YY1 complex in M2 macrophage promotes prostate cancer progression by upregulating IL-6.

BACKGROUND: Tumor-associated macrophages are mainly polarized into the M2 phenotype, remodeling the tumor microenvironment and promoting tumor progression by secreting various cytokines. METHODS: Tissue microarray consisting of prostate cancer (PCa), normal prostate, and lymph node metastatic samples from patients with PCa were stained with Yin Yang 1 (YY1) and CD163. Transgenic mice overexpressing YY1 were constructed to observe PCa tumorigenesis. Furthermore, in vivo and in vitro experiments, including CRISPR-Cas9 knock-out, RNA sequencing, chromatin immunoprecipitation (ChIP) sequencing, and liquid-liquid phase separation (LLPS) assays, were performed to investigate the role and mechanism of YY1 in M2 macrophages and PCa tumor microenvironment. RESULTS: YY1 was highly expressed in M2 macrophages in PCa and was associated with poorer clinical outcomes. The proportion of tumor-infiltrated M2 macrophages increased in transgenic mice overexpressing YY1. In contrast, the proliferation and activity of anti-tumoral T lymphocytes were suppressed. Treatment targeting YY1 on M2 macrophages using an M2-targeting peptide-modified liposome carrier suppressed PCa cell lung metastasis and generated synergistic anti-tumoral effects with PD-1 blockade. IL-4/STAT6 pathway regulated YY1, and YY1 increased the macrophage-induced PCa progression by upregulating IL-6. Furthermore, by conducting H3K27ac-ChIP-seq in M2 macrophages and THP-1, we found that thousands of enhancers were gained during M2 macrophage polarization, and these M2-specific enhancers were enriched in YY1 ChIP-seq signals. In addition, an M2-specific IL-6 enhancer upregulated IL-6 expression through long-range chromatin interaction with IL-6 promoter in M2 macrophages. During M2 macrophage polarization, YY1 formed an LLPS, in which p300, p65, and CEBPB acted as transcriptional cofactors. CONCLUSIONS: Phase separation of the YY1 complex in M2 macrophages upregulated IL-6 by promoting IL-6 enhancer-promoter interactions, thereby increasing PCa progression.

A Simple and Efficient Embolization-Combined Therapy for Solid Tumors by Smart Poly(amino acid)s Nanocomposites.

Interventional embolization and minimally invasive thermal ablation are common clinical methods for treatment of unresectable solid tumors, but they both have many insurmountable disadvantages. Inspired by pH-responsive drug delivery systems, we report the tumor microenvironment-gelled nanocomposites with poly[(l-glutamic acid-ran-l-tyrosine)-b-l-threonine-b-l-cysteine]s (PGTTCs) coating nanoparticles (NPs, Au or Fe3O4) for noninterventional targeted embolization combined with noninvasive thermal ablation therapy of solid tumors by intravenous injection without catheter use. The results of the animal trial in vivo with tumor-bearing mice and rabbits showed superior targeted embolization and therapy and fluorescence/single-photon emission computed tomography/magnetic resonance multimodal imaging effects. Tumors treated with NPs@PGTTCs were shrunken and necrotized within 30 days, the long-term survival rate was more than 80%, and the same effects can be achieved within 15 days when combined with thermal ablation. The method is so simple and efficient for many hard-to-treat tumors within an acidic microenvironment, which is not only a great improvement and innovation in tumor theranostics but also an important development in nanomedicine.

Characterizing Diaschisis-Related Thalamic Perfusion and Diffusion After Middle Cerebral Artery Infarction.

Background and Purpose: Ipsilateral thalamic diaschisis (ITD) initially describes functional depression of the thalamus ipsilateral to a supratentorial lesion, but accumulating evidence has shown morphological changes also occur. Therefore, we aimed to characterize thalamic perfusion and diffusion related to ITD over time and their inter-relationships after middle cerebral artery infarction. Methods: Eighty-five patients with middle cerebral artery infarction who underwent diffusion kurtosis imaging and arterial spin labeling were retrospectively included. ITD was diagnosed as ipsilateral thalamic hypoperfusion present on ≥2 cerebral blood flow maps. The thalamic asymmetrical index was calculated as (ipsilateral value−contralateral value)/contralateral value×100%. Finally, the inter-relationships of thalamic perfusion and diffusion were analyzed. Results: ITD was present in 56/85 patients (65.9%, ITD+). In ITD+ patients, larger abnormal perfusion volume, higher perfusion-infarct mismatch and lower rates of focal hyperperfusion were observed than ITD− patients. Infarction affecting the corona radiata were more frequent among ITD+ patients. Mean kurtosis were slightly but significantly increased within the ipsilateral thalamus compared with the contralateral one in ITD+ patients of subacute and chronic groups, while fractional anisotropy was significantly increased in subacute group but decreased in chronic group for both ITD+ and ITD− patients. Mean diffusivity was significantly increased in ITD+ patients of chronic group. Furthermore, the AICBF was negatively and significantly correlated with AIMK and AIFA in ITD+ patients in subacute group, and AIMD, even after adjustment for abnormal perfusion volume and days from symptoms onset, in chronic group. ITD+ patients had significantly higher National Institutes of Health Stroke Scale and modified Rankin Scale scores at admission and discharge and also showed a trend to independent association with clinical outcome at discharge. Conclusions: The combination of arterial spin labeling and diffusion kurtosis imaging can reveal early, time-specific thalamic perfusion and diffusion changes after middle cerebral artery infarction. ITD-related hypoperfusion was significantly correlated with underlying microstructural alterations.

