Okicamelliaside targets the N-terminal chaperone pocket of HSP90 disrupts the chaperone protein interaction of HSP90-CDC37 and exerts antitumor activity.

Heat shock protein 90 (HSP90) has been recognized as a crucial target in cancer cells. However, various toxic reactions targeting the ATP binding site of HSP90 may not be the best choice for HSP90 inhibitors. In this paper, an ellagic acid derivative, namely, okicamelliaside (OCS), with antitumor effects was found. To identify potential anti-cancer mechanisms, an OCS photosensitive probe was applied to target fishing and tracing. Chemical proteomics and protein-drug interaction experiments have shown that HSP90 is a key target for OCS, with a strong binding affinity (KD = 6.45 µM). Mutation analysis of the target protein and molecular dynamics simulation revealed that OCS could competitively act on the key Glu-47 site at the N-terminal chaperone pocket of HSP90, where the co-chaperone CDC37 binds to HSP90, affect its stability and reduce the ∆Gbind of HSP90-CDC37. It was demonstrated that OCS destroys the protein-protein interactions of HSP90-CDC37; selectively affects downstream kinase client proteins of HSP90, including CDK4, P-AKT473, and P-ERK1/2; and exerts antitumor effects on A549 cells. Furthermore, tumor xenograft experiments demonstrated high antitumor activity and low toxicity of OCS in the same way. Our findings identified a novel N-terminal chaperone pocket natural inhibitor of HSP90, that is, OCS, which selectively inhibits the formation of the HSP90-CDC37 protein complex, and provided further insight into HSP90 inhibitors for anti-cancer candidate drugs.

Connecting Western and Eastern Medicine from an Energy Perspective.

Although Western medicine and Eastern medicine are worlds apart, there is a striking overlap in the basic principle of these types of medicine when we look at them from the perspective of energy. In both worlds, opposing forces provide the energy that flows through networks in an organism, which fuels life. In this concept, health is the ability of an organism to maintain the balance between these opposing forces, i.e., homeostasis (West) and harmony (East), which creates resilience. Moreover, strategies used to treat diseases are strikingly alike, namely adjusting the flow of energy by changing the connections in the network. The energy perspective provides a basis to integrate Eastern and Western medicine, and opens new directions for research to get the best of both worlds.

microRNA-1-3p and T-synthase mRNA have high diagnostic efficacy on intestinal mucosal barrier dysfunction in patients with severe acute pancreatitis.

Acute pancreatitis (AP) is an inflammatory disorder of the pancreas that can be complicated by intestinal mucosal barrier dysfunction (SAP&IBD). The current study sought to examine the diagnostic efficacy of miR-1-3p and T-synthase mRNA in SAP&IBD patients. First, SAP patients were assigned to SAP&IBD and SAP groups. Serum miR-1-3p expression and T-synthase mRNA expression patterns in peripheral blood B lymphocytes were measured using RT-qPCR. Pearson tests, ROC curve analysis, and multivariate logistic regression were used to analyze the correlation between miR-1-3p/T-synthase mRNA and clinical data, their diagnostic efficiency, and independent risk factors for SAP&IBD patients, respectively. The results showed that serum miR-1-3p in the SAP&IBD group was elevated, and T-synthase mRNA expression in peripheral blood B lymphocytes was diminished. Additionally, serum miR-1-3p expression in SAP&IBD patients was negatively correlated with T-synthase mRNA expression, and positively correlated with their Ranson score, CRP, IL-6, DAO, and D-Lactate levels. Meanwhile, T-synthase mRNA level was negatively correlated with IL-6, DAO, and D-Lactate levels. Both, serum miR-1-3p, T-synthase mRNA, and their combination were found to exhibit diagnostic efficiency for SAP&IBD patients, and were independently associated with IBD in SAP patients. Collectively, our findings suggest that miR-1-3p and T-synthase serve as independent risk factors for SAP&IBD patients and can aid the diagnosis of IBD in SAP patients.

Integration of the Image-Guided Surgery Toolkit (IGSTK) into the Medical Imaging Interaction Toolkit (MITK).

