Tumor budding in pre-neoadjuvant biopsy and post-neoadjuvant resection specimens is associated with poor prognosis in intrahepatic cholangiocarcinoma-a cohort study of 147 cases by modified ITBCC criteria.

Tumor budding (TB) has been associated with poor survival in a variety of cancers including intrahepatic cholangiocarcinoma (iCCA). As tumor histomorphological features are significantly altered after neoadjuvant therapy (NAT), our study aims to assess the prognostic significance of TB in iCCA patients before and after NAT, by the modified International Tumor Budding Consensus Conference (ITBCC) criteria. 147 NAT-treated iCCA cases were included in this study. In biopsy specimens obtained before NAT, the TB-positive subgroup had lower overall survival (OS) in univariate analysis (P = 0.010). In resection specimens obtained after NAT, the TB-positive subgroup had reduced OS (P = 0.002) and recurrence-free survival (RFS) (P = 0.013) in univariate analysis. In multivariate analysis including TNM stage, lymphovascular invasion and perineural invasion, TB-positive in post-NAT resection was also found as an independent prognostic factor for both OS and RFS (OS, HR, 3.005; 95% CI, 1.333-6.775, P = 0.008; RFS, HR, 1.748; 95% CI, 1.085-2.816, P = 0.022). In conclusion, assessing the presence of TB by modified ITBCC criteria provides robust prognostic information in the NAT setting of iCCA patients and can be considered to be included in routine pathological reporting.

Structural and covariance network alterations of the hippocampus and amygdala in congenital hearing loss children.

OBJECTIVE: The hippocampus and amygdala, as important components of the limbic system, play crucial roles in central remodeling in congenital hearing loss. This study aimed to investigate the morphological integrity and network properties of the subfields of hippocampus and amygdala in children with congenital hearing loss. METHODS: A total of 24 children with congenital hearing loss and 17 age- and sex- matched healthy controls (HC) are included in the study. T1-weighted images are analyzed by segmenting the brain into cortical and subcortical regions. Intergroup difference of volumes were explored. Structural covariance networks for the whole brain and hippocampus-amygdala subregions were constructed. Between-group differences of network property are investigated by comparing area under a range of network sparsity. RESULTS: Patients with congenital hearing loss exhibited significantly larger volumes in the right dentate gyrus and CA3 of the hippocampus. However, there were no significant differences in total hippocampal or showed decreased global efficiency and increased characteristic path length, indicating reduced network integration. Lower betweenness centrality was observed in the left hippocampal fissure in the hearing loss group. The changes in volume and network topological properties are not affected by age and sex. CONCLUSION: Children with congenital hearing loss display specific volumetric increases in hippocampal subregions, suggesting compensatory adaptations to auditory deprivation. The hippocampus-amygdala network shows significant reorganization, potentially underpinning cognitive and behavioral development issues associated with congenital hearing loss. These findings highlight the importance of targeted neural substrates in understanding and addressing the developmental challenges faced by children with congenital hearing loss.

Inhibitor Development for α-Synuclein Fibril's Disordered Region to Alleviate Parkinson's Disease Pathology.

The amyloid fibrils of α-synuclein (α-syn) are crucial in the pathology of Parkinson's disease (PD), with the intrinsically disordered region (IDR) of its C-terminal playing a key role in interacting with receptors like LAG3 and RAGE, facilitating pathological neuronal spread and inflammation. In this study, we identified Givinostat (GS) as an effective inhibitor that disrupts the interaction of α-syn fibrils with receptors such as LAG3 and RAGE through high-throughput screening. By exploring the structure-activity relationship and optimizing GS, we developed several lead compounds, including GSD-16-24. Utilizing solution-state and solid-state NMR, along with cryo-EM techniques, we demonstrated that GSD-16-24 binds directly to the C-terminal IDR of α-syn monomer and fibril, preventing the fibril from binding to the receptors. Furthermore, GSD-16-24 significantly inhibits the association of α-syn fibrils with membrane receptors, thereby reducing neuronal propagation and pro-inflammatory effects of α-syn fibrils. Our findings introduce a novel approach to mitigate the pathological effects of α-syn fibrils by targeting their IDR with small molecules, offering potential leads for the development of clinical drugs to treat PD.

The Gly103Arg variant in hereditary transthyretin amyloidosis.

