Facial and mandibular landmark tracking with habitual head posture estimation using linear and fiducial markers.

This study compared the accuracy of facial landmark measurements using deep learning-based fiducial marker (FM) and arbitrary width reference (AWR) approaches. It quantitatively analysed mandibular hard and soft tissue lateral excursions and head tilting from consumer camera footage of 37 participants. A custom deep learning system recognised facial landmarks for measuring head tilt and mandibular lateral excursions. Circular fiducial markers (FM) and inter-zygion measurements (AWR) were validated against physical measurements using electrognathography and electronic rulers. Results showed notable differences in lower and mid-face estimations for both FM and AWR compared to physical measurements. The study also demonstrated the comparability of both approaches in assessing lateral movement, though fiducial markers exhibited variability in mid-face and lower face parameter assessments. Regardless of the technique applied, hard tissue movement was typically seen to be 30% less than soft tissue among the participants. Additionally, a significant number of participants consistently displayed a 5 to 10° head tilt.

SP1-activated USP27X-AS1 promotes hepatocellular carcinoma progression via USP7-mediated AKT stabilisation.

BACKGROUND: Hepatocellular carcinoma (HCC) continues to pose a significant threat to patient survival. Emerging evidence underscores the pivotal involvement of long non-coding RNAs (lncRNAs) in the cancer process. Nevertheless, our understanding of the roles and processes of lncRNAs in HCC remains limited. METHODS: The expression level of USP27X-AS1 was assessed in an HCC patient cohort through a combination of bioinformatics analysis and qRT-PCR. Subsequent biological experiments were conducted to delve into the functional aspects of USP27X-AS1. Additional molecular biology techniques, including RNA pulldown and RNA immunoprecipitation (RIP), were employed to elucidate the potential mechanisms involving USP27X-AS1 in HCC. Finally, CUT-RUN assay and other investigations were carried out to determine the factors contributing to the heightened expression of USP27X-AS1 in HCC. RESULTS: High expression of the novel oncogene USP27X-AS1 predicted poor prognosis in HCC patients. Further investigation confirmed that USP27X-AS1 promoted the proliferation and metastasis of HCC by enabling USP7 to interact with AKT, which reduced level of AKT poly-ubiquitylation and enhanced AKT protein stability, which improves protein stabilisation of AKT and promotes the progression of HCC. Moreover, we also revealed that SP1 binds to USP27X-AS1 promoter to activate its transcription. CONCLUSIONS: Novel oncogenic lncRNA USP27X-AS1 promoted HCC progression via recruiting USP7 to deubiquitinate AKT. SP1 transcriptionally activated USP27X-AS1 expression. These findings shed light on HCC and pointed to USP27X-AS1 as a potential predictive biomarker and treatment target for the malignancy.

Integrinß-1 in disorders and cancers: molecular mechanisms and therapeutic targets.

Integrinß-1 (ITGB1) is a crucial member of the transmembrane glycoprotein signaling receptor family and is also central to the integrin family. It forms heterodimers with other ligands, participates in intracellular signaling and controls a variety of cellular processes, such as angiogenesis and the growth of neurons; because of its role in bidirectional signaling regulation both inside and outside the membrane, ITGB1 must interact with a multitude of substances, so a variety of interfering factors can affect ITGB1 and lead to changes in its function. Over the past 20 years, many studies have confirmed a clear causal relationship between ITGB1 dysregulation and cancer development and progression in a wide range of benign diseases and solid tumor types, which may imply that ITGB1 is a prognostic biomarker and a therapeutic target for cancer treatment that warrants further investigation. This review summarizes the biological roles of ITGB1 in benign diseases and cancers, and compiles the current status of ITGB1 function and therapy in various aspects of tumorigenesis and progression. Finally, future research directions and application prospects of ITGB1 are suggested. Video Abstract.

MYC in liver cancer: mechanisms and targeted therapy opportunities.