The development cycle of an image-guided surgery navigation system is too long to meet current clinical needs. This paper presents an integrated system developed by the integration of two open-source software (IGSTK and MITK) to shorten the development cycle of the image-guided surgery navigation system and save human resources simultaneously. An image-guided surgery navigation system was established by connecting the two aforementioned open-source software libraries. It used the Medical Imaging Interaction Toolkit (MITK) as a framework providing image processing tools for the image-guided surgery navigation system of medical imaging software with a high degree of interaction and used the Image-Guided Surgery Toolkit (IGSTK) as a library that provided the basic components of the system for location, tracking, and registration. The electromagnetic tracking device was used to measure the real-time position of surgical tools and fiducials attached to the patient's anatomy. IGSTK was integrated into MITK; at the same time, the compatibility and the stability of this system were emphasized. Experiments showed that an integrated system of the image-guided surgery navigation system could be developed in 2 months. The integration of IGSTK into MITK is feasible. Several techniques for 3D reconstruction, geometric analysis, mesh generation, and surface data analysis for medical image analysis of MITK can connect with the techniques for location, tracking, and registration of IGSTK. This integration of advanced modalities can decrease software development time and emphasize the precision, safety, and robustness of the image-guided surgery navigation system.

Establishment of a mouse model of Netherton syndrome based on CRISPR/Cas9 technology

Background: Netherton syndrome is a rare but severe autosomal recessive disorder with dominant impaired skin barrier function, caused by mutations in the SPINK5 (serine protease inhibitor Kazal-type 5) gene, which encodes LEKTI (lymphoepithelial Kazal-type-related inhibitor). Objectives: To establish a murine model of Netherton syndrome based on CRISPR/Cas9 gene editing technology. Materials & Methods: Spink5-sgRNA was designed to target exon 3 of the mouse Spink5 gene. Cas9 mRNA and sgRNA were microinjected into the zygotes of C57BL/6J mice. Spink5 homozygous knockout mice were born from a heterozygous intercross, and the phenotype of these mice was compared with wild-type regarding gross morphology, histopathology and immunofluorescent detection of LEKTI. Results: Following microinjection of zygotes using the CRISPR/Cas9 system, sequencing demonstrated a 22-bp deletion at exon 3 of the mouse Spink5 gene. Histological investigation revealed complete detachment of the stratum corneum from the underlying granular layer and an absence of LEKTI in skin from Spink5 homozygous knockout mice. Conclusion: The 22-bp deleted Spink5 transgenic mouse model demonstrates the clinical phenotype and genotype of human Netherton syndrome, representing a useful tool for future gene correction and skin barrier/inflammation studies.

Experimental and Preliminary Clinical Study of Real-Time Registration in Liver Tumors During Respiratory Motion Based on a Multimodality Image Navigation System.

PURPOSE: To develop a fusion imaging system that combines ultrasound and computed tomography for real-time tumor tracking and to validate the accuracy of performing registration via this approach during a specific breathing phase. MATERIALS AND METHODS: The initial part of the experimental study was performed using iodized oil injection in pig livers and was focused on determining the accuracy of registration. Eight points (A1-4 and B1-4) at different positions and with different target sizes were selected as target points. During respiratory motion, we used our self-designed system to perform the procedure either with (experimental group, E) or without (control group, C) the respiratory monitoring module. The registration errors were then compared between the 2 groups and within group E. The second part of this study was designed as a preliminary clinical study and was performed in 18 patients. Screening was performed to determine the combination of points on the body surface that provided the highest sensitivity to respiratory motion. Registration was performed either with (group E) or without (group C) the respiratory monitoring module. Registration errors were compared between the 2 groups. RESULTS: In part 1 of this study, there were fewer registration errors at each point in group E than at the corresponding points in group C (P < .01). In group E, there were more registration errors at points A1 and B1 than at the other points (P < .05). There was no significant difference in registration errors among the remaining points. During part 2 of the study, there was a significant difference in the registration errors between the 2 groups (P < .01). CONCLUSIONS: Real-time fusion registration is feasible and can be accurately performed during respiratory motions when using this system.

Impaired long contact white matter fibers integrity is related to depression in Parkinson's disease.

AIMS: Depression is one of the most common nonmotor symptoms in Parkinson's disease (PD). But the pathogenesis is still unclear. Studies have shown that depression in PD is closely related to the white matter abnormalities, but the number of studies is still very small and lack of whole brain white matter lesions study. METHODS: In this study, we investigated whole brain white matter integrity in 31 depressed PD patients and 37 nondepressed PD patients by diffusion tensor imaging. RESULTS: There was no difference in age, gender, age of onset, disease duration, Hoehn-Yahr scale, Unified Parkinson's Disease Rating Scale scores-III, and Mini-Mental State Examination scores between the two groups. The only difference was the Hamilton Depression Rating Scale. Depressed PD patients showed reduced fractional anisotropy values in the left anterior corona radiata, left posterior thalamic radiation, left cingulum, left superior longitudinal fasciculus, left sagittal stratum (including inferior longitudinal fasciculus and inferior fronto-occipital fasciculus), and left uncinate fasciculus. In patients with depression, the Hamilton Depression Rating Scale (HDRS) was negatively correlated with the FA value in the left cingulum (r = -0.712, P = .032) and left superior longitudinal fasciculus (r = -0.699, P = .025). CONCLUSIONS: This study suggested depression in PD was related to impaired white matter integrity especially the long contact fibers in the left hemisphere. These findings may be helpful for further understanding the potential mechanisms underlying depression in PD.

