Nanomedicine-based combination therapies for overcoming temozolomide resistance in glioblastomas.

Glioblastoma (GBM) is the most common malignant brain tumor. Although current treatment strategies, including surgery, chemotherapy, and radiotherapy, have achieved clinical effects and prolonged the survival of patients, the gradual development of resistance against current therapies has led to a high recurrence rate and treatment failure. Mechanisms underlying the development of resistance involve multiple factors, including drug efflux, DNA damage repair, glioma stem cells, and a hypoxic tumor environment, which are usually correlative and promote each other. As many potential therapeutic targets have been discovered, combination therapy that regulates multiple resistance-related molecule pathways is considered an attractive strategy. In recent years, nanomedicine has revolutionized cancer therapies with optimized accumulation, penetration, internalization, and controlled release. Blood-brain barrier (BBB) penetration efficiency is also significantly improved through modifying ligands on nanomedicine and interacting with the receptors or transporters on the BBB. Moreover, different drugs for combination therapy usually process different pharmacokinetics and biodistribution, which can be further optimized with drug delivery systems to maximize the therapeutic efficiency of combination therapies. Herein the current achievements in nanomedicine-based combination therapy for GBM are discussed. This review aimed to provide a broader understanding of resistance mechanisms and nanomedicine-based combination therapies for future research on GBM treatment.

TEAD4 predicts poor prognosis and transcriptionally targets PLAGL2 in serous ovarian cancer.

The oncogenic function of TEA domain transcription factor 4 (TEAD4) has been confirmed in multiple human malignancies, while its potential role and regulatory mechanism in serous ovarian cancer progression are left unknown. By the gene expression analyses from Gene Expression Profiling Interactive Analysis (GEPIA) database, TEAD4 expression is shown to be up-regulated in serous ovarian cancer samples. Here, we confirmed the high expression of TEAD4 in clinical serous ovarian cancer specimens. In the following functional experiments, we found that TEAD4 overexpression promoted serous ovarian cancer malignant phenotypes, including proliferation, migration and invasion in serous ovarian cancer SK-OV-3 and OVCAR-3 cells, while TEAD4 knockout exerted the opposite function. The tumor growth inhibition of TEAD4 depletion was also affirmed by a Xenograft model in mice. In addition, this phenotypic deterioration induced by TEAD4 overexpression was diminished by PLAG1 like zinc finger 2 (PLAGL2) silencing. More importantly, combined with the results of the dual-luciferase assay, the transcriptional regulation of TEAD4 on PLAGL2 promoter was evidenced. Our results showed that the cancer-promoting gene TEAD4 was involved in serous ovarian cancer progression via targeting PLAGL2 at the transcriptional level.

Inflammation and endothelial function-related gene polymorphisms are associated with carotid atherosclerosis-A study of community population in Southwest China.

OBJECTIVES: To investigate the relationships between 18 single nucleotide polymorphisms with carotid atherosclerosis and whether interactions among these genes were associated with an increased risk of carotid atherosclerosis. METHODS: Face-to-face surveys were conducted with individuals aged 40 or older in eight communities. A total of 2377 individuals were included in the study. Ultrasound was used to detect carotid atherosclerosis in the included population. 18 loci of 10 genes associated with inflammation and endothelial function were detected. Gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR). RESULTS: Among the 2377 subjects, 445 (18.7%) subjects had increased intima-media thickness in the common carotid artery (CCA-IMT), and 398 (16.7%) subjects were detected with vulnerable plaque. In addition, NOS2A rs2297518 polymorphism was associated with increased CCA-IMT, IL1A rs1609682, and HABP2 rs7923349 polymorphisms were associated with vulnerable plaque. Besides, GMDR analysis showed significant gene-gene interactions among TNFSF4 rs1234313, IL1A rs1609682, TLR4 rs1927911, ITGA2 rs1991013, NOS2A rs2297518, IL6R rs4845625, ITGA2 rs4865756, HABP2 rs7923349, NOS2A rs8081248, HABP2 rs932650. CONCLUSION: The prevalences of increased CCA-IMT and vulnerable plaque were high in Southwestern China's high-risk stroke population. Furthermore, inflammation and endothelial function-related gene polymorphisms were associated with carotid atherosclerosis.