MYC, a major oncogenic transcription factor, regulates target genes involved in various pathways such as cell proliferation, metabolism and immune evasion, playing a critical role in the tumor initiation and development in multiple types of cancer. In liver cancer, MYC and its signaling pathways undergo significant changes, exerting a profound impact on liver cancer progression, including tumor proliferation, metastasis, dedifferentiation, metabolism, immune microenvironment, and resistance to comprehensive therapies. This makes MYC an appealing target, despite it being previously considered an undruggable protein. In this review, we discuss the role and mechanisms of MYC in liver physiology, chronic liver diseases, hepatocarcinogenesis, and liver cancer progression, providing a theoretical basis for targeting MYC as an ideal therapeutic target for liver cancer. We also summarize and prospect the strategies for targeting MYC, including direct and indirect approaches to abolish the oncogenic function of MYC in liver cancer.

EZH2 in hepatocellular carcinoma: progression, immunity, and potential targeting therapies.

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death. The accumulation of genetic and epigenetic changes is closely related to the occurrence and development of HCC. Enhancer of zeste homolog 2 (EZH2, a histone methyltransferase) is suggested to be one of the principal factors that mediates oncogenesis by acting as a driver of epigenetic alternation. Recent studies show that EZH2 is widely involved in proliferation and metastasis of HCC cells. In this review, the functions of EZH2 in HCC progression, the role of EZH2 in tumor immunity and the application of EZH2-related inhibitors in HCC therapy are summarized.

The RAGE signaling in osteoporosis.

Osteoporosis (OP), characterized by an imbalance of bone remodeling between formation and resorption, has become a health issue worldwide. The receptor for advanced glycation end product (RAGE), a transmembrane protein in the immunoglobin family, has multiple ligands and has been involved in many chronic diseases, such as diabetes and OP. Increasing evidence shows that activation of the RAGE signaling negatively affects bone remodeling. Ligands, such as advanced glycation end products (AGEs), S100, ß-amyloid (Aß), and high mobility group box 1 (HMGB1), have been well documented that they may negatively regulate the proliferation and differentiation of osteoblasts and positively stimulate osteoclastogenesis by activating the expression of RAGE. In this review, we comprehensively discuss the structure of RAGE and its biological functions in the pathogenesis of OP. The research findings suggest that RAGE signaling has become a potential target for the therapeutic management of OP.

Machine learning derived echocardiographic image quality in patients with left ventricular systolic dysfunction: insights on the echo views of greatest image quality.

We sought to determine the cardiac ultrasound view of greatest quality using a machine learning (ML) approach on a cohort of transthoracic echocardiograms (TTE) with abnormal left ventricular (LV) systolic function. We utilize an ML model to determine the TTE view of highest quality when scanned by sonographers. A random sample of TTEs with reported LV dysfunction from 09/25/2017-01/15/2019 were downloaded from the regional database. Component video files were analyzed using ML models that jointly classified view and image quality. The model consisted of convolutional layers for extracting spatial features and Long Short-term Memory units to temporally aggregate the frame-wise spatial embeddings. We report the view-specific quality scores for each TTE. Pair-wise comparisons amongst views were performed with Wilcoxon signed-rank test. Of 1,145 TTEs analyzed by the ML model, 74.5% were from males and mean LV ejection fraction was 43.1 ± 9.9%. Maximum quality score was best for the apical 4 chamber (AP4) view (70.6 ± 13.9%, p<0.001 compared to all other views) and worst for the apical 2 chamber (AP2) view (60.4 ± 15.4%, p<0.001 for all views except parasternal short-axis view at mitral/papillary muscle level, PSAX M/PM). In TTEs scanned by professional sonographers, the view with greatest ML-derived quality was the AP4 view.

MYC-activated LINC00607 promotes hepatocellular carcinoma progression by regulating the miR-584-3p/ROCK1 axis.

