclast-specific gene transcripts and functional osteoclast-related protein expression. Moreover, we found a significant anti-osteoporotic role of SAHA in ovariectomized mice, which was probably realized through the inhibition of osteoclast formation and hyperactivation. CONCLUSION: These data reveal a high affinity between SAHA and RANKL, which results in blockade of RANKL-RANK interaction and thereby interferes with RANKL-induced signaling cascades and osteoclastic bone resorption, supporting a novel strategy for SAHA application as a promising therapeutic agent for osteoporosis.

Heat stress-induced NO enhanced perylenequinone biosynthesis of Shiraia sp. via calcium signaling pathway.

Perylenequinones (PQs) are natural photosensitizing compounds used as photodynamic therapy, and heat stress (HS) is the main limiting factor of mycelial growth and secondary metabolism of fungi. This study aimed to unravel the impact of HS-induced Ca2+ and the calcium signaling pathway on PQ biosynthesis of Shiraia sp. Slf14(w). Meanwhile, the intricate interplay between HS-induced NO and Ca2+ and the calcium signaling pathway was investigated. The outcomes disclosed that Ca2+ and the calcium signaling pathway activated by HS could effectively enhance the production of PQs in Shiraia sp. Slf14(w). Further investigations elucidated the specific mechanism through which NO signaling molecules induced by HS act upon the Ca2+/CaM (calmodulin) signaling pathway, thus propelling PQ biosynthesis in Shiraia sp. Slf14(w). This was substantiated by decoding the downstream positioning of the CaM/CaN (calcineurin) pathway in relation to NO through comprehensive analyses encompassing transcript levels, enzyme assays, and the introduction of chemical agents. Concurrently, the engagement of Ca2+ and the calcium signaling pathway in heat shock signaling was also evidenced. The implications of our study underscore the pivotal role of HS-induced Ca2+ and the calcium signaling pathway, which not only participate in heat shock signal transduction but also play an instrumental role in promoting PQ biosynthesis. Consequently, our study not only enriches our comprehension of the mechanisms driving HS signaling transduction in fungi but also offers novel insights into the PQ synthesis paradigm within Shiraia sp. Slf14(w). KEY POINTS: • The calcium signaling pathway was proposed to participate in PQ biosynthesis under HS. • HS-induced NO was revealed to act upon the calcium signaling pathway for the first time.

Identification and Validation of Prognostic Markers for Endometriosis-Associated Ovarian Cancer.

Background: Growing evidence suggests that endometriosis (EMs) is a risk factor for endometriosis-associated ovarian cancer (EAOC). The aim was to identify and validate gene signatures associated with EMs that may serve as potential biomarkers for evaluating the prognosis of patients with EAOC. Methods: The data of EMs and control samples was obtained from GEO database. The weighted gene co-expression network analysis (WGCNA) identified modular genes significantly associated with EMs. The KEGG pathway and GO functional enrichment analyses were also performed. Univariate Cox regression analysis was conducted to screen marker genes associated with the prognosis of EAOC patients. Finally, RT-qPCR and immunohistochemical verified the expression of ADAMTS19 and TUBB in normal ovarian and EAOC tissues, and the biological functions of ADAMTS19 and TUBB were preliminarily explored by CCK8 and Transwell assays. Results: The WGCNA identified 2 co-expression modules, which in total included 615 genes, and 7642 differentially expressed genes (DEGs) were detected thorough analysis of the EAOC dataset. After taking the intersection of 615 modular genes and 7642 DEGs, 214 shared genes were obtained, and univariate COX regression analysis pointed 10 genes associated with the prognosis of EAOC. Moreover, it was demonstrated by RT-qPCR and immunohistochemical staining experiments that ADAMTS19 expression was elevated, while TUBB expression was reduced in EAOC compared with normal ovarian cells and tissues. Finally, cell experiments revealed that ADAMTS19 promoted the proliferation and invasion in EAOC cells, while overexpression of TUBB inhibited these processes. Conclusions: The present study identified and validated new EMs-associated gene markers, which could serve as potential biomarkers for assessing the prognostic risk of EAOC patients. In addition, some of these genes may have significance as novel therapeutic targets and could be used to guide clinical applications.