Comparative microstructural study on the teeth of Mesozoic birds and non-avian dinosaurs.

Although it is commonly considered that, in birds, there is a trend towards reduced dentition, teeth persisted in birds for 90 Ma and numerous macroscopic morphologies are observed. However, the extent to which the microstructure of bird teeth differs from other lineages is poorly understood. To explore the microstructural differences of the teeth of birds in comparison with closely related non-avialan dinosaurs, the enamel and dentine-related features were evaluated in four Mesozoic paravian species from the Yanliao and Jehol biotas. Different patterns of dentinal tubular tissues with mineralized extensions of the odontoblast processes were revealed through the examination of histological sectioning under electron microscopy. Secondary modification of the tubular structures, forming reactive sclerotic dentin of Longipteryx, and the mineralization of peritubular dentin of Sapeornis were observed in the mantle dentin region. The new observed features combined with other dentinal-associated ultrastructure suggest that the developmental mechanisms controlling dentin formation are quite plastic, permitting the evolution of unique morphologies associated with specialized feeding behaviours in the toothed birds. Proportionally greater functional stress placed on the stem bird teeth may have induced reactive dentin mineralization, which was observed more often within tubules of these taxa. This suggests modifications to the dentin to counteract potential failure.

Circuit- and laminar-specific regulation of medial prefrontal neurons by chronic stress.

BACKGROUND: Chronic stress exposure increases the risk of mental health problems such as anxiety and depression. The medial prefrontal cortex (mPFC) is a hub for controlling stress responses through communicating with multiple limbic structures, including the basolateral amygdala (BLA) and nucleus accumbens (NAc). However, considering the complex topographical organization of the mPFC neurons in different subregions (dmPFC vs. vmPFC) and across multiple layers (Layer II/III vs. Layer V), the exact effects of chronic stress on these distinct mPFC output neurons remain largely unknown. RESULTS: We first characterized the topographical organization of mPFC neurons projecting to BLA and NAc. Then, by using a typical mouse model of chronic restraint stress (CRS), we investigated the effects of chronic stress on the synaptic activity and intrinsic properties of the two mPFC neuronal populations. Our results showed that there was limited collateralization of the BLA- and NAc-projecting pyramidal neurons, regardless of the subregion or layer they were situated in. CRS significantly reduced the inhibitory synaptic transmission onto the BLA-projecting neurons in dmPFC layer V without any effect on the excitatory synaptic transmission, thus leading to a shift of the excitation-inhibition (E-I) balance toward excitation. However, CRS did not affect the E-I balance in NAc-projecting neurons in any subregions or layers of mPFC. Moreover, CRS also preferentially increased the intrinsic excitability of the BLA-projecting neurons in dmPFC layer V. By contrast, it even caused a decreasing tendency in the excitability of NAc-projecting neurons in vmPFC layer II/III. CONCLUSION: Our findings indicate that chronic stress exposure preferentially modulates the activity of the mPFC-BLA circuit in a subregion (dmPFC) and laminar (layer V) -dependent manner.

Identifying therapeutic biomarkers of zoledronic acid by metabolomics.

Zoledronic acid (ZOL) is a potent antiresorptive agent that increases bone mineral density (BMD) and reduces fracture risk in postmenopausal osteoporosis (PMOP). The anti-osteoporotic effect of ZOL is determined by annual BMD measurement. In most cases, bone turnover markers function as early indicators of therapeutic response, but they fail to reflect long-term effects. We used untargeted metabolomics to characterize time-dependent metabolic shifts in response to ZOL and to screen potential therapeutic markers. In addition, bone marrow RNA-seq was performed to support plasma metabolic profiling. Sixty rats were assigned to sham-operated group (SHAM, n = 21) and ovariectomy group (OVX, n = 39) and received sham operation or bilateral ovariectomy, respectively. After modeling and verification, rats in the OVX group were further divided into normal saline group (NS, n = 15) and ZOL group (ZA, n = 18). Three doses of 100 µg/kg ZOL were administrated to the ZA group every 2 weeks to simulate 3-year ZOL therapy in PMOP. An equal volume of saline was administered to the SHAM and NS groups. Plasma samples were collected at five time points for metabolic profiling. At the end of the study, selected rats were euthanatized for bone marrow RNA-seq. A total number of 163 compound were identified as differential metabolites between the ZA and NS groups, including mevalonate, a critical molecule in target pathway of ZOL. In addition, prolyl hydroxyproline (PHP), leucyl hydroxyproline (LHP), 4-vinylphenol sulfate (4-VPS) were identified as differential metabolites throughout the study. Moreover, 4-VPS negatively correlated with increased vertebral BMD after ZOL administration as time-series analysis revealed. Bone marrow RNA-seq showed that the PI3K-AKT signaling pathway was significantly associated with ZOL-mediated changes in expression (adjusted-p = 0.018). In conclusion, mevalonate, PHP, LHP, and 4-VPS are candidate therapeutic markers of ZOL. The pharmacological effect of ZOL likely occurs through inhibition of the PI3K-AKT signaling pathway.

