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Great challenges still remain in the management of patients with castration-resistant prostate cancer (CRPC) based on traditional treatments, and the rapid development of nanotechnology may find a breakthrough. Herein, a novel type of multifunctional self-assembly magnetic nanocarriers (IR780-MNCs) containing iron oxide nanoparticles (Fe3O4 NPs) and IR780 iodide was synthesized by an optimized process. With a hydrodynamic diameter of 122 nm, a surface charge of –28.5 mV and the drug loading efficiency of 89.6%, IR780-MNCs have increased cellular uptake efficiency, long-term stability, ideal photothermal conversion ability and excellent superparamagnetic behavior. The in vitro study indicated that IR780-MNCs have excellent biocompatibility and could induce significant cell apoptosis under the 808 nm laser irradiation. The in vivo study showed that IR780-MNCs highly accumulated at the tumor area could reduce the tumor volume of tumor-bearing mice by 88.5% under the 808 nm laser irradiation, but minimal damage to surrounding normal tissues. Since IR780-MNCs encapsulated a large number of 10 nm homogeneous spherical Fe3O4 NPs, which can be used as T2 contrast agent, the best window for photothermal therapy can be determined through MRI. In conclusion, IR780-MNCs have initially showed excellent antitumor effect and biosafety in the treatment of CRPC. This work provides novel insights into the precise treatment of CRPC by using a safe nanoplatform based on the multifunctional nanocarriers.

Epilepsy is most common in patients with tuberous sclerosis complex (TSC). However, in addition to the challenging treatment, the pathogenesis of epilepsy is still controversial. To determine the transcriptome characteristics of perituberal tissue (PT) and clarify its role in the pathogenesis of epilepsy, GSE16969 was downloaded from the GEO database for further study by comprehensive bioinformatics analysis. Identification of differentially expressed genes (DEGs), functional enrichment analysis, construction of protein-protein interaction (PPI) network, and selection of Hub genes were performed using R language, Metascape, STRING, and Cytoscape, respectively. Comparing with cortical tuber (CT), 220 DEGs, including 95 upregulated and 125 downregulated genes, were identified in PT and mainly enriched in collagen-containing extracellular matrix and positive regulation of receptor-mediated endocytosis, as well as the pathways of ECM-receptor interaction and neuroactive ligand-receptor interaction. As for normal cortex (NC), 1549 DEGs, including 30 upregulated and 1519 downregulated genes, were identified and mainly enriched in presynapse, dendrite and axon, and also the pathways of dopaminergic synapse and oxytocin signaling pathway. In the PPI network, 4 hub modules were found between PT and CT, and top 5 hub modules were selected between PT and NC. C3, APLNR, ANXA2, CD44, CLU, CP, MCHR2, HTR1E, CTSG, APP, and GNG2 were identified as Hub genes, of which, C3, CD44, ANXA2, HTR1E, and APP were identified as Hub-BottleNeck genes. In conclusion, PT has the unique characteristics different from CT and NC in transcriptome and makes us further understand its importance in the TSC-associated epilepsy.

Background: The emergence of castration resistance is fatal for patients with prostate cancer (PCa); however, there is still a lack of effective means to detect the early progression. In this study, a novel combined nomogram was established to predict the risk of progression related to castration resistance.Methods: The castration-resistant prostate cancer (CRPC)-related differentially expressed genes (DEGs) were identified by R packages “limma” and “WGCNA” in GSE35988-GPL6480 and GSE70768-GPL10558, respectively. Relationships between DEGs and progression-free interval (PFI) were analyzed using the Kaplan–Meier method in TCGA PCa patients. A multigene signature was built by lasso-penalized Cox regression analysis, and assessed by the receiver operator characteristic (ROC) curve and Kaplan–Meier curve. Finally, the univariate and multivariate Cox regression analyses were used to establish a combined nomogram. The prognostic value of the nomogram was validated by concordance index (C-index), calibration plots, ROC curve, and decision curve analysis (DCA).Results: 15 CRPC-related DEGs were identified finally, of which 13 genes were significantly associated with PFI and used as the candidate genes for modeling. A two-gene (KIFC2 and BCAS1) signature was built to predict the risk of progression. The ROC curve indicated that 5-year area under curve (AUC) in the training, testing, and whole TCGA dataset was 0.722, 0.739, and 0.731, respectively. Patients with high-risk scores were significantly associated with poorer PFI (p < 0.0001). A novel combined nomogram was successfully established for individualized prediction integrating with T stage, Gleason score, and risk score. While the 1-year, 3-year, and 5-year AUC were 0.76, 0.761, and 0.762, respectively, the good prognostic value of the nomogram was also validated by the C-index (0.734), calibration plots, and DCA.Conclusion: The combined nomogram can be used to predict the individualized risk of progression related to castration resistance for PCa patients and has been preliminarily verified to have good predictive ability.