Background: Hereditary transthyretin amyloidosis (ATTRv) is an autosomal dominant inherited systematic disease primarily affecting the peripheral and autonomic nervous system, heart, eyes and kidney. Over 140 variants have been identified worldwide, with the Gly103Arg variant reported exclusively in China. This variant is characterized by early onset eye manifestations, making accurate and timely diagnosis difficult. Therefore, we conducted a case study and literature review to investigate the clinical characteristics of the Gly103Arg variant in hereditary transthyretin amyloidosis. Methods: We identified three patients and an asymptomatic carrier in a four-generation family by sequencing the TTR gene. The proband underwent a lumbar puncture, electromyography, abdominal fat biopsy, among other tests. Case reports of Gly103Arg variant were retrieved through a literature search for an analysis of clinical characteristics. Results: The study included clinical data of 44 patients. Our literature review collected data on 41 patients and the present report supplied 3 patients with the Gly103Arg variant. The mean age at onset was 39.1 ± 4.27 years (range 30-47 years) with a female ratio of 52.3%. All cases were reported in China, predominantly in southern regions, especially Yunan and Guizhou Provinces. The initial manifestation was blurred vision, except for one case presenting with numbness in the upper extremities. All of them had vitreous opacity; 17 cases had peripheral neuropathy,6 cases had autonomic neuropathy, and 3 cases had cardiopathy. No disease-related deaths have been reported to date. Conclusion: The Gly103Arg variant is unique to the Chinese population, frequently occurring in southern China. The main clinical manifestations are blurred vision, vitreous opacity, and neuropathy, with cardiopathy being rare. ATTRv should be considered if a patient diagnosed with CIDP does not respond to related therapy. Abdominal fat biopsy is a convenient and accurate diagnostic method.

Investigation of Persistent Photoconductivity of Gallium Nitride Semiconductor and Differentiation of Primary Neural Stem Cells.

A gallium nitride (GaN) semiconductor is one of the most promising materials integrated into biomedical devices to play the roles of connecting, monitoring, and manipulating the activity of biological components, due to its excellent photoelectric properties, chemical stability, and biocompatibility. In this work, it was found that the photogenerated free charge carriers of the GaN substrate, as an exogenous stimulus, served to promote neural stem cells (NSCs) to differentiate into neurons. This was observed through the systematic investigation of the effect of the persistent photoconductivity (PPC) of GaN on the differentiation of primary NSCs from the embryonic rat cerebral cortex. NSCs were directly cultured on the GaN surface with and without ultraviolet (UV) irradiation, with a control sample consisting of tissue culture polystyrene (TCPS) in the presence of fetal bovine serum (FBS) medium. Through optical microscopy, the morphology showed a greater number of neurons with the branching structures of axons and dendrites on GaN with UV irradiation. The immunocytochemical results demonstrated that GaN with UV irradiation could promote the NSCs to differentiate into neurons. Western blot analysis showed that GaN with UV irradiation significantly upregulated the expression of two neuron-related markers, ßIII-tubulin (Tuj-1) and microtubule-associated protein 2 (MAP-2), suggesting that neurite formation and the proliferation of NSCs during differentiation were enhanced by GaN with UV irradiation. Finally, the results of the Kelvin probe force microscope (KPFM) experiments showed that the NSCs cultured on GaN with UV irradiation displayed about 50 mV higher potential than those cultured on GaN without irradiation. The increase in cell membrane potential may have been due to the larger number of photogenerated free charges on the GaN surface with UV irradiation. These results could benefit topical research and the application of GaN as a biomedical material integrated into neural interface systems or other bioelectronic devices.

A scoring-based clinical grading model for xanthelasma palpebrarum: predicting treatment frequency and prognosis.

