DCX knockout ferret reveals a neurogenic mechanism in cortical development.

Lissencephaly is a rare brain malformation for which our understanding remains limited due to the absence of suitable animal models that accurately represent human phenotypes. Here, we establish doublecortin (DCX) knockout ferrets as a model that faithfully replicates key features of the disorder. We reveal the critical roles of DCX in neural progenitor cell proliferation and radial glial fiber extension, processes essential for normal cortical development. Utilizing single-nucleus RNA sequencing (snRNA-seq) and spatial transcriptomics, we provide a detailed atlas of the lissencephalic cortex, illustrating disrupted neuronal lamination and the specific interactions between inhibitory and excitatory neurons. These findings enhance our understanding of the cellular and molecular mechanisms underlying lissencephaly and highlight the potential of DCX knockout ferrets as a valuable tool for neurodevelopmental research, offering insights into both the pathology of lissencephaly and the general principles of brain development.

GDF10 and IDO1 as a thyroid cancer prognostic biomarker associated with immune infiltration.

Objection: The aim of this work is to screen the immune-related genes to predict the prognosis and provide a new direction of treatment for patients with thyroid cancer (THCA). Methods: The mRNA and clinical features of THCA patients were collected from the Cancer Genome Atlas (TCGA) databases. The immune-related genes were obtained from the ImmPort databases. The bio-information methods were performed to screen the differential expression genes (DEGs) and genes related to immunity between the THCA patients and normal individuals. On this basis, the hub prognosis immunity genes were screened by Veen. The related genes were obtained by constructing the protein-protein interaction network. The enrichment analyses were performed based on the protein and protein interaction (PPI) related genes. The hub immune checkpoint was screened by correlation analysis. Finally, the hub gene and the immunity checkpoint-miRNA (or transcription factor, drug) interaction network were constructed. A drug-sensitive analysis also was performed. Results: The GDF10 was screened. The PPI genes were enriched in the TGF-beta signaling pathway, signaling pathways regulating, the pluripotency of stem cells, Cytokine-cytokine receptor interaction, and so on. The hub immunity checkpoint IDO1 was obtained. The joint indicator of two hub genes was positively related to the thyroid differentiation score. Three interaction factors were found to be related to the two hub genes, and 7 kinds of drugs screened act on the two hub genes at the same time. Conclusion: This work indicated that immune-related gene GDF10 and immune checkpoint IDO1 are important for the prognosis prediction of THCA patients, and immunity is involved in the proliferation, and differentiation of tumor cells.

Proton-sensing ion channels, GPCRs and calcium signaling regulated by them: implications for cancer.

Extracellular acidification of tumors is common. Through proton-sensing ion channels or proton-sensing G protein-coupled receptors (GPCRs), tumor cells sense extracellular acidification to stimulate a variety of intracellular signaling pathways including the calcium signaling, which consequently exerts global impacts on tumor cells. Proton-sensing ion channels, and proton-sensing GPCRs have natural advantages as drug targets of anticancer therapy. However, they and the calcium signaling regulated by them attracted limited attention as potential targets of anticancer drugs. In the present review, we discuss the progress in studies on proton-sensing ion channels, and proton-sensing GPCRs, especially emphasizing the effects of calcium signaling activated by them on the characteristics of tumors, including proliferation, migration, invasion, metastasis, drug resistance, angiogenesis. In addition, we review the drugs targeting proton-sensing channels or GPCRs that are currently in clinical trials, as well as the relevant potential drugs for cancer treatments, and discuss their future prospects. The present review aims to elucidate the important role of proton-sensing ion channels, GPCRs and calcium signaling regulated by them in cancer initiation and development. This review will promote the development of drugs targeting proton-sensing channels or GPCRs for cancer treatments, effectively taking their unique advantage as anti-cancer drug targets.

Cuproptosis: A novel therapeutic target for overcoming cancer drug resistance.

