Posttranslational modifications of E2F family members in the physiological state and in cancer: Roles, mechanisms and therapeutic targets.

The E2F transcription factor family, whose members are encoded by the E2F1-E2F8 genes, plays pivotal roles in the cell cycle, apoptosis, metabolism, stemness, metastasis, aging, angiogenesis, tumor promotion or suppression, and other biological processes. The activity of E2Fs is regulated at multiple levels, with posttranslational modifications being an important regulatory mechanism. There are numerous types of posttranslational modifications, among which phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, neddylation, and poly(ADP-ribosyl)ation are the most commonly studied in the context of the E2F family. Posttranslational modifications of E2F family proteins regulate their biological activity, stability, localization, and interactions with other biomolecules, affecting cell proliferation, apoptosis, DNA damage, etc., and thereby playing roles in physiological and pathological processes. Notably, these modifications do not always act alone but rather form an interactive regulatory network. Currently, several drugs targeting posttranslational modifications are being studied or clinically applied, in which the proteolysis-targeting chimera and molecular glue can target E2Fs. This review aims to summarize the roles and regulatory mechanisms of different PTMs of E2F family members in the physiological state and in cancer and to briefly discuss their clinical significance and potential therapeutic use.

Quality of cementing in hemiarthroplasty for elderly neck of femur fractures does not affect short term functional outcomes.

INTRODUCTION: Cemented hip hemiarthroplasty is a routine surgical option for elderly neck of femur (NOF) fractures. It is uncertain if quality of cementing has any effect on functional outcomes. The aim of this study was to determine if the quality of cementing would affect short term functional outcomes in elderly neck of femur fractures. MATERIALS AND METHODS: Retrospective analysis of 637 single-centre cemented hip hemiarthroplasties from 2014 to 2021 was performed. Each post-operative radiograph was double-read by 2 authors (1 resident and 1 fellowship trained surgeon) to determine quality of cementing via the Barrack grading. Disagreements were reviewed by a third reader. Cement grades were grouped as Optimal (Barrack grade A-B), or Suboptimal (Barrack grade C-D). Functional outcomes were compared using mobility (community- or home-ambulant), assistance required for mobility, and Modified Barthel Index (MBI). Surgical parameters were compared between the groups. RESULTS: There were 429 Optimal and 208 Suboptimal cases of cementing performed. There was no difference in age, American Society of Anesthesiologists score, mobility, assistance required, and MBI score pre-operatively (p > 0.05). Patients in the "Suboptimal" cementing group had a higher Charlson Comorbidity Index (CCI) score (p < 0.001). At 1 year post-operation, there was no significant difference between "Optimal" and "Suboptimal" cementing with regards to the proportion of community ambulators (30.2% vs. 25.7%, p = 0.252), walking independence (independent walkers (19.8% vs.17.3%), independent walkers with aids (41.3%vs.42.1%), walker with caregiver assistance (29.2%vs.33.7%), wheelchair-bound (9.6%vs.6.9%), p = 0.478), and distribution of MBI score (81.1%vs.82.2% achieving MBI > 60, p = 0.767). There was no significant difference in the proportion of patients with postoperative delirium (7.9% vs. 5.8, p = 0.324) or 1-year mortality rates (3.5% vs. 2.9%, p = 0.685). Except for stem design (12.2% tapered vs 20.1% collared; p = 0.011), no other surgical parameters were significantly different. The kappa value for inter-reader agreement was "substantial" at 0.727 (95% CI 0.682-0.772) (p < 0.001). CONCLUSION: Quality of cementing in cemented hip hemiarthroplasty for elderly NOF fractures does not affect the short-term functional outcomes. In low demand patients and patients at risk of BCIS, optimal cementing may not be necessary to achieve similar short-term functional outcomes. Further studies should be conducted to determine the effect of sub-optimal cementing on long-term functional outcomes.

Deep Learning-Based Microscopic Cell Detection using Inverse Distance Transform and Auxiliary Counting.