Lei Dong,1,&ast; Nana Li,1,&ast; Xixi Wei,2 Yongling Wang,2 Liansheng Chang,3 Hongwei Wu,4 Liujiang Song,5 Kang Guo,6 Yuqiao Chang,1 Yaling Yin,2 Min Pan,7 Yuanyuan Shen,8 Feng Wang1 1Henan Key Laboratory of Medical Tissue Regeneration, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China; 2Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China; 3Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China; 4Department of Chemistry, Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China; 5Department of Ophthalmology, Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27517, USA; 6Department of Oncology, The Third affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, 453003, People’s Republic of China; 7Department of Ultrasound, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, 518034, People’s Republic of China; 8National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, 518060, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Feng Wang, Henan Key Laboratory of Medical Tissue Regeneration, School of Basic Medical Sciences, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, Henan, 453002, People’s Republic of China, Email wfeng100@126.com Min Pan, Department of Ultrasound, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, No. 6001 Beihuan Avenue, Shenzhen, 518034, People’s Republic of China, Email min.pan@siat.ac.cnBackground: The blood–brain barrier (BBB) inhibits the delivery of macromolecular chemotherapeutic drugs to brain tumors, leading to low utilization rates and toxic side effects to surrounding tissues and organs. Ultrasonic targeted microbubble destruction (UTMD) technology can open the BBB, leading to a new type of drug delivery system with particular utility in glioma.Purpose: We have developed a new type of drug-loaded microbubble complex based on poly(lactic-co-glycolic acid) (PLGA) that targets gambogic acid (GA) to the area of brain tumors through UTMD.Methods: GA/PLGA nanoparticles were prepared by the double emulsification method, and cationic microbubbles (CMBs) were prepared by a thin film hydration method. The GA/PLGA-CMB microbubble complex was assembled through electrostatic attractions and was characterized chemically. The anti-glioblastoma effect of GA/PLGA-CMB combined with focused ultrasound (FUS) was evaluated by biochemical and imaging assays in cultured cells and model mice.Results: GA/PLGA-CMB combined with FUS demonstrated a significant inhibitory effect on glioblastoma cell lines U87 and U251 as compared with controls (P< 0.05). Tumor access and imaging analyses demonstrated that administration of GA/PLGA-CMBs combined with FUS can open the BBB and target the treatment of glioblastoma in a mouse model, as compared with control groups (P< 0.05).Conclusion: The combination of PLGA-CMB with FUS provides an effective and biocompatible drug delivery system, and its application to the delivery of GA in a mouse glioblastoma model was successful.Keywords: microbubbles, cavitation effect, glioblastoma, focused ultrasound

A 2-year field experiment of wheat-maize rotation was conducted on a cinnamon soil of east Hebei Province to study the effects of returning maize straw into field on the dynamics of soil microbial biomass C, N and P, and their relationships with soil nutrients and enzyme activities. The results showed that under the condition of returning maize straw combined with applying chemical fertilizer to adjust straw C/N, the application of effective microorganisms could increase soil microbial biomass C, N and P in each crop growth period, advance their peak time, and better regulate soil nutrient supply, compared with no application of effective microorganisms. Soil microbial biomass had a significantly positive correlation with soil enzyme activities, but its correlation with soil hydrolysable N and available P was strongly affected by crop growth and fertilization system.

