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Upper abdominal surgical treatment may reduce respiratory muscle function and mucociliary clearance, which might be a cause of postoperative pulmonary complications (PPCs). Threshold inspiratory muscle training (IMT) may serve as an effective modality to improve respiratory muscle strength and endurance in patients. However, whether this training could help patients with upper abdominal surgery remains to be determined. The aim of the present investigation was to determine the effect of a fully engaged IMT on PPCs and respiratory function in patients undergoing upper abdominal surgery. We hypothesized that the fully engaged IMT could reduce PPCs and improve respiratory muscle function in patients with upper abdominal surgery. This is a randomized controlled trial (RCT) with 28 patients who underwent upper abdominal surgery. Patients were randomly assigned to the control (CLT) group or the IMT group. The CTL group received regular health care. The IMT group received 3 weeks of IMT with 50% of MIP as the initial intensity before the operation. The intensity of MIP increased by 5–10% per week. The IMT was continued for 4 weeks after the operation. The study investigated the outcomes including PPCs, respiratory muscle strength, diaphragmatic function, cardiopulmonary function, and quality of life (QoL). We found that IMT improved respiratory muscle strength and diaphragmatic excursion. IMT also had a beneficial effect on the incidence of postoperative pulmonary complications (PPCs) compared to CLT care. The results from this study revealed that IMT provided positive effects on parameters associated with the respiratory muscle function and reduced the incidence of PPCs. We propose that fully engaged IMT should be a part of clinical management in patients with upper abdominal surgery.KEY MESSAGESThe fully engaged inspiratory muscle training reduces postoperative pulmonary complications rate in patients with upper abdominal surgery.The fully engaged inspiratory muscle training increases maximal inspiratory pressure in patients with upper abdominal surgery.The fully engaged inspiratory muscle training increases diaphragm function in patients with upper abdominal surgery.The fully engaged inspiratory muscle training increases the quality of life in patients with upper abdominal surgery. The fully engaged inspiratory muscle training reduces postoperative pulmonary complications rate in patients with upper abdominal surgery. The fully engaged inspiratory muscle training increases maximal inspiratory pressure in patients with upper abdominal surgery. The fully engaged inspiratory muscle training increases diaphragm function in patients with upper abdominal surgery. The fully engaged inspiratory muscle training increases the quality of life in patients with upper abdominal surgery.

Background Theta burst stimulation (TBS), a patterned repetitive transcranial magnetic stimulation (rTMS) protocol with shorter simulation duration and lower stimulus intensity, could be a better protocol for individuals with autism spectrum disorder (ASD). Our study aimed to explore the impacts of intermittent TBS (iTBS) over the bilateral posterior superior temporal sulcus (pSTS) on intellectually able adults with ASD. Material and methods In this randomized, single-blinded, sham-controlled crossover trial, 13 adults with ASD completed iTBS for 5 consecutive days over the bilateral pSTS and inion (as a sham control) in a 16-weeks interval and in a randomly assigned order. The neuropsychological function was measured with the Wisconsin Card Sorting Test (WCST) for cognitive flexibility while the clinical outcomes were measured with both self-rate and parents-rate Autism Spectrum Quotient (AQ) before and after 5-day iTBS interventions. Results The results revealed significantly immediate effects of multi-session iTBS over the bilateral pSTS on parent-rate autistic symptoms in adults with ASD. The post-hoc analysis revealed the impacts of multi-session iTBS on cognitive flexibility were affected by baseline social-communicative impairment and baseline cognitive performance. Besides, the impacts of multi-session iTBS on clinical symptoms was affected by the concurrent psychotropic medication use and baseline autistic symptoms. Conclusions Given the caveat of the small sample size and discrepancy of multiple informants, this pilot study suggests the therapeutic potential of 5-day multi-session iTBS over the pSTS in adults with ASD. Individual factors modulating the response to rTMS should be explicitly considered in the future trial.

The typical symptoms of patients with Alzheimer’s disease (AD) are amyloid-β (Aβ) plaques and tau hyperphosphorylation. However, recent studies show that these symptoms are not the cause of the disease but are generated after the pathogenesis. Compared with other types of dementia, AD has the obvious features of pineal gland calcification and decreased melatonin production. The pineal gland is mainly composed of pinealocytes that release melatonin and astrocytes. Astrocytes function to maintain a balanced concentration of calcium ions, provide nerve cell nutrients, and migrate nutrients in vivo. Calcium ions are among the most important neurotransmitters. Once triggered, a calcium wave can be formed between astrocytes to activate other astrocytes to transmit information. Most calcium is stored in the skeleton. Bone tissue is composed mainly of osteocytes, osteoblasts, and osteoclasts. Of these, osteocyte is a kind of astrocyte which regulates the activity of osteoclasts and osteoblasts. The pineal gland is composed mainly of astrocytes; osteocytes are also a kind of astrocyte. Therefore, we conclude that when astrocytes are gradually disabled, calcium may be lost from the bones, prompting osteoporosis. The calcium ions then released into the blood may accumulate and cause ectopic calcification in the pineal gland, which promotes the occurrence of AD. Finally, this study used aspects of drugs and hormones (bone and calcium metabolism hormones and melatonin) to infer the hypothesis, which proposes that astrocyte dysregulation promotes the long-term imbalance of calcium ions in vivo and leads to osteoporosis and AD.

Population stratification analyses targeting genetically closely related East Asians have revealed that distinguishable differentiation exists between Han Chinese, Korean, and Japanese individuals, as well as between southern (S-) and northern (N-) Han Chinese. Previous studies offer a number of choices for ancestry informative single nucleotide polymorphisms (AISNPs) to discriminate East-Asian populations. In this study, we collected and examined the efficiency of 1185 AISNPs using frequency and genotype data from various publicly available databases. With the aim to perform fine-scale classification of S-Han, N-Han, Korean, and Japanese subjects, machine-learning methods (Softmax and Random Forest) were used to screen a panel of highly informative AISNPs and to develop a superior classification model. Stepwise classification was implemented to increase and balance the discrimination in the process of AISNP selection, first discriminating Han, Korean, and Japanese individuals, and then characterizing stratification between S-Han and N-Han. The final 272-AISNP panel is an alternative optimization of various previous works, which promises reliable and90% accuracy in classification of the four East-Asian groups. This AISNP panel and the machine-learning model could be a useful and superior choice in medical genome-wide association studies and in forensic investigations for unknown suspect identity.

Background: The COVID-19 pandemic has negatively impacted the eating behaviours of people especially fruits and vegetable intake. No study has addressed the fruits and vegetables intake during the COVID-19 in Malaysia. Aim: to assess the daily intake of fruits and vegetables among Malaysian adults during the COVID-19 outbreak, perceived changes in intake, as well as factors associated with the changes in intake. Methods: A cross-sectional study was conducted through online platforms and a total of 506 participants were recruited. Semi food-frequency questionnaires were used to assess participants’ fruit and vegetable intake. Socio-demographics information, knowledge, attitude and practices (KAP) of fruits and vegetables were collected. All statistical analyses were performed using SPSS. Results: The majority of participants (99.8%) did not achieve the recommended five servings per day, in which they consumed an average of 0.84 servings of fruits and vegetables per day. 46.4% of participants reported no changes in intake compared to before the outbreak. Fruits and vegetables intake was associated with physical activity level, knowledge, and beliefs of foods that may prevent/cure COVID-19. Binary logistic regression identified two significant risk factors of daily fruits and vegetables intake namely, being a non-Chinese (AOR = 1.905, 95% CI = 1.114–3.257) and having good practices scores (AOR = 2.543, 95% CI = 1.611–4.015). Conclusion: The study found a low daily intake of fruits and vegetables. The findings suggested that nutritional interventions are necessary to improve awareness on consuming more fruits and vegetables to improve overall health.

