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Aim Hypothyroxinemia might be easily ignored, due to attention is typically paid to individuals with elevated thyroid stimulating hormone (TSH). In this study, we aimed to evaluate the association of oxcarbazepine use as adjuvant for treatment of schizophrenia with hypothyroxinemia and central set point of thyroid homeostasis. Methods This retrospective cohort study was conducted in the "Second Affiliated Hospital of Xinxiang Medical University". Inpatients with a diagnosis of schizophrenia admitted between January 2016 and October 2019 with normal thyroid function at admission were included. Oxcarbazepine use was the exposure measure. Newly developed hypothyroxinemia was the primary outcome measure and parameters of thyroid homeostasis central set point as measured by "TSH index" and "thyroid feedback quantile-based index (TFQI)" were the secondary outcome measures. Results A total of 1,207 eligible patients were included. The occurrence of hypothyroxinemia in patients who received oxcarbazepine was higher (35/107, 32.7%) than in those patients who did not (152/1099, 13.8%), with adjusted relative risk of 2.24 and 95% confidence interval of 1.57 and 3.17. Oxcarbazepine use was associated with greater reduction in TSH index (adjusted β -0.33 and 95% confidence interval -0.48, -0.19) and TFQI (adjusted β -0.24 and 95% confidence interval -0.31, -0.16). Conclusion Oxcarbazepine use was independently associated with increased risk of developing hypothyroxinemia, and greater reduction in TSH index and TFQI, suggesting that impaired central set point of thyroid homeostasis might be involved in the mechanism of oxcarbazepine induced hypothyroxinemia.

Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm of early childhood with a poor survival rate, thus there is a requirement for improved treatment strategies. Induced pluripotent stem cells offer the ability to model disease and develop new treatment strategies. JMML is frequently associated with mutations in PTPN11. Children with Noonan syndrome, a development disorder, have an increased incidence of JMML associated with specific germline mutations in PTPN11. We undertook a proteomic assessment of myeloid cells derived from induced pluripotent stem cells obtained from Noonan syndrome patients with PTPN11 mutations, either associated or not associated with an increased incidence of JMML. We report that the proteomic perturbations induced by the leukemia-associated PTPN11 mutations are associated with TP53 and NF-Kκb signaling. We have previously shown that MYC is involved in the differential gene expression observed in Noonan syndrome patients associated with an increased incidence of JMML. Thus, we employed drugs to target these pathways and demonstrate differential effects on clonogenic hematopoietic cells derived from Noonan syndrome patients, who develop JMML and those who do not. Further, we demonstrated these small molecular inhibitors, JQ1 and CBL0137, preferentially extinguish primitive hematopoietic cells from sporadic JMML patients as opposed to cells from healthy individuals.

Objective: To evaluate the efficacy of the Chinese herbal compound GAPT for the treatment of Alzheimer’s disease (AD) and to provide current evidence for potential treatment mechanisms. Methods: A comprehensive search of PubMed, Embase, Web of Science, SinoMed, China Network Knowledge Infrastructure, Wanfang Data, and Chinese Scientific Journals Database was performed to identify GAPT mouse/rat studies published from inception to July 2019. The outcomes extracted were Morris water maze results and molecular biological quantifications. Results: A total of 19 studies were included in this analysis. The analysis indicated that GAPT was able to significantly improve learning and memory abilities compared with model mice/rats, as assessed by Morris water maze, and showed similar efficacy as donepezil. Subgroup analyses showed that low, medium, and high doses resulted in no obvious dose-dependent effects. Additionally, the GAPT group had significantly reduced expression levels of amyloid-beta peptide, presenilin 1, phosphorylated tau, acetylcholinesterase, and glycogen synthase kinase-3β, but increased expression levels of Shank1, and protein phosphatase-2A, and improved synapses structures compared with the model group, and subgroup analyses showed the medium dose of GAPT was superior to the low and high doses. Conclusions: Based on the pooled analysis, GAPT improved the learning and memory abilities and regulated the expression levels of related proteins during the progression of AD in mouse/rat studies. Notably, the medium dose of GAPT exhibited better performance than the other two doses, providing experimental evidence for further applications of GAPT during clinical practice. Keywords: Chinese herbal compound, Alzheimer’s disease, Mouse, Systematic review, Meta-analysis