Lumbar lordosis and sacral slope do not differ in two types of postoperative lumbar disc re-herniation: a cross-sectional observational study.

BACKGROUND: To identify the differences of lumbar lordosis (LL) and sacral slope (SS) angles between two types of postoperative lumbar disc re-herniation, including the recurrence of same level and adjacent segment herniation (ASH). METHODS: We searched the medical records of lumbar disc herniation (LDH) patients with re-herniation with complete imaging data (n = 58) from January 1, 2013 to December 30, 2020 in our hospital. After matching for age and sex, 58 patients with LDH without re-herniation from the same period operated by the same treatment group in our hospital were served as a control group. Re-herniation patients were divided into two groups, same-level recurrent lumbar disc herniation group (rLDHG) and adjacent segment herniation group with or without recurrence (ASHG). The preoperative, postoperative and one month after operation LL and SS were measured on standing radiographs and compared with the control group by using t-test, ANOVA, and rank-sum test. Next, we calculated the odds ratios (ORs) by unconditional logistic regression, progressively adjusted for other confounding factors. RESULTS: Compared with the control group, the postoperative LL and SS were significantly lower in LDH patients with re-herniation. However, there were no differences in LL and SS between ASHG and rLDHG at any stage. After progressive adjustment for confounding factors, no matter what stage is, LL and SS remained unassociated with the two types of re-herniation. CONCLUSIONS: Low postoperative LL and SS angles are associated with degeneration of the remaining disc. Low LL and SS may be independent risk factors for re-herniation but cannot determine type of recurrence (same or adjacent disc level).

PI3K/AKT/mTORC1 signalling pathway regulates MMP9 gene activation via transcription factor NF-κB in mammary epithelial cells of dairy cows.

Matrix metalloproteinase 9 (MMP9) plays a pivotal role in mammary ductal morphogenesis, angiogenesis and glandular tissue architecture remodeling. However, the molecular mechanism of MMP9 expression in mammary epithelial cells of dairy cows remains unclear. This study aimed to explore the underlying mechanism of MMP9 expression. In this study, to determine whether the PI3K/AKT/mTORC1/NF-κB signalling pathway participates in the regulation of MMP9 expression, we treated mammary epithelial cells with specific pharmacological inhibitors of PI3K (LY294002), mTORC1 (Rapamycin) or NF-κB (Celastrol), respectively. Western blotting results indicated that LY294002, Rapamycin and Celastrol markedly decreased MMP9 expression and P65 nuclear translocation. Furthermore, we found that NF-κB (P65) overexpression resulted in elevated expression of MMP9 protein and activation of MMP9 promoter. In addition, we observed that Celastrol markedly decreases P65-overexpression-induced MMP9 promoter activity. Moreover, the results of the promoter assay indicated that the core regulation sequence for MMP9 promoter activation may be located at -420 ∼ -80 bp downstream from the transcription start site. These observations indicated that the PI3K/AKT/mTORC1 signalling pathway is involved in MMP9 expression by regulating MMP9 promoter activity via NF-κB in the mammary epithelial cells of dairy cows.

Bioactive prenylated c6-c3 derivatives from the roots of Illicium brevistylum.

Three new prenylated C6-C3 compounds (1-3), together with two known prenylated C6-C3 compounds (4-5) and one known C6-C3 derivative (6), were isolated from the roots of Illicium brevistylum A. C. Smith. The structures of 1-3 were elucidated by spectroscopic methods including 1D and 2D NMR, HRESIMS, CD experiments and ECD calculations. The structure of illibrefunone A (1) was confirmed by single-crystal X-ray diffraction analysis. All compounds were evaluated in terms of their anti-inflammatory potential on nitric oxide (NO) generation in lipopolysaccharide-stimulated murine RAW264.7 macrophages and murine BV2 microglial cells, antiviral activity against Coxsackievirus B3 (CVB3) and influenza virus A/Hanfang/359/95 (H3N2). Compounds 3 and 4 exhibited potent inhibitory effects on the production of NO in RAW 264.7 cells with IC50 values of 20.57 and 12.87 µM respectively, which were greater than those of dexamethasone (positive control). Compounds 1 and 4-6 exhibited weak activity against Coxsackievirus B3, with IC50 values ranging from 25.87 to 33.33 µM.