Severe burn injuries have profound mental health impacts on individuals, such as posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). Many burn survivors also report positive psychosocial changes, termed posttraumatic growth (PTG). This study investigated long-term mental health of severe burn injury (i.e., PTSD, MDD, and PTG) and the longitudinal influences of coping strategies and social support.Ninety-nine adult burn survivors of the 2015 Formosa Fun Coast Water Park fire disaster participated in the 5-year follow-up (Wave 3, W3), with 93% completing the earlier 2- (Wave 1, W1) and 3-year follow-up (Wave 2, W2). Participants averaged 22.1 years of age at burn, and 62.6% were females. The mean total body surface area burned (TBSA) was 50.3%, with a mean length of hospital stay of 87.6 days.Five years after the 2015 fire disaster, 13.1%, and 14.1% of the survivors met probable DSM-5 PTSD and MDD, while 51.5% reported significant PTG. After controlling for demographic, burn-specific, and baseline outcome variables, avoidance coping at W2 prospectively predicted PTSD and depressive symptoms at W3 (p = .003 and 0.04), with medium-to-large and medium effect sizes (srRates of probable PTSD and MDD were still relatively high in long-term burn survivors. However, PTG continued to be highly prevalent. Our findings highlight the importance of coping in affecting the long-term mental health of severe burn injury.

Nab-paclitaxel (Abraxane), which is a nanoparticle form of albumin-bound paclitaxel, is one of the standard chemotherapies for pancreatic ductal adenocarcinoma (PDAC). This study determined the effect of Abraxane in combination with a fusion protein, hIL15-ABD, on subcutaneous Panc02 and orthotopic KPC C57BL/6 murine PDAC models. Abraxane combined with hIL15-ABD best suppressed tumour growth and produced a 40%-60% reduction in the tumour size for Panc02 and KPC, compared to the vehicle group. In the combination group, the active form of interferon-γ (IFN-γ)-secreting CD8

We present a mechanism for how ornithine decarboxylase (ODC) regulates the crosstalk between autophagy and apoptosis. In cancer cells, low-intensity ultraviolet B (UVB

Yogurt consumption shows a wide range of effects on the gut microbial composition, and correlation of components in yogurt with the changes of gut microbia remains largely uncharacterized. We aimed to determine the effect of brown yogurt (SSN) on the composition of the gut microbiota and to explore the effects of the major components. We performed a randomized study of 70 healthy adults to compare the effects of SSN and standard probiotic-containing yogurt (YJD) during a 28-day intervention and a 10-day follow-up period. The results showed that the SSN group showed significant increases in the butyrate-producer

Breast cancer (BC) is a common female malignancy, worldwide. BC death is predominantly caused by lung metastasis. According to previous studies, Dihydrotanshinone I (DHT), a bioactive compound in Salvia miltiorrhiza Bunge (S. miltiorrhiza), has inhibitory effects on numerous cancers. Here, we investigated the anti-metastatic effect of DHT on BC, where DHT more strongly inhibited the growth of BC cells (MDA-MB-231, 4T1, MCF-7, and SKBR-3) than breast epithelial cells (MCF-10a). Additionally, DHT repressed the wound healing, invasion, and migration activities of 4T1 cells. In the 4T1 spontaneous metastasis model, DHT (20 mg/kg) blocked metastasis progression and distribution in the lung tissue by 74.9%. DHT reversed the formation of neutrophil extracellular traps (NETs) induced by phorbol 12-myristate 13-acetate, as well as ameliorated NETs-induced metastasis. Furthermore, it inhibited Ly6G+Mpo+ neutrophils infiltration and H3Cit expression in the lung tissues. RNA sequencing, western blot, and bioinformatical analysis indicated that TIMP1 could modulate DHT acting on lung metastasis inhibition. The study demonstrated a novel suppression mechanism of DHT on NETs formation to inhibit BC metastasis.

Han Chinese, Korean and Japanese are the main populations of East Asia, and Han Chinese presents a gradient admixture from north to south. There are differences among the East Asian populations in genetic structure. To achieve fine-scale genetic classification of southern (S-) and northern (N-) Han Chinese, Korean and Japanese individuals in this study, we collected and analyzed 1185 ancestry informative SNPs (AISNPs) from previous literature reports and our laboratory findings. First, two machine learning algorithms, softmax and randomForest, were used to build genetic classification models. Then, phylogenetic tree, STRUCTURE and principal component analysis were used to evaluate the performance of classification for different AISNP panels. The 234-AISNP panel achieved a fine-scale differentiation among the target populations in four classification schemes. The accuracy of the softmax model was 92%, which realized the accurate classification of the S-Han, N-Han, Korean and Japanese individuals. The two machine learning models tested in this study provided important references for the high-resolution discrimination of close-range populations and will be useful tools to optimize marker panels for developing forensic DNA ancestry inference systems.中国汉族人、韩国人和日本人作为东亚主体人群，其中中国汉族人呈现由北向南的梯度混合，在遗传结构上存在不同程度的差异。为实现对中国南-北方汉族人、韩国人和日本人的高分辨率遗传划分，本研究收集和分析了文献报道和实验室前期数据筛选出的1185个东亚人群祖先信息性SNPs (ancestry informative SNPs, AISNPs)，应用softmax与随机森林两种机器学习算法构建族群遗传划分模型，然后利用系统发育树、STRUCTURE和主成分分析方法进一步评估不同模型AISNPs位点组合的族群分类效果，最终筛选出234-AISNP的最优组合，softmax模型准确率为92%，实现了南方汉族人、北方汉族人、韩国人和日本人的高精度区分。本研究测试的两种机器学习算法模型为近距离人群的高分辨率划分提供了重要参考，可作为法医DNA族群推断体系位点开发的重要工具。.

Myeloid-derived suppressor cells (MDSCs) are key players under various pathologic conditions, such as cancer. Epigenetic modifications such as DNA methylation, RNA-mediated processes, and histone modification can alter gene transcription, and thus regulating pathological process. Studies have shown that epigenetic modification contributes to the accumulation and function of MDSCs. This review summarizes the crosstalk between the epigenetic alterations and MDSCs functions, and briefly introduces how the accumulation and function of MDSCs caused by epigenetic modification impact on the disease development, which represents as a promising therapeutic strategy for the related disorders.

Previously, we published that 4′-azid-2′-deoxy-2′-fluorarabinoside (FNC), a novel cytosine nucleoside analog, has good anti-viral and anti-tumor activity. This study aimed to further explore the role and molecular mechanism of FNC in non-small cell lung cancer (NSCLC). FNC was tested in the NSCLC H460 cell line, the Lewis mouse model, and the H460 cell xenograft model. The effects of FNC were assessed by cell viability, transwell migration, and wound scratch analyses of cell migration and invasion. Apoptosis was assessed by flow cytometry. Proteins expression was assessed by western blot and immunohistochemistry staining (IHC). FNC inhibits the proliferation and metastasis of H460 cells in a time- and dose-dependent manner. FNC treatment showed efficacy and low toxicity in the Lewis mouse lung cancer model as well as in the H460 cell xenograft model. Further, FNC induced H460 cell apoptosis through the activation of the mitochondrial pathway. Notably, FNC inhibited invasion by increasing E-cadherin protein and reducing the protein expression of VEGF, MMP-2, MMP-9, and CD31. FNC inhibits NSCLC by activating the mitochondrial apoptosis pathway and regulating the expressions of multiple proteins related to cell adhesion and invasion, highlighting its potential as an NSCLC therapeutic.

