Abstract Background Five-Year survival after pelvic exenteration for gynecologic malignancies has been reported as high as 60%. The objective of this study was to determine overall survival (OS) ...after pelvic exenteration and evaluate factors impacting outcome. Methods A retrospective review of all women who underwent pelvic exenteration at our institution between February 1993 and December 2010 was performed. OS was defined as time from exenteration to date of death or last contact. Survival analysis was performed using the Kaplan Meyer method. Multivariate analysis was performed to determine the impact of clinical and pathologic factors on survival outcomes. Results One hundred sixty patients with gynecologic malignancy underwent pelvic exenteration. Five-year recurrence free survival (RFS) was 33% (95%CI 0.25–0.40). Factors which negatively impacted RFS included shorter treatment-free interval (p = .050), vulvar primary (p = .032), positive margins (p < .001), lymphovascular space invasion (LVSI, p < .001), positive lymph nodes (p < .001) and perineural invasion (p = 0.030). In multivariate analysis, positive margins (p = .040), positive nodes (p < .001) and lymphovascular space invasion (LVSI, p = .003) retained a significant impact on RFS. Five-year OS was 40% (95% CI 0.32–0.48). Factors which negatively impacted OS included vulvar primary (p = .04), positive margins (p < .001), LVSI (p < .001), positive lymph nodes (p < .001) and perineural invasion (p = .008). In multivariate analysis, positive nodes (p = .001) and LVSI (p = .001) retained a significant impact on OS. Conclusion Five-year OS after pelvic exenteration was 40%. Survival outcomes have not significantly improved despite improvements in technique and patient selection. Multiple non-modifiable factors at the time of exenteration are associated with poor survival.
Despite progress in solid-state battery engineering, our understanding of the chemo-mechanical phenomena that govern electrochemical behaviour and stability at solid-solid interfaces remains limited ...compared to at solid-liquid interfaces. Here, we use operando synchrotron X-ray computed microtomography to investigate the evolution of lithium/solid-state electrolyte interfaces during battery cycling, revealing how the complex interplay among void formation, interphase growth and volumetric changes determines cell behaviour. Void formation during lithium stripping is directly visualized in symmetric cells, and the loss of contact that drives current constriction at the interface between lithium and the solid-state electrolyte (Li
SnP
S
) is quantified and found to be the primary cause of cell failure. The interphase is found to be redox-active upon charge, and global volume changes occur owing to partial molar volume mismatches at either electrode. These results provide insight into how chemo-mechanical phenomena can affect cell performance, thus facilitating the development of solid-state batteries.
Patent foramen ovale (PFO) is implicated in platypnea-orthodeoxia, stroke and decompression sickness (DCS) in divers and astronauts. However, PFO size in relation to clinical illness is largely ...unknown since few studies evaluate PFO, either functionally or anatomically. The autopsy incidence of PFO is approximately 27% and 6% for a large defect (0.6 cm to 1.0 cm). A PFO is often associated with atrial septal aneurysm and Chiari network, although these anatomic variations are uncommon. Methodologies for diagnosis and anatomic and functional sizing of a PFO include transthoracic echocardiography (TTE), transesophageal echocardiography (TEE) and transcranial Doppler (TCD), with saline contrast. Saline injection via the right femoral vein appears to have a higher diagnostic yield for PFO than via the right antecubital vein. Saline contrast with TTE using native tissue harmonics or transmitral pulsed wave Doppler have quantitated PFO functional size, while TEE is presently the reference standard. The platypnea-orthodeoxia syndrome is associated with a large resting PFO shunt. Transthoracic echocardiography, TEE and TCD have been used in an attempt to quantitate PFO in patients with cryptogenic stroke. The larger PFOs (approximately ≥4 mm size) or those with significant resting shunts appear to be clinically significant. Approximately two-thirds of divers with unexplained DCS have a PFO that may be responsible and may be related to PFO size. Limited data are available on the incidence of PFO in high altitude aviators with DCS, but there appears to be a relationship. A large decompression stress is associated with extra vehicular activity (EVA) from spacecraft. After four cases of serious DCS in EVA simulations, a resting PFO was detected by contrast TTE in three cases. Patent foramen ovales vary in both anatomical and functional size, and the clinical impact of a particular PFO in various situations (platypnea-orthodeoxia, thromboembolism, DCS in underwater divers, DCS in high-altitude aviators and astronauts) may be different.
