Identification of novel variants in BRF1 gene from patient with developmental delay, hearing abnormality, and nervous system anomalies.

Cerebellofaciodental syndrome characterized with dysmorphic features, intellectual disability, and brain anomalies. Now its clinical spectrum expanded more manifestations including bilateral sensorineural hearing impairment and inner ear malformation. Here, we report a 14-month-old boy with global developmental delay and hearing disorder. Whole exome sequencing (WES) revealed the compound heterozygous variants [NM_001519.4: c.652 T > G (p.W218G); c.915 + 1G > T] in the BRF1 gene which inherited from his parents, respectively. The MRI results showed hypoplastic cerebellar vermis, enlarged cisterna magna, and prominent fourth ventricle, the rehabilitation therapy failed to improve the symptoms for our patient. Our finding expands the genetic spectrum of BRF1 variants, which indicates patients with the developmental delay caused by BRF1 variants require other treatments instead of rehabilitation.

Expanding the genetic and phenotypic relevance of CLCN4 variants in neurodevelopmental condition: 13 new patients.

OBJECTIVES: CLCN4 variations have recently been identified as a genetic cause of X-linked neurodevelopmental disorders. This study aims to broaden the phenotypic spectrum of CLCN4-related condition and correlate it with functional consequences of CLCN4 variants. METHODS: We described 13 individuals with CLCN4-related neurodevelopmental disorder. We analyzed the functional consequence of the unreported variants using heterologous expression, biochemistry, confocal fluorescent microscopy, patch-clamp electrophysiology, and minigene splicing assay. RESULTS: We identified five novel (p.R41W, p.L348V, p.G480R, p.R603W, c.1576 + 5G > A) and three known (p.T203I, p.V275M, p.A555V) pathogenic CLCN4 variants in 13 Chinese patients. The p.V275M variant is found at high frequency and seen in four unrelated individuals. All had global developmental delay (GDD)/intellectual disability (ID). Seizures were present in eight individuals, and 62.5% of them developed refractory epilepsy. Five individuals without seizures showed moderate to severe GDD/ID. Developmental delay precedes seizure onset in most patients. The variants p.R41W, p.L348V, and p.R603W compromise the anion/exchange function of ClC-4. p.R41W partially impairs ClC-3/ClC-4 association. p.G480R reduces ClC-4 expression levels and impairs the heterodimerization with ClC-3. The c.1576 + 5G > A variant causes 22 bp deletion of exon 10. CONCLUSIONS: We further define and broaden the clinical and mutational spectrum of CLCN4-related neurodevelopmental conditions. The p.V275M variant may be a potential hotspot CLCN4 variant in Chinese patients. The five novel variants cause loss of function of ClC-4. Transport dysfunction, protein instability, intracellular trafficking defect, or failure of ClC-4 to oligomerize may contribute to the pathophysiological events leading to CLCN4-related neurodevelopmental disorder.

Developing and validating machine learning-based prediction models for frailty occurrence in those with chronic obstructive pulmonary disease.

Background: Frailty is a medical syndrome caused by multiple factors, characterized by decreased strength, endurance, and diminished physiological function, resulting in increased susceptibility to dependence and/or death. Patients with chronic obstructive pulmonary disease (COPD) tend to be more vulnerable to frailty due to their physical and psychological burdens. Therefore, the aim of this study was to develop a reliable and accurate vulnerability risk prediction model for frailty in patients with COPD in order to improve the identification and prediction of patient frailty. The specific objectives of this study were to determine the prevalence of frailty in patients with COPD and develop a prediction model and evaluate its predictive power. Methods: Clinical information was analyzed using data from the 2018 China Health and Retirement Longitudinal Study (CHARLS) database, and 34 indicators, including behavioral factors, health status, mental health parameters, and various sociodemographic variables, were examined in the study. The adaptive synthetic sampling technique was used for unbalanced data. Three methods, ridge regressor, extreme gradient boosting (XGBoost) classifier, and random forest (RF) regressor, were used to filter predictors. Seven machine learning (ML) techniques including logistic regression (LR), support vector machines (SVM), multilayer perceptron, light gradient-boosting machine, XGBoost, RF, and K-nearest neighbors were used to analyze and determine the optimal model. For customized risk assessment, an online predictive risk modeling website was created, along with Shapley additive explanation (SHAP) interpretations. Results: Depression, smoking, gender, social activities, dyslipidemia, asthma, and residence type (urban vs. rural) were predictors for the development of frailty in patients with COPD. In the test set, the XGBoost model had an area under the curve of 0.942 (95% confidence interval: 0.925-0.959), an accuracy of 0.915, a sensitivity of 0.873, and a specificity of 0.911, indicating that it was the best model. Conclusions: The ML predictive model developed in this study is a useful and easy-to-use instrument for assessing the vulnerability risk of patients with COPD and may aid clinical physicians in screening high-risk patients.