The complete chloroplast genome of Gardenia stenophylla Merr (Rubiaceae) and its phylogenetic analysis.

Gardenia stenophylla Merr, a member of the genus Gardenia in the family Rubiaceae, possesses significant medicinal and ornamental value and is widely distributed in China. This study reports the newly sequenced chloroplast genome of Gardenia stenophylla Merr. The complete chloroplast genome of Gardenia stenophylla Merr (155,109 bp, GC content of 37.5%) was shown to have a typical quadripartite structure, containing a pair of inverted repeat regions (IRs) of 28,802 bp separated by a large single-copy (LSC) region of 85,396 bp and a small single-copy (SSC) region of 18,109 bp. The chloroplast genome contained 151 genes encoding 106 proteins, 37 tRNAs, and eight rRNAs. The Gardenia stenophylla Merr chloroplast genome displayed the closest phylogenetic relationship to Gardenia jasminoides and Gardenia jasminoides var. grandiflora. These data will assist in future molecular phylogenetics of the Rubiaceae.

Percutaneous kyphoplasty with or without posterior pedicle screw fixation for the management of severe osteoporotic vertebral compression fractures with nonunion.

OBJECTIVE: To assess the radiographic outcomes, clinical outcomes and complications of percutaneous kyphoplasty (PKP) with and without posterior pedicle screw fixation (PPSF) in the treatment of severe osteoporotic vertebral compression fractures (sOVCF) with nonunion. METHODS: This study involved 51 patients with sOVCF with nonunion who underwent PKP or PPSF + KP. The operation time, intraoperative blood loss, volume of injected bone cement, operation costs and hospital stays were all recorded. In addition, the Visual Analogue Scale (VAS) and the Oswestry Disability Index (ODI) were assessed separately for each patient before and after surgery. RESULTS: Compared with the PPSF + KP group, the PKP group had shorter operation time, less intraoperative blood loss, shorter hospital stays and fewer operation costs. However, cobb's angle improvement (13.4 ± 4.3° vs. 21.4 ± 5.3°), VWR improvement ratio (30.4 ± 11.5% vs. 52.8 ± 12.7%), HA (34.9 ± 9.0% vs. 63.7 ± 7.6%) and HM (28.4 ± 11.2% vs. 49.6 ± 7.7%) improvement ratio were all higher in PPSF + KP group than that in PKP group. In addition, the ODI index and VAS score in both groups were significantly decreased at the postoperative and final follow-up. PKP group's postoperative VAS score was significantly lower than that in PPSF + KP group, but there was no statistically significant difference in VAS score at the last follow-up. CONCLUSION: PKP and PPSF + KP can both effectively relieve the pain associated with sOVCF with nonunion. PPSF + KP can achieve more satisfactory vertebral reduction effects compared to PKP. However, PKP was less invasive and it has more advantages in shortening operation time and hospital stay, as well as decreasing intraoperative blood loss and operation costs.

Sequential treatment of concomitant odontoid fracture and lower cervical fracture-dislocation: A case report.

INTRODUCTION AND IMPORTANCE: To report the sequential treatment of a Type II odontoid fracture combined with a severe lower cervical (C6-7) fracture-dislocation featuring bilateral facet joint interlocking. CASE PRESENTATION: A 58-year-old male who had suffered an injury in a car accident, He presented neck pain and extremity paralysis. His neurological function was classified as per the American Spinal Injury Association (ASIA) impairment scale as Grade A, indicating complete deficits below the C6 spinal cord level. A cervical CT scan and magnetic resonance image showed a type II odontoid fracture, C6 slipped anteriorly, C6-7 bilateral facet joint fracture and interlocking, slightly compression change of C7 upper endplate. CLINICAL DISCUSSION: Emergency closed reduction using cranial tong traction was success 6 h after the injury. A subsequent CT scan proved the successful reduction of bilateral facet joint dislocations and the odontoid fracture. After careful overall assessment, anterior cervical decompression and fusion (ACDF) was performed at C5-6 and C6-7 segments three days later，while odontoid fracture was treated conservatively. At the 4 months follow-up, a CT scan demonstrated solid bone fusion at C5-6, C6-7 segments, along with successful healing at the odontoid fracture site. However, spinal cord was necrosis at C5-7 segments, and the patient's neurological function had no improvement. CONCLUSION: The initial closed reduction could restore the alignment and preliminary stability of cervical spine at sub-axial cervical fracture-dislocation segment as well as displaced odontoid fracture. This timely and effective closed reduction significantly diminished sequential surgical trauma and mitigated associated risks.