BACKGROUND: There have been many reports of long non-coding RNAs (lncRNAs) in tumors, and abnormally expressed lncRNA is closely related to hepatocellular carcinoma (HCC). The mechanism of LINC00607 in HCC has not been reported. METHODS: We utilized qPCR to evaluate the RNA expression level. The mechanism of MYC binding to the LINC00607 promoter was revealed through chromatin immunoprecipitation assay and dual luciferase reporter assay. The proliferation and invasive ability were evaluated by CCK-8 and transwell assays. The relation between LINC00607 and miR-584-3p was assessed by RNA immunoprecipitation assay and dual luciferase reporter assay. The level of ROCK1 was evaluated by qPCR and western blot. RESULTS: In this research, we found that the expression of LINC00607 was higher in HCC tissues when compared with that in the adjacent non-tumor tissues. Meanwhile, MYC was observed to interact with the LINC00607 promoter, leading to the upregulation of LINC00607 in HCC. We further revealed that LINC00607 functioned as a sponge for miR-584-3p. Cell proliferation and migration assays showed that miR-584-3p may inhibit the HCC progression. Moreover, we found that the miR-584-3p inhibitor could reverse the effects of LINC00607 downregulation in HCC through rescue experiments. Through verification, miR-584-3p bound to the 3' UTR of ROCK1 to downregulate its expression. CONCLUSION: LINC00607 regulated by MYC can promote the proliferation, migration and invasion of HCC cells through the miR-584-3p/ROCK1 axis.

Targeting VPS72 inhibits ACTL6A/MYC axis activity in HCC progression.

BACKGROUND AND AIMS: HCC is a highly heterogeneous disease that is caused largely by genomic copy number variations. Herein, the mechanistic and therapeutically targeted role of vacuolar protein sorting 72 homologue (VPS72), a novel copy number variation cis-driven gained gene identified by genome-wide copy number variation and transcriptome analyses in HCC, is not well understood. APPROACH AND RESULTS: First, overexpression of VPS72 enhanced the initiation and progression of HCC in vitro and in vivo . Mechanistically, VPS72 interacted with the oncoproteins MYC and actin-like 6A (ACTL6A) and promoted the formation of the ACTL6A/MYC complex. Furthermore, ACTL6A regulated VPS72 protein stability by weakening the interaction between tripartite motif containing 21 (TRIM21) and VPS72. Thus, the interaction between VPS72 and ACTL6A enhanced the affinity of MYC for its target gene promoters and promoted their transcription, thereby contributing to HCC progression, which was inhibited by adeno-associated virus serotype 8 (AAV8)-mediated short hairpin RNA (shRNA) against VPS72. CONCLUSIONS: This study reveals the molecular mechanism of ACTL6A/VPS72/MYC in HCC, providing a theoretical basis and therapeutic target for this malignancy.

ALKBH5 prevents hepatocellular carcinoma progression by post-transcriptional inhibition of PAQR4 in an m6A dependent manner.

BACKGROUND: N6-methyladenosine (m6A) is a prevalent modification of mRNA and is known to play important roles in tumorigenesis in many types of cancer. The function of N6-methyladenosine (m6A) RNA methylation depends on a variety of methyltransferases and demethylases. AlkB homolog 5 (ALKBH5) is a demethylase, and its biological function has not been completely explored in HCC. RESULTS: ALKBH5 is downregulated and has antitumor effects in HCC cells. In addition, Progestin and AdipoQ Receptor 4 (PAQR4) was identified as a downstream target of ALKBH5 based on transcriptome sequencing and validation studies. We found that ALKBH5 decreases PAQR4 mRNA and protein expression in an N6-methyladenosine (m6A)-dependent manner. The study also showed that ALKBH5 changes PAQR4 expression via the m6A reader IGF2BP1. In both in vivo and in vitro experiments, PAQR4 showed a strong association with the development of HCC. Finally, we found that PAQR4 interacts with AKT and enhances PI3K/AKT pathway activation. CONCLUSIONS: ALKBH5 inhibits HCC growth by downregulating PAQR4 expression in an m6A-dependent manner, therefore suppressing PI3K/AKT pathway activation.

A micropeptide JunBP regulated by TGF-ß promotes hepatocellular carcinoma metastasis.