Microscopic cell detection is a challenging task due to significant inter-cell occlusions in dense clusters and diverse cell morphologies. This paper introduces a novel framework designed to enhance automated cell detection. The proposed approach integrates a deep learning model that produces an inverse distance transform-based detection map from the given image, accompanied by a secondary network designed to regress a cell density map from the same input. The inverse distance transform-based map effectively highlights each cell instance in the densely populated areas, while the density map accurately estimates the total cell count in the image. Then, a custom counting-aided cell center extraction strategy leverages the cell count obtained by integrating over the density map to refine the detection process, significantly reducing false responses and thereby boosting overall accuracy. The proposed framework demonstrated superior performance with F-scores of 96.93%, 91.21%, and 92.00% on the VGG, MBM, and ADI datasets, respectively, surpassing existing state-of-the-art methods. It also achieved the lowest distance error, further validating the effectiveness of the proposed approach. These results demonstrate significant potential for automated cell analysis in biomedical applications.

Comparison of soil addition, foliar spraying, seed soaking, and seed dressing of selenium and silicon nanoparticles effects on cadmium reduction in wheat (Triticum turgidum L.).

Wheat cadmium (Cd) contamination is a critical food security issue worldwide, and selenium (Se) and silicon (Si) are widely reported to reduce Cd accumulation in cereal crops. However, few studies have compared the most effective pathway to reduce Cd accumulation in crops using Se nanoparticles (nano-Se), Si nanoparticles (nano-Si), and their mixtures. Here, we investigated the concentrations of Cd in wheat using four application modes: soil addition, foliar spraying, seed soaking, and seed dressing combined with three different materials. The concentration of Cd in wheat grains can be significantly reduced by 31.30-62.99% and 36.96-51.04% through four applications of nano-Se and soil application and seed soaking of nano-Si, respectively. However, all treatments involving mixtures of nano-Si and nano-Se did not show a reduction in Cd concentration. The applications of both nano-Se and nano-Si can enhance antioxidant enzyme systems and regulate Cd-related gene expression to safeguard wheat tissues from Cd stress. Downregulation of the influx transporter from soil to root (TaNramp5) and from root to shoot (TaLCT1), along with the upregulation of the efflux transporter from cytoplasm to vacuole (TaHMA3), contributed to the nano-Si/nano-Se dependent Cd transport and reduced Cd accumulation in wheat grains. Overall, the application of nano-Se instead of nano-Si, and soil addition rather than foliar spraying, seed soaking, and seed dressing, can be efficiently utilized to reduce grain Cd accumulation from Cd-contaminated soils.

Any region can be perceived equally and effectively on rotation pretext task using full rotation and weighted-region mixture.

In recent years, self-supervised learning has emerged as a powerful approach to learning visual representations without requiring extensive manual annotation. One popular technique involves using rotation transformations of images, which provide a clear visual signal for learning semantic representation. However, in this work, we revisit the pretext task of predicting image rotation in self-supervised learning and discover that it tends to marginalise the perception of features located near the centre of an image. To address this limitation, we propose a new self-supervised learning method, namely FullRot, which spotlights underrated regions by resizing the randomly selected and cropped regions of images. Moreover, FullRot increases the complexity of the rotation pretext task by applying the degree-free rotation to the region cropped into a circle. To encourage models to learn from different general parts of an image, we introduce a new data mixture technique called WRMix, which merges two random intra-image patches. By combining these innovative crop and rotation methods with the data mixture scheme, our approach, FullRot + WRMix, surpasses the state-of-the-art self-supervision methods in classification, segmentation, and object detection tasks on ten benchmark datasets with an improvement of up to +13.98% accuracy on STL-10, +8.56% accuracy on CIFAR-10, +10.20% accuracy on Sports-100, +15.86% accuracy on Mammals-45, +15.15% accuracy on PAD-UFES-20, +32.44% mIoU on VOC 2012, +7.62% mIoU on ISIC 2018, +9.70% mIoU on FloodArea, +25.16% AP50 on VOC 2007, and +58.69% AP50 on UTDAC 2020. The code is available at https://github.com/anthonyweidai/FullRot_WRMix.

Single position, prone oblique lateral interbody fusion (OLIF)-case illustration and technical considerations.