Identification of Genes and Key Pathways Associated with the Pathophysiology of Lung Cancer and Atrial Fibrillation.

Background: Lung cancer is a malignant tumor originating from respiratory epithelial cells in the bronchi, bronchioles, and alveoli, often associated with atrial fibrillation; However, there is a lack of in-depth understanding of its genetic basis and molecular mechanisms. Our goal is to study the genes and signaling networks associated with cancer and atrial fibrillation. Materials and methods: We obtained microarray datasets for lung tumors from the Gene Expression Omnibus (GEO) database and AF for this investigation: GSE30219, GSE79768, and screened the candidate specimens in both microarrays for differential genes at P < .05 using GEO2R. The outcomes were also examined using the Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Gene and Gene Combinations (KEGG) pathway analysis methods. Using STRING and Cytoscape, protein interaction networks (PPI) were analyzed and visualized. The Molecular Complex Detection (MOCDE) plugin is responsible for filtering important compounds. Candidate genes are then screened by the cytoHubba plugin according to MCC criteria. After taking the intersection of the Hub genes by the Wayne diagram, the ROC curves were plotted separately by combining the data from one lung cancer dataset GSE19804, two AF datasets GSE41177/GSE14975 in the GEO database. Results: An aggregate of 49 co-expressed differentially expressed genes (co-DEGs) were discovered in lung cancer/AF and healthy controls. Most co-DEGs were found in neutrophil activation, where they were linked to immunological response and interactions between cytokines and cytokine receptors, according to GO and KEGG pathway analyses. Furthermore, due of their significant connectedness in both the lung carcinoma and AF datasets, we chose six key genes. They are MNDA, HP, LYZ, S100A9, S100A8, and S100A12, among others. Conclusions: The findings of this research indicate that the onset of lung cancer and AF depends on a small number of distinctive genes. We investigated the functional enrichment, differential gene expression, and PPI of DEGs in lung cancer and AF, and the results offer fresh perspectives on the discovery of prospective biomarkers and priceless therapeutic precursors in these two diseases.

Fabry-Pérot optical frequency comb based mm-wave RoF system using pilot-assisted equalizer.

The emergence of the millimeter wave (mm-Wave; 30 GHz to 300 GHz) frequency band holds a lot of promise for addressing the congestion at low frequency in future mobile networks. Among many mm-Wave generation schemes, optical heterodyning is considered one of the most promising approaches due to its scalability and potential for integration on chip. Employing optical frequency combs (OFC) for optical heterodyning alleviates the significant phase distortions/noise introduced by the optical sources. However, any residual phase noise in these systems can deteriorate the transmission performance. Here we demonstrate a high-capacity mm-Wave radio-over-fiber (RoF) system using Fabry-Pérot (FP) laser comb overcoming the typical limitations of this source. The temporal phase perturbation induced by the frequency fluctuation of the FP laser is theoretically analyzed, and then estimated and compensated by a pilot-based phase equalizer. Performance evaluation of the proposed phase equalizer is conducted through experiment and simulation. Enabled by the proposed compensation scheme, ten 200 MHz filtered orthogonal frequency division multiplexing (f-OFDM) signal bands modulated by 16-quadrature amplitude modulation (QAM) are transmitted over 10 km fiber, with the ability to serve multiple users. The transmission of 16-QAM modulated single carrier signals with 2 GBd and 8 Gbps data rate is also performed for comparison, which offers better resilience to phase noise, demonstrating the first commercial Quantum Well FP laser-based optical heterodyning mm-Wave RoF system for both multi-carrier and single carrier signals.

Elimination of methicillin-resistant Staphylococcus aureus biofilms on titanium implants via photothermally-triggered nitric oxide and immunotherapy for enhanced osseointegration.