A predictive model for identifying secondary underlying diseases of hemophagocytic lymphohistiocytosis.

Background: Secondary hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disease of immune hyperactivation that arises in the context of infectious, inflammatory, or neoplastic triggers. The aim of this study was to establish a predictive model for the timely differential diagnosis of the original disease resulting in HLH by validating clinical and laboratory findings to further improve the efficacy of therapeutics for HLH. Methods: We retrospectively enrolled 175 secondary HLH patients in this study, including 92 patients with hematologic disease and 83 patients with rheumatic disease. The medical records of all identified patients were retrospectively reviewed and used to generate the predictive model. We also developed an early risk score using multivariate analysis weighted points proportional to the ß regression coefficient values and calculated its sensitivity and specificity for the diagnosis of the original disease resulting in HLH. Results: The multivariate logistic analysis revealed that lower levels of hemoglobin and platelets (PLT), lower levels of ferritin, splenomegaly and Epstein-Barr virus (EBV) positivity were associated with hematologic disease, but young age and female sex were associated with rheumatic disease. The risk factors for HLH secondary to rheumatic diseases were female sex [OR 4.434 (95% CI, 1.889-10.407), P =0.001], younger age [OR 6.773 (95% CI, 2.706-16.952), P<0.001], higher PLT level [OR 6.674 (95% CI, 2.838-15.694), P<0.001], higher ferritin level [OR 5.269 (95% CI, 1.995-13.920), P =0.001], and EBV negativity [OR 27.656 (95% CI, 4.499-169.996), P<0.001]. The risk score included assessments of female sex, age, PLT count, ferritin level and EBV negativity, which can be used to predict HLH secondary to rheumatic diseases with an AUC of 0.844 (95% CI, 0.836~0.932). Conclusion: The established predictive model was designed to help clinicians diagnose the original disease resulting in secondary HLH during routine practice, which might be improve prognosis by enabling the timely treatment of the underlying disease.

Performance of Two Matrix-Assisted Laser Desorption Ionization-Time-of-Flight Mass Spectrometry (MALDI-TOF MS) Systems for Identification of the Viridans Group Streptococci.

Background: Due to similar colony morphology among viridans group streptococci (VGS), the differentiation of VGS species remains difficult in routine clinical microbiology. Recently, matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS) has been described as a fast method for identifying various bacteria at species level, and also for the VGS strains. Methods: A total of 277 VGS isolates were identified with the two MALDI-TOF MS systems (VITEK MS and Bruker Biotyper). The tuf and rpoB gene sequencing was used as the reference identification method for comparison. Results: Based on tuf and rpoB gene sequencing, 84 isolates were S. pneumoniae and 193 strains were other VGS isolates including S. anginosus group (n=91, 47.2%), S. mitis group (n=80, 41.5%), S. bovis group (n=11, 5.7%), S. salivarius group (n=10, 5.2%), and S. mutans group (n=1, 0.5%). VITEK MS and Bruker Biotyper accurately identified 94.6% and 89.9% of all VGS isolates, respectively. VITEK MS showed better identification results than Bruker Biotyper for S. mitis group including S. pneumoniae and S. bovis group, but for other VGS isolates, two MALDI-TOF MS systems showed comparable identification performance. However, VITEK MS was able to identify S. gallolyticus to the subspecies level with high-confidence (S. gallolyticus ssp. pasteurianus), while the Bruker Biotyper system could not. While Bruker Biotyper system could be able to correctly differentiate the subspecies of S. salivarius from S. vestibularis, VITEK MS poorly identify. Conclusion: This study demonstrated that two MALDI-TOF MS systems allowed discrimination for most VGS isolates with different identification performance, but Bruker Biotyper could produce more misidentifications and VITEK MS system. It is crucial to be familiar with the performance of MALDI-TOF MS systems used in clinical microbiology.