Xanthelasma palpebrarum is one of the most common cutaneous xanthomas in humans. Currently, there are various methods available for treating xanthelasma palpebrarum, but the high treatment frequency and recurrence rate remain significant challenges for patients. Therefore, it is necessary to establish a reasonable and effective clinical grading system to guide the diagnosis and treatment of xanthelasma palpebrarum. We developed a clinical scoring system related to local injection of pingyangmycin for the treatment of xanthelasma palpebrarum, which can be used to predict early prognosis and treatment outcomes in patients. We collected and retrospectively studied 246 outpatient cases of xanthelasma palpebrarum treated with local injection of pingyangmycin in the Department of Plastic Surgery at Shanghai East Hospital from February 2020 to August 2022. Potential independent risk factors for adverse outcomes (recurrence or non-recurrence) were considered in univariate and multivariate logistic regression models. Predictive factors were determined based on the multivariate logistic regression model and Cox model, and a scoring grading system was established. External validation was conducted on an independent cohort of 110 patients. Based on logistic regression analysis, the number, area, and color of lesions were identified as significant predictive indicators (P < 0.05), with respective AUCs of 0.710, 0.799, and 0.755. The Cox model established hazard ratios for four new severity indicators of xanthelasma palpebrarum: hyperlipidemia, number of lesions, lesion area, and lesion grayscale value. Based on these findings, a new clinical grading model was developed, which was validated to be effective in the external cohort. The new scoring-based clinical predictive model can effectively predict the number of pingyangmycin injection treatments and prognosis in patients with xanthelasma palpebrarum. It holds promise for broader application in clinical practice.

Integrated Analysis Reveals COL4A3 as a Novel Diagnostic and Therapeutic Target in UV-Related Skin Cutaneous Melanoma.

Background: High levels of UV exposure are a significant factor that can trigger the onset and progression of SKCM. Moreover, this exposure is closely linked to the malignancy of the tumor and the prognosis of patients. Our objective is to identify a tumor biomarker database associated with UV exposure, which can be utilized for prognostic analysis and diagnosis and treatment of SKCM. Methods: This study used the weighted gene co-expression network analyses (WGCNA) and gene mutation frequency analyses to screen for UV-related target genes using the GSE59455 and the cancer genome atlas databases (TCGA). The prognostic model was created using Cox regression and least absolute shrinkage and selection operator analyses (LASSCO). Furthermore, in vitro experiments further validated that the overexpression or knockdown of COL4A3 could regulate the proliferation and migration abilities of SKMEL28 and A357 melanoma cells. Results: A prognostic model was created that included six genes with a high UV-related mutation in SKCM: COL4A3, CHRM2, DSC3, GIMAP5, LAMC2, and PSG7. The model had a strong patient survival correlation (P˂0.001, hazard ratio (HR) = 1.57) and significant predictor (P˂0.001, HR = 3.050). Furthermore, the model negatively correlated with immune cells, including CD8+ T cells (Cor=-0.408, P˂0.001), and M1-type macrophages (Cor=-0.385, P˂0.001), and immune checkpoints, including programmed cell death ligand-1. Moreover, we identified COL4A3 as a molecule with significant predictive functionality. Overexpression of COL4A3 significantly inhibited the proliferation, migration, and invasion abilities of SKMEL28 and A357 melanoma cells, while knockdown of COL4A3 yielded the opposite results. And overexpression of COL4A3 enhanced the inhibitory effects of imatinib on the proliferation, migration, and invasion abilities of SKMEL28 and A357 cells. Conclusion: The efficacy of the prognostic model was validated by analyzing the prognosis, immune infiltration, and immune checkpoint profiles. COL4A3 stands out as a novel diagnostic and therapeutic target for SKCM, offering new strategies for small-molecule targeted drug therapies.

Single-cell transcriptome reveals the heterogeneity of malignant ductal cells and the prognostic value of REG4 and SPINK1 in primary pancreatic ductal adenocarcinoma.

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths, with very limited therapeutic options available. This study aims to comprehensively depict the heterogeneity and identify prognostic targets for PDAC with single-cell RNA sequencing (scRNA-seq) analysis. Methods: ScRNA-seq analysis was performed on 16 primary PDAC and three adjacent lesions. A series of analytical methods were applied for analysis in cell clustering, gene profiling, lineage trajectory analysis and cell-to-cell interactions. In vitro experiments including colony formation, wound healing and sphere formation assay were performed to assess the role of makers. Results: A total of 32,480 cells were clustered into six major populations, among which the ductal cell cluster expressing high copy number variants (CNVs) was defined as malignant cells. Malignant cells were further subtyped into five subgroups which exhibited specific features in immunologic and metabolic activities. Pseudotime trajectory analysis indicated that components of various oncogenic pathways were differentially expressed along tumor progression. Furthermore, intensive substantial crosstalk between ductal cells and stromal cells was identified. Finally, genes (REG4 and SPINK1) screened out of differentially expressed genes (DEGs) were upregulated in PDAC cell lines. Silencing either of them significantly impaired proliferation, invasion, migration and stemness of PDAC cells. Conclusions: Our findings offer a valuable resource for deciphering the heterogeneity of malignant ductal cells in PDAC. REG4 and SPINK1 are expected to be promising targets for PDAC therapy.