Patients with Parkinson's disease (PD) present various responsiveness to levodopa, but the cause of such differences in levodopa responsiveness is unclear. Previous studies related the damage of brain white matter (WM) to levodopa responsiveness in PD patients, but no study investigated the relationship between the structural brain network change in PD patients and their levodopa responsiveness.PD patients were recruited and evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS). Each patient received a diffusion tensor imaging (DTI) scan and an acute levodopa challenge test. The improvement rate of UPDRS-III was calculated. PD patients were grouped into irresponsive group (improvement rate 30%) and responsive group (improvement rate ≥ 30%). Tract-based spatial statistics (TBSS), deterministic tracing (DT), region of interest (ROI) analysis, and automatic fiber identification (AFQ) analyses were performed. The structural brain network was also constructed and the topological parameters were calculated.Fifty-four PD patients were included. TBSS identified significant differences in fractional anisotropy (FA) values in the corpus callosum and other regions of the brain. DT and ROI analysis of the corpus callosum found a significant difference in FA between the two groups. Graph theory analysis showed statistical differences in global efficiency, local efficiency, and characteristic path length.PD patients with poor responsiveness to levodopa had WM damage in multiple brain areas, especially the corpus callosum, which might cause disruption of information integration of the structural brain network.

Neurodegenerative processes are widespread in the brains of type 2 diabetes mellitus (T2DM) patients; gaps remain to exist in the current knowledge of the associated gray matter (GM) microstructural alterations.A cross-sectional study was conducted to investigate alterations in GM microarchitecture in T2DM patients by diffusion tensor imaging and neurite orientation dispersion and density imaging (NODDI). Seventy-eight T2DM patients and seventy-four age-, sex-, and education level-matched healthy controls (HCs) without cognitive impairment were recruited. Cortical macrostructure and GM microstructure were assessed by surface-based analysis and GM-based spatial statistics (GBSS), respectively. Machine learning models were trained to evaluate the diagnostic values of cortical intracellular volume fraction (ICVF) for the classification of T2DM versus HCs.There were no differences in cortical thickness or area between the groups. GBSS analysis revealed similar GM microstructural patterns of significantly decreased fractional anisotropy, increased mean diffusivity and radial diffusivity in T2DM patients involving the frontal and parietal lobes, and significantly lower ICVF values were observed in nearly all brain regions of T2DM patients. A support vector machine model with a linear kernel was trained to realize the T2DM versus HC classification and exhibited the highest performance among the trained models, achieving an accuracy of 74% and an area under the curve of 83%.NODDI may help to probe the widespread GM neuritic density loss in T2DM patients occurs before measurable macrostructural alterations. The cortical ICVF values may provide valuable diagnostic information regarding the early GM microstructural alterations in T2DM.

Periodontitis (PD) is a common oral disease associated with various other diseases, particularly those affecting the cardiovascular system. This study explored whether peripheral artery occlusive disease (PAOD) is associated with PD and dental scaling. This study was a retrospective cohort study design from 2000 to 2018. The study population was newly diagnosed with periodontitis. The comparison group was defined as never diagnosed with periodontitis. The outcome variable was defined with the diagnosis of peripheral arterial occlusive disease (PAOD). The propensity score matching was performed by age, sex, comorbidities, and dental scaling between the two groups. Kaplan–Meier analysis was used to calculate the cumulative incidence of PAOD among the two groups. To perform the independent risk of the PAOD group, the multivariate Cox proportional hazard model was used to estimate the hazard ratios. First, 792,681 patients with PD and 458,521 patients with no history of PD were selected from Taiwan’s Longitudinal Health Insurance Database, which comprises the data of two million beneficiaries. After propensity score matching between the PD and non-PD groups for age, sex, comorbidities, and dental scaling, 357,106 patients in each group were analyzed for PAOD risk. The incidence density, relative risk, and cumulative incidence of PAOD were higher in the PD group than in the non-PD group. After adjusting for all variables, the risk of PAOD for the PD group was greater than for the non-PD group (adjusted hazard ratio = 1.03; 95% CI, 1.01–1.06). Undergoing at least one dental scaling procedure reduced the risk of PAOD. Age over 65 years was also a risk factor. In conclusion, patients with PD have an increased risk of PAOD. In addition, our results can lead to increased attention to oral hygiene, as dental scaling has a trend towards a lower risk of PAOD.

The aim of the current study was to evaluate the combined effect of the single nucleotide polymorphism (SNP) in long non-coding RNA growth arrest-specific 5 (GAS5) and the phenotypes of epidermal growth factor receptor (EGFR) on the clinicopathological characteristics of lung adenocarcinoma. The present study examined the relationship between the GAS5 single-nucleotide polymorphisms (SNPs; rs145204276 Ins/Del, rs55829688 T/C) and the clinicopathological factors in 539 lung adenocarcinoma patients with or without EGFR mutations. We found that the genotype distributions of the two GAS5 SNPs between different EGFR genotypes were similar after adjusting for age, gender and smoking history. The GAS5 SNP rs145204276 Ins/Del + Del/Del illustrated a higher distribution with an advanced tumor stage (p = 0.030), larger tumor T status (p = 0.019), positive lymph node status (p = 0.014) and distal metastases (p = 0.011) in the EGFR wild type group. In the subgroup analysis of the EGFR wild type population, the presence of GAS5 SNP rs145204276 Ins/Del + Del/Del was correlated to an advanced tumor stage (p = 0.014) and distal metastases (p = 0.020) in non-smokers. In conclusion, these data indicate that the GAS5 SNP rs145204276 variant may help predict tumor stage, lymph node metastasis and distal metastases in patients with EGFR wild type lung adenocarcinoma.

Type 2 diabetes mellitus (T2DM) is associated with cognitive impairment and may progress to dementia. However, the brain functional mechanism of T2DM‐related dementia is still less understood. Recent resting‐state functional magnetic resonance imaging functional connectivity (FC) studies have proved its potential value in the study of T2DM with cognitive impairment (T2DM‐CI). However, they mainly used a mass‐univariate statistical analysis that was not suitable to reveal the altered FC “pattern” in T2DM‐CI, due to lower sensitivity. In this study, we proposed to use high‐order FC to reveal the abnormal connectomics pattern in T2DM‐CI with a multivariate, machine learning‐based strategy. We also investigated whether such patterns were different between T2DM‐CI and T2DM without cognitive impairment (T2DM‐noCI) to better understand T2DM‐induced cognitive impairment, on 23 T2DM‐CI and 27 T2DM‐noCI patients, as well as 50 healthy controls (HCs). We first built the large‐scale high‐order brain networks based on temporal synchronization of the dynamic FC time series among multiple brain region pairs and then used this information to classify the T2DM‐CI (as well as T2DM‐noCI) from the matched HC based on support vector machine. Our model achieved an accuracy of 79.17% in T2DM‐CI versus HC differentiation, but only 59.62% in T2DM‐noCI versus HC classification. We found abnormal high‐order FC patterns in T2DM‐CI compared to HC, which was different from that in T2DM‐noCI. Our study indicates that there could be widespread connectivity alterations underlying the T2DM‐induced cognitive impairment. The results help to better understand the changes in the central neural system due to T2DM., We used high‐order functional connectivity to reveal the abnormal connectomics pattern in T2DM with cognitive impairment with a multivariate, machine learning‐based strategy. We also investigated whether such patterns were different between T2DM with cognitive impairment and T2DM without cognitive impairment to better understand T2DM‐induced cognitive impairment. Our study is well suited for publication in Human Brain Mapping as we used this method is highly advanced and desirable for extensive applications in the future. Meanwhile, it is of great help for standardizing the methodology and boosting clinical applications of the functional imaging‐based machine learning with improved reproducibility, generalizability, and interpretability.

