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2.
Sci Total Environ ; 732: 139334, 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32438188

RESUMO

Humans can undergo circadian disruption and misalignment when living in closed environments without sufficient daylight. Therefore, it is of great significance to investigate the effects of artificial light on the circadian rhythm. In this work, the red, green, blue, warm white, and cool white (RGBWW) five-channel light-emitting diodes (LEDs) were fabricated as the only light sources in the closed environment. The LED mixed lighting showed a high color rendering index (CRI) all the time. During the day, the light simulated the daylight and increased the tunability of the circadian action factor (CAF) and correlated color temperature (CCT). At night, it maintained low CAF and CCT. Three subjects did irregular shift work in the closed environment for 38 days. Their plasma melatonin and daily activity were measured to assess the circadian rhythm. After 38 days, the subjects' peak melatonin times did not shift significantly (p = 0.676), while their peak melatonin concentrations increased apparently (p = 0.005). The start times of the least active 5-h period (L5) in one day fluctuated in a small range. The standard deviation (SD) was <15.11 min in most times. These results demonstrated that the subjects' rhythms maintained stable and were enhanced. The periods of circular cross-correlation between activity and CAF oscillated around 24 h (SD = 15.4 min), indicating the entrainment of light on the stable 24-h rhythm. It was concluded that the daylight-like LED lighting effectively entrained and enhanced the circadian rhythm in the closed environment.

3.
BMC Med Genomics ; 13(1): 56, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32228601

RESUMO

BACKGROUND: The established role miRNA-mRNA regulation of gene expression has in oncogenesis highlights the importance of integrating miRNA with downstream mRNA targets. These findings call for investigations aimed at identifying disease-associated miRNA-mRNA pairs. Hierarchical integrative models (HIM) offer the opportunity to uncover the relationships between disease and the levels of different molecules measured in multiple omic studies. METHODS: The HIM model we formulated for analysis of mRNA-seq and miRNA-seq data can be specified with two levels: (1) a mechanistic submodel relating mRNAs to miRNAs, and (2) a clinical submodel relating disease status to mRNA and miRNA, while accounting for the mechanistic relationships in the first level. RESULTS: mRNA-seq and miRNA-seq data were acquired by analysis of tumor and normal liver tissues from 30 patients with hepatocellular carcinoma (HCC). We analyzed the data using HIM and identified 157 significant miRNA-mRNA pairs in HCC. The majority of these molecules have already been independently identified as being either diagnostic, prognostic, or therapeutic biomarker candidates for HCC. These pairs appear to be involved in processes contributing to the pathogenesis of HCC involving inflammation, regulation of cell cycle, apoptosis, and metabolism. For further evaluation of our method, we analyzed miRNA-seq and mRNA-seq data from TCGA network. While some of the miRNA-mRNA pairs we identified by analyzing both our and TCGA data are previously reported in the literature and overlap in regulation and function, new pairs have been identified that may contribute to the discovery of novel targets. CONCLUSION: The results strongly support the hypothesis that miRNAs are important regulators of mRNAs in HCC. Furthermore, these results emphasize the biological relevance of studying miRNA-mRNA pairs.

4.
Macromol Rapid Commun ; : e2000088, 2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-32329178

RESUMO

Surface properties are essential for substrates exhibiting high sensitivity in surface-enhanced Raman scattering (SERS) applications. In this work, novel SERS hybrid substrates using polystyrene-block-poly(methyl methacrylate) and anodic aluminum oxide templates is presented. The hybrid substrates not only possess hierarchical porous nanostructures but also exhibit superhydrophilic surface properties with the water contact angle ≈0°. Such surfaces play an important role in providing uniform enhanced intensities over large areas (relative standard deviation ≈10%); moreover, these substrates are found to be highly sensitive (limit of detection ≈10-12 m for rhodamine 6G (R6G)). The results show that the hybrid SERS substrates can achieve the simultaneous detection of multicomponent mixtures of different target molecules, such as R6G, crystal violet, and methylene blue. Furthermore, the bending experiments show that about 70% of the SERS intensities are maintained after bending from ≈30° to 150°.

