p21-Activated Kinases 1, 2 and 4 in Endometrial Cancers: Effects on Clinical Outcomes and Cell Proliferation

p21-activated kinases (Paks) are serine/threonine protein kinases involved in biological events linked to malignant tumor progression. In this study, expression of Pak1, p-Pak2 Ser20, Pak4, pPak4 Ser474 in 21 normal endometrium, 16 hyperplastic endometrium without atypia, 17 atypical complex hyperplasia and 67 endometrial cancers was assessed by immunohistochemistry and correlated with clinicopathological parameters. We also accessed the proliferative role and downstream targets of Pak1 in endometrial cancer. Pak1 was expressed in cytoplasm whereas Pak4 and p-Pak4 were expressed in both cytoplasm and nucleus of endometrial tissues. In normal endometrium, significantly higher Pak1 (P = 0.028) and cytoplasmic p-Pak2 (P = 0.048) expression was detected in proliferative endometrium than secretory endometrium. Pak1, cytoplasmic and nuclear Pak4 and nuclear p-Pak4 was significantly overexpressed in endometrial cancer when compared to atrophic endometrium (all P<0.05). Moreover, type I endometrioid carcinomas showed significantly higher Pak1 expression than type II non-endometrioid carcinomas (P<0.001). On the other hand, Pak1, Pak4 and p-Pak4 expression negatively correlated with histological grade (all P<0.05) while p-Pak2 and cytoplasmic Pak4 expression inversely correlated with myometrial invasion (all P<0.05). Furthermore, patients with endometrial cancers with lower cytoplasmic Pak4 expression showed poorer survival (P = 0.026). Multivariate analysis showed cytoplasmic Pak4 is an independent prognostic factor. Functionally, knockdown of Pak1, but not Pak4, in endometrial cancer cell line led to reduced cell proliferation along with reduced cyclin D1, estrogen receptor (ERα) and progestogen receptor (PR) expression. Significant correlation between Pak1 and PR expression was also detected in clinical samples. Our findings suggest that Pak1 and cytoplasmic p-Pak2 may promote cell proliferation in normal endometrium during menstral cycle. Pak1, cytoplasmic and nuclear Pak4 and nuclear p-Pak4 are involved in the pathogenesis of endometrial cancer especially in postmenopausal women. Pak1 promote endometrial cancer cell proliferation, particular in type I endometrioid carcinoma. Cytoplasmic Pak4 can be potential prognostic marker in endometrial cancer.published_or_final_versio

Recent progress in organic-based radiative cooling materials: fabrication methods and thermal management properties

Organic-based materials capable of radiative cooling have attracted widespread interest in recent years due to their ease of engineering and good adaptability to different application scenarios. As a cooling material for walls, clothing, and electronic devices, these materials can reduce the energy consumption load of air conditioning, improve thermal comfort, and reduce carbon emissions. In this paper, an overview is given of the current fabrication strategies of organic-based radiative cooling materials, and of their properties. The methods and joint thermal management strategies including evaporative cooling, phase-change materials, fluorescence, and light-absorbing materials that have been demonstrated in conjunction with a radiative cooling function are also discussed. This review provides a comprehensive overview of organic-based radiative cooling, exemplifying the emerging application directions in this field and highlighting promising future research directions in the field