Cuproptosis is a newly identified form of cell death driven by copper. Recently, the role of copper and copper triggered cell death in the pathogenesis of cancers have attracted attentions. Cuproptosis has garnered enormous interest in cancer research communities because of its great potential for cancer therapy. Copper-based treatment exerts an inhibiting role in tumor growth and may open the door for the treatment of chemotherapy-insensitive tumors. In this review, we provide a critical analysis on copper homeostasis and the role of copper dysregulation in the development and progression of cancers. Then the core molecular mechanisms of cuproptosis and its role in cancer is discussed, followed by summarizing the current understanding of copper-based agents (copper chelators, copper ionophores, and copper complexes-based dynamic therapy) for cancer treatment. Additionally, we summarize the emerging data on copper complexes-based agents and copper ionophores to subdue tumor chemotherapy resistance in different types of cancers. We also review the small-molecule compounds and nanoparticles (NPs) that may kill cancer cells by inducing cuproptosis, which will shed new light on the development of anticancer drugs through inducing cuproptosis in the future. Finally, the important concepts and pressing questions of cuproptosis in future research that should be focused on were discussed. This review article suggests that targeting cuproptosis could be a novel antitumor therapy and treatment strategy to overcome cancer drug resistance.

FBXO38 mediates FGL1 ubiquitination and degradation to enhance cancer immunity and suppress inflammation.

Upregulation of FGL1 helps tumors escape from immune surveillance, and therapeutic antibodies targeting FGL1 have potential as another immune checkpoint inhibitor. However, the underlying mechanism of high FGL1 protein level in cancers is not well defined. Here, we report that FBXO38 interacts with and ubiquitylates FGL1 to negatively regulate its stability and to mediate cancer immune response. Depletion of FBXO38 markedly augments FGL1 abundance, not only suppressing CD8+ T cell infiltration and enhancing immune evasion of tumor but also increasing inflammation in mice. Importantly, we observe a negative correlation of FBXO38 with FGL1 and IL-6 in non-small cell lung cancer specimens. FGL1 and IL-6 levels positively correlate with TNM (tumor, lymph node, metastasis) stages, while FBXO38 and the infiltrating CD8+ T cells negatively correlate with TNM stages. Our study identifies a mechanism regulating FGL1 stability and a target to enhance the immunotherapy and suggests that the combination of anti-FGL1 and anti-IL-6 is a potential therapeutic strategy for cancer immunotherapy.

Single-cell epigenomics and spatiotemporal transcriptomics reveal human cerebellar development.

Human cerebellar development is orchestrated by molecular regulatory networks to achieve cytoarchitecture and coordinate motor and cognitive functions. Here, we combined single-cell transcriptomics, spatial transcriptomics and single cell chromatin accessibility states to systematically depict an integrative spatiotemporal landscape of human fetal cerebellar development. We revealed that combinations of transcription factors and cis-regulatory elements (CREs) play roles in governing progenitor differentiation and cell fate determination along trajectories in a hierarchical manner, providing a gene expression regulatory map of cell fate and spatial information for these cells. We also illustrated that granule cells located in different regions of the cerebellar cortex showed distinct molecular signatures regulated by different signals during development. Finally, we mapped single-nucleotide polymorphisms (SNPs) of disorders related to cerebellar dysfunction and discovered that several disorder-associated genes showed spatiotemporal and cell type-specific expression patterns only in humans, indicating the cellular basis and possible mechanisms of the pathogenesis of neuropsychiatric disorders.

Squamous cell carcinoma of the cystic duct: A case report and literature review.

