Garrisonclancy5745

orting men to make better use of treatment.Muscle-invasive bladder carcinomas (MIBCs) are aggressive genitourinary malignancies. Metastatic urothelial carcinoma of the bladder is generally incurable by current chemotherapy and leads to early mortality. Recent studies have identified molecular subtypes of MIBCs with different sensitivities to frontline therapy, suggesting tumor heterogeneity. We have performed multi-omic profiling of the kinome in bladder cancer patients with the goal of identify therapeutic targets. Our analyses revealed amplification, overexpression, and elevated kinase activity of P21 (RAC1) activated kinase 4 (PAK4) in a subset of Bladder cancer (BLCA). Using bladder cancer cells, we confirmed the role of PAK4 in BLCA cell proliferation and invasion. Furthermore, we observed that a PAK4 inhibitor was effective in curtailing growth of BLCA cells. Transcriptomic analyses identified elevated expression of another kinase, protein tyrosine kinase 6 (PTK6), upon treatment with a PAK4 inhibitor and RNA interference of PAK4. Treatment with a combination of kinase inhibitors (vandetanib and dasatinib) showed enhanced sensitivity compared with either drug alone. Thus, PAK4 may be therapeutically actionable for a subset of MIBC patients with amplified and/or overexpressed PAK4 in their tumors. Our results also indicate that combined inhibition of PAK4 and PTK6 may overcome resistance to PAK4. These observations warrant clinical investigations with selected BLCA patients.Genome-wide association studies (GWAS) have identified numerous genetic variants that are associated with lung cancer risk, but the biological mechanisms underlying these associations remain largely unknown. Here we investigated the functional relevance of a genetic region in 6q22.2 which was identified to be associated with lung cancer risk in our previous GWAS. We performed linkage disequilibrium (LD) analysis and bioinformatic prediction to screen functional SNPs linked to a tagSNP in 6q22.2 loci, followed by two case-control studies and a meta-analysis with 4403 cases and 5336 controls to identify if these functional SNPs were associated with lung cancer risk. A novel SNP rs17079281 in the DCBLD1 promoter was identified to be associated with lung cancer risk in Chinese populations. Compared with those with C allele, patients with T allele had lower risk of adenocarcinoma (adjusted OR = 0.86; 95% CI 0.80-0.92), but not squamous cell carcinoma (adjusted OR = 0.99; 95% CI 0.91-1.10), and patients with the C/T or T/T genotype had lower levels of DCBLD1 expression than those with C/C genotype in lung adenocarcinoma tissues. We performed functional assays to characterize its biological relevance. The results showed that the T allele of rs17079281 had higher binding affinity to transcription factor YY1 than the C allele, which suppressed DCBLD1 expression. Selleckchem SM04690 DCBLD1 behaved like an oncogene, promoting tumor growth by influencing cell cycle progression. These findings suggest that the functional variant rs17079281C>T decreased lung adenocarcinoma risk by creating an YY1-binding site to suppress DCBLD1 expression, which may serve as a biomarker for assessing lung cancer susceptibility.Multivalent interactions at biological interfaces occur frequently in nature and mediate recognition and interactions in essential physiological processes such as cell-to-cell adhesion. Multivalency is also a key principle that allows tight binding between pathogens and host cells during the initial stages of infection. One promising approach to prevent infection is the design of synthetic or semisynthetic multivalent binders that interfere with pathogen adhesion1-4. Here, we present a multivalent binder that is based on a spatially defined arrangement of ligands for the viral spike protein haemagglutinin of the influenza A virus. Complementary experimental and theoretical approaches demonstrate that bacteriophage capsids, which carry host cell haemagglutinin ligands in an arrangement matching the geometry of binding sites of the spike protein, can bind to viruses in a defined multivalent mode. These capsids cover the entire virus envelope, thus preventing its binding to the host cell as visualized by cryo-electron tomography. As a consequence, virus infection can be inhibited in vitro, ex vivo and in vivo. Such highly functionalized capsids present an alternative to strategies that target virus entry by spike-inhibiting antibodies5 and peptides6 or that address late steps of the viral replication cycle7.Traditional von Neumann computing systems involve separate processing and memory units. However, data movement is costly in terms of time and energy and this problem is aggravated by the recent explosive growth in highly data-centric applications related to artificial intelligence. This calls for a radical departure from the traditional systems and one such non-von Neumann computational approach is in-memory computing. Hereby certain computational tasks are performed in place in the memory itself by exploiting the physical attributes of the memory devices. Both charge-based and resistance-based memory devices are being explored for in-memory computing. In this Review, we provide a broad overview of the key computational primitives enabled by these memory devices as well as their applications spanning scientific computing, signal processing, optimization, machine learning, deep learning and stochastic computing.To meet the requirements of potential applications, it is of great importance to explore new catalysts for formic acid oxidation that have both ultra-high mass activity and CO resistance. Here, we successfully synthesize atomically dispersed Rh on N-doped carbon (SA-Rh/CN) and discover that SA-Rh/CN exhibits promising electrocatalytic properties for formic acid oxidation. The mass activity shows 28- and 67-fold enhancements compared with state-of-the-art Pd/C and Pt/C, respectively, despite the low activity of Rh/C. Interestingly, SA-Rh/CN exhibits greatly enhanced tolerance