Transforming growth factor beta (TGF-ß) signaling pathway plays important roles in hepatocellular carcinoma (HCC) progression. Long intergenic non-protein coding RNAs (lincRNAs) are important components of TGF-ß signaling pathway and perform their functions through different mechanisms. Here, we found that LINC02551 was activated by TGF-ß transcriptionally and identified a 174-amino-acid peptide, Jun binding micropeptide (JunBP), encoded by LINC02551 in HCC tissues and HCC cell lines. Functional study showed that JunBP promotes HCC metastasis through binding to c-Jun and subsequent promotion of its phosphorylated activation. Activated c-Jun has higher binding affinity to SMAD3, which in turn leads to more SMAD3 recruited to the promoter region of LINC02551. We find a positive feedback among them, and this mechanism provides a novel potential prognostic biomarker and therapeutic target in HCC.

LINC01608 activated by YY1 facilitate hepatocellular carcinoma progression by modulating the EGFR/ERK axis.

BACKGROUND: Long non-coding RNAs (LncRNAs) have been demonstrated to associate with a variety of cancers. However, the mechanisms of LncRNAs in hepatocellular carcinoma (HCC) progression are still not fully clarified. METHODS: LINC01608 expression level in HCC and adjacent normal tissues was detected by real-time-quantitively PCR (RT-qPCR) in clinical samples and in situ hybridization (ISH) in tissue microarray. Several functional assays were performed to determine the biological effects of LINC01608 in HCC cells in vitro, while subcutaneous xenograft models and lung metastasis models in nude mice and immunohistochemistry (IHC) results showed the role of LINC01608 in HCC progression in vivo. The combination of LINC01608 with miR-875-5p and target genes was elucidated by dual-luciferase report assays, RNA immunoprecipitation (RIP) assays and fluorescence in situ hybridization (FISH) assays. Finally, bioinformatics analysis and chromatin immunoprecipitation (CHIP) were performed to investigate the mechanism of Yin Yang-1 (YY1) regulating LINC01608 transcription. RESULTS: LINC01608 was overexpressed in HCC tissues, and high LINC01608 expression predicted poor overall survival (OS) and disease-free survival (DFS) in HCC patients. LINC01608 could promote HCC cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) in vitro and in vivo. Furthermore, we demonstrated that LINC01608 could sponge to miR-875-5p and activate the EGFR/ERK pathway. Moreover, we identified transcriptional factor YY1 could bind to the promoter of LINC01608 and induce its transcription. CONCLUSION: LINC01608 could serve as a promising prognostic biomarker of HCC. YY1-activated LINC01608 could promote HCC progression by associating with miR-875-5p to induce the EGFR/ERK signalling pathway. This discovery might provide therapeutic strategies for HCC.

Development and external validation of automated detection, classification, and localization of ankle fractures: inside the black box of a convolutional neural network (CNN).

PURPOSE: Convolutional neural networks (CNNs) are increasingly being developed for automated fracture detection in orthopaedic trauma surgery. Studies to date, however, are limited to providing classification based on the entire image-and only produce heatmaps for approximate fracture localization instead of delineating exact fracture morphology. Therefore, we aimed to answer (1) what is the performance of a CNN that detects, classifies, localizes, and segments an ankle fracture, and (2) would this be externally valid? METHODS: The training set included 326 isolated fibula fractures and 423 non-fracture radiographs. The Detectron2 implementation of the Mask R-CNN was trained with labelled and annotated radiographs. The internal validation (or 'test set') and external validation sets consisted of 300 and 334 radiographs, respectively. Consensus agreement between three experienced fellowship-trained trauma surgeons was defined as the ground truth label. Diagnostic accuracy and area under the receiver operator characteristic curve (AUC) were used to assess classification performance. The Intersection over Union (IoU) was used to quantify accuracy of the segmentation predictions by the CNN, where a value of 0.5 is generally considered an adequate segmentation. RESULTS: The final CNN was able to classify fibula fractures according to four classes (Danis-Weber A, B, C and No Fracture) with AUC values ranging from 0.93 to 0.99. Diagnostic accuracy was 89% on the test set with average sensitivity of 89% and specificity of 96%. External validity was 89-90% accurate on a set of radiographs from a different hospital. Accuracies/AUCs observed were 100/0.99 for the 'No Fracture' class, 92/0.99 for 'Weber B', 88/0.93 for 'Weber C', and 76/0.97 for 'Weber A'. For the fracture bounding box prediction by the CNN, a mean IoU of 0.65 (SD ± 0.16) was observed. The fracture segmentation predictions by the CNN resulted in a mean IoU of 0.47 (SD ± 0.17). CONCLUSIONS: This study presents a look into the 'black box' of CNNs and represents the first automated delineation (segmentation) of fracture lines on (ankle) radiographs. The AUC values presented in this paper indicate good discriminatory capability of the CNN and substantiate further study of CNNs in detecting and classifying ankle fractures. LEVEL OF EVIDENCE: II, Diagnostic imaging study.