5.
Artigo em Inglês | MEDLINE | ID: mdl-32314164

RESUMO

Intense heat stress induces damage to the heart, whereas mild to moderate heat stress protects the heart against subsequent ischemic injury. The mechanisms underlying the detrimental and beneficial effects of heat stress remain unclear. In this study, we investigated the role of p53 in the responses of cardiac muscle cells to acute heat exposure and heat acclimation (HA). Heat exposure increased the levels of caspase and annexin, and levels of cytosolic, nuclear, and mitochondrial p53 protein in H9c2 cells. Pifithrin-α or pifithrin-µ reduced heat-induced apoptotic response in these cells. HA reduced localization of p53 in the mitochondria and improved cell viability during heat exposure. The effects of heat exposure and HA on p53 were further verified in vivo in mouse heart tissue. These results suggest that p53 plays a role in heat-induced apoptosis in cardiac muscle cells. The protective effect of HA against heat injury likely involves a p53-dependent mechanism.

7.
Poult Sci ; 99(4): 2185-2195, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32241504

RESUMO

The signal pathway of target of rapamycin (TOR) plays an important role in regulating cell growth and proliferation, follicular development, and ovulation. Melatonin (N-acetyl-5-methoxytryptamine) (MT) is involved in the regulation of many physiological functions in animals. Recent studies have shown that MT affects the number and the degree of maturation of follicles in the ovary, but there are few studies concerning its mechanism. Therefore, the aim of this study was to investigate the mechanism of TOR signal pathway in the regulation of ovarian function by MT in aging laying hens. In the present study, a total of 60 hens (70-week-old) were randomly divided into 2 groups: control group and melatonin group (M). Melatonin was administered intraperitoneally at a dose of 20 mg/kg/D for 28 D in the M group. The results showed that MT significantly increased the levels of the antioxidant enzymes superoxide dismutase and total antioxidant capacity (P < 0.01) as well as levels of immunoglobulin (IgA, IgG, and IgM) (P < 0.05) and the reproductive hormones estradiol and luteinizing hormone (P < 0.01) in the plasma and also increased the numbers of middle white follicles and small white follicles (P < 0.05) and decreased the level of reactive oxygen species in plasma (P < 0.01) in laying hens. There were higher expression levels in MT receptor A (P < 0.05), melatonin receptor B (P < 0.01), and tuberous sclerosis complex 2 (P < 0.01). Activation of TOR, 4E binding protein-l (4E-BP1), and ribosomal protein 6 kinase (P < 0.01) was found in the M. The levels of mTOR and p-mTOR protein were increased in the M (P < 0.05). The mTORC1-dependent 4E-BP1 and p-4E-BP1 were increased in the M (P < 0.05). This study indicated that MT may enhance follicle growth by increasing levels of antioxidant enzymes and reproductive hormones and by activating the mTOR and downstream components in aging laying hens.

8.
Artigo em Inglês | MEDLINE | ID: mdl-32306075

RESUMO

PURPOSE: Tumor microenvironment is important in the progression of clear cell renal cell carcinoma (ccRCC), and its prognostic value is still unclear. Recent reports demonstrated tumor-infiltrating CD39+CD8+ T cells are abundant, but their function remains obscure. We aim to assess clinical value of CD39+CD8+ T cells and seek a potential therapeutic target in ccRCC. EXPERIMENTAL DESIGN: We immunohistochemically evaluated clinical value of CD39+CD8+ T cells in a retrospective Zhongshan Hospital cohort of 243 ccRCC patients. Fresh tumor samples (n = 48), non-tumor tissues and peripheral blood for flow cytometry analyses were collected to analyze immune cell functions from Zhongshan Hospital. The survival benefit of tyrosine kinase inhibitors (TKIs) in this subpopulation was evaluated. Kaplan-Meier analysis and COX regression model were applied for survival analyses. Bioinformatics analysis performed in TCGA KIRC cohort and the scRNA-seq cohort. RESULTS: We found that accumulation of CD39+CD8+ T cells indicated poor prognosis (p < 0.0001) and indicated therapeutic benefit of TKIs therapy (p = 0.015). CD39+CD8+ T cells showed decreased TNF-α and IFN-γ with elevated PD-1 and TIM-3 expression. Further analysis of tumor-infiltrating immune cell landscape in the ccRCC revealed the positive correlation between CD39+CD8+ T cells and Tregs (p = 0.037) and M2-polarized macrophages (p < 0.0001). Finally, inhibition of CD39 partially restores the anti-tumor function of CD8+ T cells. CONCLUSIONS: High CD39+CD8+ T cells indicated poor prognosis in ccRCC, due to impaired anti-tumor function of CD39+CD8+ T cells and indicated therapeutic benefit of TKIs therapy.