BACKGROUND: Treatment of methicillin-resistant Staphylococcus aureus (MRSA) biofilm infections in implant placement surgery is limited by the lack of antimicrobial activity of titanium (Ti) implants. There is a need to explore more effective approaches for the treatment of MRSA biofilm infections. METHODS: Herein, an interfacial functionalization strategy is proposed by the integration of mesoporous polydopamine nanoparticles (PDA), nitric oxide (NO) release donor sodium nitroprusside (SNP) and osteogenic growth peptide (OGP) onto Ti implants, denoted as Ti-PDA@SNP-OGP. The physical and chemical properties of Ti-PDA@SNP-OGP were assessed by scanning electron microscopy, X-ray photoelectron spectroscope, water contact angle, photothermal property and NO release behavior. The synergistic antibacterial effect and elimination of the MRSA biofilms were evaluated by 2',7'-dichlorofluorescein diacetate probe, 1-N-phenylnaphthylamine assay, adenosine triphosphate intensity, o-nitrophenyl-ß-D-galactopyranoside hydrolysis activity, bicinchoninic acid leakage. Fluorescence staining, assays for alkaline phosphatase activity, collagen secretion and extracellular matrix mineralization, quantitative real­time reverse transcription­polymerase chain reaction, and enzyme-linked immunosorbent assay (ELISA) were used to evaluate the inflammatory response and osteogenic ability in bone marrow stromal cells (MSCs), RAW264.7 cells and their co-culture system. Giemsa staining, ELISA, micro-CT, hematoxylin and eosin, Masson's trichrome and immunohistochemistry staining were used to evaluate the eradication of MRSA biofilms, inhibition of inflammatory response, and promotion of osseointegration of Ti-PDA@SNP-OGP in vivo. RESULTS: Ti-PDA@SNP-OGP displayed a synergistic photothermal and NO-dependent antibacterial effect against MRSA following near-infrared light irradiation, and effectively eliminated the formed MRSA biofilms by inducing reactive oxygen species (ROS)-mediated oxidative stress, destroying bacterial membrane integrity and causing leakage of intracellular components (P < 0.01). In vitro experiments revealed that Ti-PDA@SNP-OGP not only facilitated osteogenic differentiation of MSCs, but also promoted the polarization of pro-inflammatory M1 macrophages to the anti-inflammatory M2-phenotype (P < 0.05 or P < 0.01). The favorable osteo-immune microenvironment further facilitated osteogenesis of MSCs and the anti-inflammation of RAW264.7 cells via multiple paracrine signaling pathways (P < 0.01). In vivo evaluation confirmed the aforementioned results and revealed that Ti-PDA@SNP-OGP induced ameliorative osseointegration in an MRSA-infected femoral defect implantation model (P < 0.01). CONCLUSIONS: These findings suggest that Ti-PDA@SNP-OGP is a promising multi-functional material for the high-efficient treatment of MRSA infections in implant replacement surgeries.

Compromised word-level neural tracking in the high-gamma band for children with attention deficit hyperactivity disorder.

Children with attention deficit hyperactivity disorder (ADHD) exhibit pervasive difficulties in speech perception. Given that speech processing involves both acoustic and linguistic stages, it remains unclear which stage of speech processing is impaired in children with ADHD. To investigate this issue, we measured neural tracking of speech at syllable and word levels using electroencephalography (EEG), and evaluated the relationship between neural responses and ADHD symptoms in 6-8 years old children. Twenty-three children participated in the current study, and their ADHD symptoms were assessed with SNAP-IV questionnaires. In the experiment, the children listened to hierarchical speech sequences in which syllables and words were, respectively, repeated at 2.5 and 1.25 Hz. Using frequency domain analyses, reliable neural tracking of syllables and words was observed in both the low-frequency band (<4 Hz) and the high-gamma band (70-160 Hz). However, the neural tracking of words in the high-gamma band showed an anti-correlation with the ADHD symptom scores of the children. These results indicate that ADHD prominently impairs cortical encoding of linguistic information (e.g., words) in speech perception.