Role of cyclosporin A in the treatment of kidney disease and nephrotoxicity.

The clinical use of cyclosporin A (CsA) has led to significant advances and achievements in the field of transplantation and immune diseases. However, the nephrotoxicity of CsA is a major concern in current immunosuppression regimens. CsA causes abnormal kidney function while treating kidney disease, causing problems for clinicians and patients. Evidence of CsA nephrotoxicity is almost always present in transplant recipients after long-term CsA administration (up to 10 years), and similar phenomena occur with other calcineurin inhibitors. In this review, we summarize the mechanisms and influencing factors of CsA for the treatment of primary nephrotic syndrome. The mechanisms of CsA nephrotoxicity, clinical-pathological features, diagnosis, prevention strategies, and risk factors are summarized. We discuss the correlates and mechanisms of the switch between kidney disease prevention and nephrotoxicity of CsA to better understand the function of CsA in the kidney and to provide a basis for the prevention and treatment of CsA nephrotoxicity.

Increased frequency of hospital admissions with active systemic lupus erythematosus disease activity defined by two different disease activity indices: A cohort study.

The objective of this cohort study was to evaluate the association between the frequency of hospital admissions and disease activity, as defined by two different disease activity measurements: the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) and the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), in adult patients with systemic lupus erythematosus (SLEs). Patients with SLE were recruited from the rheumatology outpatient department of a regional hospital in southern Taiwan. SLE-DAS and SLEDAI-2K were used to define SLE disease activity and the cause of hospital admissions was identified by a rheumatologist based on medical records. A generalized linear model (GLM) with gamma distribution and log-linked function was used to analyze variables associated with the frequency of admission. The mean frequency of hospitalization was 0.34 times per year for all-cause and 0.21 times per year for SLE-related admission. Multivariate GLM analysis showed that moderate/severe SLE disease activity defined by SLE-DAS was associated with an increased frequency of all-cause and SLE-related hospital admissions while adjusting for other covariates. Moderate/severe SLE disease activity defined by SLEDAI-2K was only significantly associated with an increased frequency of all-cause hospitalization. When steroid dosage was included in the model, moderate/severe SLE disease activity defined by the SLE-DAS remained significantly associated with SLE-related hospital admissions (p = 0.032). In conclusion, disease activity defined by the SLE-DAS, but not SLEDAI-2K was associated with an increased frequency of SLE-related hospitalization. Steroid dosage, a lower educational level, and smoking were associated with an increased frequency of hospital admissions, whereas underweight and alcohol use were associated with a decreased frequency of hospital admissions. Rheumatologists should promptly control SLE disease activity of their patients, provide them with adequate health education, and maintain steroid doses to as low as possible to reduce the risk of hospital admissions.

A sequential Bayesian changepoint detection procedure for aberrant behaviours in computerized testing.

Changepoints are abrupt variations in a sequence of data in statistical inference. In educational and psychological assessments, it is essential to properly differentiate examinees' aberrant behaviours from solution behaviour to ensure test reliability and validity. In this paper, we propose a sequential Bayesian changepoint detection algorithm to monitor the locations of changepoints for response times in real time and, subsequently, further identify types of aberrant behaviours in conjunction with response patterns. Two simulation studies were conducted to investigate the efficiency and accuracy of the proposed detection procedure in terms of identifying one or multiple changepoints at different locations. In addition to manipulating the number and locations of changepoints, two types of aberrant behaviours were also considered: rapid guessing behaviour and cheating behaviour. Simulation results indicate that ability estimates could be improved after removing responses from aberrant behaviours identified by our approach. Two empirical examples were analysed to illustrate the application of the proposed sequential Bayesian changepoint detection procedure.

Effect of extended field-of-view approaches on the accuracy of stopping power ratio estimation for single-energy computed tomography simulators.