to CO poisoning, and Rh atoms in SA-Rh/CN resist sintering after long-term testing, resulting in excellent catalytic stability. Density functional theory calculations suggest that the formate route is more favourable on SA-Rh/CN. According to calculations, the high barrier to produce CO, together with the relatively unfavourable binding with CO, contribute to its CO tolerance.Non-collinear and non-coplanar spin textures, such as chiral domain walls1 and helical or triangular spin structures2,3, bring about diverse functionalities. Among them, magnetic skyrmions, particle-like non-coplanar topological spin structures characterized by a non-zero integer topological charge called the skyrmion number (Nsk), have great potential for various spintronic applications, such as energy-saving, non-volatile memory and non-von Neumann devices4-7. Current pulses can initiate skyrmion creation in thin-film samples8-10 but require relatively large current densities, which probably causes Joule heating. Moreover, skyrmion creation is localized at a specific position in the film depending on the sample design. Here, we experimentally demonstrate an approach to skyrmion creation employing surface acoustic waves (SAWs); in asymmetric multilayers of Pt/Co/Ir, propagating SAWs induce skyrmions in a wide area of the magnetic film. Micromagnetic simulations reveal that inhomogeneous torque arising from both SAWs and thermal fluctuations creates magnetic textures, with pair structures consisting of a Néel skyrmion-like and an antiskyrmion-like structure. Subsequently, such pairs transform to a Néel skyrmion due to the instability of the antiskyrmion-like structure in a system with interfacial Dzyaloshinskii-Moriya interaction. Our findings provide a tool for efficient manipulation of topological spin objects without heat dissipation and over large areas, given that the propagation length of SAWs is of the order of millimetres.It has been reported that Cu(II) ions in human blood are bound mainly to serum albumin (HSA), ceruloplasmin (CP), alpha-2-macroglobulin (α2M) and His, however, data for α2M are very limited and the thermodynamics and kinetics of the copper distribution are not known. We have applied a new LC-ICP MS-based approach for direct determination of Cu(II)-binding affinities of HSA, CP and α2M in the presence of competing Cu(II)-binding reference ligands including His. The ligands affected both the rate of metal release from Cu•HSA complex and the value of KD. Slow release and KD = 0.90 pM was observed with nitrilotriacetic acid (NTA), whereas His showed fast release and substantially lower KD = 34.7 fM (50 mM HEPES, 50 mM NaCl, pH 7.4), which was explained with formation of ternary His•Cu•HSA complex. High mM concentrations of EDTA were not able to elicit metal release from metallated CP at pH 7.4 and therefore it was impossible to determine the KD value for CP. In contrast to earlier inconclusive evidence, we show that α2M does not bind Cu(II) ions. In the human blood serum ~75% of Cu(II) ions are in a nonexchangeable manner bound to CP and the rest exchangeable copper is in an equilibrium between HSA (~25%) and Cu(II)-His-Xaa ternary complexes (~0.2%).We aimed to evaluate the prognostic value of seminal vesicle invasion (SVI) on preoperative multiparametric MRI (mpMRI) in pathological T3b prostate cancer (PCa). We retrospectively reviewed the clinical data of patients who underwent preoperative mpMRI and subsequent radical prostatectomy (RP). A total of 159 patients with pathologic T3b PCa were stratified into two groups based on mpMRI findings (negative vs. positive SVI). A positive SVI was defined as the presence of mpMRI evidence of SVI. In addition, 290 patients with pathologic T3a were also included in this study for further comparative analysis. Fifty-two patients (32.7%) had a positive SVI on preoperative mpMRI. Biochemical recurrence (BCR) occurred in a total of 45 (28.3%) patients, with 25 (23.4%) cases in the negative SVI group and 20 (38.5%) cases in the positive SVI group. Kaplan-Meier survival analysis of the two groups revealed significantly decreased BCR-free survival in the positive SVI group (median, 21 vs. 9 months, log-rank test, P  less then  0.001). On multivariate Cox regression analysis, pre-biopsy PSA (P = 0.035) and positive SVI on preoperative mpMRI (P = 0.049) were identified as significant predictors of BCR. Upon further comparative analysis with the pathologic T3a group, we also found significant differences among the groups throughout the Kaplan-Meier curve (P  less then  0.001). Conclusively, the unpredicted (negative) SVI group had a favorable BCR-free survival compared to the positive SVI group. In addition, significant differences were observed in the prognosis of pathologic T3a and these two groups. This suggests that pathologic T3b can be stratified into two categories.An amendment to this paper has been published and can be accessed via a link at the top of the paper.'Reactive oxygen species' (ROS) is an umbrella term for an array of derivatives of molecular oxygen that occur as a normal attribute of aerobic life. Elevated formation of the different ROS leads to molecular damage, denoted as 'oxidative distress'. Here we focus on ROS at physiological levels and their central role in redox signalling via different post-translational modifications, denoted as 'oxidative eustress'. Two species, hydrogen peroxide (H2O2) and the superoxide anion radical (O2·-), are key redox signalling agents generated under the control of growth factors and cytokines by more than 40 enzymes, prominently including NADPH oxidases and the mitochondrial electron transport chain. At the low physiological levels in the nanomolar range, H2O2 is the major agent signalling through specific protein targets, which engage in metabolic regulation and stress responses to support cellular adaptation to a changing environment and stress. In addition, several other reactive species are involved in redox signalling, for instance nitric oxide, hydrogen sulfide and oxidized lipids.