Reactive Oxygen Species Induced Upregulation of TRPV1 in Dorsal Root Ganglia Results in Low Back Pain in Rats.

Background: Dorsal root ganglia (DRGs) contain sensory neurons that innervate intervertebral discs (IVDs) and may play a critical role in mediating low-back pain (LBP), but the potential pathophysiological mechanism needs to be clarified. Methods: A discogenic LBP model in rats was established by penetration of a lumbar IVD. The severity of LBP was evaluated through behavioral analysis, and the gene and protein expression levels of pro-algesic peptide substance P (SP) and calcitonin gene-related peptide (CGRP) in DRGs were quantified. The level of reactive oxygen species (ROS) in bilateral lumbar DRGs was also quantified using dihydroethidium staining. Subsequently, hydrogen peroxide solution or N-acetyl-L-cysteine was injected into DRGs to evaluate the change in LBP, and gene and protein expression levels of transient receptor potential vanilloid-1 (TRPV1) in DRGs were analyzed. Finally, an inhibitor or activator of TRPV1 was injected into DRGs to observe the change in LBP. Results: The rats had remarkable LBP after disc puncture, manifesting as mechanical and cold allodynia and increased expression of the pro-algesic peptides SP and CGRP in DRGs. Furthermore, there was significant overexpression of ROS in bilateral lumbar DRGs, while manipulation of the level of ROS in DRGs attenuated or aggravated LBP in rats. In addition, excessive ROS in DRGs stimulated upregulation of TRPV1 in DRGs. Finally, activation or inhibition of TRPV1 in DRGs resulted in a significant increase or decrease of discogenic LBP, respectively, suggesting that ROS-induced TRPV1 has a strong correlation with discogenic LBP. Conclusion: Increased ROS in DRGs play a primary pathological role in puncture-induced discogenic LBP, and excessive ROS-induced upregulation of TRPV1 in DRGs may be the underlying pathophysiological mechanism to cause nerve sensitization and discogenic LBP. Therapeutic targeting of ROS or TRPV1 in DRGs may provide a promising method for the treatment of discogenic LBP.

Persistent Colonization of Ciprofloxacin-Resistant and Extended-Spectrum ß-Lactamase (ESBL)-Producing Salmonella enterica Serovar Kentucky ST198 in a Patient with Inflammatory Bowel Disease.

Objective: Salmonella enterica serovar Kentucky ST198 has emerged as a global threat to humans. In this study, we aimed to characterize the prolonged carriage of ciprofloxacin-resistant and extended-spectrum ß-lactamase (ESBL)-producing S. Kentucky ST198 in a single patient with inflammatory bowel disease (IBD). Methods: Three S. Kentucky strains were collected from a single patient with IBD on 11th January, 23rd January, and 8th February, 2022, respectively. Antimicrobial susceptibility testing, whole-genome sequencing, and phylogenetic analysis with 38 previously described Chinese S. Kentucky ST198 strains from patients and food were performed. Results: All three S. Kentucky isolates belonged to ST198. They carried identical 16 resistance genes, such as blaCTX-M-55, tet(A), and qnrS1, and had identical mutations within gyrA (S83F and D87N) and parC (S80I). Therefore, they exhibited identical multidrug-resistant profiles, including the clinically important antibiotics cephalosporins (ceftazidime and cefepime), fluoroquinolones (ciprofloxacin and levofloxacin), and third-generation tetracycline (tigecycline). Our three S. Kentucky strains were classified into the subclade ST198.2-2, and were genetically identical (2-6 SNPs) to each other. They exhibited a close genetic similarity (15-20 SNPs) to the isolate NT-h3189 from a patient and AH19MCS1 from chicken meat in China, indicating a possible epidemiological link between these S. Kentucky ST198 isolates from the patients and chicken meat. Conclusion: Long-term colonization of ciprofloxacin-resistant and ESBL-producing S. Kentucky ST198 in a single patient is a matter of concern. Due to the potential transfer of S. Kentucky ST198 from food sources to humans, ongoing surveillance of this particular clone in animals, animal-derived food products, and humans should be strengthened.