Summary Human extended pluripotent stem cells (EPSCs), with bidirectional chimeric ability to contribute to both embryonic and extraembryonic lineages, can be obtained and maintained by converting conventional pluripotent stem cells using chemicals. However, the transition system is based on inactivated mouse fibroblasts, and the underlying mechanism is not clear. Here we report a Matrigel-based feeder-free method to convert human embryonic stem cells and induced pluripotent stem cells into EPSCs and demonstrate the extended pluripotency in terms of molecular features, chimeric ability, and transcriptome. We further identify chemicals targeting glycolysis and histone methyltransferase to facilitate the conversion to and maintenance of feeder-free EPSCs. Altogether, our data not only establish a feeder-free system to generate human EPSCs, which should facilitate the mechanistic studies of extended pluripotency and further applications, but also provide additional insights into the transitions among different pluripotent states., Graphical abstract, Highlights • EPSCs can be generated under feeder-free (LCDM-IY-Matrigel) conditions • Feeder-free EPSCs exhibit bidirectional developmental ability • GSK126 promotes the transition to human feeder-free EPSCs from ESCs/iPSCs • Inhibitors of glycolysis benefit the maintenance of feeder-free EPSCs, In this article, Zheng et al. establish human feeder-free extended pluripotent stem cells (ffEPSCs) from ESCs and iPSCs and characterize the extended pluripotency in terms of molecular markers and bidirectional developmental ability. They further identify that chemicals targeting histone modifiers andglycolysis could facilitate the transition and maintenance of ffEPSCs.

Introduction Metastasis is the primary cause of lung cancer-related death. Nevertheless, the underlying molecular mechanisms and evolutionary patterns of lung cancer metastases are still elusive. Methods We performed whole-exome sequencing for 40 primary tumors (PTs) and 61 metastases from 47 patients with lung cancer, of which 40 patients had paired PTs and metastases. The PT-metastasis genomic divergence, metastatic drivers, timing of metastatic dissemination, and evolutionary origins were analyzed using appropriate statistical tools and mathematical models. Results There were various degrees of genomic heterogeneity when comparing the paired primary and metastatic lesions or comparing metastases of different sites. Multiple metastasis-selected/enriched genetic alterations were found, such as MYC amplification, NKX2-1 amplification, RICTOR amplification, arm 20p gain, and arm 11p loss, and these results were were also featured in a meta-analysis cross-validated using an independent cohort from Memorial Sloan-Kettering Cancer Center database. To elucidate the metastatic seeding time, we applied a metastatic model and found 61.1% of the tumors were late dissemination, in which the metastatic seeding happened approximately 2.74 years before clinical detection. One exception was lymph node metastases whose dissemination time was relatively early. By analyzing the evolutionary origins, we reported that nonlymph node metastases were mainly seeded by the PT (87.5%) rather than the earlier colonized lymph node metastases. Conclusions Our results shed light on the molecular features that potentially drive lung cancer metastases. The distinct temporospatial pattern of disease progression revealed that lung cancer was susceptible to either late dissemination or indolent early lymph node metastases, leaving a potential time window to minimize metastases by early cancer detection.

To estimate the prevalence of primary immune thrombocytopenia (ITP) and describe ITP-associated healthcare resource utilization (HRU) among Texas Medicaid beneficiaries.A retrospective analysis using 2012-2015 Texas Medicaid claims data was conducted to estimate the annual prevalence of ITP. HRU was summarized for the 12-month period following initial ITP diagnosis. Logistic regression and generalized linear model were used to investigate predictors for all-cause and ITP-related HRU.The average annual prevalence of ITP was 17.0 per 100,000 persons; higher among females vs males (17.4 vs 13.6 per 100,000) and highest among adults aged ≥ 65 years (36.7 per 100,000). Among 325 patients included in the HRU analyses, 49.2% received ITP therapies. More than half of patients had at least one all-cause emergency department (ED) visit (70.5%) and/or hospitalization (56.0%). One-third (32.6%) experienced at least one ITP-related ED visit and 40.3% had at least one ITP-related hospitalization. Compared to adults aged 18-49 with ITP, children aged 0-4 (odds ratio [OR] = 3.65,There are 17 patients diagnosed with ITP for every 100,000 Texas Medicaid enrollees annually, with higher prevalence in females and the elderly. Children are more likely to experience hospitalizations and ED visits associated with ITP. ITP patients in Texas Medicaid utilize more healthcare resources compared to the general Medicaid population.

Summary Background & aims To date, the prevalence of Gestational diabetes mellitus (GDM) in China was 17.5%. Given the substantial relevance of GDM for medium- and long-term health of both mother and offspring and the paucity of existing data on the link between maternal diet and glucose homeostasis during pregnancy in Asian population, additional studies are needed. To examine the relevance of dietary glycemic index (GI), glycemic load (GL) and fiber intake before and during pregnancy for the development of GDM and glucose homeostasis over the course of pregnancy. Methods Cox proportional hazards analysis and linear mixed effects regressions were performed on data from 9317 women for whom three food frequency questionnaires (pre-pregnancy, 1st and 2nd trimesters) and biochemical measures during pregnancy were available. Investigated outcome variables included GDM risk, fasting plasma glucose (FPG), glycated hemoglobin (HbA1C), and homeostasis model assessment insulin resistance (HOMA-IR) in the 1st, 2nd and 3rd trimesters. Results Women in the highest tertile of dietary GI (or GL) before pregnancy, in the 1st, or the 2nd trimester respectively had a 12% (15%), 25% (23%) or 29% (25%) higher risk of developing GDM than those in the lowest tertile (all p for trend ≤ 0.02). Women with the highest dietary fiber intake before pregnancy, in the 1st or 2nd trimester had a 11%, 17% or 18% lower GDM risk (all p for trend ≤ 0.03). Moreover, increases in GI or GL and decreases in fiber intake over the course of pregnancy (1st to 3rd trimesters) were independently associated with adverse concurrent developments in FPG, HbA1C and HOMA-IR (p ≤ 0.03). Conclusions Our study indicates that dietary GI, GL and fiber intake before and during pregnancy affects glucose homeostasis of pregnant Chinese women.

