Ultrasensitive FET biosensor chip based on self-assembled organic nanoporous membrane for femtomolar detection of Amyloid-ß.

Early diagnosis of Alzheimer's disease (AD) is critical for preventing disease progression, however, the diagnosis of AD remains challenging for most patients due to limitations of current sensing technologies. A common pathological feature found in AD-affected brains is the accumulation of Amyloid-ß (Aß) polypeptides, which lead to neurofibrillary tangles and neuroinflammatory plaques. Here, we developed a portable ultrasensitive FET biosensor chip based on a self-assembled nanoporous membrane for ultrasensitive detection of Aß protein in complex environments. The microscale semiconductor channel was covered with a self-assembled organic nanoporous membrane modified by antibody molecules to pick up and amplify the Aß protein signal. The nanoporous structure helps protect the sensitive channel from non-target proteins and improves its stability since no chemical functionalization process involved, largely reduces background noise of the sensing platform. When a bio-gated target is captured, the doping state of the polymer bulk could be tuned and amplified the strength of the weak signal, achieving ultrasensitive detecting performance (enabling the device to detect target protein less than 1 fg/ml in 1 µl sample). Moreover, the device simplifies the circuit connection by integrating all the connections on a 2 cm × 2 cm chip, avoiding expensive and complex manufacturing processes, and makes it usable for portable prognosis. We believe that this ultrasensitive, portable, low-cost Aß sensor chip shows the great potential in the early diagnosis of AD and large-scale population screening applications.

Rosai-Dorfman disease in the central nervous system with two isolated lesions originated from a single clone: a case report.

BACKGROUND: Rosai-Dorfman disease (RDD) is a rare, benign, idiopathic non-Langerhans cell histiocytosis. Cases of RDD in the CNS are extremely rare but lethal. RDD is thought to represent a reactive process. Recent studies proposed a subset of RDD cases that had a clonal nature. However, its clone origin is poorly understood. CASE PRESENTATION: We present a rare case of RDD in the CNS with two isolated lesions. These two lesions were removed successively after two operations. No seizure nor recurrence appears to date (2 years follow-up). Morphological and immunohistochemical profiles of these two lesions support the diagnosis of RDD. Based on the whole-exome sequencing (WES) data, we found the larger lesion has a higher tumor mutational burden (TMB) and more driver gene mutations than the smaller lesion. We also found seven common truncal mutations in these two lesions, raising the possibility that they might stem from the same ancestor clone. CONCLUSIONS: Overall, this is the first report about clonal evolution of RDD in the CNS with two isolated lesions. Our findings contribute to the pathology of RDD, and support the notion that a subset of cases with RDD is a clonal histiocytic disorder driven by genetic alterations.

Polymorphous low-grade neuroepithelial tumor of the young: case report and review focus on the radiological features and genetic alterations.

BACKGROUND: A new type of epileptogenic tumor, the polymorphous low-grade neuroepithelial tumor of the young (PLNTY) was firstly reported by Jason T. Huse et al. at 2016. After that, only 1 case of PLNTY was reported by article. The radiological characteristics of PLNTY have not been concluded. The objective of our study was to report 3 cases of PLNTYs in details and to analyze the image characteristics and genetic alterations of PLNTYs by reviewing our cases and articles. CASE PRESENTATION: There were 3 cases diagnosed as PLNTY by pathology in our hospital during the last 10 years, with the average age of 15. They were all suffered from different degrees of epilepsy. All of them underwent magnetic resonance (MR) imaging and 2 of them underwent computer tomography (CT) imaging. The PLNTYs are all appearing as a solid or solid-cystic cortical mass with little mass effect and unclear boundary with normal brain tissue. They are all shown as hyperintensity in T2WI and iso-/hypointensity in T1WI with slight or no enhancement after contract enhanced in MR imaging. The "salt and pepper sign" in T2WI and grit calcification in CT images might be specific characteristics of PLNTY. All of them recovered after excision of the tumors. The gene tests revealed fibroblast growth factor receptors 3 (FGFR3)-TACC3 fusion and FGFR3 amplification in one case, and the B-Raf proto-oncogene (BRAF) V600E mutation in another case. CONCLUSION: In the image, the partial ill-marginated cortical mass with "salt and pepper sign" in T2WI or grit calcification in CT imaging might be the typical imaging characteristics of PLNTY. We also prove that the BRAF V600E mutation as well as the FGFR2 and FGFR3 have a close relationship with PLNTY.