RATIONALE: Pure squamous cell carcinoma (SCC) of the gallbladder is a rare malignant biliary tract tumor predominantly found in the body and neck of the gallbladder. However, its occurrence in the cystic duct is even rarer. Given its rarity, no established guidelines or consensus currently exist regarding the treatment of pure SCC of the gallbladder. We report an unusual case of SCC originating from the cystic duct with the intent of providing insights into the therapeutic approach for this type of malignancy. PATIENT CONCERNS: A male patient presented to our hospital with acute cholecystitis. Unexpectedly, imaging revealed gallbladder malignancy. DIAGNOSES: Pathologic examination after surgery confirmed SCC of the cystic duct. INTERVENTIONS: Despite elevated bilirubin levels, we were able to exclude hilar involvement, enabling radical tumor resection. Intraoperatively, we discovered that the tumor was located in the cystic duct, a site associated with a high likelihood of invasion into neighboring organs. The tumor demonstrated a predominantly exophytic growth pattern, which prompted us to refrain from extending the resection range, thereby striking a balance between complete tumor removal and surgical trauma. We performed liver wedge resection only to ensure a negative resection margin while preserving the anatomical structure to the greatest extent possible. Postoperative recovery was rapid and uncomplicated. Pathological examination confirmed pure SCC, which led us to initiate a regimen of nab-paclitaxel and cisplatin, which is known to be effective in other organ SCCs. Remarkably, the patient experienced a rare and severe posttreatment cardiovascular event. Consequently, we switched the patient to a chemotherapy regimen of gemcitabine and cisplatin, which ultimately yielded positive clinical outcomes. OUTCOMES: no evidence of tumor recurrence was observed within 1 year after surgery. LESSONS: The diagnosis and therapeutic strategy for rare tumors such as gallbladder SCC should be meticulously tailored based on their unique characteristics to optimize postoperative patient outcomes.

Audit to assess the quality of 916 prosthetic prescriptions of removable partial dentures.

OBJECTIVES: The objectives of this study were to assess the quality of prosthetic prescriptions of removable partial dentures (RPDs) and to analyze the current situation of the communication and information delivery between clinicians and technicians. METHODS: All RPD prosthetic prescriptions received by a major dental laboratory in 4 weeks were involved in a quality audit, and the prescriptions were divided into three groups in accordance with the grades of clients. The filling of prosthetic prescriptions was recorded. The items in the prescriptions for audit included the general information of the patient, the general information of the clinician, the design diagram information, other detailed information, and the return date. The prescriptions were categorized into four levels on the basis of their quality by two quality inspectors who have been working for more than 10 years. RESULTS: A total of 916 prescriptions were collected and assessed. The names in the general information of the patient and the clinician were filled out best, both at the rate of 97.6% (n=894). The return date was filled out worst, only at the rate of 6.4% (n=59). Of those prescriptions, 86.8% (n=795) exhibited inadequate design diagram information. The results of the quality assessment demonstrated that 74.2% of prescriptions were assessed as noncompliant ones and failed to meet the acceptable clinical quality standard. CONCLUSIONS: At present, the overall quality of RPD prosthetic prescriptions is poor. The responsibilities of clinicians and technicians are unclear, and the communication between them is not ideal.

Digital technology for fluid resin injection to close anterior diastema after orthodontic treatment.

Anterior diastema and tooth defects are common clinical issues in restorative dentistry and are often restored by veneers or crowns based on the results of digital smile design and wax-up. Traditional direct resin restoration for closing a diastema is relatively minimally invasive but is time consuming and laborious, and shape control depends on experience. Digital technology can be used to design and transfer the shape of aesthetic restoration more accurately and quickly; thus, it could close anterior diastema and restore defects easily. According to the workflow, this technical process integrates virtual design and practical wax-up, transfers the designed restoration shape by templates, and injects through the preset channel after the template is in place. This clinical technique simplifies the clinical operation and saves clinical time, which can effectively improve the predictability and accuracy of the restoration and reduce technical sensitivity. This digital workflow provides a new technology for closing diastema quickly and effectively.

Kidney ion handling genes and their interaction in blood pressure control.

Hypertension affects 30% of adults and is the leading risk factor for cardiovascular disease. Kidney sodium reabsorption plays a vital role in the initial stage and development of essential hypertension. It has been extensively reported that the variants of kidney ion handling genes are associated to blood pressure, and clinical features of hypertension. However, the underlying mechanisms by which these variants alter protein function are rarely summarized. In addition, the variation of one single gene is often limited to induce a significant effect on blood pressure. In the past few decades, the influence by genes × genes (G × G) and/or genotype × environment (G × E) interactions on a given trait, for example, blood pressure, have been widely considered, especially in studies on polygenic genetic traits. In the present review, we discuss the progress in genetics studies on kidney ion handling genes, encoding Na+ channels (Na+-Cl- cotransporter [NCC], Na-K-2Cl cotransporter [NKCC2], epithelial Na+ channels [ENaCs]), K+ channel (renal outer medullary potassium channel [ROMK]), and Cl- channels (Pendrin, chloride voltage-gated channel Kb [CLC-Kb]), respectively, and their upstream kinases, WNKs and SGK1. We seek to clarify how these genes are involved in kidney sodium absorption and influence blood pressure, especially emphasizing the underlying mechanisms by which genetic variants alter protein functions and interaction in blood pressure regulation. The present review aims to enhance our understanding of the important role of kidney ion handling genes/channels in blood pressure control.