ObjectiveOur knowledge of associations between specific types of food and mental health problems in preschool children, an important developmental period, remains scarce. Using a large sample size and a brief measure, we aimed to examine associations between food groups and mental health problems in preschoolers.MethodsA descriptive cross-sectional study was conducted among 19,548 preschoolers in nine counties in China using a two-stage cluster sampling method. Information on food frequencies, physical activity, sedentary behavior, and sleep conditions was collected by a parent-reported questionnaire. Mental health status was assessed by a parent-reported Strength and Difficulty Questionnaire (SDQ). Height and weight were measured, and BMI was calculated. Relationships between specific types of food groups and mental health status were examined using multivariable regression modeling.ResultsOf the present study sample, 47.45% of children were girls. Boys had higher scores relating to total difficulties, conduct problems, hyperactivity, and peer problems than girls but lower scores in emotional symptoms and prosocial behavior. Children with more types of food categories tended to get lower SDQ total scores even after adjusting for confounding variables (p < 0.0001). The subscale scores of SDQ varied depending on the types and numbers of food consumed. Notably, boys' mental health problems were more likely to be associated with their consumed food type. Processed meat frequency intake among boys and girls was positively related to prosocial behavior (Girls: pickled food: p = 0.003, fried food: p < 0.0001, barbecued food: p = 0.006, smoked food: p = 0.005; Boys: pickled food: p = 0.3, fried food: p < 0.0001, barbecued food: p = 0.006, smoked food: p = 0.005) and negatively associated with the SDQ total and the other subscale scores (Girls: pickled food: p ≤ 0.02, fried food: p ≤ 0.005 except for emotions (p = 0.1), barbecued food: p ≤ 0.047, smoked food: p ≤ 0.04 (except for emotions (p = 0.06) and conduct behaviors (p = 0.2)); Boys: pickled food: p < 0.01 except for hyperactivity (p = 0.5), fried food: p ≤ 0.005 except for emotions (p = 0.1), barbecued food: p ≤ 0.007 except for hyperactivity (p = 0.8), smoked food: p ≤ 0.001 except for hyperactivity (p = 0.1) and peer problem (p = 0.08)). Adequate intake frequency of confectionery (2–4 times/week) was beneficial to their emotions, conduct, and total difficulties and was also beneficial for peer and prosocial behavior for boys (Girls: emotions: p = 0.02, conduct: p = 0.02, hyperactivity: p = 0.4, peer: p = 0.06, total difficulties: p = 0.01, prosocial behavior: p = 0.1; Boys: emotions: p = 0.009, conduct: p = 0.0009, hyperactivity: p = 0.7, peer: p = 0.02: total difficulties: p = 0.003, prosocial behavior: p = 0.0002).ConclusionDiverse food categories and adequate frequency of confectionery were found to be beneficial for children's mental health, with the exception of processed meat. These findings provide novel information and supportive data for children's dietary guidelines and the improvement of mental health.

To observe the clinical effect of moxibustion combined with plucking technique at Jiquan (HT 1) for preventing peripherally inserted central catheter (PICC)-related venous thrombosis in the upper limbs of malignant tumor patients.A total of 80 malignant tumor patients undergoing PICC were randomized into an observation group and a control group, 40 cases in each one. In the control group, the routine care for PICC was exerted. In the observation group, besides the routine care, moxibustion combined with plucking technique at Jiquan (HT 1) was added. Mild moxibustion was exerted along the venous distribution of PICC (avoiding the entry site) for 10 to 15 min, and then, the circling moxibustion was applied to Quchi (LI 11), Xuehai (SP 10) and Tianfu (LU 3), 3 to 5 min at each acupoint. Finally, plucking technique was given at Jiquan (HT 1) for 5 to 10 min. This combined therapy was intervened since the 2nd day of PICC placement, once daily, 5 times a week, for 3 weeks totally. The incidence of the PICC-related venous thrombosis in the upper limbs was compared between the two groups on day 42 of placement. On day 2, 7, 14, 21, 28, 35 and 42 of PICC placement, the peak systolic velocity (PSV) and the end-diastolic velocity (EDV) of the subclavicular vein on the placement side were observed separately in the two groups.The incidence of the PICC-related venous thrombosis in the upper limbs in the observation group was lower than that in the control group (2.5% [1/40]The combined treatment of moxibustion with plucking technique at Jiquan (HT 1) can effectively prevent PICC-related venous thrombosis in the upper limbs and improve venous blood flow velocity in malignant tumor patients.

Background The aims of this study were to evaluate the levels of preretinal oxygen tension in patients with diabetes who did not have hypertension by using three-dimensional spoiled gradient-recalled (3D-SPGR) echo sequence imaging and to explore the correlation between diabetic retinopathy (DR) and changes in preretinal oxygen tension. Method This study involved 15 patients with type 2 diabetes without hypertension, who were divided into a diabetic retinopathy (DR) group (n = 10 eyes) and a diabetic non-retinopathy (NDR) group (n = 20 eyes), according to the results of a fundus photography test. Another healthy control group (n = 14 eyes) also participated in the study. The preretinal vitreous optic disc area, nasal side, and temporal side signal intensity of the eyes was assessed before and after oxygen inhalation with the use of 3D-SPGR echo magnetic resonance imaging (MRI). The signal acquisition time was 10, 20, 30, 40, and 50 min after oxygen inhalation. Results The results showed that, in the DR and NDR groups, the preretinal vitreous oxygen tension increased rapidly at 10 min after oxygen inhalation and peaked at 30–40 min, and the increased slope of the DR group was higher than that of the NDR group. The oxygen tension of the preretinal vitreous gradually increased after oxygen inhalation, and the difference between the DR and NDR groups and the control group was statistically significant (P P P Conclusion Three-dimensional-SPGR echo MRI sequencing technology is useful for detecting preretinal oxygen tension levels in patients with diabetes. It can be used as one of the functional and imaging observation indicators for the early diagnosis of DR.

Background Data from the Global Burden of Disease, Injury, and Risk Factor Study 2019 (GBD 2019) was used to assess the burden and change in prevalence, incidence, deaths, disability-adjusted life years, and risk factors for atrial fibrillation/flutter in 204 countries and territories between 1990 and 2019. Methods Incidence, prevalence, deaths, disability-adjusted life years (DALYs), and their age-standardized rates of AF/AFL were analyzed by age, sex, socio-demographic index (SDI), and human development index (HDI) using the Global Burden of Disease study 2019 (GBD2019) results，and risk factors for AF/AFL (mainly high systolic blood pressure, high body-mass index, alcohol use, smoking and diet high in sodium) were differentially analyzed. Results There are 59.70 million (95% uncertainty interval (UI) 45.73–75.29 million) AF/AFL patients worldwide in 2019, with 4.72 million (95% uncertainty interval (UI) 3.64–5.96 million) new cases and 0.315 million deaths (95% uncertainty interval (UI) 0.268–0.361 million) and 8.39 million disability-adjusted years (95% uncertainty interval (UI) 6.69–10.54 million). The highest risk factor for deaths, DALYs attributable to AF/AFL in 2019 was high systolic blood pressure, high body-mass index, alcohol use, smoking, and diet high in sodium. It is estimated that between 2030 and 2034, the total incidence of male AF/ AFL will be 16.08 million, and the total number of deaths will be 1.01 million. For females, the total number of incidence is 16.85 million, and the total number of deaths is 1.49 million. Conclusions AF/AFL remains a major global public health problem, although the ASR of prevalence, incidence, and DALY at the worldwide level showed a decreasing trend from 1990 to 2019(the ASR of deaths increased slightly). However, the unfavorable trend observed in this study in countries with lower SDI suggests that current prevention and treatment strategies should be reoriented. Some countries should develop more targeted and specific strategies to prevent the increase of AF/AFL.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. Misfolded Cu, Zn-superoxide dismutase (SOD1) has been linked to both familial and sporadic ALS. SOD1 fibrils formed in vitro share toxic properties with ALS inclusions. Here we produced cytotoxic amyloid fibrils from full-length apo human SOD1 under reducing conditions and determined the atomic structure using cryo-EM. The SOD1 fibril consists of a single protofilament with a left-handed helix. The fibril core exhibits a serpentine fold comprising N-terminal segment (residues 3–55) and C-terminal segment (residues 86–153) with an intrinsic disordered segment. The two segments are zipped up by three salt bridge pairs. By comparison with the structure of apo SOD1 dimer, we propose that eight β-strands (to form a β-barrel) and one α-helix in the subunit of apo SOD1 convert into thirteen β-strands stabilized by five hydrophobic cavities in the SOD1 fibril. Our data provide insights into how SOD1 converts between structurally and functionally distinct states.