Observations of N2O5 and NO3 at a suburban environment in Yangtze river delta in China: Estimating heterogeneous N2O5 uptake coefficients.

The nitrate radical (NO3) and dinitrogen pentoxide (N2O5) play an important role in the nocturnal atmosphere chemistry. Observations of NO3 radicals and N2O5 were performed in a semirural ground site at Tai'Zhou in polluted southern China using cavity ring down spectroscopy (CRDS) from 23 May to 15 June 2018. The observed NO3 and N2O5 concentrations were relatively low, with 1 min average value of 4.4 ± 2.2 and 26.0 ± 35.7 pptV, respectively. The N2O5 uptake coefficient was determined to be from 0.027 to 0.107 based on steady state lifetime method. Fast N2O5 hydrolysis was the largest contributor to the loss of NO3 and contributed to substantial nitrate formation, with an average value of 14.83 ± 6.01 µg/m3. Further analysis shows that the N2O5 heterogeneous reactions dominated the nocturnal NOx loss and the nocturnal NOx loss rate is 0.14 ± 0.02 over this region.

Development of a field system for measurement of tropospheric OH radical using laser-induced fluorescence technique.

A ground-based system for measuring tropospheric OH radical based on laser-induced fluorescence (AIOFM-LIF) was developed in this work. In this system, ambient air is expanded through a 0.4 mm nozzle to low pressure in a detection chamber, where OH radical is irradiated by the 308 nm laser pulse at a repetition rate of 8.5 kHz. Then, the resultant fluorescence corresponding to the A2Σ+(υ'=0)←X2Πi(ν''=0) transition at 308 nm is detected using gated photon counting. The AIOFM-LIF system was integrated into a mobile observing platform for the field observation following the series of laboratory characterization. A portable standard OH radical source by water photolysis-ozone actinometry was established and optimized for accurate system calibration. The factors affecting the system sensitivity were quantified. It was shown that the ultimate system sensitivity is 9.9 × 10-8 cps (molecules cm-3)-1 mw-1; the minimum detection limits are (1.84 ± 0.26) × 105 cm-3 and (3.69 ± 0.52) × 105 cm-3 at night and noon, respectively; and the whole error of AIOFM-LIF system is about 16%. Then, the system was deployed in Shenzhen, China, during the "A comprehensive STudy of the Ozone foRmation Mechanism in Shenzhen" (STORM) campaign. Valid OH radical concentrations for 31 days were obtained, and the peak of the daily average concentration was 6.6 × 106 cm-3 around 12:00. And a high correlation (R2 = 0.77) between OH and j(O1D) was also observed in this field campaign. The relationship between OH concentration and NOx was attentively discussed. The deployment of AIOFM-LIF system in STORM campaign has demonstrated its capability of measuring tropospheric OH radical with high sensitivity and accuracy in a polluted environment.

CTRP13 alleviates palmitic acid-induced inflammation, oxidative stress, apoptosis and endothelial cell dysfunction in HUVECs.

C1q/tumor necrosis factor-related protein 13 (CTRP13) has been reported to participate in cardiovascular diseases. However, the role and molecular mechanism of CTRP13 in obesity-induced endothelial cell damage is still unclear. In palmitic acid (PA)-induced human umbilical vein endothelial cells (HUVECs), qRT-PCR and western blot were used to examine CTRP13 expression. CCK-8 and TUNEL assays were adopted to assess cell viability and apoptosis, respectively. ROS level and MDA content were evaluated by their commercial kits and inflammatory cytokines were measured using ELISA. Endothelial cell dysfunction was evaluated by detecting NO production and eNOS expression, and tube formation assay was performed to assess angiogenesis. AMPK pathway-related proteins were detected by western blot. The results showed that CTRP13 was downregulated in PA-induced HUVECs. CTRP13 overexpression reduced PA-induced cell viability loss and oxidative stress in HUVECs. Moreover, CTRP13 overexpression suppressed PA-induced inflammation and apoptosis, improved angiogenesis ability, and alleviated endothelial cell dysfunction in HUVECs. In addition, CTRP13 overexpression activated AMPK pathway and regulated the expressions of downstream NOX1/p38 and KLF2. Furthermore, compound C countervailed the impacts of CTRP13 overexpression on cell viability, oxidative stress, inflammation, apoptosis and endothelial function in PA-induced HUVECs. To sum up, CTRP13 overexpression may alleviate PA-induced endothelial cell damage.

