Advances in targeted Alpha therapy for prostate cancer

BACKGROUND: Amongst therapeutic radiopharmaceuticals, targeted alpha therapy (TαT) can deliver potent and local radiation selectively to cancer cells as well as the tumor microenvironment and thereby control cancer while minimizing toxicity. DESIGN: In this review, we discuss the history, progress, and future potential of TαT in the treatment of prostate cancer, including dosimetry-individualized treatment planning, combinations with small-molecule therapies, and conjugation to molecules directed against antigens expressed by prostate cancer cells, such as prostate-specific membrane antigen (PSMA) or components of the tumor microenvironment. RESULTS: A clinical proof of concept that TαT is efficacious in treating bone-metastatic castration-resistant prostate cancer has been demonstrated by radium-223 via improved overall survival and long-term safety/tolerability in the phase III ALSYMPCA trial. Dosimetry calculation and pharmacokinetic measurements of TαT provide the potential for optimization and individualized treatment planning for a precision medicine-based cancer management paradigm. The ability to combine TαTs with other agents, including chemotherapy, androgen receptor (AR)-targeting agents, DNA repair inhibitors, and immuno-oncology agents, is under investigation. Currently, TαTs that specifically target prostate cancer cells expressing PSMA represents a promising therapeutic approach. Both PSMA-targeted actinium-225 and thorium-227 conjugates are under investigation. CONCLUSIONS: The described clinical benefit, safety and tolerability of radium-223 and the recent progress in TαT trial development suggest that TαT occupies an important new role in prostate cancer treatment. Ongoing studies with newer dosimetry methods, PSMA targeting, and novel approaches to combination therapies should expand the utility of TαT in prostate cancer treatment

Star formation thresholds and galaxy edges: why and where

We study global star formation thresholds in the outer parts of galaxies by investigating the stability of disk galaxies embedded in dark halos. The disks are self-gravitating, contain metals and dust, and are exposed to UV radiation. We find that the critical surface density for the existence of a cold interstellar phase depends only weakly on the parameters of the model and coincides with the empirically derived surface density threshold for star formation. Furthermore, it is shown that the drop in the thermal velocity dispersion associated with the transition from the warm to the cold gas phase triggers gravitational instability on a wide range of scales. The presence of strong turbulence does not undermine this conclusion if the disk is self-gravitating. Models based on the hypothesis that the onset of thermal instability determines the star formation threshold in the outer parts of galaxies can reproduce many observations, including the threshold radii, column densities, and the sizes of stellar disks as a function of disk scale length and mass. Finally, prescriptions are given for implementing star formation thresholds in (semi-)analytic models and three-dimensional hydrodynamical simulations of galaxy formation.Comment: 16 pages, 6 figures, accepted for publication in the Astrophysical Journal. Version 2: text significantly revised (major improvements), physics unchanged. Version 3: minor correction

Influence of the ceramic translucency on the relative degree of conversion of a direct composite and dual-curing resin cement through lithium disilicate onlays and endocrowns

INTRODUCTION: The goal of this study was to investigate the influence of the ceramic translucency, restoration type and polymerization time on the relative degree of conversion of a dual-curing resin cement and a conventional microhybrid resin composite using a high-power light-curing device. METHODS AND MATERIALS: Two 4.0 mm thick onlay (O) and two 7.5 mm thick endocrown (E) lithium disilicate restorations in high and low translucency (HT/LT) were fabricated on a decapitated molar. The pulp chamber was prepared to accommodate a 2 mm layer of a microhybrid resin composite (MHC) or dual-curing resin cement (DCC). Composite specimens were light-cured (n = 15; 1200 mW/cm2) without or through an onlay or endocrown restoration. Fourier-transform infrared spectroscopy (FTIR) absorbance curves were collected for the same composite specimen after 3 × 20, 3 × 40, 3 × 60 and 3 × 90 s of light-curing. The relative degree of conversion (DC%) was calculated and results analyzed using Kruskal-Wallis test and Friedman's ANOVA. Alpha was set at 0.05. RESULTS: After 3 × 60 s, the DC of MHC was significantly lower (p = 0.03; r = 0.61) under LT/EC restorations (Mdn: 77.8%) than HT/EC restorations (Mdn: 95.2%). DC of the DCC was not significantly affected by the ceramic translucency or restoration type. MHC had a significant higher DC than DCC under the HT/O, LT/O and HT/E restorations. There were no significant differences between MHC and DCC cured through LT/E restorations. CONCLUSION: DC for DCC was not significantly affected by the ceramic translucency or restoration type. DC for MHC was significantly lower for LT/EC than HT/EC restorations after 3 × 60s polymerization, but not different for the high translucent restorations and low translucent onlays. CLINICAL RELEVANCE: the use of light-curing microhybrid composite for bonding high translucent onlays and endocrowns and low translucent onlays seems feasible

Characterization of immune response to neurofilament light in experimental autoimmune encephalomyelitis

PMCID: PMC3856490This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.PMCID: PMC385649