Band structure engineering in (Bi1-xSbx)2Te3 ternary topological insulators

Three-dimensional (3D) topological insulators (TI) are novel quantum materials with insulating bulk and topologically protected metallic surfaces with Dirac-like band structure. The spin-helical Dirac surface states are expected to host exotic topological quantum effects and find applications in spintronics and quantum computation. The experimental realization of these ideas requires fabrication of versatile devices based on bulk-insulating TIs with tunable surface states. The main challenge facing the current TI materials exemplified by Bi2Se3 and Bi2Te3 is the significant bulk conduction, which remains unsolved despite extensive efforts involving nanostructuring, chemical doping and electrical gating. Here we report a novel approach for engineering the band structure of TIs by molecular beam epitaxy (MBE) growth of (Bi1-xSbx)2Te3 ternary compounds. Angle-resolved photoemission spectroscopy (ARPES) and transport measurements show that the topological surface states exist over the entire composition range of (Bi1-xSbx)2Te3 (x = 0 to 1), indicating the robustness of bulk Z2 topology. Most remarkably, the systematic band engineering leads to ideal TIs with truly insulating bulk and tunable surface state across the Dirac point that behave like one quarter of graphene. This work demonstrates a new route to achieving intrinsic quantum transport of the topological surface states and designing conceptually new TI devices with well-established semiconductor technology.Comment: Minor changes in title, text and figures. Supplementary information adde

Darkroom prone provocative testing in primary angle closure suspects and those with open angles

PURPOSE: To describe the results of darkroom prone provocative testing (DRPPT) in primary angle closure suspects (PACS) and to compare the findings to controls with open angles. METHODS: 889 subjects with PACS in the Zhongshan Angle Closure Prevention Trial (a randomised controlled trial to compare prophylactic laser iridotomy to no treatment in PACS) and 89 with open angles in the 5-year follow-up of Liwan Eye Study were placed in a darkroom face down for 15 min. Intraocular pressure (IOP) was measured immediately before and after DRPPT. RESULTS: PACS participants were of similar age than controls (59.3 vs 60.5), more often female (82.9% vs 58.4%) and had lower IOP (14.3 vs 15.2 mm Hg). The average IOP increases after DRPPT was 4.3±3 mm Hg in PACS and 5.2±2.8 in controls (p<0.05). 20.5% of controls and 13.9 % of those with PACS developed an IOP spike ≥8 mm Hg after DRPPT (p<0.05). Among PACS, 15.8 % of those with all four quadrants closed had an IOP elevation of ≥ 8 mm Hg as opposed to 10.0%-12.4 % with two or three closed quadrants (p<0.05). DRPPT failed to predict who would reach a clinical trial endpoint over 6-year follow-up of those with PACS. CONCLUSIONS: A modified DRPPT failed to separate PACS from those with open angle. Although the test resulted in greater IOP elevation among those PACS participants with all four quadrants closed than in those with two or three closed quadrants, it did not offer any insight into the risk of developing acute or chronic angle closure disease over 6-year follow-up

Backbone and side-chain 1H, 15N and 13C resonance assignments of S18Y mutant of ubiquitin carboxy-terminal hydrolase L1

Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), also known as PGP9.5, is a protein of 223 amino acids. Although it was originally characterized as a deubiquitinating enzyme, recent studies indicate that it also functions as a ubiquitin (Ub) ligase and a mono-Ub stabilizer. It is highly abundant in brain, constituting up to 2% of total brain proteins. Down-regulation and extensive oxidative modification of UCH-L1 have been observed in the brains of Alzheimer’s disease (AD) and Parkinson’s disease (PD) patients. Mutations in the UCH-L1 gene have been reported to be linked to Parkinson’s disease, in particular, the I93 M variant is associated with a higher susceptibility of PD in contrast to a higher protection against PD for the S18Y variant. Hence, the structure of UCH-L1 and the underlying effects of disease associated mutations on the structure and function of UCH-L1 are of considerable interest. Here, we report the NMR spectral assignments of the S18Y human UCH-L1 mutant with the aim to obtain better understanding about the risk of Parkinson’s disease against structural and dynamical changes induced by this mutation on UCH-L1

Backbone and side-chain 1H, 13C and 15N assignments of the ubiquitin-associated domain of human X-linked inhibitor of apoptosis protein