Research progress of child athlete’s speech sound disorders

Child athletes with speech sound disorders may experience difficulties communicating with coaches, teammates, and others in sports-related contexts. To improve communication abilities and overall athletic performance, research has made progress in exploring the impact of speech therapy and exercise programs on child athletes with speech sound disorders. These programs aim to enhance neural connections between the brain regions responsible for speech production and motor skills needed for sports, as well as boost confidence in social situations. By utilizing advanced diagnostic tools, such as speech sound assessments and imaging techniques, researchers have identified new methods for identifying and treating speech sound disorders in child athletes. This paper reviews the recent research progress on child athlete's speech sound disorders, discussing the implications for speech therapy and exercise programs in sports training, as well as the potential for improved communication and athletic performance. (AU)

A novel variant in BCL11B in an individual with neurodevelopmental delay: A case report.

BACKGROUND: B-Cell CLL/Lymphoma 11B (BCL11B) is a C2 H2 zinc finger transcription factor that has broad biological functions and is essential for the development of the immune system, neural system, cardiovascular system, dermis, and dentition. Variants of BCL11B have been found in patients with neurodevelopmental disorders and immunodeficiency. MATERIALS AND METHODS: Whole-exome sequencing (WES) and clinical examinations were performed to identify the etiology of our patient. A variant in the BCL11B gene, NM_138576.4: c.1206delG (p.Phe403Serfs*2) was found and led to frameshift truncation. RESULTS: We reported a male patient with developmental delay and cerebral palsy who carried the BCL11B variant. The detailed clinical features, such as brain structure and immune detection, were described and reviewed in comparison to previous patients. CONCLUSIONS: The BCL11B-related neurodevelopmental disorders are rare, and only 17 variants in 25 patients have been found to date. Our report expands the variants spectrum of BCL11B and increases the case of neurodevelopmental abnormalities.

Case report and literature review: Novel compound heterozygous FIG4 variants causing both of peripheral and central nervous system defects.

Background: Pathogenic variants in the FIG4 gene have been described to be associated with a diverse spectrum of syndromes, such as autosomal recessive bilateral temporooccipital polymicrogyria (OMIM 612691), autosomal dominant amyotrophic lateral sclerosis-11 (ALS11; OMIM 612577), autosomal recessive Charcot-Marie-Tooth disease, type 4J (CMT4J; OMIM 611228), and autosomal recessive Yunis-Varon syndrome (YVS; OMIM 216340). Heterozygous FIG4 variants are responsible for ALS11 characterized by progressive muscular weakness, atrophy, and bulbar palsy. CMT4J is a disorder of peripheral nervous system defects mainly presenting with a highly variable onset of proximal and/or distal muscle weakness. YVS is a disorder of severe neurological involvement with central nervous system (CNS) dysfunction and extensive skeletal anomalies. Case Presentation: We reported two Chinese siblings born with a weakness in all limbs. They experienced rapidly progressive weakness in distal limbs. At the age of 6 years, the elder brother presented with severe scoliosis and cervical kyphosis. They both had global developmental delay and a CNS involvement with cognitive deficits and swallowing problems. Genetic screening in the patients' family for inherited diseases was recommended. Novel compound heterozygous variants in the FIG4 gene (c.2148delTinsAA and c.317A > G) were found by whole-exome sequencing in the patients. These variants were confirmed by Sanger sequencing in family members. Conclusions: Herein, we reported two Chinese male patients with CMT4J who presented with abnormal CNS features. CMT4J with CNS involvement has been very rarely reported. We hoped this study could expand the phenotypic and genetic spectrum of FIG4-related diseases. And we helped physicians to understand the genotype-phenotype correlation.

Fabrication of gelatin-based and Zn2+-incorporated composite hydrogel for accelerated infected wound healing.

Gelatin-based hydrogels have a broad range of biomedical fields due to their biocompatibility, convenience for chemical modifications, and degradability. However, gelatin-based hydrogels present poor antibacterial ability that hinders their applications in treating infected wound healing. Herein, a series of multifunctional hydrogels (Gel@Zn) were fabricated through free-radical polymerization interaction based on gelatin methacrylate (GelMA) and dopamine methacrylate (DMA), and then immersed them into zinc nitrate solutions based on the metal coordination and ionic bonding interaction. These designed hydrogels wound dressings show strong antibacterial activity against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) by increasing intracellular reactive oxygen species (ROS) level and changing bacterial membrane permeability. Meanwhile, the hydrogels exhibit good cytocompatibility, enhance the adhesion, proliferation, and migration of NIH-3T3 cells. Furthermore, Gel@Zn-0.08 (0.08 â€‹M Zn2+ immersed with Gel sample) presents a good balance between antibacterial effect, cell viability, and hemolytic property. Compared with 3 â€‹M commercial dressings, Gel@Zn-0.04, and Gel@Zn-0.16, the Gel@Zn-0.08 could significantly improve the healing process of S. aureus-infected full-thickness wounds via restrained the inflammatory responses, enhanced epidermis and granulation tissue information, and stimulated angiogenesis. Our study indicates that the Zn-incorporated hydrogels are promising bioactive materials as wound dressings for infected full-thickness wound healing and skin regeneration.