Critical bloodstream infection caused by Chromobacterium violaceum: a case report in a 15-year-old male with sepsis-induced cardiogenic shock and purpura fulminans.

Chromobacterium violaceum (C. violaceum) is a gram-negative bacillus that is widespread in tropical and subtropical areas. Although C. violaceum rarely infects humans, it can cause critical illness with a mortality rate above 50%. Here, we report the successful treatment of a 15-year-old male who presented with bloodstream infection of C. violaceum along with sepsis, specific skin lesions, and liver abscesses. Cardiogenic shock induced by sepsis was reversed by venoarterial extracorporeal membrane oxygenation (VA ECMO). Moreover, C. violaceum-related purpura fulminans, which is reported herein for the first time, was ameliorated after treatment. This case report demonstrates the virulence of C. violaceum with the aim of raising clinical awareness of this disease.

Radiomics Based on Multimodal magnetic resonance imaging for the Differential Diagnosis of Benign and Malignant Vertebral Compression Fractures.

OBJECTIVES: Recent studies have indicated that radiomics may have excellent performance and clinical application prospects in the differential diagnosis of benign and malignant vertebral compression fractures (VCFs). However, multimodal magnetic resonance imaging (MRI)-based radiomics model is rarely used in the differential diagnosis of benign and malignant VCFs, and is limited to lumbar. Herein, this study intends to develop and validate MRI radiomics models for differential diagnoses of benign and malignant VCFs in patients. METHODS: This cross-sectional study involved 151 adult patients diagnosed with VCF in The First Affiliated Hospital of Soochow University in 2016-2021. The study was conducted in three steps: (i) the original MRI images were segmented, and the region of interest (ROI) was marked out; (ii) among the extracted features, those features with Pearson's correlation coefficient lower than 0.9 and the top 15 with the highest variance and Lasso regression coefficient less than and more than 0 were selected; (iii) MRI images and combined data were studied by logistic regression, decision tree, random forest and extreme gradient boosting (XGBoost) models in training set and the test set (ratio of 8:2), respectively; and the models were further verified and evaluated for the differential diagnosis performance. The evaluated indexes included area under receiver (AUC) of operating characteristic curve, accuracy, sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and 95% confidence intervals (CIs). The AUCs were used to assess the predictive performance of different machine learning modes for benign and malignant VCFs. RESULTS: A total of 1144 radiomics features, and 14 clinical features were extracted. Finally, 12 radiomics features were included in the radiomics model, and 12 radiomics features with 14 clinical features were included in the combined model. In the radiomics model, the differential diagnosis performance in the logistic regression model with the AUC of 0.905 ± 0.026, accuracy of 0.817 ± 0.057, sensitivity of 0.831 ± 0.065, and negative predictive value of 0.813 ± 0.042, was superior to the other three. In the combined model, XGBoost model had the superior differential diagnosis performance with specificity (0.979 ± 0.026) and positive predictive value (0.971 ± 0.035). CONCLUSION: The multimodal MRI-based radiomics model performed well in the differential diagnosis of benign and malignant VCFs, which may provide a tool for clinicians to differentially diagnose VCFs.

The Relationship Between MRI Findings of Posterior Ligamentous Complex and Lumbar Instability in Degenerative Spondylolisthesis.