BACKGROUND: Extended field-of-view (eFOV) methods have been proposed to generate larger demonstration FOVs for computed tomography (CT) simulators with a limited scanning FOV (sFOV) size in order to ensure accurate dose calculation and patient collision avoidance. Although the efficacy of these strategies has been evaluated for photon applications, the effect of stopping power ratio (SPR) estimation on proton therapy has not been studied. This study investigated the effect of an eFOV approach on the accuracy of SPR to water estimation in homogeneous and heterogeneous phantoms. MATERIALS AND METHODS: To simulate patient geometries, tissue-equivalent material (TEM) and customized extension phantoms were used. The TEM phantom supported various rod arrangements through predefined holes. Images were reconstructed to three FOV sizes using a commercial eFOV technique. A single-energy CT stoichiometric method was used to generate Hounsfield unit (HU) to SPR (HU-to-SPR) conversion curves for each FOV. To investigate the effect of rod location in the sFOV and eFOV regions, eight TEM rods were placed at off-center distances in the homogeneous phantom and scanned individually. Similarly, 16 TEM rods were placed in the heterogeneous TEM phantom and scanned simultaneously. RESULTS: The conversion curves derived from the sFOV and eFOV data were identical. The average SPR differences of soft-tissue, bone, and lung materials for rods placed at various off-center locations were 3.3%, 4.8%, and 39.6%, respectively. In the heterogeneous phantom, the difference was within 1.0% in the absence of extension. However, in the presence of extension, the difference increased to 2.8% for all rods, except for lung materials, whose difference was 4.8%. CONCLUSIONS: When an eFOV method is used, the SPR variation in phantoms considerably increases for all TEM rods, especially for lung TEM rods. This phenomenon may substantially increase the uncertainty of HU-to-SPR conversion. Therefore, image reconstruction with a standard FOV size is recommended.

Cardiovascular outcomes in hepatitis C virus infected patients treated with direct acting antiviral therapy: a retrospective multi-institutional study.

BACKGROUND: Chronic hepatitis C virus (HCV) infection is associated with increased cardiovascular risks. We aimed to investigate the impact of direct acting antiviral (DAA) on HCV-associated cardiovascular events. METHODS: In this retrospective cohort study, patients with the diagnosis of chronic HCV were retrieved from multi-institutional electronic medical records, where diagnosis of HCV was based on serum HCV antibody and HCV-RNA test. The patients eligible for analysis were then separated into patients with DAA treatment and patient without DAA treatment. Primary outcomes included acute coronary syndrome, heart failure (HF), venous thromboembolism (VTE), stroke, cardiovascular death, major adverse cardiovascular event (MACE), and all-cause mortality. Outcomes developed during follow-up were compared between DAA treatment and non-DAA treatment groups. RESULTS: There were 41 565 patients with chronic HCV infection identified. After exclusion criteria applied, 1984 patients in the DAA treatment group and 413 patients in the non-DAA treatment group were compared for outcomes using inverse probability of treatment weighting. Compared to patients in non-DAA treatment group, patients in DAA treatment group were associated with significantly decreased HF (hazard ratio [HR]: 0.65, 95% confidence interval [CI]: 0.44-0.97, P = 0.035), VTE (HR: 0.19, 95% CI: 0.07-0.49, P = 0.001), MACE (HR: 0.73, 95% CI 0.59-0.92, P = 0.007), and all-cause mortality (HR: 0.50, 95% CI: 0.38-0.67, P < 0.001) at 3-year follow-up. CONCLUSIONS: Chronic HCV patients treated with DAA experienced lower rates of cardiovascular events and all-cause mortality than those without treatment. The reduction of VTE was the most significant impact of DAA treatment among the cardiovascular outcomes.

Blood eosinophil percentage as a predictor of response to inhaled corticosteroid in bronchiectasis.