Novel SNX13 Frameshift Variant in an Individual with Developmental Delay.

Recently, an increasing number of genes have been associated with global developmental delay (GDD) and intellectual disability (ID). The sorting nexin (SNX) protein family plays multiple roles in protein trafficking and intracellular signaling. SNXs have been reported to be associated with several disorders, including Alzheimer disease and Down syndrome. Despite the growing evidence of an association of SNXs with neurodegeneration, SNX13 deficiency has not been associated with GDD or ID. In this study, we present the case of a 4-year-old boy with brain dysplasia and GDD, including language delay, cognitive delay, and dyskinesia. Exome sequencing revealed a 1-bp homozygous deletion in SNX13 (NM_015132.5: exon8: c.742_743del; p.Tyr248Leufs*20), which caused a frameshift and predicted early termination. Sanger sequencing confirmed that the variant was inherited from his parents respectively. Our findings associate SNX13 variation with GDD for the first time and provide a new GDD candidate gene.

Effects of titanium with different micro/nano structures on the ability of osteoblasts to resist oxidative stress.

Excessive accumulation of oxidative intermediates in the elderly significantly aggravates bone degradation and hinders the osseointegration of topological titanium (Ti) implants. Thus, it is of great significance to evaluate the antioxidant and osteoinduction capabilities of various nano, micro or micro/nano-composite structures under oxidative stress (OS) microenvironment. In this study, we discovered that 110 nm titania nanotubes (TNTs) enhanced the adsorption of fibronectin (FN) proteins onto smooth and rough titanium surfaces to varying degrees. Compared with Ti and 30 nm TNTs (T30) groups, cells on 110 nm TNTs (T110), microstructure/30 nm TNTs (M30) and microstructure/110 nm TNTs (M110) had smaller area, lower reactive oxygen species (ROS), and better proliferation/osteogenic differentiation abilities under OS condition, but there was no significant difference among the three groups. In addition, combined with our previous study, we suggested that T110, M30 and M110 resistance to OS was also strongly associated with the high expression of FN-receptor integrin α5 or ß1. All the findings indicated that the micro/nano-composed structures (M30 & M110) had similar anti-oxidation and osteogenesis abilities to T110, which provided guidance for the application of different titanium implants with different topologies in the elderly.

Association Between MTHFR C677T Polymorphism and Susceptibility to Autism Spectrum Disorders: A Meta-Analysis in Chinese Han Population.

Prior studies have examined the influence of MTHFR C677T on autism susceptibility, however, there are no consensus conclusions and specific analyses of a Chinese population. This meta-analysis included a false-positive report probability (FPRP) test to comprehensively evaluate the association of MTHFR C677T polymorphism with autism susceptibility among a Chinese Han population. A large-scale literature retrieval was conducted using various databases including PubMed, Embase, Wan Fang, and the Chinese National Knowledge Infrastructure (CNKI) up to July 31, 2020, with a total of 2,258 cases and 2,073 controls included. The strength of correlation was assessed by odds ratios (ORs) and 95% confidence intervals (95% CIs). MTHFR C677T showed a significant correlation with increased ASD susceptibility under all genetic models (T vs. C, OR = 1.89, 95% CI 1.28 to 2.79; TT vs. CC: OR = 2.44, 95% CI 1.43 to 4.15; CT vs. CC, OR = 1.73; 95% CI 1.19 to 2.51; CT + TT vs. CC: OR = 2.03, 95% CI 1.31 to 3.15; TT vs. CT + CC, OR = 1.95, 95% CI 1.21 to 3.13). Stratification analysis by region also revealed a consistent association in the Northern Han subgroup, but not in the Southern Han subgroup. Pooled minor allele frequency (MAF) of 30 studies were 45% in Northern Han and 39% in Southern Han. To avoid a possible "false positive report," we further investigated the significant associations observed in the present meta-analysis using the FPRP test, which consolidated the results. In conclusion, MTHFR C677T polymorphism is associated with the increased risk of autism in China, especially in Northern Han. For those mothers and children who are generally susceptible to autism, prenatal folate and vitamin B12 may reduce the risk that children suffer from autism, especially in Northern Han populations. In the future, more well-designed studies with a larger sample size are expected.