9.
Br J Cancer ; 122(10): 1525-1534, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32205862

RESUMO

BACKGROUND: Intratumoural CD103+CD8+ T cells have been linked to prolonged survival in several malignancies. However, the clinical significance of CD103+CD8+ T cells in gastric cancer remains unexplored. METHODS: Gastric cancer tissues from Zhongshan Hospital and data from Gene Expression Omnibus were obtained and analysed. Immunohistochemistry and flow cytometry were performed to detect the number and phenotypical characteristics of CD103+CD8+ T cells. The effect of programmed cell death protein-1 (PD-1) blockade on CD103+CD8+ T cells was evaluated with the use of an in vitro study based on fresh tumour tissues. RESULTS: CD103+CD8+ T cells predicted superior overall survival and provided better prognostic power than total CD8+ T cells in gastric cancer. Patients with high CD103+CD8+ T cell infiltration also gained more benefit from adjuvant chemotherapy. Flow cytometry analysis showed that CD103+CD8+ T cells exerted superior anti-tumour effects with stronger retention capacity and cytotoxicity. Moreover, an in vitro study showed that CD103+CD8+ T cells were more functionally restored after PD-1 blockade than CD103-CD8+ T cells. CONCLUSIONS: CD103+CD8+ T cells might be a useful marker to predict prognosis and therapeutic efficacy for gastric cancer patients. Efforts to increase intratumoural CD103+CD8+ T cell frequency might be a novel therapeutic strategy in gastric cancer.

10.
Macromol Rapid Commun ; 41(8): e2000035, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32125049

RESUMO

1D polymer nanomaterials have attracted significant interest in recent years because of their unique properties and promising applications in various fields. It is, however, still a challenge to fabricate polymer nanoarrays with desired sizes and controlled morphologies. Here, an unprecedented approach, the laser-assisted nanowetting (LAN) method, to selectively fabricate polymer nanoarrays is presented. Polystyrene (PS) is blended with gold nanorods (AuNRs), which are used to absorb the energy from the laser. After the blend films are brought in contact with AAO templates, the AuNRs at regions shone by the laser beams absorb the energy and heat the surrounding polymer chains, resulting in the formation of PS/AuNRs arrays in selected areas. This work paves a new research direction for developing template-based polymer nanomaterials.

11.
ACS Appl Mater Interfaces ; 12(14): 16168-16177, 2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32182427

RESUMO

Peripheral nerve injury (PNI) was the leading cause of permanent dysfunction in movement and sensation. Synthesized nerve guide conduits (NGCs) with Schwann Cells (SCs) can help peripheral nerve regeneration. However, poor accessibility of SCs and lack of full coverage of seeded cells on NGCs can lead to failure of nerve regeneration across long gaps and full functional recovery. To overcome these limitations, bone marrow stromal cells (BMSCs) and a novel culture method were proposed in the current study. BMSCs were harvested and seeded on a never growth factor (NGF)-loaded PCL nanofibrous NGCs and cultured with a rotary cell culture system (RCCS) before implantation. The NGCs were tested in vitro with PC-12 cells to validate the bioactivity of released NGF and to access its ability to promote neurite extension. Also, the NGCs were tested in vivo with rat sciatic nerve model to exam its potential in bridging the long gap (15 mm segmental defect). The efficacy of the NGCs was investigated based on the results of the functional test, electrophysiology test, muscle atrophy, and histological analysis. The results of in vitro PC-12 cell study confirmed the bioactivity of released NGF and showed a significant increase in the neurite extension with the help of PEG-diamine and BSA. These results showed that the novel loading method could preserve the bioactivity of growth factors and achieve a sustained release in vitro. Besides, the results of the in vivo study exhibited a significant increase with the combination of all additives. These results showed that with the help of NGF and RCCS, the NGCs with the seeded BMSCs could enhance peripheral nerve regeneration across long nerve injury gaps.