Oblique lateral interbody fusion (OLIF) is a powerful method to treat various spinal conditions and is frequently combined with posterior instrumentation. This is traditionally performed in dual positions, with the patient first in lateral then turned prone. Single position lateral surgery (SPS-L) has been studied in a bid to improve surgical efficiency and reduce operative costs, but various limitations have been identified. More recently, the single position prone surgery (SPS-P) has been described as an alternative to address some of these limitations. This case illustrates a patient who underwent SPS-P using an OLIF corridor with subsequent posterior decompression and instrumentation. The benefits and limitations of this procedure compared to the conventional techniques are highlighted in this case. We present the case of a 75-year-old female presenting with thoracic myelopathy over T11/12 and concurrent L2-4 spinal stenosis. She underwent OLIF of L2/3 and L3/4, posterior decompression of T11/12 and L2/3, and posterior instrumented fusion from T10-L4 via a single prone position. We aim to describe the advantages of this approach and the challenges encountered through our experience. SPS-P offers numerous benefits compared to the already powerful SPS-L. In the upper levels of the lumbar spine, a pre-psoas approach may also be feasible. However, the prone lateral technique does not replace all patients suited for a lateral interbody fusion but should be seen as a viable option for selected cases such as those with previous fusion at the L5/S1 with adjacent degeneration requiring extension and posterior fixation.

Learning spiking neuronal networks with artificial neural networks: neural oscillations.

First-principles-based modelings have been extremely successful in providing crucial insights and predictions for complex biological functions and phenomena. However, they can be hard to build and expensive to simulate for complex living systems. On the other hand, modern data-driven methods thrive at modeling many types of high-dimensional and noisy data. Still, the training and interpretation of these data-driven models remain challenging. Here, we combine the two types of methods to model stochastic neuronal network oscillations. Specifically, we develop a class of artificial neural networks to provide faithful surrogates to the high-dimensional, nonlinear oscillatory dynamics produced by a spiking neuronal network model. Furthermore, when the training data set is enlarged within a range of parameter choices, the artificial neural networks become generalizable to these parameters, covering cases in distinctly different dynamical regimes. In all, our work opens a new avenue for modeling complex neuronal network dynamics with artificial neural networks.

Tendon ball arthroplasty and proximal carpal stabilization with tendon graft for advanced Kienbock's disease.

This study reports the surgical technique and outcomes of tendon ball arthroplasty combined with proximal carpal stabilization using the extensor carpi radialis longus tendon for treating advanced Kienbock's disease. The collapsed lunate is excised and a tendon ball inserted as a spacer. A distally based extensor carpi radials longus graft is passed through the scaphoid, tendon ball and triquetrum, reconstructing the proximal carpal row. In total, 16 patients were included and the mean follow-up was 25 months. Pain improved from 5.6 preoperatively to 1.3 postoperatively on a 10-point visual analogue scale. Mean wrist motion improved by 17.8° and grip strength compared with the non-operative side increased by 22.1% on average. Radiographic outcomes demonstrated correction of scaphoid flexion and carpal height ratio. The modified tendon ball arthroplasty may be an alternative wrist salvage procedure for the treatment of advanced Kienbock's disease.Level of evidence: IV.

Deeply Supervised Skin Lesions Diagnosis With Stage and Branch Attention.

Accurate and unbiased examinations of skin lesions are critical for the early diagnosis and treatment of skin diseases. Visual features of skin lesions vary significantly because the images are collected from patients with different lesion colours and morphologies by using dissimilar imaging equipment. Recent studies have reported that ensembled convolutional neural networks (CNNs) are practical to classify the images for early diagnosis of skin disorders. However, the practical use of these ensembled CNNs is limited as these networks are heavyweight and inadequate for processing contextual information. Although lightweight networks (e.g., MobileNetV3 and EfficientNet) were developed to achieve parameter reduction for implementing deep neural networks on mobile devices, insufficient depth of feature representation restricts the performance. To address the existing limitations, we develop a new lite and effective neural network, namely HierAttn. The HierAttn applies a novel deep supervision strategy to learn the local and global features by using multi-stage and multi-branch attention mechanisms with only one training loss. The efficacy of HierAttn was evaluated by using the dermoscopy images dataset ISIC2019 and smartphone photos dataset PAD-UFES-20 (PAD2020). The experimental results show that HierAttn achieves the best accuracy and area under the curve (AUC) among the state-of-the-art lightweight networks.