Extra-proliferation and increased migration of vascular smooth cells con-tribute to the formation of atherosclerosis. Ras small G proteins play a critical role in the prolif-eration and migration of a wide range of cells. Mulberry, an economic fruit in Asia, exhibits anti-inflammation, anti-migration, and anti-oxidant properties. The mechanisms of action of mulberry extracts on K-Ras small G protein-induced proliferation and migration of vascular smooth muscle cell have not been extensively investigated. In this study, we explored the effects of mulberry polyphenol extracts (MPE) on the proliferation and migration of K-Ras-overexpressing A7r5 smooth muscle cells. The overexpression of K-Ras enhanced the ex-pression and activity of matrix metalloproteinase (MMP)-2, promoted vascular endothelial growth factor (VEGF) production, and eventually triggered the migration of A7r5 cells. Treatment with MPE attenuated K-Ras-induced phenomenon. In addition, MPE blocked K-Ras-induced actin fibril stress. MPE dose-dependently diminished K-Ras-induced Rho A, Rac1, CDC42, and phosphorylated focal adhesion kinase (FAK) expression. MPE elevated Rho B ex-pression. Phosphorylated AKT and glycogen synthase kinase (GSK) induced by K-Ras were also repressed by MPE treatment. MPE enhanced the interaction of IκB with NFκB. MPE restored the G0/G1 population and p21 and p27 expressions, which were repressed by K-Ras. Finally, MPE triggered the degradation of K-Ras by ubiquitination. MPE inhibited the migration and proliferation of vascular smooth cell through K-Ras-induced pathways and eventually pre-vented atherosclerosis.

Hyperpolarized carbon-13 MRI has the advantage of allowing the study of glycolytic flow in vivo or in vitro dynamically in real-time. The apparent exchange rate constant of a metabolite dynamic signal reflects the metabolite changes of a disease. Downstream metabolites can have a low signal-to-noise ratio (SNR), causing apparent exchange rate constant inconsistencies. Thus, we developed a method that estimates a more accurate metabolite signal. This method utilizes a kinetic model and background noise to estimate metabolite signals. Simulations and in vitro studies with photon-irradiated and control groups were used to evaluate the procedure. Simulated and in vitro exchange rate constants estimated using our method were compared with the raw signal values. In vitro data were also compared to the Area-Under-Curve (AUC) of the cell medium in

Purpose: Investigate the quality of mothers’ interactions with children with ADHD and a marginal disturbance in socioemotional competence (MDSC). Research Methods: A total of 49 mother-boy dyads were included, and we observed their communication on neutral and conflict topics for children with ADHD and MDSC, children with ADHD alone, and children with typical development (TD). The Chinese version of the Specific Affect Coding System 20-code was used to examine the affective presentation in communication. Results: Mothers of children with ADHD and MDSC had less negative disengagement affect compared with those of children with ADHD alone. Boys with ADHD and MDSC and boys with TD had constant positive engagement between neutral and conflict conditions in parent-child interaction. Boys with ADHD and MDSC had significantly less positive affect and more neutral affect than children with ADHD only. Conclusions and Implications: Boys with ADHD and MDSC and their mothers had worse quality of observed mother-child communication than children with ADHD only and their mothers.

Postoperative atrial fibrillation is a common consequence of cardiac sur-gery with increased stroke complications and mortality. Although dexmedetomidine is thought to prevent postoperative atrial fibrillation and stroke because of its sympa-tholytic and anti-inflammatory properties, data from different studies show the effect of dexmedetomidine on postoperative atrial fibrillation and stroke uncertain in adult patients with cardiac surgery.A database including EMBASE, PubMed, and Cochrane CENTRAL was searched for randomized controlled trials comparing dexmedetomidine with placebo or other anesthetic drugs in adult cardiac surgery. The primary outcome was the incidence of postoperative atrial fibrillation. The secondary outcomes were the incidence of postop-erative stroke, mechanical ventilation duration, intensive care unit length of stay, hospi-tal length of stay, and mortality.Eighteen trials with a total of 2933 patients were enrolled in the meta-analyses. Compared with controls, dexmedetomidine significantly reduced the incidence of post-operative atrial fibrillation [odds ratio, 0.82; 95% CI, 0.69-0.98; P = .03]. There was no sig-nificant difference between groups in stroke (odds ratio, 1.36; 95% CI, 0.59-3.16; P = .47), mechanical ventilation duration [weighted mean difference, -0.17; 95% CI, -0.35 to 0.14;P=.39], intensive care unit length of stay (weighted mean difference, -0.03; 95% CI,-0.93 to 0.87; P = .95), hospital length of stay (weighted mean difference, -0.04; 95% CI,-0.40 to 0.32; P = .83) and mortality (odds ratio, 0.72; 95% CI, 0.32-1.60; P = .42).Perioperative dexmedetomidine reduced the incidence of postoperative atrial fibrillation in adult patients undergoing cardiac surgery. But there was no signifi-cant difference in the incidence of stroke, mechanical ventilation duration, intensive care unit length of stay, hospital length of stay, and mortality.

This review aims to develop an appropriate review tool for systematically collating metabolites that are dysregulated in disease and applies the method to identify novel diagnostic biomarkers for hepatocellular carcinoma (HCC). Studies that analyzed metabolites in blood or urine samples where HCC was compared with comparison groups (healthy, precirrhotic liver disease, cirrhosis) were eligible. Tumor tissue was included to help differentiate primary and secondary biomarkers. Searches were conducted on Medline and EMBASE. A bespoke “risk of bias” tool for metabolomic studies was developed adjusting for analytic quality. Discriminant metabolites for each sample type were ranked using a weighted score accounting for the direction and extent of change and the risk of bias of the reporting publication. A total of 84 eligible studies were included in the review (54 blood, 9 urine, and 15 tissue), with six studying multiple sample types. High-ranking metabolites, based on their weighted score, comprised energy metabolites, bile acids, acylcarnitines, and lysophosphocholines. This new review tool addresses an unmet need for incorporating quality of study design and analysis to overcome the gaps in standardization of reporting of metabolomic data. Validation studies, standardized study designs, and publications meeting minimal reporting standards are crucial for advancing the field beyond exploratory studies.

A 60‐year‐old man was hospitalized because of numbness and weakness in the right upper limb. Magnetic resonance imaging revealed a large mass in the right upper lobe invading the right eighth cervical and first thoracic nerve root. Biopsy pathology confirmed primary lung adenocarcinoma with a clinical stage of cT4N0M0 IIIA, negative for anaplastic lymphoma kinase fusion gene and epidermal growth factor receptor mutations but positive for programmed death ligand 1 (3%). Neoadjuvant tislelizumab and chemotherapy were offered to this patient with Pancoast tumor, and tumor shrinkage of 71% was achieved. After the operation, surgical pathology indicated pathologic complete response (pCR). Circulating tumor cells testing was negative after the first adjuvant treatment. In this case, we provide real‐world evidence of encouraging pCR with neoadjuvant tislelizumab and chemotherapy for a patient with Pancoast tumor., • Neoadjuvant tislelizumab and chemotherapy was offered for a patient with Pancoast tumor (TNM stage, cT4N0M0 IIIA). • Surgical resection was successfully performed and a pCR was achieved.

