Locally advanced solitary fibrous tumour of the prostate.

Solitary fibrous tumours (SFTs) are rare mesenchymal neoplasms composed of spindle cells, most often occurring in the pleura. SFTs arising from the prostate are exceptionally rare, with only around 40 cases reported in literature to date. We report a man in his 60s who was referred to our clinic for elevated prostate-specific antigen and presented with mild obstructive lower urinary tract and defecatory symptoms. Prostate needle-core biopsy revealed neoplastic spindle cells that strongly expressed CD34. Cross-sectional imaging demonstrated a 12 cm locally advanced heterogeneous prostate mass with intravesical extension and mass effect on the anterior rectum. Radical cystoprostatectomy with orthotopic neobladder reconstruction was performed, and the diagnosis of primary prostatic SFT was made based on histological characteristics and immunophenotyping. We present diagnostic, clinical management and prognostic considerations in patients with primary prostatic SFT.

KIF13B mediates VEGFR2 recycling to modulate vascular permeability.

Excessive vascular endothelial growth factor-A (VEGF-A) signaling induces vascular leakage and angiogenesis in diseases. VEGFR2 trafficking to the cell surface, mediated by kinesin-3 family protein KIF13B, is essential to respond to VEGF-A when inducing angiogenesis. However, the precise mechanism of how KIF13B regulates VEGF-induced signaling and its effects on endothelial permeability is largely unknown. Here we show that KIF13B-mediated recycling of internalized VEGFR2 through Rab11-positive recycling vesicle regulates endothelial permeability. Phosphorylated VEGFR2 at the cell-cell junction was internalized and associated with KIF13B in Rab5-positive early endosomes. KIF13B mediated VEGFR2 recycling through Rab11-positive recycling vesicle. Inhibition of the function of KIF13B attenuated phosphorylation of VEGFR2 at Y951, SRC at Y416, and VE-cadherin at Y685, which are necessary for endothelial permeability. Failure of VEGFR2 trafficking to the cell surface induced accumulation and degradation of VEGFR2 in lysosomes. Furthermore, in the animal model of the blinding eye disease wet age-related macular degeneration (AMD), inhibition of KIF13B-mediated VEGFR2 trafficking also mitigated vascular leakage. Thus, the present results identify the fundamental role of VEGFR2 recycling to the cell surface in mediating vascular permeability, which suggests a promising strategy for mitigating vascular leakage associated with inflammatory diseases.

Imaging in urethral stricture disease: an educational review of current techniques with a focus on MRI.

Urethral stricture disease refers to narrowing of the urethral lumen obstructing the flow of urine. Urethral strictures can significantly impact daily life due to incontinence, incomplete emptying, hesitancy, and increased risk of urinary tract infections. Imaging is central to the evaluation of suspected urethral stricture, as assessment of stricture length and severity is crucial for guidance of surgical management. The currently employed modalities include radiography, chiefly retrograde urethrography (RUG) and voiding cystourethrography (VCUG); magnetic resonance urethrography (MRU); and sonourethrography (SUG). MRU has become a recent focus of research as it provides high spatial resolution, multiplanar capacity, and soft tissue type differentiation for evaluation of periurethral compartments and concurrent soft tissue defects. The protocol for MRU has evolved over the years to now include dynamic micturition imaging and image reconstruction options. In this review, we discuss each of the imaging modalities used in the diagnosis and evaluation of urethral stricture and provide an overview of literature on MRU over the last decade, including suggested indications that have not yet been incorporated into current guidelines. We delineate scenarios where special diagnostic imaging beyond radiography is beneficial, providing examples from our practice and description of our techniques for each modality.

VEGFR2 Trafficking by KIF13B Is a Novel Therapeutic Target for Wet Age-Related Macular Degeneration.