Minimally-invasive implantable device enhances brain cancer suppression.

Current brain tumor treatments are limited by the skull and BBB, leading to poor prognosis and short survival for glioma patients. We introduce a novel minimally-invasive brain tumor suppression (MIBTS) device combining personalized intracranial electric field therapy with in-situ chemotherapeutic coating. The core of our MIBTS technique is a wireless-ultrasound-powered, chip-sized, lightweight device with all functional circuits encapsulated in a small but efficient "Swiss-roll" structure, guaranteeing enhanced energy conversion while requiring tiny implantation windows ( ~ 3 × 5 mm), which favors broad consumers acceptance and easy-to-use of the device. Compared with existing technologies, competitive advantages in terms of tumor suppressive efficacy and therapeutic resolution were noticed, with maximum ~80% higher suppression effect than first-line chemotherapy and 50-70% higher than the most advanced tumor treating field technology. In addition, patient-personalized therapy strategies could be tuned from the MIBTS without increasing size or adding circuits on the integrated chip, ensuring the optimal therapeutic effect and avoid tumor resistance. These groundbreaking achievements of MIBTS offer new hope for controlling tumor recurrence and extending patient survival.

Predicting diagnostic gene biomarkers in patients with diabetic kidney disease based on weighted gene co expression network analysis and machine learning algorithms.

The present study was designed to identify potential diagnostic markers for diabetic kidney disease (DKD). Two publicly available gene expression profiles (GSE142153 and GSE30528 datasets) from human DKD and control samples were downloaded from the GEO database. Differentially expressed genes (DEGs) were screened between 23 DKD and 10 control samples using the gene data from GSE142153. Weighted gene co expression network analysis was used to find the modules related to DKD. The overlapping genes of DEGs and Turquoise modules were narrowed down and using the least absolute shrinkage and selection operator regression model and support vector machine-recursive feature elimination analysis to identify candidate biomarkers. The area under the receiver operating characteristic curve value was obtained and used to evaluate discriminatory ability using the gene data from GSE30528. A total of 110 DEGs were obtained: 64 genes were significantly upregulated and 46 genes were significantly downregulated. Weighted gene co expression network analysis found that the turquoise module had the strongest correlation with DKD (R = -0.58, P = 4 × 10-4). Thirty-eight overlapping genes of DEGs and turquoise modules were extracted. The identified DEGs were mainly involved in p53 signaling pathway, HIF-1 signaling pathway, JAK - STAT signaling pathway and FoxO signaling pathway between and the control. C-X-C motif chemokine ligand 3 was identified as diagnostic markers of DKD with an area under the receiver operating characteristic curve of 0.735 (95% CI 0.487-0.932). C-X-C motif chemokine ligand 3 was identified as diagnostic biomarkers of DKD and can provide new insights for future studies on the occurrence and the molecular mechanisms of DKD.

Interrelationship between 2019-nCov receptor DPP4 and diabetes mellitus targets based on protein interaction network.

