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

Evaluation of a new airborne microwave remote sensing radiometer by measuring the salinity gradients across the shelf of the Great Barrier Reef lagoon

Over the last ten years, some operational airborne remote sensing systems have become available for mapping surface salinity over large areas in near real time. A new dual-polarized Polarimetric L-band Multibeam Radiometer (PLMR) has been developed to improve accuracy and precision when compared with previous instrument generations. This paper reports on the first field evaluation of the performance of the PLMR by measuring salinity gradients in the central Great Barrier Reef. Before calibration, the raw salinity values of the PLMR and conductivity-temperature-depth (CTD) differed by 3-6 psu. The calibration, which uses in situ salinity data to remove long-term drifts in the PLMR as well as environmental effects such as surface roughness and radiation from the sky and atmosphere, was carried out by equating the means of the PLMR and CTD salinity data over a subsection of the transect, after which 85% of the salinity values between the PLMR and CTD are within 0.1 psu along the complete transect. From offshore to inshore across the shelf, the PLMR shows an average cross-shelf salinity increase of about 0.4 psu and a decrease of 2 psu over the inshore 20 km at -19deg S (around Townsville) and -18deg S (around Lucinda), respectively. The average cross-shelf salinity increase was 0.3 psu for the offshore 100 km over all transects. These results are consistent with the in situ CTD results. This survey shows that PLMR provided an effective method of rapidly measuring the surface salinity in near real time when a calibration could be made

Mobilisation and remobilisation of a large archetypal pathogenicity island of uropathogenic Escherichia coli in vitro support the role of conjugation for horizontal transfer of genomic islands

Background: A substantial amount of data has been accumulated supporting the important role of genomic islands (GEIs) - including pathogenicity islands (PAIs) - in bacterial genome plasticity and the evolution of bacterial pathogens. Their instability and the high level sequence similarity of different (partial) islands suggest an exchange of PAIs between strains of the same or even different bacterial species by horizontal gene transfer (HGT). Transfer events of archetypal large genomic islands of enterobacteria which often lack genes required for mobilisation or transfer have been rarely investigated so far. Results: To study mobilisation of such large genomic regions in prototypic uropathogenic E. coli (UPEC) strain 536, PAI II536 was supplemented with the mobRP4 region, an origin of replication (oriVR6K), an origin of transfer (oriTRP4) and a chloramphenicol resistance selection marker. In the presence of helper plasmid RP4, conjugative transfer of the 107-kb PAI II536 construct occured from strain 536 into an E. coli K-12 recipient. In transconjugants, PAI II536 existed either as a cytoplasmic circular intermediate (CI) or integrated site-specifically into the recipient’s chromosome at the leuX tRNA gene. This locus is the chromosomal integration site of PAI II536 in UPEC strain 536. From the E. coli K-12 recipient, the chromosomal PAI II536 construct as well as the CIs could be successfully remobilised and inserted into leuX in a PAI II536 deletion mutant of E. coli 536. Conclusions: Our results corroborate that mobilisation and conjugal transfer may contribute to evolution of bacterial pathogens through horizontal transfer of large chromosomal regions such as PAIs. Stabilisation of these mobile genetic elements in the bacterial chromosome result from selective loss of mobilisation and transfer functions of genomic islands

Capability assessment for application of clay mixture as barrier material for irradiated zirconium alloy structure elements long-term processing for storage during decommissioning of uranium-graphite nuclear reactors

The radionuclide composition and the activity level of the irradiated zirconium alloy E110, the radionuclide immobilization strength and the retention properties of the mixed clay barrier material with respect to the radionuclides identified in the alloy were investigated to perform the safety assessment of handling structural units of zirconium alloy used for the technological channels in uranium-graphite reactors. The irradiated zirconium alloy waste contained the following activation products:{93m}Nb and the long-lived {94}Nb, {93}Zr radionuclides. Radionuclides of {60}Co, {137}Cs, {90}Sr, and actinides were also present in the alloy. In the course of the runs no leaching of niobium and zirconium isotopes from the E110 alloy was detected. Leach rates were observed merely for {60}Co and {137}Cs present in the deposits formed on the internal surface of technological channels. The radionuclides present were effectively adsorbed by the barrier material. To ensure the localization of radionuclides in case of the radionuclide migration from the irradiated zirconium alloy into the barrier material, the sorption properties were determined of the barrier material used for creating the long-term storage point for the graphite stack from uranium-graphite reactors

Exploring sex differences in attitudes towards the descriptive and substantive representation of women

This article unpacks the rationales that might be behind individual-level support for the idea that there ought to be more women present in political institutions. We outline two distinct rationales: the substantive position that sees an increase in women’s descriptive representation as important in bringing about a subsequent improvement in women’s substantive representation, or the justice-plus position that sees an increase in the descriptive representation of women as important for reasons of justice or other symbolic benefits. We find that women are more likely than men to support an increase in descriptive representation and that women are more likely to hold both the view that an increase in descriptive representation was desirable and that such an increase would improve the representation of women’s political interests. Men are found to be more likely to support an increase in descriptive representation but not relate descriptive representation to substantive representation in any way: the justice-plus rationale