Influence of glucagon-like peptide-1 receptor agonists on fat accumulation in patients with diabetes mellitus and non-alcoholic fatty liver disease or obesity: A systematic review and meta-analysis of randomized control trials.

AIM: This systematic review and meta-analysis aimed to comprehensively evaluate the impact of glucagon-like peptide 1 receptor agonists (GLP-1RAs) on visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in individuals with diabetes mellitus and non-alcoholic fatty liver disease (NAFLD) or obesity. METHODS: A search of PubMed, Embase, and Web of Science until October 2023 identified 13 Randomized Controlled Trials (RCTs) meeting the inclusion criteria. Bias risk was assessed using the Cochrane risk-of-bias instrument. Statistical analysis utilized standard mean differences (SMD) in Review Manager 5.4. Heterogeneity and publication bias were assessed. This study used the protocol registered with the Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY2023110020). RESULTS: GLP-1RA treatment significantly reduced VAT (SMD -0.55, 95 % CI [-0.90, -0.19]), SAT (SMD -0.59, 95 % CI [-0.99, -0.19]), body weight (SMD -1.07, 95 % CI [-1.67, -0.47]), and body mass index (BMI) (SMD -1.10, 95 % CI [-1.74, -0.47]) compared to controls. Heterogeneity was observed for VAT (I2 = 79 %, P < 0.01), SAT (I2 = 73 %, P < 0.01), body weight (I2 = 82 %, P < 0.01), and BMI (I2 = 82 %, P < 0.01). No publication bias was detected for VAT (P = 0.57) and SAT (P = 0.18). GLP-1RA treatment improved fasting blood glucose (FBG), postprandial glucose (PPG), hemoglobin A1c (HbA1c), Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), and fibrosis-4 (FIB-4). CONCLUSIONS: This meta-analysis highlights GLP-1RAs' potential to reduce fat accumulation, body weight, and BMI and improve glycemic control in individuals with diabetes mellitus and NAFLD or obesity. These findings supported using GLP-1RAs as promising therapeutic agents to address abnormal adipose tissue distribution and metabolic dysfunction.

Tinnitus classification based on resting-state functional connectivity using a convolutional neural network architecture.

OBJECTIVES: Many studies have investigated aberrant functional connectivity (FC) using resting-state functional MRI (rs-fMRI) in subjective tinnitus patients. However, no studies have verified the efficacy of resting-state FC as a diagnostic imaging marker. We established a convolutional neural network (CNN) model based on rs-fMRI FC to distinguish tinnitus patients from healthy controls, providing guidance and fast diagnostic tools for the clinical diagnosis of subjective tinnitus. METHODS: A CNN architecture was trained on rs-fMRI data from 100 tinnitus patients and 100 healthy controls using an asymmetric convolutional layer. Additionally, a traditional machine learning model and a transfer learning model were included for comparison with the CNN, and each of the three models was tested on three different brain atlases. RESULTS: Of the three models, the CNN model outperformed the other two models with the highest area under the curve, especially on the Dos_160 atlas (AUC = 0.944). Meanwhile, the model with the best classification performance highlights the crucial role of the default mode network, salience network, and sensorimotor network in distinguishing between normal controls and patients with subjective tinnitus. CONCLUSION: Our CNN model could appropriately tackle the diagnosis of tinnitus patients using rs-fMRI and confirmed the diagnostic value of FC as measured by rs-fMRI.

Retention of titanium copings to implant-supported fixed dental prostheses.