Genetic Association Analysis of Copy Number Variations for Meat Quality in Beef Cattle.

Meat quality is an economically important trait for global food production. Copy number variations (CNVs) have been previously implicated in elucidating the genetic basis of complex traits. In this article, we detected a total of 112,198 CNVs and 10,102 CNV regions (CNVRs) based on the Bovine HD SNP array. Next, we performed a CNV-based genome-wide association analysis (GWAS) of six meat quality traits and identified 12 significant CNV segments corresponding to eight candidate genes, including PCDH15, CSMD3, etc. Using region-based association analysis, we further identified six CNV segments relevant to meat quality in beef cattle. Among these, TRIM77 and TRIM64 within CNVR4 on BTA29 were detected as candidate genes for backfat thickness (BFT). Notably, we identified a 34 kb duplication for meat color (MC) which was supported by read-depth signals, and this duplication was embedded within the keratin gene family including KRT4, KRT78, and KRT79. Our findings will help to dissect the genetic architecture of meat quality traits from the aspects of CNVs, and subsequently improve the selection process in breeding programs.

Genetic and cultural adaptations underlie the establishment of dairy pastoralism in the Tibetan Plateau.

BACKGROUND: Domestication and introduction of dairy animals facilitated the permanent human occupation of the Tibetan Plateau. Yet the history of dairy pastoralism in the Tibetan Plateau remains poorly understood. Little is known how Tibetans adapted to milk and dairy products. RESULTS: We integrated archeological evidence and genetic analysis to show the picture that the dairy ruminants, together with dogs, were introduced from West Eurasia into the Tibetan Plateau since ~ 3600 years ago. The genetic admixture between the exotic and indigenous dogs enriched the candidate lactase persistence (LP) allele 10974A > G of West Eurasian origin in Tibetan dogs. In vitro experiments demonstrate that - 13838G > A functions as a LP allele in Tibetans. Unlike multiple LP alleles presenting selective signatures in West Eurasians and South Asians, the de novo origin of Tibetan-specific LP allele - 13838G > A with low frequency (~ 6-7%) and absence of selection corresponds - 13910C > T in pastoralists across eastern Eurasia steppe. CONCLUSIONS: Results depict a novel scenario of genetic and cultural adaptations to diet and expand current understanding of the establishment of dairy pastoralism in the Tibetan Plateau.

Deep phenotyping of 11,880 highlanders reveals novel adaptive traits in native Tibetans.

Tibetans are the ideal population to study genetic adaptation in extreme environments. Here, we performed systematic phenotyping of 11,880 highlanders, covering 133 quantitative traits of 13 organ systems. We provided a comprehensive phenotypic atlas by comparing altitude adaptation and altitude acclimatization. We found the differences between adaptation and acclimatization are quantitative rather than qualitative, with a whole-system "blunted effect" seen in the adapted Tibetans. We characterized twelve different functional changes between adaptation and acclimatization. More importantly, we established a landscape of adaptive phenotypes of indigenous Tibetans, including 45 newly identified Tibetan adaptation-nominated traits, involving specific changes of Tibetans in internal organ state, metabolism, eye morphology, and skin pigmentation. In addition, we observed a sex-biased pattern between altitude acclimatization and adaptation. The generated atlas of phenotypic landscape provides new insights into understanding of human adaptation to high-altitude environments, and it serves as a valuable blueprint for future medical and physiological studies.

High Arterial Oxygen Saturation in the Acclimatized Lowlanders Living at High Altitude.