ALKBH5-mediated m6A modification of lincRNA LINC02551 enhances the stability of DDX24 to promote hepatocellular carcinoma growth and metastasis.

As the most important RNA epigenetic regulation in eukaryotic cells, N6-metheyladenosine (m6A) modification has been demonstrated to play significant roles in cancer progression. However, this modification in long intergenic non-coding RNAs (lincRNAs) and the corresponding functions remain elusive. Here, we showed a lincRNA LINC02551 was downregulated by AlkB Homolog 5 (ALKBH5) overexpression in a m6A-dependent manner in hepatocellular carcinoma (HCC). Functionally, LINC02551 was required for the growth and metastasis of HCC. Mechanistically, LINC02551, a bona fide m6A target of ALKBH5, acted as a molecular adaptor that blocked the combination between DDX24 and a E3 ligase TRIM27 to decrease the ubiquitination and subsequent degradation of DDX24, ultimately facilitating HCC growth and metastasis. Thus, ALKBH5-mediated LINC02551 m6A methylation was required for HCC growth and metastasis.

USF2-mediated upregulation of TXNRD1 contributes to hepatocellular carcinoma progression by activating Akt/mTOR signaling.

Thioredoxin reductase 1 (TXNRD1) is one of the major redox regulators in mammalian cells, which has been reported to be involved in tumorigenesis. However, its roles and regulatory mechanism underlying the progression of HCC remains poorly understood. In this study, we demonstrated that TXNRD1 was significantly upregulated in HCC tumor tissues and correlated with poor survival in HCC patients. Functional studies indicated TXNRD1 knockdown substantially suppressed HCC cell proliferation and metastasis both in vitro and in vivo, and its overexpression showed opposite effects. Mechanistically, TXNRD1 attenuated the interaction between Trx1 and PTEN which resulting in acceleration of PTEN degradation, thereby activated Akt/mTOR signaling and its target genes which conferred to elevated HCC cell mobility and metastasis. Moreover, USF2 was identified as a transcriptional suppressor of TXNRD1, which directly interacted with two E-box sites in TXNRD1 promoter. USF2 functioned as tumor suppressor through the downstream repression of TXNRD1. Further clinical data revealed negative co-expression correlations between USF2 and TXNRD1. In conclusion, our findings reveal that USF2-mediated upregulation of TXNRD1 contributes to hepatocellular carcinoma progression by activating Akt/mTOR signaling.

The RNA m6A writer WTAP in diseases: structure, roles, and mechanisms.

N6-methyladenosine (m6A) is a widely investigated RNA modification in studies on the "epigenetic regulation" of mRNAs that is ubiquitously present in eukaryotes. Abnormal changes in m6A levels are closely related to the regulation of RNA metabolism, heat shock stress, tumor occurrence, and development. m6A modifications are catalyzed by the m6A writer complex, which contains RNA methyltransferase-like 3 (METTL3), methyltransferase-like 14 (METTL14), Wilms tumor 1-associated protein (WTAP), and other proteins with methyltransferase (MTase) capability, such as RNA-binding motif protein 15 (RBM15), KIAA1429 and zinc finger CCCH-type containing 13 (ZC3H13). Although METTL3 is the main catalytic subunit, WTAP is a regulatory subunit whose function is to recruit the m6A methyltransferase complex to the target mRNA. Specifically, WTAP is required for the accumulation of METTL3 and METTL14 in nuclear speckles. In this paper, we briefly introduce the molecular mechanism of m6A modification. Then, we focus on WTAP, a component of the m6A methyltransferase complex, and introduce its structure, localization, and physiological functions. Finally, we describe its roles and mechanisms in cancer.