Structural change of thalamus in cirrhotic patients with or without minimal hepatic encephalopathy and the relationship between thalamus volume and clinical indexes related to cirrhosis.

Aberrant brain structural change in cirrhotic patients with or without hepatic encephalopathy is one of the most typical cases in voxel-based morphometry (VBM) studies. However, there exist inconsistent results regarding to the volume change of the thalamus. Furthermore, the relationship between thalamus structural change and cirrhotic symptoms has not yet been fully elucidated. To address these two issues, we repeated two VBM analyses in SPM and FreeSurfer and compared the two measurements with manually measured thalamic volumes. We also correlated the VBM results with clinical indexes related to cirrhosis to further investigate the relationship between thalamic structural change and liver cirrhosis. The inconsistent result of thalamic structural change was successfully reproduced in regard to the volume measurements of SPM and FreeSurfer. The manually measured results demonstrate an increase in the volume of the thalamus in cirrhotic patients compared to healthy controls, which differs from the results of FreeSurfer. The structural change of thalamus closely correlated with the blood biochemical indexes, including albumin levels, blood coagulation time, and AST/ALT ratio. All of these biochemical indexes are closely related to the severity of liver cirrhosis. Beyond all the results, this study also provides a good demonstration of the difference between multiple VBM measurements for clinicians.

Thalamic resting-state functional connectivity: disruption in patients with type 2 diabetes.

To explore the disrupted thalamic functional connectivity and its relationships with cognitive dysfunction in type 2 diabetes mellitus (T2DM) by using resting-state functional magnetic resonance imaging (fMRI). A total of 38 T2DM patients and 39 well-matched healthy controls participated in the resting-state fMRI and T1-weighted imaging scans. The thalamic functional connectivity was characterized by using a seed-based whole-brain correlation method and compared T2DM patients with healthy controls. Pearson correlation analysis was performed between thalamic functional connectivity and clinical data. When compared with healthy controls, T2DM showed significantly decreased functional connectivity of the thalamus mainly in the right middle temporal gyrus (MTG), right precentral gyrus and bilateral occipital cortex; Increased functional connectivity of the thalamus was detected in the left cerebellum, bilateral middle frontal gyrus and middle cingulate gyrus (p < 0.05, corrected for AlphaSim). In T2DM patients, the decreased thalamic functional connectivity of the right MTG was positively associated with the Verbal Fluency Test score (r = 0.438, p = 0.006). Meanwhile, the decreased thalamic functional connectivity of the right cuneus was positively correlated with the Complex Figure Test-delayed score and negatively correlated with the Trail Making Test-B score, respectively (r = 0.492, p = 0.002; r = -0.504, p = 0.001). Moreover, there was no structural damage in the thalamus of T2DM patients. T2DM patients develop disrupted thalamocortical functional connectivity, which is associated with cognitive impairment in selected brain regions. Resting-state thalamocortical connectivity disturbance may play a central role in the underlying neuropathological process of T2DM-related cognitive dysfunction.

Synthesis of gold nanorods and their functionalization with bovine serum albumin for optical hyperthermia.

Although gold nanorods (GNRs) have been investigated extensively for optical hyperthermia therapies, the synthesis of rods is far from ideal. In this report, we optimized the synthesis of gold nanorods using hydroquinone as a reducing agent. Compared with the GNRs prepared by traditional ways, the as-synthesized rods have a flexibly tunable size and wider range of longitudinal surface plasmon resonance (LSPR). Furthermore, a series of small-length gold nanorods with length ranging from 30 to 90 nm were synthesized and they are more suitable for in vivo biomedical applications. Finally, we exploited a convenient approach for preparing water-soluble GNRs with less toxicity, better dispersion and flexible functionalization by exchanging hexadecyltrimethylammonium bromide (CTAB) on the surface of the rods with carboxylated bovine serum albumin (BSA) derivative, the BSA modified GNRs showed significant anticancer efficacy through near infrared (NIR) hyperthermia. We believe that the as-prepared gold nanorods will find promising applications in biomedical fields, especially in cancer therapy.