Blood oxygen saturation (SpO2) is a key indicator of oxygen availability in the body. It is known that a low SpO2 at high altitude is associated with morbidity and mortality risks due to physiological hypoxemia. Previously, it was proposed that the lowlander immigrants living at high altitude should have a lower SpO2 level compared to the highlander natives, but this proposal has not been rigorously tested due to the lack of data from the lowlander immigrants living at high altitude. In this study, we compared arterial oxygen saturation of 5929 Tibetan natives and 1034 Han Chinese immigrants living at altitudes ranging from 1120 m to 5020 m. Unexpectedly, the Han immigrants had a higher SpO2 than the Tibetan natives at the same high altitudes. At the same time, there is a higher prevalence of chronic mountain sickness in Han than in Tibetans at the same altitude. This result suggests that the relatively higher SpO2 level of the acclimatized Han is associated with a physiological cost, and the SpO2 level of Tibetans tends to be sub-optimal. Consequently, SpO2 alone is not a robust indicator of physiological performance at high altitude. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-023-00117-x.

Nimbolide targeting SIRT1 mitigates intervertebral disc degeneration by reprogramming cholesterol metabolism and inhibiting inflammatory signaling.

Inflammation, abnormal cholesterol metabolism, and macrophage infiltration are involved in the destruction of the extracellular matrix of the nucleus pulposus (NP), culminating in intervertebral disc degeneration (IDD). Whether nimbolide (Nim), a natural extract, can alleviate IDD is unclear. In this study, we demonstrated that Nim promotes cholesterol efflux and inhibits the activation of the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways by activating sirtuin 1 (SIRT1) in nucleus pulposus cells (NPCs) during inflammation. Thus, Nim balanced matrix anabolism and catabolism of NPCs. However, the inhibition of SIRT1 significantly attenuated the effects of Nim. We also found that Nim promoted the expression of SIRT1 in RAW 264.7, which enhanced the proportion of M2 macrophages by facilitating cholesterol homeostasis reprogramming and impeded M1-like macrophages polarization by blocking the activation of inflammatory signaling. Based on these results, Nim can improve the microenvironment and facilitate matrix metabolism equilibrium in NPCs. Furthermore, in vivo treatment with Nim delayed IDD progression by boosting SIRT1 expression, modulating macrophage polarization and preserving the extracellular matrix. In conclusion, Nim may represent a novel therapeutic strategy for treating IDD.

Effects of astragaloside IV on glucocorticoid-induced avascular necrosis of the femoral head via regulating Akt-related pathways.

We investigated the role of astragaloside IV (AS-IV) in preventing glucocorticoid-induced avascular necrosis of the femoral head (ANFH) and the underlying molecular mechanisms. Network pharmacology was used to predict the molecular targets of AS-IV. Molecular dynamic simulations were performed to explore the binding mechanism and interaction mode between AS-IV and Akt. Rat models of glucocorticoid-induced ANFH with AS-IV intervention were established, and osteogenesis, angiogenesis, apoptosis and oxidative stress were evaluated before and after blocking the PI3K/Akt pathway with LY294002. The effects of glucocorticoid and AS-IV on bone marrow mesenchymal stem cells and human umbilical vein endothelial cells incubated with and without LY294002 were determined. Downregulated p-Akt expression could be detected in the femoral heads of glucocorticoid-induced ANFH patients and rats. AS-IV increased trabecular bone integrity and vessel density of the femoral head in the model rats. AS-IV increased Akt phosphorylation and upregulated osteogenesis-, angiogenesis-, apoptosis- and oxidative stress-related proteins and mRNA and downregulated Bax, cleaved caspase-3 and cytochrome c levels. AS-IV promoted human umbilical vein endothelial cell migration, proliferation and tube formation ability; bone marrow mesenchymal stem cell proliferation; and osteogenic differentiation under glucocorticoid influence. AS-IV inhibited apoptosis. LY294002 inhibited these effects. AS-IV prevented glucocorticoid-induced ANFH by promoting osteogenesis and angiogenesis via the Akt/Runx2 and Akt/HIF-1α/VEGF pathways, respectively, and suppressing apoptosis and oxidative stress via the Akt/Bad/Bcl-2 and Akt/Nrf2/HO-1 pathways, respectively.

Multi-band oscillations emerge from a simple spiking network.