Baryon polarization in low-energy unpolarized meson-baryon scattering

We compute the polarization of the final-state baryon, in its rest frame, in low-energy meson--baryon scattering with unpolarized initial state, in Unitarized BChPT. Free parameters are determined by fitting total and differential cross-section data (and spin-asymmetry or polarization data if available) for $pK^-$, $pK^+$ and $p\pi^+$ scattering. We also compare our results with those of leading-order BChPT

Structure/Function Analysis of Recurrent Mutations in SETD2 Protein Reveals a Critical and Conserved Role for a SET Domain Residue in Maintaining Protein Stability and Histone H3 Lys-36 Trimethylation

The yeast Set2 histone methyltransferase is a critical enzyme that plays a number of key roles in gene transcription and DNA repair. Recently, the human homologue, SETD2, was found to be recurrently mutated in a significant percentage of renal cell carcinomas, raising the possibility that the activity of SETD2 is tumor-suppressive. Using budding yeast and human cell line model systems, we examined the functional significance of two evolutionarily conserved residues in SETD2 that are recurrently mutated in human cancers. Whereas one of these mutations (R2510H), located in the Set2 Rpb1 interaction domain, did not result in an observable defect in SETD2 enzymatic function, a second mutation in the catalytic domain of this enzyme (R1625C) resulted in a complete loss of histone H3 Lys-36 trimethylation (H3K36me3). This mutant showed unchanged thermal stability as compared with the wild type protein but diminished binding to the histone H3 tail. Surprisingly, mutation of the conserved residue in Set2 (R195C) similarly resulted in a complete loss of H3K36me3 but did not affect dimethylated histone H3 Lys-36 (H3K36me2) or functions associated with H3K36me2 in yeast. Collectively, these data imply a critical role for Arg-1625 in maintaining the protein interaction with H3 and specific H3K36me3 function of this enzyme, which is conserved from yeast to humans. They also may provide a refined biochemical explanation for how H3K36me3 loss leads to genomic instability and cancer

Chiral effective field theories of the strong interactions

Effective field theories of the strong interactions based on the approximate chiral symmetry of QCD provide a model-independent approach to low-energy hadron physics. We give a brief introduction to mesonic and baryonic chiral perturbation theory and discuss a number of applications. We also consider the effective field theory including vector and axial-vector mesons.Comment: 22 pages, 9 figures, proceedings of "Many-Body Structure of Strongly Interacting Systems", Mainz, Germany, Feb. 23-25 201

Toll-like receptor signaling adapter proteins govern spread of neuropathic pain and recovery following nerve injury in male mice.

BackgroundSpinal Toll-like receptors (TLRs) and signaling intermediaries have been implicated in persistent pain states. We examined the roles of two major TLR signaling pathways and selected TLRs in a mononeuropathic allodynia.MethodsL5 spinal nerve ligation (SNL) was performed in wild type (WT, C57BL/6) male and female mice and in male Tlr2-/-Tlr3-/-, Tlr4-/-, Tlr5-/-, Myd88-/-, Triflps2, Myd88/Triflps2, Tnf-/-, and Ifnar1-/- mice. We also examined L5 ligation in Tlr4-/- female mice. We examined tactile allodynia using von Frey hairs. Iba-1 (microglia) and GFAP (astrocytes) were assessed in spinal cords by immunostaining. Tactile thresholds were analyzed by 1- and 2-way ANOVA and the Bonferroni post hoc test was used.ResultsIn WT male and female mice, SNL lesions resulted in a persistent and robust ipsilateral, tactile allodynia. In males with TLR2, 3, 4, or 5 deficiencies, tactile allodynia was significantly, but incompletely, reversed (approximately 50%) as compared to WT. This effect was not seen in female Tlr4-/- mice. Increases in ipsilateral lumbar Iba-1 and GFAP were seen in mutant and WT mice. Mice deficient in MyD88, or MyD88 and TRIF, showed an approximately 50% reduction in withdrawal thresholds and reduced ipsilateral Iba-1. In contrast, TRIF and interferon receptor null mice developed a profound ipsilateral and contralateral tactile allodynia. In lumbar sections of the spinal cords, we observed a greater increase in Iba-1 immunoreactivity in the TRIF-signaling deficient mice as compared to WT, but no significant increase in GFAP. Removing MyD88 abrogated the contralateral allodynia in the TRIF signaling-deficient mice. Conversely, IFNβ, released downstream to TRIF signaling, administered intrathecally, temporarily reversed the tactile allodynia.ConclusionsThese observations suggest a critical role for the MyD88 pathway in initiating neuropathic pain, but a distinct role for the TRIF pathway and interferon in regulating neuropathic pain phenotypes in male mice