X-linked inhibitor of apoptosis protein (XIAP), a leading member of the family of inhibitor of apoptosis (IAP) proteins, is considered as the most potent and versatile inhibitor of caspases and apoptosis. It has been reported that XIAP is frequently overexpressed in cancer and its expression level is implicated in contributing to tumorigenesis, disease progression, chemoresistance and poor patient-survival. Therefore, XIAP is one of the leading targets in drug development for cancer therapy. Recently, based on bioinformatics study, a previously unrecognized but evolutionarily conserved ubiquitin-associated (UBA) domain in IAPs was identified. The UBA domain is found to be essential for the oncogenic potential of IAP, to maintain endothelial cell survival and to protect cells from TNF-α-induced apoptosis. Moreover, the UBA domain is required for XIAP to activate NF-κB. In the present study, we report the near complete resonance assignments of the UBA domain-containing region of human XIAP protein. Secondary structure prediction based on chemical shift index (CSI) analysis reveals that the protein is predominately α-helical, which is consistent with the structures of known UBA proteins

Identification and optimization of small molecule antagonists of vasoactive intestinal peptide receptor-1 (VIPR1)

Identification, synthesis and structure-activity relationship of small-molecule VIPR1 antagonists encompassing two chemical series are described

Hyperthermia and Thermosensitive Liposomes for Improved Delivery of Chemotherapeutic Drugs to Solid Tumors

Lipid-based nanocarriers or liposomes have been proven successful in the delivery of chemotherapeutic agents and are currently applied clinically in the treatment of various types of cancer. Liposomes offer the advantage of a high drug payload, decreased drug toxicity and enhanced drug accumulation at tumor sites. Increased accumulation is due to the relatively leaky tumor vasculature that allows liposome extravasation. Between different types of tumors and even within one tumor, vascular permeability and thus liposome extravasation may differ greatly. Furthermore, upon accumulation of liposomes in the tumor area, drug bioavailability is not guaranteed. At present, these are the major issues for clinically used liposomal drugs

Detection of Hepatocyte Growth Factor (HGF) Ligand-c-MET Receptor Activation in Formalin-Fixed Paraffin Embedded Specimens by a Novel Proximity Assay

Aberrant activation of membrane receptors frequently occurs in human carcinomas. Detection of phosphorylated receptors is commonly used as an indicator of receptor activation in formalin-fixed paraffin embedded (FFPE) tumor specimens. FFPE is a standard method of specimen preparation used in the histological analysis of solid tumors. Due to variability in FFPE preparations and the labile nature of protein phosphorylation, measurements of phospho-proteins are unreliable and create ambiguities in clinical interpretation. Here, we describe an alternative, novel approach to measure receptor activation by detecting and quantifying ligand-receptor complexes in FFPE specimens. We used hepatocyte growth factor (HGF)-c-MET as our model ligand-receptor system. HGF is the only known ligand of the c-MET tyrosine kinase receptor and HGF binding triggers c-MET phosphorylation. Novel antibody proximity-based assays were developed and used to detect and quantify total c-MET, total HGF, and HGF-c-MET ligand-receptor interactions in FFPE cell line and tumor tissue. In glioma cells, autocrine activation of c-MET by HGF-c-MET increased basal levels of c-MET phosphorylation at tyrosine (Tyr) 1003. Furthermore, HGF-c-MET activation in glioma cell lines was verified by Surface Protein-Protein Interaction by Crosslinking ELISA (SPPICE) assay in corresponding soluble cell lysates. Finally, we profiled levels o

The Escherichia coli transcriptome mostly consists of independently regulated modules

Underlying cellular responses is a transcriptional regulatory network (TRN) that modulates gene expression. A useful description of the TRN would decompose the transcriptome into targeted effects of individual transcriptional regulators. Here, we apply unsupervised machine learning to a diverse compendium of over 250 high-quality Escherichia coli RNA-seq datasets to identify 92 statistically independent signals that modulate the expression of specific gene sets. We show that 61 of these transcriptomic signals represent the effects of currently characterized transcriptional regulators. Condition-specific activation of signals is validated by exposure of E. coli to new environmental conditions. The resulting decomposition of the transcriptome provides: a mechanistic, systems-level, network-based explanation of responses to environmental and genetic perturbations; a guide to gene and regulator function discovery; and a basis for characterizing transcriptomic differences in multiple strains. Taken together, our results show that signal summation describes the composition of a model prokaryotic transcriptome