In the brain, coherent neuronal activities often appear simultaneously in multiple frequency bands, e.g., as combinations of alpha (8-12 Hz), beta (12.5-30 Hz), and gamma (30-120 Hz) oscillations, among others. These rhythms are believed to underlie information processing and cognitive functions and have been subjected to intense experimental and theoretical scrutiny. Computational modeling has provided a framework for the emergence of network-level oscillatory behavior from the interaction of spiking neurons. However, due to the strong nonlinear interactions between highly recurrent spiking populations, the interplay between cortical rhythms in multiple frequency bands has rarely been theoretically investigated. Many studies invoke multiple physiological timescales (e.g., various ion channels or multiple types of inhibitory neurons) or oscillatory inputs to produce rhythms in multi-bands. Here, we demonstrate the emergence of multi-band oscillations in a simple network consisting of one excitatory and one inhibitory neuronal population driven by constant input. First, we construct a data-driven, Poincaré section theory for robust numerical observations of single-frequency oscillations bifurcating into multiple bands. Then, we develop model reductions of the stochastic, nonlinear, high-dimensional neuronal network to capture the appearance of multi-band dynamics and the underlying bifurcations theoretically. Furthermore, when viewed within the reduced state space, our analysis reveals conserved geometrical features of the bifurcations on low-dimensional dynamical manifolds. These results suggest a simple geometric mechanism behind the emergence of multi-band oscillations without appealing to oscillatory inputs or multiple synaptic or neuronal timescales. Thus, our work points to unexplored regimes of stochastic competition between excitation and inhibition behind the generation of dynamic, patterned neuronal activities.

Isoginkgetin-loaded reactive oxygen species scavenging nanoparticles ameliorate intervertebral disc degeneration via enhancing autophagy in nucleus pulposus cells.

Excessive reactive oxygen species (ROS) in nucleus pulposus cells (NPCs) promote extracellular matrix (ECM) degradation and cellular inflammatory responses by activating a variety of cellular pathways, ultimately inducing cell apoptosis and leading to the development of low back pain. Here, we designed and fabricated an isoginkgetin-loaded ROS-responsive delivery system (IGK@SeNP) based on diselenide block copolymers. Successfully encapsulated IGK was released intelligently and rapidly in a microenvironment with high ROS levels in degenerative disc. Controlled-release IGK not only efficiently scavenged ROS from the intervertebral disc together with diselenide block copolymers but also effectively enhanced autophagy in NPCs to inhibit ECM degradation and cell apoptosis, and showed significant therapeutic effects in the rat intervertebral disc degeneration (IDD) model. Overall, the synergistic effects of IGK@SeNP in ROS scavenging and autophagy enhancement endowed it with an attractive therapeutic strategy for IDD treatment.

Ginsenoside Rg3 liposomes regulate tumor microenvironment for the treatment of triple negative breast cancer.

OBJECTIVE: To improve the solubility and targeting of Ginsenoside Rg3 (G-Rg3), in the current study, we constructed a novel targeting functional material folic acid -poly(2-ethyl-2-oxazoline)-cholesteryl methyl carbonate (FA-PEOz-CHMC, FPC) modified G-Rg3 liposomes (FPC-Rg3-L). METHODS: FPC was synthesized by using folic acid (FA) as a targeted head coupling with acid-activated poly(2-ethyl-2-oxazoline)-cholesteryl methyl carbonate. The inhibitory effects of the G-Rg3 preparations on mouse breast cancer cells (4T1) were investigated by CCK-8 assay. Paraffin sections of female BALB/c mice viscera were taken for hematoxylin-eosin (H&E) staining after continuous tail vein injection of G-Rg3 preparations. BALB/c mice bearing triple-negative breast cancer (TNBC) were used as animal models to investigate the inhibition of G-Rg3 preparations on tumor growth and improving quality of life. Transforming growth factor-ß1 (TGF-ß1) and α-smooth muscular actin (α-SMA) were used to investigate the expression of two fibrosis factors in tumor tissues by western blotting. RESULTS: Compared with G-Rg3 solution (Rg3-S) and Rg3-L, FPC-Rg3-L had a significant inhibitory effect on 4T1 cells (p < .01), and the half maximal inhibitory concentration (IC50) of FPC-Rg3-L was significantly lower (p < .01). The H&E results showed that the injection of FPC-Rg3-L and Rg3-S did not cause damage to the organs of mice. Compared with the control group, tumor growth was significantly inhibited in mice treated with FPC-Rg3-L and G-Rg3 solutions (p < .01). CONCLUSIONS: This study presents a new and safe treatment for TNBC, reduces the toxic and side effects of the drug, and provides a reference for the efficient use of Chinese herbal medicine components.