Purpose Studies regarding the association between dietary fat intake and gestational diabetes mellitus (GDM) are limited and provide conflicting findings. Thus, the study aims to examine the association of dietary fat intake in the year preceding pregnancy and during pregnancy with the risk of GDM, taking the relevance of dietary protein intake on GDM into consideration. Methods A prospective study was conducted in 6299 singleton pregnancies, using the data from the Nutrition in Pregnancy and Growth in Southwest China (NPGSC). A validated food frequency questionnaire was used to assess dietary fat intake in the year preceding pregnancy and during the first and second trimesters of pregnancy. Logistic regression analysis was used to assess the prospective associations of dietary fat intake and the type and source of dietary fats in different time windows with GDM risk. Results Higher intake of total fat [OR (95% CI): 2.21 (1.19–4.20), P = 0.02] during 12–22 weeks of gestation was associated with higher GDM risk. However, adjustment for animal protein intake greatly attenuated this association [OR (95% CI): 1.81 (0.93, 3.64), P = 0.11]. Total fat intake neither in the year preceding pregnancy nor during the early pregnancy was associated with GDM risk. Moreover, insignificant associations were observed between intakes of vegetable fat, animal fat, cholesterol, saturated fatty acid, monounsaturated fatty acid and polyunsaturated fatty acid one year before pregnancy and during the first and second trimesters and GDM risk. Conclusion Our study indicated that dietary fat intake one year before pregnancy and across the two pregnancy trimesters preceding the diagnosis of GDM has no relevance on GDM risk among Chinese women, particularly those with normal BMI, low, or normal calorie intake.

Interleukin (IL)-17 and its related cytokines have been shown to be involved in myocardial fibrosis and irreversible ventricular remodelling, which have predictive values in the development of left ventricular diastolic dysfunction (LVDD). This study aimed to assess the correlation between IL-17 and LVDD, and investigate the prognostic value of IL-17 among patients with normal left ventricular ejection fraction (LVEF).A total of 120 patients with normal LVEF underwent left ventricular (LV) catheterisation for LV end-diastolic pressure (LVEDP) measurement and routine echocardiography. The follow-up period was 30 (18, 35) months.The levels of IL-17 and IL-6 from the systemic blood were significantly increased in non-heart failure (HF) patients with LVDD (p0.001). Receiver operating characteristic (ROC) revealed that the combination of IL-17 and IL-6 showed the highest diagnostic accuracy in predicting LVDD (AUC, 0.890; 95% CI, 0.835-0.945; p0.001), and the cut-off value was 41.5 pg/mL. On logistic regression analysis, the increment of the combination of IL-17 and IL-6 was an independent predictor for the prognosis of LVDD (odds ratio, 1.25; 95% CI, 1.01-1.12; p0.05). According to the cut-off value of the combination of IL-17 and IL-6, the patients with lower levels of IL-17 and IL-6 (41.5 pg/mL group) had a better prognosis. The increased levels of IL17 and IL-6 were significantly correlated with the levels of fibrotic parameters.Assessment of LVDD by measuring the combination of IL-17 and IL-6 might provide valuable prognostic significance for non-HF patients with LVDD.

Purpose: Although enzalutamide (ENZ) has been widely used to treat de novo or castration-resistant metastatic prostate cancer, resistance develops and disease progression is ultimately inevitable. There are currently no approved targeted drugs to specifically delay or overcome ENZ resistance. Experimental Design: We selected several ENZ-resistant cell lines that replicated clinical characteristics of the majority of patients with ENZ-resistant disease. A high-throughput pharmacologic screen was utilized to identify compounds with greater cytotoxic effect for ENZ-resistant cell lines, compared with parental ENZ-sensitive cells. We validated the potential hits in vitro and in vivo, and used knockdown and overexpression assays to study the dependencies in ENZ-resistant prostate cancer. Results: ABT199 (BCL-2 inhibitor) and IMD0354 (IKKB inhibitor) were identified as potent and selective inhibitors of cell viability in ENZ-resistant cell lines in vitro and in vivo which were further validated using loss-of-function assays of BCL-2 and IKKB. Notably, we observed that overexpression of BCL-2 and IKKB in ENZ-sensitive cell lines was sufficient for the emergence of ENZ resistance. In addition, we confirmed that BCL-2 or IKKB inhibitors suppressed the development of ENZ resistance in xenografts. However, validation of both BCL-2 and IKKB in matched castration-sensitive/resistant clinical samples showed that, concurrent with the development of ENZ/abiraterone resistance in patients, only the protein levels of IKKB were increased. Conclusions: Our findings identify BCL-2 and IKKB dependencies in clinically relevant ENZ-resistant prostate cancer cells in vitro and in vivo, but indicate that IKKB upregulation appears to have greater relevance to the progression of human castrate-resistant prostate cancer.

This study reveals an uncovered mechanism for the regulation of polyamine homeostasis through protein arginyl citrullination of antizyme (AZ), a natural inhibitor of ornithine decarboxylase (ODC). ODC is critical for the cellular production of polyamines. AZ binds to ODC dimers and promotes the degradation of ODC via the 26S proteasome. This study demonstrates the protein citrullination of AZ catalyzed by peptidylarginine deiminase type 4 (PAD4) both in vitro and in cells. Upon PAD4 activation, the AZ protein was citrullinated and accumulated, leading to higher levels of ODC proteins in the cell. In the PAD4-overexpressing and activating cells, the levels of ODC enzyme activity and the product putrescine increased with the level of citrullinated AZ proteins and PAD4 activity. Suppressing cellular PAD4 activity reduces the cellular levels of ODC and downregulates cellular polyamines. Furthermore, citrullination of AZ in the C-terminus attenuates AZ function in the inhibition, binding, and degradation of ODC. This paper provides evidence to illustrate that PAD4-mediated AZ citrullination upregulates cellular ODC and polyamines by retarding ODC degradation, thus interfering with the homeostasis of cellular polyamines, which may be an important pathway regulating AZ functions that is relevant to cancer biology.

Amyotrophic lateral sclerosis (ALS) was initially thought to be associated with oxidative stress when it was first linked to mutant superoxide dismutase 1 (SOD1). The subsequent discovery of ALS-linked genes functioning in RNA processing and proteostasis raised the question of how different biological pathways converge to cause the disease. Both familial and sporadic ALS are characterized by the aggregation of the essential DNA- and RNA-binding protein TDP-43, suggesting a central role in ALS etiology. Here we report that TDP-43 aggregation in neuronal cells of mouse and human origin causes sensitivity to oxidative stress. Aggregated TDP-43 sequesters specific microRNAs (miRNAs) and proteins, leading to increased levels of some proteins while functionally depleting others. Many of those functionally perturbed gene products are nuclear-genome-encoded mitochondrial proteins, and their dysregulation causes a global mitochondrial imbalance that augments oxidative stress. We propose that this stress-aggregation cycle may underlie ALS onset and progression.

Drug refractory epilepsy (RE) is believed to be associated with structural lesions, but some RE patients show no significant structural abnormalities (RE-no-SA) on conventional magnetic resonance imaging scans. Since most of the medically controlled epilepsy (MCE) patients also do not exhibit structural abnormalities, a reliable assessment needs to be developed to differentiate RE-no-SA patients and MCE patients to avoid misdiagnosis and inappropriate treatment. Using resting-state scalp electroencephalogram (EEG) datasets, we extracted the spatial pattern of network (SPN) features from the functional and effective EEG networks of both RE-no-SA patients and MCE patients. Compared to the performance of traditional resting-state EEG network properties, the SPN features exhibited remarkable superiority in classifying these two groups of epilepsy patients, and accuracy values of 90.00% and 80.00% were obtained for the SPN features of the functional and effective EEG networks, respectively. By further fusing the SPN features of functional and effective networks, we demonstrated that the highest accuracy value of 96.67% could be reached, with a sensitivity of 100% and specificity of 92.86%. Overall, these findings not only indicate that the fused functional and effective SPN features are promising as reliable measurements for distinguishing RE-no-SA patients and MCE patients but also may provide a new perspective to explore the complex neurophysiology of refractory epilepsy.