12.
Artigo em Inglês | MEDLINE | ID: mdl-32200421

RESUMO

With dichotomous etiology and pathogenesis, intestinal type and diffuse type gastric cancers vary in their clinical and molecular features to the point of representing distinct entities. However, the differences of tumor-infiltrating immune cells within the two types of gastric cancer have not been well researched. This study was aimed to evaluate the functional impact of Lauren classification on immune contexture in gastric cancer patients. Tumor tissues of gastric cancer patients from Zhongshan Hospital and gastric cancer data from The Cancer Genome Atlas (TCGA) cohort were analyzed. By immunohistochemistry and flow cytometry, we found that intratumoral CD8+ T cells were more abundant but less functional in diffuse type as compared with those in intestinal type tumor tissues. Survival analysis indicated that CD8+ T cells yielded favorable prognosis only in intestinal type patients other than diffuse type cancer patients. Moreover, such diffuse type-associated CD8+ T cell dysfunction was featured by elevated expression of immunosuppressive factors including interleukin-10 (IL-10), transforming growth factor-ß1 (TGF-ß1) and indoleamine 2,3-dioxygenase 1 (IDO1). In summary, we found that the density, prognostic significance and functional status of intratumoral CD8+ T cells varied with Lauren subtypes in gastric cancer. These results further indicated Lauren classification might be a potential therapeutic marker, and should be considered in therapeutic decisions, especially immunotherapeutic eligibility.

13.
Pain ; 161(6): 1237-1254, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32068666

RESUMO

The role of immune mediators, including proinflammatory cytokines in chemotherapy-induced peripheral neuropathy (CIPN), remains unclear. Here, we studied the contribution of interleukin-20 (IL-20) to the development of paclitaxel-induced peripheral neuropathy. Increased serum levels of IL-20 in cancer patients with chemotherapy were accompanied by increased CIPN risk. In mouse models, proinflammatory IL-20 levels in serum and dorsal root ganglia fluctuated with paclitaxel treatment. Blocking IL-20 with the neutralizing antibody or genetic deletion of its receptors prevented CIPN, alleviated peripheral nerve damage, and dampened inflammatory responses, including macrophage infiltration and cytokine release. Mechanistically, paclitaxel upregulated IL-20 through dysregulated Ca homeostasis, which augmented chemotherapy-induced neurotoxicity. Importantly, IL-20 suppression did not alter paclitaxel efficacy on cancer treatment both in vitro and in vivo. Together, targeting IL-20 ameliorates paclitaxel-induced peripheral neuropathy by suppressing neuroinflammation and restoring Ca homeostasis. Therefore, the anti-IL-20 monoclonal antibody is a promising therapeutic for the prevention and treatment of paclitaxel-induced neuropathy.

14.
Cancer Res ; 80(8): 1707-1719, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32060149

RESUMO

Tumor-associated macrophages (TAM) play an indispensable role in the modulation of the cancer immune microenvironment. Despite the fact that TAMs may exert both antitumor and protumor activities, the molecular mechanisms involved remain poorly understood. Here, we characterized a subpopulation of TAMs expressing dendritic cell-specific C-type lectin (DC-SIGN) and investigated its relevance to the prognosis and immune microenvironment of muscle-invasive bladder cancer (MIBC). DC-SIGN+ TAMs were abundant in a significant proportion of human MIBC specimens. High levels of DC-SIGN+ TAMs were associated with dismal prognosis and unresponsiveness to adjuvant chemotherapy in MIBC. Notably, multiple anti-inflammatory cytokines were enriched in DC-SIGN+ TAMs. RNA-seq analysis revealed that multiple M2-like signaling pathways were significantly upregulated in DC-SIGN+ TAMs. High infiltration of DC-SIGN+ TAMs was associated with CD8+ T-cell tolerance in MIBC. Moreover, abrogating DC-SIGN function using a neutralizing antibody led to impaired expression of anti-inflammatory cytokines and augmented PD-1 inhibitor pembrolizumab-mediated cytotoxic effects of CD8+T cells toward MIBC cells. In summary, these results suggest that DC-SIGN+ TAM infiltration is closely linked to a protumor immune microenvironment and may serve as a promising therapeutic target in the immunotherapy of MIBC. SIGNIFICANCE: DC-SIGN+ TAMs have an immunosuppressive and tumor-promoting function and may serve as a prognostic indicator and therapeutic target in MIBC.