Distal Ulnar Bifurcation Arthroplasty in the Treatment of Bayne and Klug Types 3 and 4 Radial Club Hands: Preliminary Outcomes.

BACKGROUND: The treatment of Bayne and Klug types 3 and 4 radial club hands (RCHs) remains challenging and controversial. In this study, the authors reported a new procedure called distal ulnar bifurcation arthroplasty and reviewed the preliminary results. METHODS: Between 2015 and 2019, 11 patients with 15 affected forearms having type 3 or 4 RCHs underwent distal ulnar bifurcation arthroplasty. The mean age was 55.5 months (range, 29 to 86 months). The surgical protocol consisted of (1) bifurcation of the distal ulna to accommodate the wrist with stable support; (2) pollicization to treat hypoplastic or absent thumb; and (3) in the case of significant bowed ulna, ulnar corrective osteotomy. In all patients, clinical and radiologic parameters including hand-forearm angle, hand-forearm position, ulnar length, wrist stability, and motion were recorded. RESULTS: The mean duration of follow-up was 42.2 months (range, 24 to 60 months). The average correction of hand-forearm angle was 80.2 degrees. The overall range of active wrist motion was approximately 87.5 degrees. Ulna growth per year was 6.7 mm (range, 5.2 to 9.2 mm). No major complications were recorded during follow-up. CONCLUSIONS: The distal ulnar bifurcation arthroplasty offers a technically feasible alternative for the treatment of type 3 or 4 RCH, which enables satisfactory appearance, provides stable support to the wrist, and maintains wrist function. Despite the promising preliminary results, longer follow-up is necessary to evaluate this procedure. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Kinesin Family Member C1 Overexpression Exerts Tumor-Promoting Properties in Head and Neck Squamous Cell Carcinoma via the Rac1/Wnt/ß-catenin Pathway.

Kinesin family member C1 (KIFC1) is a kinesin-14 motor protein, and its abnormal upregulation promotes the malignant behavior of cancer cells. N6-methyladenosine (m6A) RNA methylation is a common modification of eukaryotic messenger RNA and affects RNA expression. In this study, we explored how KIFC1 regulated head and neck squamous cell carcinoma (HNSCC) tumorigenesis and how m6A modification affected KIFC1 expression. A bioinformatics analysis was performed to screen for genes of interest, and in vitro and in vivo studies were carried out to investigate the function and mechanism of KIFC1 in HNSCC tissues. We observed that the expression of KIFC1 in HNSCC tissues was significantly higher than that in normal or adjacent normal tissues. Patients with cancer with higher KIFC1 expression have a lower tumor differentiation status. Demethylase alkB homolog 5, a cancer-promoting factor in HNSCC tissues, could interact with KIFC1 messenger RNA and posttranscriptionally activate KIFC1 through m6A modification. KIFC1 downregulation suppressed HNSCC cell growth and metastasis in vivo and in vitro. However, overexpression of KIFC1 promoted these malignant behaviors. We demonstrated that KIFC1 overexpression activated the oncogenic Wnt/ß-catenin pathway. KIFC1 interacted with the small GTPase Ras-related C3 botulinum toxin substrate 1 (Rac1) at the protein level and increased its activity. The Rho GTPase Rac1 was indicated to be an upstream activator of the Wnt/ß-catenin signaling pathway, and its Rac1 inhibitor, NSC-23766, treatment reversed the effects caused by KIFC1 overexpression. Those observations demonstrate that abnormal expression of KIFC1 may be regulated by demethylase alkB homolog 5 in an m6A-dependent manner and promote HNSCC progression via the Rac1/Wnt/ß-catenin pathway.