A modified kidney-sparing portal vein arterialization model of heterotopic auxiliary liver transplantation increases liver IL-6, TNF-α, and HGF levels and enhances liver regeneration: an animal model.

BACKGROUND AND AIM: The success of partial donor liver transplantation is affected by the implantation site of the donor liver and the vascular reconstruction approach. We investigated the effects of different donor liver implantation sites and vascular reconstruction approaches on liver regeneration using a rat kidney-sparing heterotopic auxiliary liver transplantation model, with portal vein arterialization (PVA). METHODS: Sixty male Sprague-Dawley rats underwent end-to-end anastomosis of the donor liver portal vein and the right renal artery stent (control group), or end-to-side anastomosis of the donor liver portal vein and the left common iliac artery (experimental group). RESULTS: The experimental group had significantly lower plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, and cholinesterase than the control group (all, P < 0.05). The levels of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and hepatocyte growth factor (HGF) in the liver were significantly higher in the experimental group than that in the control group (all, P < 0.05). Hematoxylin and eosin (HE) staining of the liver tissue specimens indicated that the experimental group had greater hepatocyte regeneration compared to the control group. CONCLUSIONS: The modified kidney-sparing PVA model of heterotopic auxiliary liver transplantation is more conducive to liver regeneration with quicker return of liver function.

A digital workflow for layering composite resin restorations by using 3-dimensionally printed templates to replicate the contralateral tooth accurately and rapidly.

This article described a digital workflow for layering composite resin restorations by using a digital software program and 3-dimensionally printed templates. To mimic the appearance of the natural tooth, the computer-aided design was used to copy the shape of the contralateral tooth. Three-dimensionally printed templates to replicate the contralateral tooth accurately and rapidly can help dentists build different layers of dentin and enamel composite resin, achieving layered esthetic outcomes. This workflow provides an efficient and accurate procedure, reduces chairside time, and simplifies the application of the technically sensitive composite resin layering technique.

A digital workflow with the virtual enamel evaluation and stereolithographic template for accurate tooth preparation to conservatively manage a case of complex exogenous dental erosion.

OBJECTIVE: This article describes a digital workflow using virtual enamel evaluation and a stereolithographic template for accurate tooth preparation for a complex exogenous dental erosion. CLINICAL CONSIDERATIONS: A 22-year-old man with different degrees of defects on the labial surface in esthetic area was diagnosed as exogenous dental erosion. The residual undamaged enamel area and depth of defect were measured and analyzed accurately by creating a digital virtual patient based on the pretreatment data. According to the different conditions of residual enamel and tooth defect, the treatment plans of porcelain veneer, crown and composite resin were chosen for corresponding involved teeth. Based on the virtual wax-up and the suggested material thickness, a template for tooth preparation was designed and three-dimensional printed. This template together with a special bur indicating the reduction depth accurately guided the teeth preparation and achieved a long-term effect. CONCLUSIONS: The virtual enamel evaluation contributes to obtaining the appropriate corresponding treatment plan objectively. The stereolithographic template effectively meets the accuracy of tooth preparation, preserving the tooth hard tissue to the greatest extent. CLINICAL SIGNIFICANCE: The digital workflow described here may provide a quantifiable evaluation method and an accurate tooth preparation method for exogenous dental erosion.

Mouse and human share conserved transcriptional programs for interneuron development.