Patients with diabetes are more likely to be infected with Coronavirus disease 2019 (COVID-19), and the risk of death is significantly higher than ordinary patients. Dipeptidyl peptidase-4 (DPP4) is one of the functional receptor of human coronavirus. Exploring the relationship between diabetes mellitus targets and DPP4 is particularly important for the management of patients with diabetes and COVID-19. We intend to study the protein interaction through the protein interaction network in order to find a new clue for the management of patients with diabetes with COVID-19. Diabetes mellitus targets were obtained from GeneCards database. Targets with a relevance score exceeding 20 were included, and DPP4 protein was added manually. The initial protein interaction network was obtained through String. The targets directly related to DPP4 were selected as the final analysis targets. Importing them into String again to obtain the protein interaction network. Module identification, gene ontology (GO) analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis were carried out respectively. The impact of DPP4 on the whole network was analyzed by scoring the module where it located. 43 DPP4-related proteins were finally selected from the diabetes mellitus targets and three functional modules were found by the cluster analysis. Module 1 was involved in insulin secretion and glucagon signaling pathway, module 2 and module 3 were involved in signaling receptor binding. The scoring results showed that LEP and apoB in module 1 were the highest, and the scores of INS, IL6 and ALB of cross module associated proteins of module 1 were the highest. DPP4 is widely associated with key proteins in diabetes mellitus. COVID-19 may affect DPP4 in patients with diabetes mellitus, leading to high mortality of diabetes mellitus combined with COVID-19. DPP4 inhibitors and IL-6 antagonists can be considered to reduce the effect of COVID-19 infection on patients with diabetes.

Novel Nano-Drug Delivery System for Brain Tumor Treatment.

As the most dangerous tumors, brain tumors are usually treated with surgical removal, radiation therapy, and chemotherapy. However, due to the aggressive growth of gliomas and their resistance to conventional chemoradiotherapy, it is difficult to cure brain tumors by conventional means. In addition, the higher dose requirement of chemotherapeutic drugs caused by the blood-brain barrier (BBB) and the untargeted nature of the drug inevitably leads to low efficacy and systemic toxicity of chemotherapy. In recent years, nanodrug carriers have attracted extensive attention because of their superior drug transport capacity and easy-to-control properties. This review systematically summarizes the major strategies of novel nano-drug delivery systems for the treatment of brain tumors in recent years that cross the BBB and enhance brain targeting, and compares the advantages and disadvantages of several strategies.

Integrative Genomic and Transcriptomic Analysis of Primary Malignant Gliomas Revealed Different Patterns Between Grades and Somatic Mutations Related to Glioblastoma Prognosis.

Background: As reflected in the WHO classification of glioma since 2020, genomic information has been an important criterion in addition to histology for glioma classification. There is a significant intergrade difference as well as intragrade difference of survival probability among glioma patients. Except the molecular criteria used in the WHO classification, few studies have explored other genomic factors that may be underlying these survival differences, especially in Chinese populations. Here, we used integrative genomic approaches to characterize a Chinese glioma cohort to search for potential prognostic biomarkers. Methods: We recruited 46 Chinese patients with primary malignant glioma. All the patients were analyzed with whole-exome sequencing (WES) and 27 of them were analyzed with RNA-seq. We compared the molecular features between patients in different WHO grades. We classified the glioblastoma (GBM) patients into two groups (good vs poor survival) using six-month progression-free survival (PFS6) status and compared the genomic profiles between the two groups. Results: We found grade II and grade III patients cluster together (LGG) and they are different from GBM in unsupervised clustering analysis with RNA-seq data. Gene set enrichment analysis (GSEA) comparing GBM and the LGG group suggested that GBM had upregulation of multiple pathways related to genome integrity and immune cell infiltration. Further comparison of somatic mutations between the two groups revealed TOPAZ1 as a novel mutation associated with GBM and prevalence of CNV in multiple genes in GBM. Comparison between PFS6 good and poor GBM patients revealed six genes (TRIML2, ROCK1, PKD1, OBSCN, HECTD4, and ADCY7) were significantly mutated and two genes (NTRK1 and B2M) had more CNV alterations in the poor prognosis group. Conclusion: Taken together, our molecular data revealed that GBM patient showed distinct characteristics related to individual gene, chromosome integrity, and infiltrating immune cells compared to LGG (grade II/III) patients. We also identified few novel genes with SNV or CNV, which might be the potential markers for clinical outcome of GBM.

Characteristics and trends of globally registered glioma clinical trials in the past 16 years.