Background: To determine the factors in posterior ligamentous complex indicating lumbar instability in patients diagnosed with degenerative spondylolisthesis on conventional magnetic resonance imaging (MRI). Methods: We retrospectively analyzed patients who underwent PLIF surgery for degenerative spondylolisthesis at our institution between 2018 and 2020 and who had complete eligible preoperative imaging data for review and study, including lumbar MRI and anteroposterior and flexion-extension radiographs. Results: Fifty-three patients were confirmed to have lumbar instability (Unstable Group, 44%), while sixty-seven patients (Stable Group, 56%) did not have instability on radiographs. The patients in the stable group had more advanced status of the degeneration of intervertebral disc than in the unstable group (p<0.05). The degeneration of supraspinous ligament (SSL) was more severe in the unstable group (p<0.05). Compared with the patients with rotatory instability, advanced degeneration of interspinous ligament (ISL) and SSL was observed in patients with translatory instability (p<0.05). However, there was no significant difference with regard to the height of the spinous process and the interspinous distance in patients with or without instability. Conclusion: This MRI analysis showed that abnormal segmental motion is closely associated with the pathological characteristics of supraspinal ligament. Advanced degeneration of SSL in patients with degenerative spondylolisthesis should raise the suspicion for lumbar instability and additional evaluations. The status of ISL and ligamentum flavum (LF) may not be helpful for the diagnosis of lumbar instability. Functional radiographs combined with MRI may provide valuable information when diagnosing lumbar instability in patients with mechanical back pain.

Comparative analysis of risk factors associated with degeneration of adjacent segments: zero-profile anchored spacer vs. anterior cervical plate and cage construct.

Objective: Anterior cervical discectomy and fusion (ACDF) is an established treatment for cervical degenerative disc disease, but cervical spine surgery may affect sagittal alignment parameters and induce adjacent segment degeneration (ASD). This study aimed to determine the risk factors for developing ASD following anterior cervical plate and cage (ACPC) compared with the use of zero-profile anchored spacer (ROI-C). Methods: A retrospective contrastive study included 105 patients who underwent ACPC or ROI-C between January 2014 and October 2019 at our treatment centre. There were 50 cases in the ROI-C group and 55 patients in the ACPC group. Clinical and radiological results and the incidence of ASD were assessed after surgery. All patients were further divided into the ASD and non-ASD groups for subgroup analysis. Results: At each follow-up time, there was no statistically significant in radiographic parameters between the two groups. The overall ASD rate was higher in the ACPC group than in the ROI-C group (65.5% vs. 44.0%, p = 0.027). The low preoperative Cobb angle, low preoperative segment angle (SA), and loss of Cobb (ΔCobb) were significantly correlated with ASD. However, clinical outcomes were not associated with ASD at any postoperative follow-up visit. Conclusion: Equally good therapeutic effects were achieved with both the ROI-C and ACPC. The occurrence of ASD was considerably higher in the ACPC group than in the ROI-C group. The preoperative Cobb angle, preoperative SA, and ΔCobb were the most associated with an increase in the risk of ASD.

Targeting POLRMT by a first-in-class inhibitor IMT1 inhibits osteosarcoma cell growth in vitro and in vivo.

Osteosarcoma (OS) is a highly aggressive form of bone cancer that predominantly affects adolescents and young adults. In this study, we have undertaken an investigation into the potential anti-OS cell activity of IMT1 (inhibitor of mitochondrial transcription 1), a first-in-class inhibitor of RNA polymerase mitochondrial (POLRMT). IMT1 exhibited a profound inhibitory effect on cell survival, proliferation, cell cycle progression, and migration in primary and immortalized OS cells. Furthermore, this POLRMT inhibitor elicited apoptosis in the OS cells, without, however, inducing cytotoxicity in human osteoblasts or osteoblastic cells. IMT1 disrupted mitochondrial functions in OS cells, resulting in mitochondrial depolarization, oxidative injury, lipid peroxidation, and ATP reduction in OS cells. Silencing POLRMT using targeted shRNA closely mimicked the actions of IMT1 and exerted potent anti-OS cell activity. Importantly, IMT1's effectiveness was diminished in POLRMT-silenced OS cells. Subsequent investigations revealed that IMT1 suppressed the activation of the Akt-mammalian target of rapamycin (mTOR) cascade in OS cells. IMT1 treatment or POLRMT silencing in primary OS cells led to a significant reduction in Akt1-S6K-S6 phosphorylation. Conversely, it was enhanced upon POLRMT overexpression. The restoration of Akt-mTOR activation through the introduction of a constitutively active S473D mutant Akt1 (caAkt1) mitigated IMT1-induced cytotoxicity in OS cells. In vivo, oral administration of IMT1 robustly curtailed the growth of OS xenografts in nude mice. Furthermore, IMT1 suppressed POLRMT activity, impaired mitochondrial function, repressed Akt-mTOR activation, and induced apoptosis within xenograft tissues. Collectively, these findings underscore the potent growth-inhibitory effects attributed to IMT1 via targeted POLRMT inhibition. The utilization of this POLRMT inhibitor carries substantial therapeutic promise in the context of OS treatment.