INTRODUCTION: The role of inhaled corticosteroid (ICS) among patients with bronchiectasis remains controversial. There is limited evidence of using baseline eosinophil count (absolute and percentage) as a marker to predict the role of ICS among patients with bronchiectasis. METHODS: A retrospective case-control study was conducted in a major regional hospital and tertiary respiratory referral centre in Hong Kong, including 140 Chinese patients with noncystic fibrosis (CF) bronchiectasis, to investigate the exacerbation risks of bronchiectasis among ICS users and nonusers with different baseline eosinophil counts. RESULTS: ICS user had significantly lower risk to develop bronchiectasis exacerbation with adjusted odds ratio (OR) of 0.461 (95% confidence interval [CI] 0.225-0.945, p-value 0.035). Univariate logistic regression was performed for different cut-offs of blood eosinophil count (by percentage) from 2% to 4% (with a 0.5% grid each time). Baseline eosinophil 3.5% was found to be the best cut-off among all with adjusted OR of 0.138 (95% CI = 0.023-0.822, p-value = 0.030). CONCLUSION: Baseline eosinophil count of 3.5% might serve as a marker to predict the benefits of ICS on exacerbation risk among patients with non-CF bronchiectasis.

Association between modifiable vascular risk factors and rapid progression of post-radiation carotid artery stenosis.

BACKGROUND: Postradiotherapy carotid vasculopathy is a clinically relevant complication in patients with head and neck cancer receiving radiotherapy. In this study, we investigated the factors associated with the development and progression of carotid artery stenosis (CAS) in such patients. METHODS: Patients who received radiotherapy for head and neck cancers between October 2011 and May 2019 at a medical center in Taiwan were eligible for inclusion in this study. This study included patients who underwent 2 consecutive carotid duplex examinations within an interval of 1 to 3 years. The factors associated with ≥50% CAS at baseline and follow-up were analyzed. RESULTS: In total, 694 patients (mean age, 57.8±9.9 years; men, 75.2%; nasopharyngeal cancer, 73.3%) were included. The mean interval between radiotherapy and carotid duplex examination was 9.9 ± 5.9 years. At baseline, 103 patients had ≥50% CAS, which was significantly associated with tobacco smoking, hypercholesterolemia, and a prolonged interval between radiotherapy and carotid duplex examination. A total of 586 patients did not have CAS at baseline; of them, 68 developed ≥50% CAS during follow-up. Hypertension and hypercholesterolemia were identified as independent risk factors for CAS progression. CONCLUSION: Modifiable vascular risk factors, such as hypertension and hypercholesterolemia, appear to be significantly associated with the rapid progression of postradiotherapy CAS in patients with head and neck cancer.

Disseminated visceral Kaposi's sarcoma after allogeneic hematopoietic stem cell transplantation: a case report.

Cases of disseminated visceral Kaposi's sarcoma (KS) after allogenic hematopoietic stem cell transplantation (HSCT) are very rare worldwide, and disseminated visceral KS is often rapidly progressive and life-threatening, especially in paediatric patients. Here, the case of a 6-year-old female patient with disseminated visceral KS after allogeneic HSCT for treating severe aplastic anaemia is presented. The authors encountered difficulties in making the diagnosis due to lack of experience, but the diagnosis was achieved relatively quickly and accurately using metagenomic next-generation sequencing. After tapering and withdrawal of immunosuppressant drugs, the patient's condition was controlled. In conclusion, although HSCT-related KS is very rare, it should be considered during differential diagnosis.

Differentiated Embryo-Chondrocyte Expressed Gene1 and Parkinson's Disease: New Insights and Therapeutic Perspectives.

Differentiated embryo-chondrocyte expressed gene1 (DEC1), an important transcription factor that has a basic helix-loop-helix domain, is ubiquitously expressed in both human embryonic and adult tissues. DEC1 is involved in neural differentiation and neural maturation in the central nervous system (CNS). Recent studies suggest that DEC1 protects against Parkinson's disease (PD) by regulating apoptosis, oxidative stress, lipid metabolism, immune system, and glucose metabolism disorders. In this review, we summarize the recent progress on the role of DEC1 in the pathogenesis of PD and provide new insights into the prevention and treatment of PD and neurodegenerative diseases.

Causal relationships between autoimmune diseases and celiac disease: A Mendelian randomization analysis.