Background: Advancement in the treatment of glioma has been vacant since temozolomide has proved its therapeutic value in glioblastoma in 2005. Aim: To help investigators understand the landscape of glioma clinical research, we analyzed the characteristics and trends of globally registered glioma trials in the past decades. Methods: This is a cross-sectional analysis of glioma trials registered on ClinicalTrials.gov between January 2006 and December 2021. Characteristics regarding phase, enrollment number, study design and type, funding source, tumor site, pathology, patient status, age of population, trial purpose, and participating country were abstracted, and chronological shifts were analyzed. Results: There were 1531 registered glioma trials involved 58 participating countries. The trial purpose concerning surgery, radiotherapy, chemotherapy, targeted therapy, tumor-treating fields, immunotherapy, other antiglioma therapy and non-antiglioma research trial accounts for 3.5%, 6.5%, 9.5%, 28.9%, 2.0%, 16.4%, 12.5%, and 20.6%, respectively. In the past 16 years, the numbers of chemotherapy and targeted therapy trials declined; tumor-treating fields and immune checkpoint inhibitor application trials sprang at the latter half period; Immunotherapy, other antiglioma therapy and non-antiglioma research trials escalated (all above p trend < 0.005). The trend also showed the phased trials registered diminishingly and that the trials which focused on glioblastoma registered incrementally (those two p trend < 0.05). Among 784 drug therapy trials, it was included 45 cytotoxic drugs, 186 targeted drugs, 19 immune checkpoint inhibitors, 78 other drugs, and five immunomodulatory drugs. Two trials belonged to Bayesian adaptive randomized design. By the end of December 2021, 309 trials had publications. Only everolimus and tumor-treating fields exhibited meaningful survival benefit in specific glioma patients in phase 3 trials. Conclusion: Meaningful effective treatments regarding drugs or methods for glioma were difficult to be found. Bayesian adaptive platform trials may accelerate clinical research in glioma. Development of novel treatment modalities for glioma is still challenged.

An implantable ultrasound-powered device for the treatment of brain cancer using electromagnetic fields.

Brain tumors have been proved challenging to treat. Here, we present a promising alternative by developing an implantable ultrasound-powered tumor treating device (UP-TTD) that electromagnetically disrupts the rapid division of cancer cells without any adverse effects on normal neurons, thereby safely inhibiting brain cancer recurrence. In vitro and in vivo experiments confirmed the significant therapeutic effect of the UP-TTD, with ~58% inhibition on growth rate of clinical tumor cells and ~78% reduction of cancer area in tumor-bearing rats. This UP-TTD is wireless ultrasound-powered, chip-sized, lightweight, and easy to operate on complex surfaces, with a largely boosting therapeutic efficiency and reducing energy consumption. Meanwhile, various treatment parameters could be tuned from the UP-TTD without increasing its size or adding circuits on the integrated chip. The tuning process was simulated and discussed, showing an excellent agreement with the experimental data. The encouraging results of the UP-TTD raise the possibility of a new modality for brain cancer treatment.

The efficacy and safety of glucokinase activators for the treatment of type-2 diabetes mellitus: A meta-analysis.

BACKGROUND: Glucokinase activators (GKAs) are a novel family of glucose-lowering agents used for the treatment of type-2 diabetes mellitus. Treatment with different GKAs has been shown to reduce blood glucose levels in these patients. We compared the efficacy/safety of GKAs in patients with type-2 diabetes mellitus through a meta-analysis. METHODS: We searched the PubMed, Excerpt Medica Database, and Cochrane Central Register of Controlled Trials databases for articles published before December 30, 2020. We computed the weighted mean difference (WMD) and 95% confidence interval (CI) for the change from baseline to the study endpoint for GKA versus placebo treatments. RESULTS: A total of 4 articles (5 studies) were included in the meta-analysis. GKAs were associated with reductions in glycated hemoglobin levels from baseline (WMD, -0.3%; 95% CI, -0.466% to -0.134%). No significant difference between GKA and placebo treatment was observed in the results of fasting plasma glucose levels from baseline (WMD 0.013 mmol/L; 95% CI, -0.304-0.33 mmol/L). A significantly higher change in 2-hour postprandial plasma glucose (2-h PPG) levels (WMD -2.434 mmol/L; 95% CI, -3.304 to -1.564 mmol/L) was observed following GKA than placebo treatment. GKAs were associated with a higher prevalence of causing hypoglycemic events than placebo treatment (risk difference [RD], 0.06; 95% CI 0.013-0.106). GKAs had no association with the risk of developing adverse effects (RD, 0.038; 95% CI, -0.03-0.106) and serious adverse events (RD, 0.01; 95% CI, -0.004-0.023). CONCLUSIONS: GKAs were more effective for postprandial blood glucose control. However, these agents showed a significantly high risk of causing hypoglycemia. PROSPERO REGISTRATION NUMBER: CRD42021220364.