Low-power and high-speed 2 × 2 thermo-optic MMI-MZI switch with suspended phase arms and heater-on-slab structure.

We propose a ${2} \times {2}$ thermo-optic switch with high switching performance. The switch is based on multimode interferometer (MMI) couplers and a Mach-Zehnder interferometer (MZI) structure, where the phase arms are designed as laterally supported suspended ridge waveguides (LSSRWs) with a metallic heater placed on the slab. It is experimentally demonstrated that this switch has a power consumption of 1.07 mW, a thermal time constant ${\sim}{4.7}\;\unicode{x00B5} {\rm s}$, an extinction ratio ${\sim}{30}\;{\rm dB}$, and an insertion loss ${\sim}{0.5}\;{\rm dB}$. Particularly, the corresponding figure of merit (FOM) has been improved by 1 order magnitude compared with general thermo-optic switches. This ${2} \times {2}$ thermo-optic MMI-MZI switch may find potential application for network reconfiguration and on-chip optical information processing.

Exosomal miR-182 regulates the effect of RECK on gallbladder cancer.

BACKGROUND: As the most common biliary malignancy, gallbladder cancer (GC) is an elderly-biased disease. Although extensive studies have elucidated the molecular mechanism of microRNA 182 (miR-182) and reversion-inducing-cysteine-rich protein with kazal motifs (RECK) in various cancers, the specific role of exosomal miR-182 and RECK in GC remains poorly understood. AIM: To explore the relationship between exosomal miR-182/RECK and metastasis of GC. METHODS: Paired GC and adjacent normal tissues were collected from 78 patients. Quantitative polymerase chain reaction was employed to detect miR-182 and exosomal miR-182 expression, and Western blotting was conducted to determine RECK expression. In addition, the effects of exosomal miR-182/RECK on the biological function of human GC cells were observed. Moreover, the double luciferase reporter gene assay was applied to validate the targeting relationship between miR-182 and RECK. RESULTS: Compared with normal gallbladder epithelial cells, miR-182 was highly expressed in GC cells, while RECK had low expression. Exosomal miR-182 could be absorbed and transferred by cells. Exosomal miR-182 inhibited RECK expression and promoted the migration and invasion of GC cells. CONCLUSION: Exosomal miR-182 can significantly promote the migration and invasion of GC cells by inhibiting RECK; thus miR-182 can be used as a therapeutic target for GC.

Novel variants in AP4B1 cause spastic tetraplegia, moderate psychomotor development delay and febrile seizures in a Chinese patient: a case report.

INTRODUCTION: The AP4B1 gene encodes a subunit of adaptor protein complex-4 (AP4), a component of intracellular transportation of proteins which plays important roles in neurons. Bi-allelic mutations in AP4B1 cause autosomal recessive spastic paraplegia-47(SPG47). CASE PRESENTATION: Here we present a Chinese patient with spastic tetraplegia, moderate psychomotor development delay and febrile seizures plus. Brain MRIs showed dilated supratentorial ventricle, thin posterior and splenium part of corpus callosum. The patient had little progress through medical treatments and rehabilitating regimens. Whole exome sequencing identified novel compound heterozygous truncating variants c.1207C > T (p.Gln403*) and c.52_53delAC (p.Cys18Glnfs*7) in AP4B1 gene. Causal mutations in AP4B1 have been reported in 29 individuals from 22 families so far, most of which are homozygous mutations. CONCLUSIONS: Our study enriched the genetic and phenotypic spectrum of SPG47. Early discovery, diagnosis and proper treatment on the conditions generally increase chances of improvement on the quality of life for patients.

Overcoming the hypoxia-induced drug resistance in liver tumor by the concurrent use of apigenin and paclitaxel.