Purpose: Vascular endothelial growth factor (VEGF) and its receptor VEGFR2 are promising therapeutic targets for wet age-related macular degeneration (AMD). As a topically applicable option, we developed the peptide KAI to selectively interfere with VEGFR2 trafficking to the cell surface where it receives VEGF. This study sought to determine the efficacy of KAI in the mouse model of choroidal neovascularization (CNV). Methods: The specificity of KAI was tested by surface plasmon resonance. The drug delivery was analyzed by cryosection and the ELISA after treatment of KAI eyedrop to the mouse eyes. For the laser-induced CNV model, mice with laser-induced ruptures in Bruch's membrane received daily treatment of KAI eyedrop or control peptide. The other groups of mice received intravitreal injection of anti-VEGF or IgG control. After two weeks, CNV was quantified and compared. Results: First, we showed the specificity and high affinity of KAI to VEGFR2. Next, biodistribution revealed successful delivery of KAI eyedrop to the back of the mouse eyes. KAI significantly reduced the disease progression in laser-induced CNV. The comparison with current therapy suggests that KAI eyedrop is as effective as current therapy to prevent CNV in wet AMD. Moreover, the genetic deletion of a kinesin KIF13B, which mediates VEGFR2 trafficking to the cell surface, confirmed the pivotal role of KIF13B in disease progression of wet AMD and neovascularization from choroidal vessels. Conclusions: Taken together, pharmacologic inhibition and genetic deletion complementarily suggest the therapeutic possibility of targeting VEGFR2 trafficking to inhibit pathological angiogenesis in wet AMD.

Thermochemistry of Tungsten-3p Elements for Density Functional Theory, Caveat Lector!

There are two primary foci in this research on WE (E = Si, P, and S) bonds: prediction of their bond dissociation enthalpies (BDEs), including σ- and π-bond energy components, and assessing the uncertainty of these BDE predictions for levels of theory commonly used in the literature. The internal standards for computational accuracy include metal-element bond lengths (mean absolute error = 1.8 ± 1.2%), main group homolog BDEs versus higher levels of ab initio theory (W1U and G4 BDEs, R2 = 0.98), and DLPNO-CCSD(T)/def2-QZVPP calculations for metal-ligand BDEs (R2 = 0.88). The W═Si first π-bond is underreported for density functional theory (DFT)/MP2 methods versus DLPNO-CCSD(T), while the latter shows negligible strength for the W;Si second π-bond, consistent with the literature. This research highlights clear issues with the underlying assumptions required for the use of perturbation theory methods for the fragments derived from W-P homolysis. The difficulties associated with modeling the metal thermochemistry with DFT (and MP2) levels of theory are manifest in the broad standard deviations observed. However, the average BDEs found using 48 popular DFT and MP2 levels of theory are reliable, 10.8 ± 6.8% mean absolute error (with W-P removed) versus DLPNO-CCSD(T), with the caveat that the individual basis set/pseudopotential/valence basis set combination can vary wildly. Analysis of the absolute error percentages with respect to the level of theory indicates little benefit to going higher on Jacob's Ladder, as simpler methods have lower error versus high-level ab initio techniques such as G4 and DLPNO-CCSD(T).

Metal and Ligand Effects on Coordinated Methane pKa: Direct Correlation with the Methane Activation Barrier.

DFT and coupled cluster methods were used to investigate the impact of 3d metals and ligands upon the acidity and activation of coordinated methane C-H bonds. A strong, direct relationship was established between the pKa of coordinated methane and the free energy barriers (ΔG⧧) to subsequent H3C-H activation. The few outliers to this relationship indicated other salient factors (such as thermodynamic stability of the product and ligand-metal coordination type) that impacted the methane activation barrier. High variations in the activation barriers and pKa values were found with a range of 34.8 kcal/mol for the former and 28.6 pKa units for the latter. Clear trends among specific metals and ligands were also derived; metal ions such as CoI, as well as Lewis acids and π-acids, consistently yielded higher acidity for ligated methane and hence lower ΔG⧧.

Computational Study of 3d Metals and Their Influence on the Acidity of Methane C-H Bonds.

CCSD(T) methods in conjunction with correlation consistent basis sets are used to predict the pK a for the deprotonation of methane in a 3d metal ion adduct, [M···CH4]+ (M = Sc-Cu), in dimethyl sulfoxide solvent, which is modeled by the SMD continuum solvent model. Results show that the coordination of methane to different M+ ions has a substantial difference of ∼27 pK a units, from most to least acidic, and increases the acidity of the methane C-H bond from ∼8 to 36 pK a units. Furthermore, even with the omission of the more expensive quadruple and quintuple zeta basis sets in the prediction process, similar trends in pK a(C-H) as a function of 3d metal ions are exhibited. This research serves to illustrate the substantial effect that metal ion identity has on the acidity of a coordinated hydrocarbon and the utility that correlation consistent basis sets have in lowering the computational cost of modeling larger systems.