The efficacy and safety of glucokinase activators for the treatment of type-2 diabetes mellitus: A protocol for systematic review and meta-analysis.

BACKGROUND: Glucokinase activators are a novel family of glucose-lowering agents used for the treatment of type-2 diabetes mellitus (T2DM). Glucokinase activators blind to GK activate the enzyme allosterically. Treatment with different GKAs has been shown to reduce fasting and postprandial glucose in patients with type 2 diabetes. We compared the efficacy/safety of glucokinase activators in T2DM patients through a meta-analysis. METHODS: We searched PubMed, Excerpt Medica Database, and Cochrane Central Register of Controlled Trials databases for articles published before December 30, 2020. Two independent reviewers extracted the information from article. The quality of articles were assessed by 2 independent reviewers using the 5 items of scale proposed by Jadad. We computed the weighted mean difference and 95% confidence interval (CI) for a change from baseline to the study endpoint for glucokinase activators vs placebo. Egger test and Begg test were used to assess the possible publication bias caused by the tendency of published studies to be positive. RESULTS: The present meta-analysis will compare the efficacy and safety of glucokinase activators and placebo for the treatment of T2DM. CONCLUSIONS: This meta-analysis will provide advanced evidence on the efficacy and safety of glucokinase activators for the treatment of T2DM. ETHICS AND DISSEMINATION: Ethical approval and patient consent are not required because this study is a literature-based study. This systematic review and meta-analysis will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42021220364.

The prolyl isomerase Pin1 is overexpressed in human esophageal cancer.

Peptidyl-prolyl isomerase Pin1 specifically catalyzes the cis/trans-isomerization of proline in the target sequence of phosphorylated Ser/Thr-Pro in over 50 critical regulatory proteins. Pin1 is abnormally overexpressed in a range of human cancers, including lung, breast, colon and prostate cancers. However, few reports of Pin1 overexpression are currently available in clinical samples. Therefore, we examined the expression of Pin1 and p53 in non-pathological human tissues and esophageal cancer tissues. In esophageal cancer tissues, Pin1 and p53 immunoreactivity was detected in cancer cells in 67 and 58% of cases, respectively. Moreover, Pin1 and p53 immunoreactivity was significantly correlated with lymph node-positive disease and more advanced cancer stage. The results demonstrated that high expression levels of Pin1 correlated with high levels of p53. Therefore, Pin1 is suggested to play key roles in the regulation of esophageal cancer.

Clinical significance of astrocyte elevated gene-1 expression in human oligodendrogliomas.

OBJECTIVE: To investigate the expression of astrocyte elevated gene-1 (AEG-1) in human oligodendrogliomas and the association between AEG-1 expression and progression of oligodendrogliomas. METHODS: The expression of AEG-1 in normal human oligodendroglial cells, oligodendroglioma cell line, and four pairs of matched oligodendroglioma tissues and their adjacent normal brain tissues was detected by quantitative RT-PCR and western blotting. In addition, AEG-1 protein expression was examined in 75 cases of histologically characterized oligodendrogliomas by immunohistochemistry. Statistical analyses were applied to test for prognostic and diagnostic associations. RESULTS: Western blotting and RT-PCR showed that AEG-1 mRNA and protein were elevated in the oligodendroglioma cell line and significantly upregulated in primary oligodendrogliomas compared with the adjacent non-cancerous brain tissues. Immunohistochemical analysis showed that 51 of 75 (68.0%) paraffin-embedded archival oligodendroglioma samples exhibited high expression of AEG-1. Statistical analysis suggested that upregulation of AEG-1 was significantly correlated with the histological grade of oligodendroglioma (p=0.000) and that patients with high AEG-1 level exhibited shorter survival time (p=0.000). Multivariate analysis revealed that AEG-1 upregulation might be an independent prognostic indicator for the survival of patients with oligodendroglioma. CONCLUSIONS: AEG-1 might represent a novel, useful diagnostic and prognostic marker for oligodendroglioma and play a role during the development and progression of the disease.