Significant perturbation in renal functional magnetic resonance imaging parameters and contrast retention for iodixanol compared with iopromide: an experimental study using blood-oxygen-level-dependent/diffusion-weighted magnetic resonance imaging and computed tomography in rats.

OBJECTIVES: The objective of this study was to investigate the renal changes after intravenous administration of a high dose of either iodixanol or iopromide using functional magnetic resonance imaging (MRI) and computed tomography (CT). MATERIALS AND METHODS: The study was approved by the institutional committee on animal research. Seventy-two male Sprague-Dawley rats were divided into 5 cohorts, comprising normal saline (NS), iopromide, iopromide + NS, iodixanol, and iodixanol + NS. Intravenous contrast was administrated at 8 g iodine/kg of body weight. Renal CT, quantitative functional MRI of blood-oxygen-level-dependent (BOLD) imaging and diffusion-weighted imaging (DWI), and histologic examinations were performed for 18 days after contrast administration. Statistical analysis was performed by using 1-way analysis of variance, Mann-Whitney test, and regression analysis. RESULTS: In the renal cortex, BOLD showed persistent elevation of R2* and DWI showed persistent suppression of apparent diffusion coefficient after iodixanol administration for 18 days. Compared with iopromide, adjusted ΔR2* (ΔR2*adj) was significantly higher in the iodixanol group from 1 hour to 18 days (P < 0.04) after contrast; adjusted ΔADC (ΔADCadj) was significantly more pronounced at day 6 (P = 0.01) after contrast. The iodixanol cohort also exhibited persistently higher attenuation in the renal cortex on CT and more severe microscopic renal cortical vacuolization up to 18 days. Intravenous hydration decreased the magnetic resonance changes in both groups but more markedly with iodixanol. CONCLUSIONS: At high doses, iodixanol induced greater changes in renal functional MRI (BOLD and DWI) relative to iopromide. Combined with longer contrast retention within the kidney, this suggests that iodixanol may produce more severe and longer-lasting contrast-induced renal damage.

Non-invasively evaluating therapeutic response of nanorod-mediated photothermal therapy on tumor angiogenesis.

Gold nanorod-mediated photothermal therapy has been widely explored for cancer treatment. However, timely evaluation of the therapeutic response is difficult as current diagnostic approaches are largely based on measurements of tumor volume. The present study developed a non-invasive imaging strategy to rapidly assess the efficacy of photothermal therapy in mice bearing human tumor xenografts. In this study, gold nanorods modified with carboxylated bovine serum albumin showed both anti-tumor and anti-angiogenesis effects under near-infrared laser irradiation. An α(v)ß3 integrin-targeted multi-modal nanoprobe, Dendrimer-arginine-glycine-aspartic acid (Den-RGD), was designed and intravenously injected into mice bearing tumor xenografts at 24 h after photothermal therapy. Magnetic resonance imaging (MRI) and near-infrared fluorescence (NIRF) imaging demonstrated that the Den-RGD not only visualized the tumors with high target-to-background ratio, but also showed the ability to evaluate the therapeutic response by monitoring the tumor neovasculature. Additionally, the target-to-background ratio on MRI and NIRF imaging correlated with the microvessel density in the Den-RGD groups. Immunofluorescence staining confirmed the targeting specificity of Den-RGD to the neovasculature at the tumor periphery. This dual-modal imaging method holds the promise of evaluating therapeutic efficacy in vivo. Nanomedicine provides a multi-functional platform for treatment of cancer and image-guided assessment of anti-cancer therapy.

Overexpression of a short human seipin/BSCL2 isoform in mouse adipose tissue results in mild lipodystrophy.

Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is a recessive disorder characterized by an almost complete loss of adipose tissue, insulin resistance, and fatty liver. BSCL2 is caused by loss-of-function mutations in the BSCL2/seipin gene, which encodes seipin. The essential role for seipin in adipogenesis has recently been established both in vitro and in vivo. However, seipin is highly upregulated at later stages of adipocyte development, and its role in mature adipocytes remains to be elucidated. We therefore generated transgenic mice overexpressing a short isoform of human BSCL2 gene (encoding 398 amino acids) using the adipocyte-specific aP2 promoter. The transgenic mice produced ∼150% more seipin than littermate controls in white adipose tissue. Surprisingly, the increased expression of seipin markedly reduced the mass of white adipose tissue and the size of adipocytes and lipid droplets. This may be due in part to elevated lipolysis rates in the transgenic mice. Moreover, there was a nearly 50% increase in the triacylglycerol content of transgenic liver. These results suggest that seipin promotes the differentiation of preadipocytes but may inhibit lipid storage in mature adipocytes.