Effects of Percutaneous Kyphoplasty for the Treatment of Thoracic Osteoporotic Vertebral Compression Fractures with or without Intravertebral Cleft in Elderly Patients.

Background: Few studies have focused on percutaneous kyphoplasty (PKP) in the treatment of thoracic osteoporotic vertebral compression fractures (OVCFs) with intervertebral cleft (IVC). Hence, the objective of this retrospective study was to compare the clinical and radiographic outcomes of PKP in elderly patients with thoracic OVCFs, with or without IVC. Methods: A total of 106 patients were enrolled in this study and divided into two groups: the IVC group and the NIVC group (without IVC). Radiographic measures included anterior vertebral height (AVH), thoracic kyphosis (TK), lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT), and sacral slope (SS). Clinical function measures included Oswestry disability index (ODI) and visual analog scale (VAS) scores. Results: There were no significant differences in the preoperative basic data between the groups classified as IVC and NIVC. However, both groups showed significant improvements in AVH and TK throughout the follow-up periods compared to the preoperative measurements (P<0.05). The recovery of AVH in the IVC group was found to be inferior to that in the NIVC group at 3 years after operation (P<0.05). There were no significant differences in LL, PI, PT and SS in both groups compared with the preoperative results and no statistically significant differences between the two groups at the same follow-up time (P>0.05). The VAS and ODI scores during all follow-up periods were significantly lower than those before operation (P<0.05). At 3 years after operation, the VAS and ODI scores of the IVC group were higher than those of the NIVC group (P<0.05). Conclusion: PKP is an adoptable measure to treat thoracic OVCFs with or without IVC. Our study revealed that the NIVC group was superior to the IVC group in terms of improved vertebral height and pain recovery at long-term follow-up (3 years).

A new modified MR dual precision positioning of thin-slice oblique sagittal fat suppression proton density weighted imaging: its diagnostic accuracy in anterior cruciate ligament injury.

To evaluate the diagnostic accuracy of a new modified MR dual precision positioning of thin-slice oblique sagittal fat suppression proton density-weighted imaging (DPP-TSO-Sag-FS-PDWI) sequence in detecting ACL injuries and its grades compared to standard sequences using arthroscopy as the standard reference. 42 patients enrolled in this retrospective study received the 1.5-T MRI with standard sequences and the new modified DPP-TSO-Sag-FS-PDWI sequence, and their arthroscopy results was recorded. The Mc Nemer-Bowker and weighted Kappa was performed to compare the consistency of MRI diagnosis with arthroscopic results. Finally, the diagnostic accuracy was calculated based on the true positive, true negative, false negative and false positive values. The diagnostic consistency of the DPP-TSO-Sag-FS-PDWI were higher than standard sequences for both reader 1 (K = 0.876 vs. 0.620) and reader 2 (K = 0.833 vs. 0.683) with good diagnostic repeatability (K = 0.794 vs. 0.598). Furthermore, the DPP-TSO-Sag-FS-PDWI can classify and diagnose three grades of ACL injury [the sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value were more than 84%], especially for grade II injury as the PPV was superior for reader 1 (92.3% vs. 53.9%) and reader 2 (84.6% vs. 69.2%). The new modified DPP-TSO-Sag-FS-PDWI sequence can display the ACL injury on one or continuous levels by maximizing the acquisition of complete ligament shape and true anatomical images, and excluding the influence of anatomical differences between individuals. It can improve the diagnostic accuracy with good repeatability and classify three grades of the ACL injury.