Background and Purpose. There are increasing evidences that show that the prognosis of patients with acute ischemic stroke (AIS) is closely related to the inflammatory response. In the inflammation caused by AIS, plasma C-reactive protein (CRP) will increase and is associated with prognosis in these patients; few studies have looked at the relationship between CRP and large artery atherosclerosis- (LAA-) type AIS. We aim to investigate the role of CRP in predicting the functional outcome of LAA-type AIS patients. Methods. We prospectively included 200 patients with LAA-type AIS and tested their CRP levels on admission. We followed these patients consecutively. The primary outcome was an adverse event, defined as a modified Rankin Scale score of 2-6 at months 3, 6, and 12 after discharge. A logistic regression model was used to analyze the relationship between CRP and the functional outcome of LAA stroke. Results. We divided 200 patients into 3 groups evenly based on CRP level. After adjustment for gender, age, smoking history, drinking history, history of hyperlipidemia, history of diabetes, lipid levels, and blood glucose levels, logistic regression showed that the incidence of LAA-type AIS poor outcome was positively associated with CRP level at admission, whether it was 3 months, 6 months, or 12 months after discharge, respectively (OR: 2.574, 95% CI: 1.213-5.463; OR: 2.806, 95% CI: 1.298-6.065; OR: 2.492, 95% CI: 1.167-5.321. In the highest tertile vs. the lowest tertile as a reference), and both were statistically different. Conclusions. High CRP level predicts poor functional outcome in LAA-type AIS patients, which provides a strong basis for clinicians to make treatment decisions for these patients.

Corneal blindness caused by limbal stem cell deficiency (LSCD) is one of the most common debilitating eye disorders. Thus far, the most effective treatment for LSCD is corneal transplantation, which is often hindered by the shortage of donors. Pluripotent stem cell technology including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have opened new avenues for treating this disease. iPSCs-derived corneal epithelial cells provide an autologous and unlimited source of cells for the treatment of LSCD. On the other hand, iPSCs of LSCD patients can be used for iPSCs-corneal disease model and new drug discovery. However, prior to clinical trial, the efficacy and safety of these cells in patients with LSCD should be proved. Here we focused on the current status of iPSCs-derived corneal epithelial cells used for cell therapy as well as for corneal disease modeling. The challenges and potential of iPSCs-derived corneal epithelial cells as a choice for clinical treatment in corneal disease were also discussed.

Background: We previously identified increased tissue localization of monomeric C-reactive protein (mCRP) in the infarcted cortical brain tissue of patients following ischaemic stroke. Here, we investigated the relationship of mCRP expression in haemorrhagic stroke, and additionally examined the capacity of mCRP to travel to or appear at other locations within the brain that might account for later chronic neuroinflammatory or neurodegenerative effects. Methods: Immunohistochemistry was performed on Formalin-fixed, paraffin-embedded archived brain tissue blocks obtained at autopsy from stroke patients and age-matched controls. We modelled mCRP migration into the brain after haemorrhagic stroke by infusing mCRP (3.5 µg) into the hippocampus of mice and localized mCRP with histological and immunohistochemistry methods. Results: On human tissue in the early stages of haemorrhage, there was no staining of mCRP. However, with increasing post-stroke survival time, mCRP immunostaining was associated with some parenchymal brain cells, some stroke-affected neurons in the surrounding areas and the lumen of large blood vessels as well as brain capillaries. Further from the peri-haematoma region, however, mCRP was detected in the lumen of micro-vessels expressing aquaporin 4 (AQP4). In the hypothalamus, we detected clusters of neurons loaded with mCRP along with scattered lipofuscin-like deposits. In the peri-haematoma region of patients, mCRP was abundantly seen adjacent to AQP4 immunoreactivity. When we stereotactically injected mCRP into the hippocampus of mice, we also observed strong expression in distant neurones of the hypothalamus as well as cortical capillaries. Conclusions: mCRP is abundantly expressed in the brain after haemorrhagic stroke, directly impacting the pathophysiological development of the haematoma. In addition, it may have indirect effects, where the microcirculatory system appears to be able to carry it throughout the cortex as far as the hypothalamus, allowing for long-distance effects and damage through its capacity to induce inflammation and degenerate neuronal perivascular compartments., This work was supported by a grant of the Romanian National Authority for Science Research and Innovation, CNCS—UEFISCDI, project number TE-41/2020 and from a grant from the Competitiveness Operational Programme 2014-2020: C-reactive protein therapy for stroke-associated dementia: ID_P_37_674, My SMIS code: 103432 contract 51/05.09.2016, and also and a grant from the Spanish Ministry of Science and Innovation SAF2016-77703 to CS. This research was also supported by the Stroke Chair-(project number R-1441-164).