Artificial intelligence and computer vision in orthopaedic trauma : the why, what, and how.

Artificial intelligence (AI) is, in essence, the concept of 'computer thinking', encompassing methods that train computers to perform and learn from executing certain tasks, called machine learning, and methods to build intricate computer models that both learn and adapt, called complex neural networks. Computer vision is a function of AI by which machine learning and complex neural networks can be applied to enable computers to capture, analyze, and interpret information from clinical images and visual inputs. This annotation summarizes key considerations and future perspectives concerning computer vision, questioning the need for this technology (the 'why'), the current applications (the 'what'), and the approach to unlocking its full potential (the 'how'). Cite this article: Bone Joint J 2022;104-B(8):911-914.

Long noncoding RNA HOXC-AS3 interacts with CDK2 to promote proliferation in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a type of cancer that affects the liver and has a high mortality rate. Long non-coding RNAs (lncRNAs) dysregulation can contribute to cancer occurrence and progression, although the underlying molecular pathways are mostly unclear. HOXC-AS3 was found to be considerably overexpressed in HCC in this investigation. The goal of this work was to look into the involvement of HOXC-AS3 in HCC and the various molecular pathways that underpin it. METHODS: Normal liver and paired HCC tissues from HCC patients were used to evaluate HOXC-AS3 expression by qRT-PCR. The role of HOXC-AS3 in HCC was assessed both in vitro and in vivo. RNA pulldown, RIP and co-IP were used to demonstrate the potential mechanism by which HOXC-AS3 regulates the progression of HCC. RESULTS: Using qRT-PCR, it was discovered that HOXC-AS3 was substantially expressed in HCC. In vitro and in vivo, overexpression of HOXC-AS3 aided proliferation and cell cycle progression. HOXC-AS3 interacted with CDK2 to facilitate CDK2's decreased binding to p21, resulting in enhanced CDK2 activity, which promoted the phosphorylation of Rb and the progression of HCC. CONCLUSIONS: HOXC-AS3 is highly expressed in HCC and can promote the progression of HCC by interacting with CDK2. Therefore, targeting HOXC-AS3 is very likely to provide a new strategy for the treatment of HCC and for improving patient prognosis.

Detection of Pyrophosphate and Alkaline Phosphatase Activity Based on PolyT Single Stranded DNA - Copper Nanoclusters.

The determination of pyrophosphate and alkaline phosphatase activity plays a significant role in medical diagnosis. In this work, a label-free "ON-OFF-ON" fluorescence strategy is developed for the analysis of pyrophosphate and alkaline phosphatase activity. Using PolyT single strand DNA as templates to synthesize fluorescent copper nanoparticles, the coordination effect of pyrophosphoric acid on Cu2+ inhibited the generation of fluorescence. Afterwards, the addition of alkaline phosphatase into hydrolyze pyrophosphoric acid resulted in the release of Cu2+, whereby the fluorescence intensity could be recovered. Thereupon enhanced-sensitivity for alkaline phosphatase was obtained (0.1 mU/L), much better than previously reported methods. Meanwhile, it could be performed directly in homogeneous solution, which was very close to the actual activity level of alkaline phosphatase under physiological conditions. Likewise, satisfactory results were also obtained in specificity assessment, which demonstrated its potential application in clinical diagnosis. Notably, a new, sensitive, low-cost, short-time, and high-sensitivity platform for alkaline phosphatase detection was constructed, and the design of biosensor using DNA-templated Copper nanoclusters (CuNCs) was instructed in this study.