Hepatocellular carcinoma (HCC), is one of the most common malignancies worldwide, which is globally the third most common cause of cancer-related mortality. This study aims to identify new potential early-stage diagnostic and prognostic biomarker for HCC. The candidate gene SLC26A6 expression was analyzed based on the Oncomine and Tumor Immune Estimation Resource (TIMER) databases and verified forwards with Gene Expression Omnibus (GEO) datasets. The protein expression was retrieved from Human Protein Atlas (HPA) database. We also validated the diagnostic and prognostic value in HCC, and the relationship between SLC26A6 and clinicopathologic parameters were also accessed. The Gene Set Enrichment Analysis (GSEA) and Protein-Protein Interaction (PPI) network were constructed to analyze the SLC26A6-related pathway. These results reveal that SLC26A6 expression was elevated in HCC, and the diagnostic sensitivity of SLC26A6 was higher than α-fetoprotein (AFP). SLC26A6 expression was independent prognostic factor for HCC. SLC26A6 up-regulation was mainly associated with excision repair, DNA replication, etc. SLC26A6-related mR-NAs was enriched in PI3K-AKT signaling pathway, axon guidance, pathways in cancer, and so on. PPI network indicated that SLC26A6 was interacted with solute carrier members, ABC transporters and other ion transport molecule. We further analyzed three positively correlated microRNAs and 10 negatively correlated microRNAs, all of these were reported participating or inhibiting in cancer progression. This is the first study demonstrated that SLC26A6 is up-regulated in HCC and correlated with poor prognosis, which might be served as a diagnostic marker or prognostic biomarker for HCC.

Background: Whether electroacupuncture (EA) stimulation at different frequencies has a similar effect on spared nerve injury (SNI) as other neuropathic pain models, and how EA at different frequencies causes distinct analgesic effects on neuropathic pain is still not clear. Methods: Adult male Sprague-Dawley rats were randomly divided into sham SNI, SNI, 2 Hz, 100 Hz and sham EA groups. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were measured. EA was performed once a day on days 1 to 14 after SNI. The expressions of transient receptor potential cation subfamily V member 1 (TRPV1) and peripheral purinergic P2X receptor 3 (P2X3) were determined by western blotting and immunofluorescence. TRPV1 siRNA and P2X3 siRNA were administered by intrathecal injection. TRPV1 or P2X3 agonists were combined with EA. Results: There were significant decreases in PWT, but no changes in PWL in the 14 days after SNI. EA using 2- or 100-Hz stimulation similarly increased PWT at every time point. The cytosol protein expression of P2X3 in the L4–L6 dorsal root ganglia (DRG) increased, but the expression of TRPV1 decreased in the SNI model. Both these effects were ameliorated by EA, with 2-Hz stimulation having a stronger effect than 100-Hz stimulation. Blocking either TRPV1 or P2X3 specific siRNAs attenuated the decreased PWT induced by SNI. Administration of either a TRPV1 or P2X3 agonist inhibited EA analgesia. Conclusion: 2- and 100-Hz EA similarly induced analgesic effects in SNI. This effect was related to up-regulation and down-regulation, respectively, of cytosol protein expression of P2X3 and TRPV1 in L4–L6 DRG, with 2 Hz having a better effect than 100 Hz.

Background: To examine the association of postpartum depression (PPD) with maternal suicide in the Taiwanese population. Methods: We examined the medical records of women aged 18–50 years who experienced childbirth and had PPD (the study cohort, n = 2882), who experienced childbirth but did not have PPD (comparison cohort 1, n = 5764), and who neither experienced childbirth nor had PPD (comparison cohort 2, n = 5764) between 2000 and 2015. The patients were followed up until suicide, withdrawal from the National Health Insurance program, or 31 December 2015. Results: The rates of anxiety and depression symptoms, as well as the cumulative risk of suicide, were significantly higher in the study cohort. PPD was significantly correlated with an increased risk of maternal suicide and was associated with a greater risk of developing comorbidities such as hypertension, diabetes mellitus, hyperlipidemia, and stroke. The comparison cohorts did not differ significantly in terms of suicide risk. Conclusion: PPD was associated with a significantly higher rate of suicide and a shorter time to suicide after childbirth. Younger age, winter, and subclinical depression and anxiety positively predicted suicide in the study cohort. To prevent maternal suicide, clinicians should be observant of subclinical depression and anxiety symptoms among patients.

Background: Causality has recently been suggested to associate early childhood caries with psychomotor deficiency in preschoolers, where their causal interactions via other risk determinants remain unclear. Methods: To analyze such causality, we randomly recruited 123 three-to-six-year-old children in a three-year longitudinal study, where the caries/dmft measures, age/gender, BMI, amended comprehensive scales for psychomotor development (CCDI-aspects), parental education/vocation, and diet were collected for assessment of their inter-relationships. Subsequently, t-tests, multiple/linear-regressions, and R2-analyses were utilized to compare the differences of variables between age/gender, BMI, and dmft vs. relationships among all variables and CCDI-aspects. Results: In the regression modeling, there were significant differences between gender vs. age (p < 0.05; not BMI) regarding established associations between caries and CCDI manifests for psychomotor deficiency. As for diet vs. socio-economic status, there were significant differences when caries/dmft were at lower- vs. higher-scales (

OBJECTIVE: To investigate the clinical treatment outcomes and the changes of the outcomes over time in extremely preterm twins in Guangdong Province, China. METHODS: A retrospective analysis was performed for 269 pairs of extremely preterm twins with a gestational age of

Dental pulp stem cells (DPSCs) from pulpitis patients showed defective osteogenic differentiation. However, as the most well-studied histone acetyltransferase, the impaired general control nonrepressed protein 5 (GCN5) plays essential roles in various developmental processes. The aim of this study was to investigate the effect of GCN5 on DPSCs odontogenic differentiation. The healthy dental pulp tissues were obtained from the extracted impacted third molar of patients with the informed consent. DPSCs were treated with a high concentration of tumor necrosis factor-alpha (TNF-α) (100 ng/mL) and odontogenic differentiation-related gene and GCN5 protein level by Western blot analysis. Proliferation of the DPSCs was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Immunofluorescence staining detected GCN5 and NF-κB signaling for p-p65. The mechanism of GCN5 regulating odontogenic differentiation of DPSCs was determined by small interfering RNA analysis. Our data suggested that TNF-α can significantly reduce mineralization and the expression of dentin matrix acidic phosphoprotein 1 and dentin sialophosphoprotein at higher concentration (100 ng/mL). Meanwhile, it showed that the inflammation in microenvironment resulted in a downregulation of GCN5 expression and GCN5 knockdown caused decreased odontogenic differentiation of DPSCs was also found. In addition, the knockdown of GCN5 increased the expression of phosphorylation of p65, thus activating NF-κB pathway of DPSCs. Meanwhile, NF-κB pathway inhibitor pyrrolidinedithiocarbamic acid reversed the siGCN5 decreased odontogenic differentiation of DPSCs. Altogether, our findings indicated that in inflammatory microenvironments GCN5 plays a protective role in pulpitis impaired odontogenic differentiation of DPSCs by activating NF-κB pathway, which may provide a potential approach to dentin regeneration.