PURPOSE: The aim of this in vitro study was to assess the effects of using different cements and titanium copings designs on the retention of implant-supported fixed dental prostheses (IFDPs) using a pull-out test. MATERIALS AND METHODS: Fifty zirconia (ZirCAD; Ivoclar Vivadent) and 20 prepolymerized denture acrylic resin (AvaDent) rectangular (36 mm × 12 mm × 8 mm) specimens were milled to mimic the lower left segmental portion of the All-on-Four IFDPs. Cylindrical titanium copings (Variobase; Straumann) (V) were used in 2 prepolymerized denture acrylic resin groups (n = 10) while conical titanium copings (Straumann) (C) were used as a control group for zirconia with 4 groups using cylindrical titanium copings. Before cementation, the outer surfaces of all titanium copings and the intaglio bonding surface of prosthetic specimens were airborne-particle abraded. All specimens were cemented following the manufacturer's recommendations and instructions according to the experimental design. After artificial aging (5000 cycles of 5°C 55°C, dwelling time 20 s; 150 N, 1.5 Hz in a 37°C water bath), all specimens were subjected to retention force testing using a pull-out test using a universal testing machine and a custom fixture with a crosshead speed 5 mm/min. Modes of failure were classified as Type 1, 2, or 3. Retention force values were analyzed by the t-test for the prepolymerized denture acrylic resin specimen groups, and 1-way ANOVA and the Tukey test for the zirconia groups at α = 0.05. RESULTS: Mean and standard deviation retention force values varied from 101.1 ± 67.1 to 509.0 ± 65.2 N for the prepolymerized denture acrylic resin specimen groups. The zirconia groups ranged from 572.8 ± 274.7 to 1416.1 ± 258.0 N. There is no statistically significant difference in retention force values between V and C specimens cementing to zirconia with Panavia SA cement (Kuraray Noritake) (p = 0.587). The retention forces and failure modes were influenced by the cement used (p < 0.05). Modes of failure were predominantly Type 2 (mixed failure) and Type 1 (adhesive fracture from prosthetic materials) except for the quick-set resin group (Type 3, adhesive failure from coping). CONCLUSIONS: When bonding IFDPs onto titanium copings, quick-set resin provided significantly higher retention force for prepolymerized denture acrylic resin prostheses. Conical and cylindrical titanium copings performed similarly when cemented to zirconia with Panavia SA cement under the same protocol. The stability of the bonded interface and retention forces between zirconia prostheses and titanium copings varied from the cement used.

The effects of propranolol on the biology and Notch signaling pathway of human umbilical vein endothelial cells.

BACKGROUND: Propranolol is the first choice for treating infantile hemangioma (IH). How propranolol works in IH remains unclear. Infantile hemangioma endothelial cells (HemECs) express Notch1, Jagged, Hey1, and other molecules in the Notch pathway, suggesting that Notch pathway-related molecules play an important role in affecting vascular endothelial cell proliferation. Whether propranolol can affect the Notch signaling pathway in IH treatment is unclear. METHODS: We performed this study to observe the effect of propranolol on the expression of Notch signaling pathway molecules in human umbilical vein endothelial cells (HUVECs) and to explore the therapeutic mechanism of propranolol on IH. HUVECs cultured in vitro were exposed to 60, 120, 240, 360, or 480 µM propranolol. The morphological changes of the HUVECs were observed under an inverted microscope. HUVECs proliferation was detected with Cell Counting Kit-8 (CCK-8). The effects of propranolol on HUVECs apoptosis were detected by flow cytometry. The role of Notch in propranolol inhibition of HUVEC proliferation was analyzed with real-time polymerase chain reaction (PCR) and western blotting. RESULTS: Propranolol reduced HUVECs numbers and altered their morphology. The inhibitory effect of propranolol on cell proliferation was dependent on the reaction time and drug concentration. Propranolol upregulated Jagged1, Notch1, and Hey1 expression and downregulated delta-like ligand4 (DLL4) expression. CONCLUSIONS: Propranolol may play a role in IH treatment by increasing Jagged1 expression in endothelial cells, activating the Notch pathway and inducing the upregulation of the downstream target gene HEY1.

Early autoimmunity and outcome in virus encephalitis: a retrospective study based on tissue-based assay.