15.
Phys Rev Lett ; 124(6): 061102, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32109092

RESUMO

With high spatial resolution, polarimetric imaging of a supermassive black hole, like M87^{⋆} or Sgr A^{⋆}, by the Event Horizon Telescope can be used to probe the existence of ultralight bosonic particles, such as axions. Such particles can accumulate around a rotating black hole through the superradiance mechanism, forming an axion cloud. When linearly polarized photons are emitted from an accretion disk near the horizon, their position angles oscillate due to the birefringent effect when traveling through the axion background. In particular, the observations of supermassive black holes M87^{⋆} (Sgr A^{⋆}) can probe the dimensionless axion-photon coupling c=2πg_{aγ}f_{a} for axions with mass around O(10^{-20}) eV [O(10^{-17}) eV] and decay constant f_{a}

16.
Eur J Cancer ; 128: 27-37, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32109848

RESUMO

AIM: Tumour-associated macrophages (TAMs) are prominent immune cells infiltrating in solid tumours with phenotypic and functional heterogeneity. However, the clinical significance of heterogeneous subtypes of TAMs in gastric cancer still remains obscure. Here, we aimed to explore the clinical significance of TAMs expressing dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN) and its relevance with immune contexture in gastric cancer. METHODS: We selected 453 formalin-fixed and paraffin-embedded samples and 51 fresh tissue specimens of patients with gastric cancer from Zhongshan Hospital. The association of DC-SIGN+ macrophages with clinicopathological parameters, overall survival (OS) and responsiveness to fluorouracil-based adjuvant chemotherapy (ACT) was inspected. Immunohistochemistry (IHC) and flow cytometry (FCM) were applied to characterize immune cells in gastric cancer. RESULTS: We demonstrated that high intratumoral DC-SIGN+ macrophages infiltration predicted poor OS and inferior therapeutic responsiveness to fluorouracil-based ACT in patients with gastric cancer. Furthermore, higher infiltration of DC-SIGN+ macrophages indicated an increased number of Foxp3+ regulatory T cells (Tregs), CD8+ T cells and a higher ratio of Foxp3+/CD8+ within the tumour microenvironment (TME). In addition, CD8+ T cells in DC-SIGN+ macrophages high subgroup were functionally impaired, showing decreased interferon-γ (IFN-γ), granzyme B (GZMB) and perforin production yet elevated programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression. CONCLUSIONS: DC-SIGN+ macrophages were associated with immunoinvasive TME and indicated poor prognosis and inferior therapeutic responsiveness to fluorouracil-based ACT. DC-SIGN+ macrophages might be an independent prognosticator and a potential immunotherapeutic target for gastric cancer.

17.
Phys Rev E ; 101(1-1): 012416, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32069643

RESUMO

Diverse biological functions of biomembranes are made possible by their rich dynamic behaviors across multiple scales. While the potential coupling between the dynamics of differing scales may underlie the machineries regulating the biomembrane-involving processes, the mechanism and even the existence of this coupling remain an open question, despite the latter being taken for granted. Via inelastic neutron scattering, we examined dynamics across multiple scales for the lipid membranes whose dynamic behaviors were perturbed by configurational changes at two membrane regions. Surprisingly, the dynamic behavior of individual lipid molecules and their collective motions were not always coupled. This suggests that the expected causal relation between the dynamics of the differing hierarchical levels does not exist and that an apparent coupling can emerge by manipulating certain membrane configurations. The findings provide insight on biomembrane modeling and how cells might individually or concertedly control the multiscale membrane dynamics to regulate their functions.