Genetic variation confers susceptibility to neurodevelopmental disorders by affecting the development of specific cell types. Changes in cortical and striatal γ-aminobutyric acid­expressing (GABAergic) neurons are common in autism and schizophrenia. In this study, we used single-cell RNA sequencing to characterize the emergence of cell diversity in the human ganglionic eminences, the transitory structures of the human fetal brain where striatal and cortical GABAergic neurons are generated. We identified regional and temporal diversity among progenitor cells underlying the generation of a variety of projection neurons and interneurons. We found that these cells are specified within the human ganglionic eminences by transcriptional programs similar to those previously identified in rodents. Our findings reveal an evolutionarily conserved regulatory logic controlling the specification, migration, and differentiation of GABAergic neurons in the human telencephalon.

An investigation of the microstructure and mechanical properties of dental zirconia manufactured by digital light processing 3D printing.

OBJECTIVES: This study was performed to investigate the microstructure and mechanical properties of dental zirconia manufactured by digital light processing (DLP) 3D printing and the clinical application prospects of this material. METHODS: The experiment (DLP) group was zirconia manufactured by DLP 3D printing, and the control (MILL) group was milled zirconia. The density, grain size, and phase composition were measured to study the microstructure. Flexural strength was measured by using three-point bending tests, while Vickers hardness was determined through a Vickers hardness tester. Fracture toughness was tested using the single-edge V-notched beam method. RESULTS: Zirconia density of the DLP group was (6.019 8±0.021 3) g·cm-3, and the average grain size was (0.603 0±0.032 6) µm, but without statistical difference with the corresponding values of the MILL group (P>0.05). Tetragonal phase was found in the X-ray diffraction patterns of the DLP and MILL groups. The flexural strength of the DLP group was (1 012.7±125.5) MPa, and Vickers hardness was (1 238.5±10.8) HV1, which was slightly lower than that of the MILL group (P<0.05). The fracture toughness of the DLP group was (7.22±0.81) MPa·m1/2, which was not statistically different from that of the MILL group (P>0.05). CONCLUSIONS: Zirconia manufactured by DLP 3D printing had microstructure and mechanical properties similar to those of the milled zirconia. Only the flexural strength and the Vickers hardness of the experimental zirconia were slightly lower than those of the milled zirconia. Therefore, DLP-manufactured zirconia has a promising future for clinical use.

Successful totally laparoscopic right trihepatectomy following conversion therapy for hepatocellular carcinoma: A case report.

BACKGROUND: About 20%-30% of newly diagnosed hepatocellular carcinoma (HCC) patients are surgically feasible due to a variety of reasons. Active conversion therapy may provide opportunities of surgery for these patients. Nevertheless, the choice of surgical procedure is controversial after successful conversion therapy. We report a patient with HCC who underwent successful laparoscopic right trisectionectomy after conversion therapy with portal vein embolization and transarterial chemoembolization. CASE SUMMARY: A 67-year-old male patient presented to our hospital with epigastric distention/ discomfort and nausea/vomiting for more than 1 mo. Contrast-enhanced computed tomography scan of the abdomen demonstrated multiple tumors (the largest was ≥ 10 cm in diameter) located in the right liver and left medial lobe, and the left lateral lobe was normal. The future remnant liver (FRL) of the left lateral lobe accounted for only 18% of total liver volume after virtual resection on the three-dimensional liver model. Conversion therapy was adopted after orally administered entecavir for antiviral treatment. First, the right portal vein was embolized. Then tumor embolization was performed via the variant hepatic arteries. After 3 wk, the FRL of the left lateral lobe accounted for nearly 30% of the total liver volume. Totally laparoscopic right trisectionectomy was performed under combined epidural and general anesthesia. The in situ resection was performed via an anterior approach. The operating time was 240 min. No clamping was required during the surgery, and the intraoperative blood loss was 300 mL. There were no postoperative complications such as bile leakage, and the incision healed well. The patient was discharged on the 8th postoperative day. During the 3-mo follow-up, there was no recurrence and obvious hyperplasia of residual liver was observed. Alpha-fetoprotein decreased significantly and tended to be normal. CONCLUSION: Due to the different biological characteristics of the liver cancer and the pathophysiological features of the liver from other organs, the conversion treatment should take into account both the feasibility of tumor downstaging and the volume and function of the remnant liver. Our case provides a reference for clinicians in terms of both conversion therapy and laparoscopic right trisectionectomy.