To explore the autoimmune response and outcome in the central nervous system (CNS) at the onset of viral infection and correlation between autoantibodies and viruses. METHODS: A retrospective observational study was conducted in 121 patients (2016-2021) with a CNS viral infection confirmed via cerebrospinal fluid (CSF) next-generation sequencing (cohort A). Their clinical information was analysed and CSF samples were screened for autoantibodies against monkey cerebellum by tissue-based assay. In situ hybridisation was used to detect Epstein-Barr virus (EBV) in brain tissue of 8 patients with glial fibrillar acidic protein (GFAP)-IgG and nasopharyngeal carcinoma tissue of 2 patients with GFAP-IgG as control (cohort B). RESULTS: Among cohort A (male:female=79:42; median age: 42 (14-78) years old), 61 (50.4%) participants had detectable autoantibodies in CSF. Compared with other viruses, EBV increased the odds of having GFAP-IgG (OR 18.22, 95% CI 6.54 to 50.77, p<0.001). In cohort B, EBV was found in the brain tissue from two of eight (25.0%) patients with GFAP-IgG. Autoantibody-positive patients had a higher CSF protein level (median: 1126.00 (281.00-5352.00) vs 700.00 (76.70-2899.00), p<0.001), lower CSF chloride level (mean: 119.80±6.24 vs 122.84±5.26, p=0.005), lower ratios of CSF-glucose/serum-glucose (median: 0.50[0.13-0.94] vs 0.60[0.26-1.23], p=0.003), more meningitis (26/61 (42.6%) vs 12/60 (20.0%), p=0.007) and higher follow-up modified Rankin Scale scores (1 (0-6) vs 0 (0-3), p=0.037) compared with antibody-negative patients. A Kaplan-Meier analysis revealed that autoantibody-positive patients experienced significantly worse outcomes (p=0.031). CONCLUSIONS: Autoimmune responses are found at the onset of viral encephalitis. EBV in the CNS increases the risk for autoimmunity to GFAP.

Conformational Dynamics of an α-Synuclein Fibril upon Receptor Binding Revealed by Insensitive Nuclei Enhanced by Polarization Transfer-Based Solid-State Nuclear Magnetic Resonance and Cryo-Electron Microscopy.

Many amyloid fibrils associated with neurodegenerative diseases consist of an ordered fibril core (FC) and disordered terminal regions (TRs). The former represents a stable scaffold, while the latter is rather active in binding with various partners. Current structural studies mainly focus on the ordered FC since the high flexibility of TRs hinders structural characterization. Here, by combining insensitive nuclei enhanced by polarization transfer-based 1H-detected solid-state NMR and cryo-EM, we explored the intact structure of an α-syn fibril including both FC and TRs and further studied the conformational dynamics of the fibril upon binding to lymphocyte activation gene 3 (LAG3)─a cell surface receptor that is involved in α-syn fibril transmission in brains. We found that both the N- and C-TRs of α-syn are disordered in free fibrils featuring similar conformation ensembles as those in soluble monomers. While in the presence of the D1 domain of LAG3 (L3D1), the C-TR directly binds to L3D1, meanwhile the N-TR folds into a ß-strand and further integrates with the FC, which leads to alteration of the overall fibril structure and surface property. Our work reveals synergistic conformational transition of the intrinsically disordered TRs of α-syn, which sheds light on mechanistic understanding of the essential role of TRs in regulating the structure and pathology of amyloid fibrils.

Understanding and Targeting the Epigenetic Regulation to Overcome EGFR-TKIs Resistance in Human Cancer.

BACKGROUND: The occurrence and progression of cancer are the results of the dysregulation of genetics and epigenetics. Epigenetic regulation can reversibly affect gene transcription activity without changing DNA structure. Covalent modification of histones is crucial in the epigenetic regulation of gene expression. Furthermore, epidermal growth factor receptor (EGFR) significantly affects cell tumorigenesis, proliferation, antitumor drug resistance, etc. Overexpression of EGFR promotes cancer development. Therefore, EGFR-targeted drugs have become the focus of tumor therapy. With the advent of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), EGFR-TKIs resistance, which occurs about half a year to a year, has become an obstacle in cancer treatment. OBJECTIVE: The objective of this study is to discuss the ways to overcome EGFR-TKIs resistance in a variety of tumors. METHODS: The combination therapy of epigenetic drugs and other drugs is used. RESULTS: The combination of the two drugs can overcome the resistance of EGFR-TKIs and prolong the survival of patients. CONCLUSION: This article depicts the concepts of epigenetics and the mechanism of EGFR-TKIs resistance and then illustrates the relationship between epigenetic mechanisms and EGFR-TKIs resistance. Finally, it discusses the clinical research and the latest patents for using epigenetic drugs to reverse EGFR-TKIs resistance in human cancer. In the future, more novel targets may be discovered for overcoming resistance to EGFR-TKIs, not just on histone deacetylases (HDACs). The dosing course and mode of administration of the combination therapy containing epigenetic drugs need further study. This review provides new ideas for using epigenetic agents to overcome EGFR-TKIs resistance.