The aim of this study was to investigate the causal relationship between autoimmune disorders and celiac disease (CeD) through Mendelian randomization (MR). Single nucleotide polymorphisms (SNPs) significantly associated with 13 autoimmune diseases were extracted from the summary statistics of European genome-wide association studies (GWAS), and their effects were examined by Inverse variance-weighted (IVW) in a large European GWAS on CeD. Finally, reverse MR was performed to investigate the causal effects of CeD on autoimmune traits. Following the application of Bonferroni correction for multiple testing, genetically determined seven autoimmune diseases are causally associated with CeD: Crohn's disease (CD) (OR [95%CI] = 1.156 [1.106 ± 1.208], P = 1.27E-10), primary biliary cholangitis (PBC) (1.229 [1.143 ± 1.321], P = 2.53E-08), primary sclerosing cholangitis (PSC) (1.688 [1.466 ± 1.944], P = 3.56E-13), rheumatoid arthritis (RA) (1.231 [1.154 ± 1.313], P = 2.74E-10), systemic lupus erythematosus (SLE) (1.127 [1.081 ± 1.176], P = 2.59E-08), type 1 diabetes (T1D) (1.41 [1.238 ± 1.606], P = 2.24E-07), and asthma (1.414 [1.137 ± 1.758], P = 1.86E-03). The IVW analysis indicated that CeD increased the risk for seven diseases: CD (1.078 [1.044 ± 1.113], P = 3.71E-06), Graves' disease (GD) (1.251 [1.127 ± 1.387], P = 2.34E-05), PSC (1.304 [1.227 ± 1.386], P = 8.56E-18), psoriasis (PsO) (1.12 [1.062 ± 1.182], P = 3.38E-05), SLE (1.301[1.22 ± 1.388], P = 1.25E-15), T1D (1.3[1.228 ± 1.376], P = 1.57E-19), and asthma (1.045 [1.024 ± 1.067], P = 1.82E-05). The sensitivity analyses deemed the results reliable without pleiotropy. There are positive genetic correlations between various autoimmune diseases and CeD, and the latter also affects the predisposition to multiple autoimmune disorders in the European population.

Genetic and neural mechanisms of sleep disorders in children with autism spectrum disorder: a review.

Background: The incidence of sleep disorders in children with autism spectrum disorder (ASD) is very high. Sleep disorders can exacerbate the development of ASD and impose a heavy burden on families and society. The pathological mechanism of sleep disorders in autism is complex, but gene mutations and neural abnormalities may be involved. Methods: In this review, we examined literature addressing the genetic and neural mechanisms of sleep disorders in children with ASD. The databases PubMed and Scopus were searched for eligible studies published between 2013 and 2023. Results: Prolonged awakenings of children with ASD may be caused by the following processes. Mutations in the MECP2, VGAT and SLC6A1 genes can decrease GABA inhibition on neurons in the locus coeruleus, leading to hyperactivity of noradrenergic neurons and prolonged awakenings in children with ASD. Mutations in the HRH1, HRH2, and HRH3 genes heighten the expression of histamine receptors in the posterior hypothalamus, potentially intensifying histamine's ability to promote arousal. Mutations in the KCNQ3 and PCDH10 genes cause atypical modulation of amygdala impact on orexinergic neurons, potentially causing hyperexcitability of the hypothalamic orexin system. Mutations in the AHI1, ARHGEF10, UBE3A, and SLC6A3 genes affect dopamine synthesis, catabolism, and reuptake processes, which can elevate dopamine concentrations in the midbrain. Secondly, non-rapid eye movement sleep disorder is closely related to the lack of butyric acid, iron deficiency and dysfunction of the thalamic reticular nucleus induced by PTCHD1 gene alterations. Thirdly, mutations in the HTR2A, SLC6A4, MAOA, MAOB, TPH2, VMATs, SHANK3, and CADPS2 genes induce structural and functional abnormalities of the dorsal raphe nucleus (DRN) and amygdala, which may disturb REM sleep. In addition, the decrease in melatonin levels caused by ASMT, MTNR1A, and MTNR1B gene mutations, along with functional abnormalities of basal forebrain cholinergic neurons, may lead to abnormal sleep-wake rhythm transitions. Conclusion: Our review revealed that the functional and structural abnormalities of sleep-wake related neural circuits induced by gene mutations are strongly correlated with sleep disorders in children with ASD. Exploring the neural mechanisms of sleep disorders and the underlying genetic pathology in children with ASD is significant for further studies of therapy.