Engineering and enhancing the breaking of inversion symmetry in solids-that is, allowing electrons to differentiate between 'up' and 'down'-is a key goal in condensed-matter physics and materials ...science because it can be used to stabilize states that are of fundamental interest and also have potential practical applications. Examples include improved ferroelectrics for memory devices and materials that host Majorana zero modes for quantum computing. Although inversion symmetry is naturally broken in several crystalline environments, such as at surfaces and interfaces, maximizing the influence of this effect on the electronic states of interest remains a challenge. Here we present a mechanism for realizing a much larger coupling of inversion-symmetry breaking to itinerant surface electrons than is typically achieved. The key element is a pronounced asymmetry of surface hopping energies-that is, a kinetic-energy-coupled inversion-symmetry breaking, the energy scale of which is a substantial fraction of the bandwidth. Using spin- and angle-resolved photoemission spectroscopy, we demonstrate that such a strong inversion-symmetry breaking, when combined with spin-orbit interactions, can mediate Rashba-like spin splittings that are much larger than would typically be expected. The energy scale of the inversion-symmetry breaking that we achieve is so large that the spin splitting in the CoO
- and RhO
-derived surface states of delafossite oxides becomes controlled by the full atomic spin-orbit coupling of the 3d and 4d transition metals, resulting in some of the largest known Rashba-like spin splittings. The core structural building blocks that facilitate the bandwidth-scaled inversion-symmetry breaking are common to numerous materials. Our findings therefore provide opportunities for creating spin-textured states and suggest routes to interfacial control of inversion-symmetry breaking in designer heterostructures of oxides and other material classes.
BCL-2 molecules are regulators of programmed cell death and defects in this pathway contribute to human diseases. One family member, MCL-1, is unique because its expression is tightly regulated and ...it is essential for promoting the survival of myriad cellular lineages. Additionally, MCL-1 promotes the maintenance of normal mitochondrial morphology and energy production. Dissection of these functions revealed recently that they depend on separate mitochondrial sublocalizations. MCL-1's antiapoptotic activity is restricted to the outer mitochondrial membrane (OMM), whereas its function in mitochondrial physiology requires localization to the matrix. These findings provide an attractive model for how MCL-1's diverse functions may contribute to normal cell homeostasis and function. MCL-1 is highly amplified in human cancer, suggesting that these functions may contribute to malignant cell growth and evasion of apoptosis.
Synapse remodeling is essential to encode experiences into neuronal circuits. Here, we define a molecular interaction between neurons and microglia that drives experience-dependent synapse remodeling ...in the hippocampus. We find that the cytokine interleukin-33 (IL-33) is expressed by adult hippocampal neurons in an experience-dependent manner and defines a neuronal subset primed for synaptic plasticity. Loss of neuronal IL-33 or the microglial IL-33 receptor leads to impaired spine plasticity, reduced newborn neuron integration, and diminished precision of remote fear memories. Memory precision and neuronal IL-33 are decreased in aged mice, and IL-33 gain of function mitigates age-related decreases in spine plasticity. We find that neuronal IL-33 instructs microglial engulfment of the extracellular matrix (ECM) and that its loss leads to impaired ECM engulfment and a concomitant accumulation of ECM proteins in contact with synapses. These data define a cellular mechanism through which microglia regulate experience-dependent synapse remodeling and promote memory consolidation.
Display omitted
•IL-33 is expressed by subsets of hippocampal neurons and is modulated by experience•Microglia drive dendritic spine plasticity and memory precision via neuronal IL-33•IL-33 gain of function mitigates some age-related decreases in spine plasticity•Neuronal IL-33 induces microglial remodeling of the extracellular matrix
A form of experience-dependent neuron-microglial communication is mediated by IL-33, which promotes hippocampal dendritic spine formation, synapse plasticity, and ECM engulfment and is required for memory consolidation.
Diffuse large B-cell lymphoma (DLBCL) with an activated B-cell (ABC) gene-expression profile has been shown to have a poorer prognosis compared with tumors with a germinal center B-cell type. ABC ...cell lines have constitutive activation of STAT3; however, the mechanisms regulating STAT3 signaling in lymphoma are unknown. In studies of class-I histone deacetylase (HDAC) expression, we found overexpression of HDAC3 in phospho STAT3-positive DLBCL and the HDAC3 was found to be complexed with STAT3. Inhibition of HDAC activity by panobinostat (LBH589) increased p300-mediated STAT3(Lys685) acetylation with increased nuclear export of STAT3 to the cytoplasm. HDAC inhibition abolished STAT3(Tyr705) phosphorylation with minimal effect on STAT3(Ser727) and JAK2 tyrosine activity. pSTAT3(Tyr705)-positive DLBCLs were more sensitive to HDAC inhibition with LBH589 compared with pSTAT3(Tyr705)-negative DLBCLs. This cytotoxicity was associated with downregulation of the direct STAT3 target Mcl-1. HDAC3 knockdown upregulated STAT3(Lys685) acetylation but prevented STAT3(Tyr705) phosphorylation and inhibited survival of pSTAT3-positive DLBCL cells. These studies provide the rationale for targeting STAT3-positive DLBCL tumors with HDAC inhibitors.
PDF