White Matter Lesions Predict Recurrent Vascular Events in Patients with Transient Ischemic Attacks.

BACKGROUND: White matter lesions (WMLs) are common findings in brain magnetic resonance imaging (MRI) and are strongly associated with stroke incidence, recurrence, and prognosis. However, the relationship between WMLs and transient ischemic attacks (TIAs) is not well established. This study aimed to determine the clinical significance of WMLs in patients with TIA. METHODS: A total of 181 consecutive inpatients with first-ever TIA were enrolled. Brain MRIs within 2 days of symptom onset were used to measure WML volumes. Recurrent vascular events within 1 year of TIA onset were assessed. The relationship between WMLs and recurrent risk of vascular events was determined by a multivariate logistic regression. RESULTS: WMLs were identified in 104 patients (57.5%). Age and ratio of hypertension were significantly different between patients with and without WMLs. The incidence of vascular events in patients with WMLs significantly increased in comparison to those without WMLs (21.15% vs. 5.19%, 95% confidence interval [CI]: 1.18-15.20, P = 0.027) after controlling for confounders. Furthermore, distributions of WML loads were found to be different between patients who developed vascular events and those who did not. WML volumes were demonstrated to be correlated with recurrent risks, and the fourth quartile of WML volumes led to an 8.5-fold elevation of recurrent risk of vascular events compared with the first quartile (95% CI: 1.52-47.65, P = 0.015) after adjusting for hyperlipidemia. CONCLUSION: WMLs occur frequently in patients with TIA and are associated with the high risk of recurrent vascular events, suggesting a predictive neuroimaging marker for TIA outcomes.

MicroRNA-3713 regulates bladder cell invasion via MMP9.

Transitional cell carcinoma (TCC) is the most common type of bladder cancer but its carcinogenesis remains not completely elucidated. Dysregulation of microRNAs (miRNAs) is well known to be involved in the development of various cancers, including TCC, whereas a role of miR-3713 in the pathogenesis of TCC has not been appreciated. Here, we reported that significantly higher levels of matrix metallopeptidase 9 (MMP9), and significantly lower levels of miR-3713 were detected in TCC tissue, compared to the adjacent non-tumor tissue, and were inversely correlated. Moreover, the low miR-3713 levels in TCC specimens were associated with poor survival of the patients. In vitro, overexpression of miR-3713 significantly decreased cell invasion, and depletion of miR-3713 increased cell invasion in TCC cells. The effects of miR-3713 on TCC cell growth appeared to result from its modification of MMP9 levels, in which miR-3713 was found to bind to the 3'-UTR of MMP9 mRNA to inhibit its protein translation in TCC cells. This study highlights miR-3713 as a previously unrecognized factor that controls TCC invasiveness, which may be important for developing innovative therapeutic targets for TCC treatment.

Presence of lacunar infarctions is associated with the spatial navigation impairment in patients with mild cognitive impairment: a DTI study.

Lacunar cerebral infarction (LI) is one of risk factors of vascular dementia and correlates with progression of cognitive impairment including the executive functions. However, little is known on spatial navigation impairment and its underlying microstructural alteration of white matter in patients with LI and with or without mild cognitive impairment (MCI). Our aim was to investigate whether the spatial navigation impairment correlated with the white matter integrity in LI patients with MCI (LI-MCI). Thirty patients with LI were included in the study and were divided into LI-MCI (n=17) and non MCI (LI-Non MCI) groups (n=13) according neuropsychological tests.The microstructural integrity of white matter was assessed by calculating a fractional anisotropy (FA) and mean diffusivity (MD) from diffusion tensor imaging (DTI) scans. The spatial navigation accuracy, separately evaluated as egocentric and allocentric, was assessed by a computerized human analogue of the Morris Water Maze tests Amunet. LI-MCI performed worse than the CN and LI-NonMCI groups on egocentric and delayed spatial navigation subtests. LI-MCI patients have spatial navigation deficits. The microstructural abnormalities in diffuse brain regions, including hippocampus, uncinate fasciculus and other brain regions may contribute to the spatial navigation impairment in LI-MCI patients at follow-up.