Clinical and functional characterisation of the SMAD4 germline variant c.1035C > A in a family with juvenile polyposis syndrome by whole-exome sequencing.

Juvenile polyposis syndrome (JPS) is a rare autosomal dominant inherited disease characterised by multiple juvenile polyps. Genes with JPS-associated mutations and their correlation with the phenotype are currently unknown. Gastrointestinal endoscopy results of a 31-year-old female patient showed multiple polyps in the digestive tract, and the presence of juvenile polyps was confirmed by pathological examination. During follow-up, the patient underwent total gastrectomy and polypectomy several times. Five members of this family were diagnosed with JPS, of which two died and three survived. Full exon gene sequencing of eight members of this family revealed a SMAD4 (NM-005359.3) c.1035C > A (p.Cys345*) mutation. This mutation leads to premature codon termination, causing protein truncation. SMAD4 is a pathogenic gene associated with JPS. This is the first report of an association between the c.1035C > A mutation and JPS pathogenesis. Detection of JPS-related mutations in family members with a genetic predisposition for JPS is very important for genetic counselling, surgical intervention, long-term monitoring and follow-up, and drug treatment.

Effect of airborne-particle abrasion with a novel spherical abrasive on the zirconia surface.

STATEMENT OF PROBLEM: A novel zirconia-alumina composite (ZAC) particle has yet to be studied for airborne-particle abrasion in a bonding protocol for the zirconia surface. PURPOSE: The purpose of this in vitro study was to evaluate the shear bond force of resin cement to yttria-stabilized tetragonal zirconia polycrystal (Y-TZP) when using spherical ZAC particles to conduct airborne-particle abrasion and modify the topography of Y-TZP. MATERIAL AND METHODS: Spherical 30- to 70-µm ZAC particles were fabricated by using a hybrid gel technique. A total of 160 Ø6.6×4.0-mm zirconia disks were fabricated from 4 commercially available zirconia blanks, e.max ZirCAD zirconia (EM), NexxZr T zirconia (NE), Lava Plus High Translucency zirconia (LP), and Imagine High Translucency Zirconia (IM), by using computer-aided manufacturing technology. As-sintered specimens without further surface treatment were used as controls (ZR0). Surface treatment groups included sharp-edged alumina airborne-particle abrasion (ABC), 50 µm, 0.2 MPa; airborne-particle abrasion with ZAC particle at 0.2 MPa (2ZA); and airborne-particle abrasion with spherical ZAC particle at 0.4 MPa (4ZA). All surface treatment groups were airborne-particle abraded at the specified pressures for 10 seconds at a standardized distance of 10 mm. The surface roughness (Ra) and area roughness (Sa) of specimens from each group were measured. Following the application of an adhesive (Scotchbond Universal), Ø6.6×4.0-mm resin cement (RelyX Ultimate) buttons were fabricated for shear bond testing by using a universal testing machine at a 5-mm/min crosshead speed (n=10). The data were analyzed by using a 2-way ANOVA, Tukey HSD test, and regression analysis (α=0.05). Scanning electron microscopy (SEM) was performed to observe changes of the zirconia surface and the failure modes of each group before and after shear bond testing. RESULTS: The mean ±standard deviation shear bond force values ranged from 272.6 ±41.4 N to 686.7 ±152.8 N. Statistically significant higher force values than those of the controls (P<.05) were obtained by using airborne-particle abrasion. No significant differences were found among any of the airborne-particle abrasion treatment groups (P>.05). The mean of Ra values ranged from 0.27 µm to 0.74 µm, and the mean of Sa values, from 0.48 µm to 1.48 µm. SEM observation revealed that the zirconia surface was made jagged by abrasion with sharp-edged alumina particles. The spherical ZAC particles create microcraters on the zirconia surface. Fractographic observation disclosed that failures were adhesive-cohesive failure modes with residual resin cement attached on the zirconia surface. CONCLUSIONS: The surface treatment of zirconia with sharp-edged alumina or the spherical ZAC abrasives improved the bonding force between the zirconia and resin cement. No statistically significant differences in shear bond force values were found between airborne-particle abrasion surface treatment groups.