18.
Nanoscale ; 12(4): 2532-2541, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31932821

RESUMO

Pd-Based nanoparticles are excellent alternatives to the typically used Pt-based materials that catalyze fuel cell reactions. Specifically, Pd-based intermetallic nanomaterials have shown great promise as electrocatalysts for the oxygen reduction reaction (ORR) in alkaline media; however, their synthesis remains a challenge and shape-controlled nanoparticles are limited. Here, a low-temperature approach to intermetallic Pd3Pb nanocubes is demonstrated and their electrocatalytic properties evaluated for the ORR. The intermetallic Pd3Pb nanocubes outperformed all reference catalysts, with a mass activity of 154 mA mgPd-1 which is a 130% increase in activity compared to the commercial Pd/C reference and a 230% increase compared to Pd nanocubes. Tafel analysis reveals that the Pd3Pb nanocubes are highly selective for the 4-electron reduction pathway, with minimal HO2- formation. Density functional theory (DFT) calculations show that the increased activity for the intermetallic nanocubes compared to Pd is likely due to the weakening of OH* adsorption, decreasing the required overpotential. These results show that intermetallic Pd3Pb nanocubes are highly efficient for the 4-electron pathway of the ORR and could inspire the study of other shape-controlled intermetallics as catalysts for fuel cell applications.

19.
Small ; 16(6): e1906026, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31899600

RESUMO

It is a great challenge to simultaneously control the size, morphology, and facets of monodispersed Pd nanocrystals under a sub-5 nm regime. Meanwhile, quantitative understanding of the thermodynamic and kinetic parameters to maneuver the shape evolution of nanocrystals in a one-pot system still deserves investigation. Herein, a systematic study of the density functional theory (DFT)-calculated adsorption energy, thermodynamic factors, and reduction kinetics on Pd growth patterns is reported by combining theory and experiments, with a focus on the dispersed state of additives. As pure models, monodispersed Pd tetrahedrons enclosed by (111) facets with a narrow size distribution of 4.9 ± 1 nm and a high purity approaching 98% can be obtained when using 1,1'-binaphthalene (C20 H14 ) +2NH3 as additives. Specifically, laciniate Pd nanourchins (Pd LUs) can evolve via anisotropic growth when replacing additive with dose-consistent 1,1'-binaphthyl-2,2'-diamine (C20 H16 N2 , two NH2 binding in C20 H14 ). Catalytic investigations show that the sub-5 nm Pd tetrahedrons exhibit higher activity in both the oxygen reduction (Eonset = 1.025 V, E1/2 = 0.864 V) and formic acid oxidation reaction with respect to the Pd LUs and Pd black, which represents a great step for the development of well-defined Pd nanocrystals with size in the sub-5 nm regime as non-Pt electrocatalysts.

20.
Urol Oncol ; 38(4): 293-304, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31889617

RESUMO

BACKGROUND: Previous studies have shown the prognostic value of PAK1 expression in different tumor patients, including nonmetastatic renal cell carcinoma. In this study, we explored the prognostic and drug predictive value of PAK1 expression in metastatic renal cell carcinoma (mRCC) patients treated with tyrosine kinase inhibitors (TKIs). MATERIALS AND METHODS: We retrospectively enrolled 138 mRCC patients treated with TKIs from a single institution from 2005 to 2014. Analyses were based on 111 patients who met our inclusion criteria. The validation set enrolled 538 RCC patients from The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma cohort (TCGA KIRC) between 1998 and 2013 in North America. PAK1 expression was assessed by immunohistochemistry (IHC) on tissue microarrays. RESULTS: High PAK1 expression was associated with short overall survival (OS) (P < 0.001) and progression-free survival (PFS) (P = 0.008). Multivariate analyses further indicated that PAK1 expression was an independent prognostic factor for OS (hazard ratio 3.301 [95% confidence interval 2.579-10.899], P < 0.001) and PFS (hazard ratio 3.108 [95% confidence interval 1.795-5.381], P < 0.001). Subgroup analyses suggested that PAK1 was more significant in patients with the intermediate risk group of Heng risk criteria (OS, P = 0.004). Of note, patients treated with Sunitinib showed improved outcome in the low PAK1 subgroup (OS, P = 0.002; PFS, P = 0.013). Finally, relationship was found between PAK1 expression and natural killer cell-mediated cytotoxicity according to gene profile investigation. CONCLUSIONS: High PAK1 expression predicted dismal prognosis in mRCC patients treated with TKIs. Besides, PAK1 was a potential predictor for TKIs treatments.

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