Evidence on continuous flow peritoneal dialysis: A review

Clinical application of continuous flow peritoneal dialysis (CFPD) has been explored since the 1960s, but despite anticipated clinical benefits, CFPD has failed to gain a foothold in clinical practice, among others due to the typical use of two catheters (or a dual-lumen catheter) and large dialysate volumes required per treatment. Novel systems applying CFPD via the existing single-lumen catheter using rapid dialysate cycling may solve one of these hurdles. Novel on-demand peritoneal dialysate generation systems and sorbent-based peritoneal dialysate regeneration systems may considerably reduce the storage space for peritoneal dialysate and/or the required dialysate volume. This review provides an overview of current evidence on CFPD in vivo. The available (pre)clinical evidence on CFPD is limited to case reports/series with inherently nonuniform study procedures, or studies with a small sample size, short follow-up, and no hard endpoints. Small solute clearance appears to be higher in CFPD compared to conventional PD, in particular at dialysate flows ≥100 mL/min using two single-lumen catheters or a double-lumen catheter. Results of CFPD using rapid cycling via a single-lumen catheter are too preliminary to draw any conclusions. Continuous addition of glucose to dialysate with CFPD appears to be effective in reducing the maximum intraperitoneal glucose concentration while increasing ultrafiltration efficiency (mL/g absorbed glucose). Patient tolerance may be an issue since abdominal discomfort and sterile peritonitis were reported with continuous circulation of the peritoneal dialysate. Thus, well-designed clinical trials of longer duration and larger sample size, in particular applying CFPD via the existing catheter, are urgently required

The Baryonic Tully-Fisher Relation

We explore the Tully-Fisher relation over five decades in stellar mass in galaxies with circular velocities ranging over 30 < Vc < 300 km/s. We find a clear break in the optical Tully-Fisher relation: field galaxies with Vc < 90 km/s fall below the relation defined by brighter galaxies. These faint galaxies are however very gas rich; adding in the gas mass and plotting baryonic disk mass Md = M* + Mg in place of luminosity restores a single linear relation. The Tully-Fisher relation thus appears fundamentally to be a relation between rotation velocity and total baryonic mass of the form Md = A Vc^4.Comment: 10 pages including 1 color figure. Accepted for publication in ApJ Letter

Bioengineered Kidney Tubules Efficiently Clear Uremic Toxins in Experimental Dialysis Conditions

Patients with end-stage kidney disease (ESKD) suffer from high levels of protein-bound uremic toxins (PBUTs) that contribute to various comorbidities. Conventional dialysis methods are ineffective in removing these PBUTs. A potential solution could be offered by a bioartificial kidney (BAK) composed of porous membranes covered by proximal tubule epithelial cells (PTECs) that actively secrete PBUTs. However, BAK development is currently being hampered by a lack of knowledge regarding the cytocompatibility of the dialysis fluid (DF) that comes in contact with the PTECs. Here, we conducted a comprehensive functional assessment of the DF on human conditionally immortalized PTECs (ciPTECs) cultured as monolayers in well plates, on Transwell® inserts, or on hollow fiber membranes (HFMs) that form functional units of a BAK. We evaluated cell viability markers, monolayer integrity, and PBUT clearance. Our results show that exposure to DF did not affect ciPTECs’ viability, membrane integrity, or function. Seven anionic PBUTs were efficiently cleared from the perfusion fluid containing a PBUTs cocktail or uremic plasma, an effect which was enhanced in the presence of albumin. Overall, our findings support that the DF is cytocompatible and does not compromise ciPTECs function, paving the way for further advancements in BAK development and its potential clinical application.</p

Occlusion and Temporomandibular Function among Subjects with Mandibular Distal Extension Removable Partial Dentures

Objective. To quantify effects on occlusion and temporomandibular function of mandibular distal extension removable partial dentures in shortened dental arches. Methods. Subjects wearing mandibular extension removable partial dentures (n = 25) were compared with subjects with shortened dental arches without extension (n = 74) and with subjects who had worn a mandibular extension removable partial denture in the past (n = 19). Subjects with complete dentitions (n = 72) were controls. Data were collected at baseline and at 3-, 6-, and 9-year observations. Results. Occlusal activity in terms of reported awareness of bruxism and occlusal tooth wear of lower anterior teeth did not differ significantly between the groups. In contrast, occlusal tooth wear of premolars in shortened dental arches with or without extension dentures was significantly higher than in the controls. Differences amongst groups with respect to signs and symptoms related to temporomandibular disorders were not found. Occlusal support of the dentures did not influence anterior spatial relationship. Occlusal contacts of the denture teeth decreased from 70% for second premolars via 50% for first molars, to 30% for second molars. Conclusions. Mandibular distal extension removable partial dentures in moderate shortened dental arches had no effects on occlusion and temporomandibular function

English in product advertisements in non-english speaking countries in western europe: Product image and comprehension of the text

Although English has been shown to be the most frequently used foreign language in product advertisements in countries where it is not the native language, little is known about its effects. This article examines the response to advertisements in English compared to the response to the same ad in the local language in Western Europe on members of the target group for which the ad was intended: 715 young, highly educated female consumers. The use of English in a product ad does not appear to have any impact on image and price of the product, but it does affect text comprehension: the meaning of almost 40% of the English phrases was not understood. These results were the same for all countries involved in the study, irrespective of whether the respondents\u27 (self-) reported proficiency in English is high or low. © Taylor & Francis Group, LLC