Increases of vascular extravasations of MR contrast agent have been implicated to be predictive of hemorrhagic transformation in acute stroke patients. However, systemic studies are lacking. In this study, we aim to determine how the increased vascular extravasations of MR contrast agent can be used to predict the presence of subsequent hemorrhages in Stroke-prone spontaneous hypertensive rats (SHRsp). SHRsp rats (n=12), fed a high-salt low-protein diet after weaning, were imaged weekly on a 3 T SIEMENS Allegra head-only scanner beginning at 12 week of age and continuing for five weeks. Three sequences were used to acquire images, including a T2-weighted, a T2*-weighted, and a turboFLASH sequence. The acquired T2-weighted images provided anatomical data as well as an indication of brain edema. T2*-weighted images allowed assessment of hemorrhage and were acquired using a 3D gradient echo sequence (TE=25 ms). To obtain estimates of vascular permeability, the Look-Locker (L-L) technique employing the T-one by multiple read-out pulses (TOMROP) sequence (1) was used for pixel-by-pixel estimates of T1. The TOMROP sequence was repeated 10 times post-contrast. Finally, the PATLAK approach was utilized with the images acquired using the TOMROP sequence for obtaining permeability maps for each rat (2). All 12 rats developed asymmetric T2 hyperintensities by 14 weeks of age; 5 rats developed 7 regions of intracerebral hemorrhage (detected by T2*) at later time-points. Four hemorrhages were located within the striatum; three were located in the cortex. All rats that developed spontaneous hemorrhages demonstrated concurrent or prior vascular permeability (determined by Gd as described above) at the site of the hemorrhage. In 4 of the 7 hemorrhages, evidence of vascular permeability was found prior to the detection of hemorrhage, preceding it by up to 2 weeks. The remaining three temporally coincided with the hemorrhage. The temporal evolution of vascular permeability, T2 and T2* images of a representative rats are shown in Fig. 1. It is immediately evident that the presence of vascular leak precedes the hemorrhage by one week. Although blood-brain-barrier (BBB) breakdown, cerebral edema, and hemorrhage have been well-described in this model, the spatial and temporal relationship between these events has not been well-delineated. Although increased vascular permeability did not precede 3 of 7 hemorrhages but rather appeared concurrently, we believe that this may be due to the poor temporal resolution of our imaging scheme. These data suggest that hypertensive intracerebral hemorrhage is preceded by focal vasculopathy resulting in breakdown of the BBB.

The balance between cerebral blood flow (CBF) and oxygen extraction fraction (OEF) is important in determining the status of tissue viability during acute cerebral ischemia 1, 2. After ischemic onset, CBF decreases, accompanied by an increase in OEF in order to maintain cerebral oxygen cerebral metabolic rate of oxygen utilization (CMRO2). A persisted or further reduced CBF results in a decline of CMRO2, leading to neural cell death. In this study, a T2* (T2') approach 3 and a dynamic tracer method 4 are used to obtain OEF and CBF, respectively, which in turn allows the estimates of MR_CMRO2, in a middle cerebral artery occlusion (MCAO) rat model. The temporal evolution of cerebral haemodynamic changes is examined. In total, three male Long Evans rats were studied. Cerebral ischemia was induced using the suture model inside the magnet bore with approved animal protocols. All images were acquired on a Siemens 3 T Allegra scanner. A 2D multi-echo gradient echo/spin echo sequence (MEGESE) was utilized to obtain OEF 3. Apparent diffusion coefficient (ADC) maps was obtained from segmented EPI diffusion weighted images (DWI). MEGESE and DWI images were acquired prior to MCAO and continued up to three hours post MCAO. A tracer dynamic perfusion weighted imaging (PWI) was utilized to obtain CBF at the end of the entire study so as to avoid the contamination of contrast agent induced susceptibility for the oxygenation measurements. CBF is assumed to remain constant throughout the entire post MCAO period in a permanent MCAO. MR_CMRO2 was calculated by multiplying OEF and CBF. ROIs were defined in both ipsilateral and contralateral hemisphere to obtain ADC, OEF, CBF and CMRO2 changes. Before MCA occlusion, ADC, OEF were not statistically different in the ipsilateral and contralateral hemisphere ROIs. Immediately after MCAO, ADC reduced, while OEF increased. As lesion progressed, the initially elevated OEF returned to or below the baseline, while the ADC might have little change. In addition, CMRO2 showed a moderate decrease to 30–55% followed by a severe reduction to 9–20% of that of normal tissue. The time period of moderate reduction of CMRO2 depends on the severity of CBF. In one rat, a 14% of CBF reduction corresponded to a 40 minutes moderate CMRO2 reduction followed by severe CMRO2 reduction. In another rat, a 21% CBF reduction allows a moderate CMRO2 reduction for about 90 minutes. With a MCAO rat model, our results demonstrate the temporal biphasic behavior of OEF with an initial increase and followed by a returning baseline values. In addition, the temporal evolution of CMRO2 agree with the reported results in the literature using PET 5. In conclusion, non-invasive methods to assess cerebral oxygenation status in vivo may provide us more insight into the ischemic tissue viability.