CD105 (endoglin), a receptor for transforming growth factor (TGF) β1 and β3 in vascular endothelial cells, is highly up-regulated in blood vessels of tissues where neovascularisation occurs. It modulates endothelial-mesenchymal signalling and is essential for angiogenesis. Indeed, CD105 knock-out mice die from malvascularisation by 11.5 day p.c. In the present study CD105, TGFβ1 and CD105/TGFβ1 complexes were quantified in plasma samples from 77 healthy individuals and 92 patients with early stage breast cancer prior to any treatment. When compared with normal controls, both CD105 and CD105/TGFβ1 complex levels were significantly elevated in breast cancer patients, whereas TGFβ1 levels were lower in cancer patients. The most important finding to emerge was that CD105 levels were significantly increased in patients who developed distant metastasis compared with disease-free patients. While there was no significant difference between CD105 levels in controls compared to disease-free patients, it was significantly higher in patients with metastatic disease. Thus patients who had died following local relapse or distant metastases possessed the highest levels of CD105. Neither CD105/TGFβ1 complex nor TGFβ1 levels correlated with tumour progression. Our data indicate that CD105 might be a valuable novel angiogenic marker for identifying breast cancer patients who are at high risk of developing metastasis. Int. J. Cancer (Pred. Oncol.) 89:122–126, 2000. © 2000 Wiley-Liss, Inc.

Bone milling is one of the most common operations in various kinds of orthopedical surgeries, such as laminectomy surgery. For safety issue and efficacy, it is very important to recognize the states in milling operation. In this paper, an approach to recognize the states of bone milling is proposed, which identify the cortical tissue layer and cancellous tissue layer. Hilbert-Huang Transform (HHT) based on Empirical Mode Decomposition (EMD) is used to analysis and extract the features of the interactive force in milling operation. The instantaneous amplitude of the Intrinsic Mode Functions (IMF) are combined by means of linear weighting method to obtain one comprehensive evaluation index. The feature vector of the index consists of average amplitude, kurtosis, crest factor and average remaining of EMD. With the feature vector, states of cortical and cancellous layer in milling process are recognized based on Support Vector Machine (SVM). Finally, the milling experiment with pig scapula is performed to show the effectiveness of the proposed approach.

Circulating extracellular nucleic acids, especially DNA, was discovered more than sixty years ago, but it is becoming hot just in the last two decades because it is now widely recognized as a very promising biomarker for the early diagnosis, monitoring, and evaluation of prognosis of cancer. In addition, compared with traditional surgical approaches and other biochemical tests, circulating DNA as a biomarker, owns many obvious advantages. It is easily accessible, reliable, reproducible and early detectable in cancer. It is also very sensitive and specific if cancer specific DNA alterations are tested instead of elevation of circulating DNA concentration. But the clinical application of this biomarker is still just limited to obstetrics and prenatal diagnosis. This review throws light on its history, current research update and potential clinical application in cancer diagnosis and management. In addition, major detection technologies of circulating DNA are summarized concisely and comprehensively.

Background:Transcription factors often play important roles in tumourigenesis. Members of the PEA3 subfamily of ETS-domain transcription factors fulfil such a role and have been associated with tumour metastasis in several different cancers. Moreover, the activity of the PEA3 subfamily transcription factors is potentiated by Ras-ERK pathway signalling, which is itself often deregulated in tumour cells.Methods:Immunohistochemical patterns of PEA3 expression and active ERK signalling were analysed and mRNA expression levels of PEA3, ER81, MMP-1 and MMP-7 were determined in gastric adenocarcinoma samples.Results:Here, we have studied the expression of the PEA3 subfamily members PEA3/ETV4 and ER81/ETV1 in gastric adenocarcinomas. PEA3 is upregulated at the protein level in gastric adenocarcinomas and both PEA3/ETV4 and ER81/ETV1 are upregulated at the mRNA level in gastric adenocarcinoma tissues. This increased expression correlates with the expression of a target gene associated with metastasis, MMP-1. Enhanced ERK signalling is also more prevalent in late-stage gastric adenocarcinomas, and the co-association of ERK signalling and PEA3 expression also occurs in late-stage gastric adenocarcinomas. Furthermore, the co-association of ERK signalling and PEA3 expression correlates with decreased survival rates.Conclusions:This study shows that members of the PEA3 subfamily of transcription factors are upregulated in gastric adenocarcinomas and that the simultaneous upregulation of PEA3 expression and ERK pathway signalling is indicative of late-stage disease and a poor survival prognosis. © 2011 Cancer Research UK All rights reserved.

To the Editor: The recent paper by Zhu et al1 in this journal provides an insight into the possible mechanism of hypoxia-induced upregulation of CD105 (endoglin). The following 3 points are relevant to their paper. Lately there has been a major debate regarding the relevance of cell culture/animal models for human stroke in general and for angiogenesis in particular. Some authors maintain that the failure of current therapies for stroke in humans based on the use of animal models is possibly owing to the fact that the pathobiology of human stroke is not mirrored by experimentally-induced stroke in animal models. If true, it would limit the value findings of Zhu et al,1 which are based on the use of murine endothelial cell culture and an in vivo mouse model of focal cerebral ischemia. However, there is strong evidence to discount this possibility. First, CD105 has been found …