The chemotherapeutic efficacy of paclitaxel against hypoxic tumors is usually unsatisfactory, which is partially due to the so-called hypoxia-induced drug resistance. The mechanism of hypoxia-induced resistance is primarily associated with hypoxia-inducible factor 1α (HIF-1α), which is an oxygen-sensitive transcriptional activator coordinating the cellular response to hypoxia. Apigenin is a natural occurring HIF-1α inhibitor that can suppress the expression of HIF-1α through multiple pathways and reverse the hypoxia-induced resistance found in cancer cells. Here we report that the use of apigenin can suppress the HIF-1α expression in hypoxic tumors through the simultaneous inhibition of the AKT/p-AKT pathway and HSP90, which is beneficial for enhancing the anticancer activity of the co-administered paclitaxel. The potential synergistic effect of apigenin and paclitaxel was further validated on HepG2 cell line and tumor-bearing mouse models.

Upregulation of miR-34c after silencing E2F transcription factor 1 inhibits paclitaxel combined with cisplatin resistance in gastric cancer cells.

BACKGROUND: MicroRNA 34c (miR-34c) has been reported to be associated with malignant types of cancer, however, it remains unknown whether miR-34c is involved in chemoresistance in gastric cancer (GC). AIM: To investigate the effect of miR-34c and its upstream transcription factor E2F1 on paclitaxel combined with cisplatin resistance in GC cells. METHODS: Paired GC tissues and adjacent normal tissues were randomly sampled from 74 GC patients. miR-34c and E2F1 were detected by real-time quantitative PCR (qPCR) and Western blot. In addition, the drug resistance of GC cells to paclitaxel and cisplatin was induced by concentration gradient increasing methods, and changes in miR-34c and E2F1 during this process were measured. Furthermore, E2F1 and miR-34c overexpression or underexpression vectors were constructed and transfected into drug-resistant GC cells. MTT was employed to test the sensitivity of cells to paclitaxel combined with cisplatin, qPCR was adopted to detect the expression of miR-34c, Western blot was applied to detect the expression levels of E2F1, drug resistance-related proteins and apoptosis-related proteins, and flow cytometry was used for the determination of cell apoptosis and cell cycle status. RESULTS: E2F1 was overexpressed while miR-34c was underexpressed in GC. After inducing GC cells to be resistant to paclitaxel and cisplatin, E2F1 expression increased while miR-34c expression decreased. Both silencing E2F1 and over-expressing miR-34c could increase the sensitivity of drug-resistant GC cells to paclitaxel combined with cisplatin, promote cell apoptosis and inhibit cell proliferation. Among which, silencing E2F1 could reduce the expression of drug resistance-related proteins and apoptosis-related proteins, while over-expression of miR-34c could upregulate the expression of apoptosis-related proteins without affecting the expression of MDR-1, MRP and other drug resistance-related proteins. Rescue experiments demonstrated that inhibiting miR-34c could significantly weaken the sensitization of drug resistant cells, and Si E2F1 to paclitaxel combined with cisplatin. CONCLUSION: E2F1 inhibits miR-34c to promote the proliferation of GC cells and enhance the resistance to paclitaxel combined with cisplatin, and silencing E2F1 is conducive to improving the efficacy of paclitaxel combined with cisplatin in GC cells.

Enzyme responsive titanium substrates with antibacterial property and osteo/angio-genic differentiation potentials.

After implantation into a host, titanium (Ti) orthopaedic materials are facing two major clinical challenges: bacterial infection and aseptic loosening, which directly determine the long-term survival of the implant. To endow Ti implant with self-defensive antibacterial properties and desirable osteo/angio-genic differentiation potentials, hyaluronic acid (HA)-gentamicin (Gen) conjugates (HA-Gen) and chitosan (Chi) polyelectrolyte multilayers were constructed on deferoxamine (DFO) loaded titania nanotubes (TNT) substrates via layer-by-layer (LBL) assembly technique, termed as TNT/DFO/HA-Gen. The HA-Gen conjugate was characterized by Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (1H NMR). The physicochemical properties of the substrates were characterized by field emission scanning electron microscopy (FE-SEM), atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS) and contact angle measurements. The on-demand DFO release was associated with the degradation of multilayers triggered by exogenous hyaluronidase, which indicated enzymatic and bacterial responsiveness. The TNT/DFO/HA-Gen substrates displayed effective antifouling and antibacterial properties against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), while were favourable for the adhesion, proliferation and osteo/angio-genic differentiation of mesenchymal stem cells (MSCs). The multifaceted drug-device combination (DDC) strategy showed potential applications in orthopaedic fields.