Preclinical Assessment of the Combination of PSMA-Targeting Radionuclide Therapy with PARP Inhibitors for Prostate Cancer Treatment

Prostate specific membrane antigen targeted radionuclide therapy (PSMA-TRT) is a promising novel treatment for prostate cancer (PCa) patients. However, PSMA-TRT cannot be used for curative intent yet, thus additional research on how to improve the therapeutic efficacy is warranted. A potential way of achieving this, is combining TRT with poly ADP-ribosylation inhibitors (PARPi), which has shown promising results for TRT of neuroendocrine tumor cells. Currently, several clinical trials have been initiated for this combination for PCa, however so far, no evidence of synergism is available for PCa. Therefore, we evaluated the combination of PSMA-TRT with three classes of PARPi in preclinical PCa models. In vitro viability and survival assays were performed using PSMA-expressing PCa cell lines PC3-PIP and LNCaP to assess the effect of increasing concentrations of PARPi veliparib, olaparib or talazoparib in combination with PSMA-TRT compared to single PARPi treatment. Next, DNA damage analyses were performed by quantifying the number of DNA breaks by immunofluorescent stainings. Lastly, the potential of the combination treatments was studied in vivo in mice bearing PC3-PIP xenografts. Our results show that combining PSMA-TRT with PARPi did not synergistically affect the in vitro clonogenic survival or cell viability. DNA-damage analysis revealed only a significant increase in DNA breaks when combining PSMA-TRT with veliparib and not in the other combination treatments. Moreover, PSMA-TRT with PARPi treatment did not improve tumor control compared to PSMA-TRT monotherapy. Overall, the data presented do not support the assumption that combining PSMA-TRT with PARPi leads to a synergistic antitumor effect in PCa. These results underline that extensive preclinical research using various PCa models is imperative to validate the applicability of the combination strategy for PCa, as it is for other cancer types.     

Experimental Evidence for Seed Metabolic Allometry in Barrel Medic (Medicago truncatula Gaertn.)

Seed size is often considered to be an important trait for seed quality, i.e., vigour and germination performance. It is believed that seed size reflects the quantity of reserve material and thus the C and N sources available for post-germinative processes. However, mechanisms linking seed size and quality are poorly documented. In particular, specific metabolic changes when seed size varies are not well-known. To gain insight into this aspect, we examined seed size and composition across different accessions of barrel medic (Medicago truncatula Gaertn.) from the genetic core collection. We conducted multi-elemental analyses and isotope measurements, as well as exact mass GC–MS metabolomics. There was a systematic increase in N content (+0.17% N mg⁻¹) and a decrease in H content (–0.14% H mg⁻¹) with seed size, reflecting lower lipid and higher S-poor protein quantity. There was also a decrease in ²H natural abundance (δ²H), due to the lower prevalence of ²H-enriched lipid hydrogen atoms that underwent isotopic exchange with water during seed development. Metabolomics showed that seed size correlates with free amino acid and hexoses content, and anticorrelates with amino acid degradation products, disaccharides, malic acid and free fatty acids. All accessions followed the same trend, with insignificant differences in metabolic properties between them. Our results show that there is no general, proportional increase in metabolite pools with seed size. Seed size appears to be determined by metabolic balance (between sugar and amino acid degradation vs. utilisation for storage), which is in turn likely determined by phloem source metabolite delivery during seed development.     

Investigation of RF sputtered PSG films for MEMS and semiconductor devices

In this work, we report the preparation of phospho-silicate-glass (PSG) films using RF magnetron sputtering process and its application as a sacrificial layer in surface micromachining technology. For this purpose, a 76 mm diameter target of phosphorus-doped silicon dioxide was prepared by conventional solid-state reaction route using P₂O₅ and SiO₂ powders. The PSG films were deposited in a RF (13.56 MHz) magnetron sputtering system at 200-300 W RF power, 10-20 mTorr pressure and 45 mm target-to-substrate spacing without external substrate heating. To confirm the presence of phosphorus in the deposited films, hot-probe test and sheet resistance measurements were performed on silicon wafers following deposition of PSG film and a drive-in step. As a final confirmatory test, a p-n diode was fabricated in a p-type Si wafer using the deposited film as a source of phosphorus diffusion. The phosphorus concentration in the target and the deposited film were analyzed using energy dispersive X-rays (EDAX) tool. The etch rate of the PSG film in buffered HF was measured to be about 30 times higher as compared to that of thermally grown SiO₂ films. The application of RF sputtered PSG film as sacrificial layer in surface micromachining technology has been explored. To demonstrate the compatibility with MEMS process, micro-cantilevers and micro-bridges of silicon nitride were fabricated using RF sputtered PSG as a sacrificial layer in surface micromachining. It is envisaged that the lower deposition temperature in RF sputtering (<150 °C) compared to CVD process for PSG film preparation is advantageous, particularly for making MEMS on temperature sensitive substrates.     

Response of Poplar and Associated Fungal Endophytic Communities to a PAH Contamination Gradient

Microbial populations associated to poplar are well described in non-contaminated and metal-contaminated environments but more poorly in the context of polycyclic aromatic hydrocarbon (PAH) contamination. This study aimed to understand how a gradient of phenanthrene (PHE) contamination affects poplar growth and the fungal microbiome in both soil and plant endosphere (roots, stems and leaves). Plant growth and fitness parameters indicated that the growth of Populus canadensis was impaired when PHE concentration increased above 400 mg kg⁻¹. Values of alpha-diversity indicators of fungal diversity and richness were not affected by the PHE gradient. The PHE contamination had a stronger impact on the fungal community composition in the soil and root compartments compared to that of the aboveground organs. Most of the indicator species whose relative abundance was correlated with PHE contamination decreased along the gradient indicating a toxic effect of PHE on these fungal OTUs (Operational Taxonomic Units). However, the relative abundance of some OTUs such as Cadophora, Alternaria and Aspergillus, potentially linked to PHE degradation or being plant-beneficial taxa, increased along the gradient. Finally, this study allowed a deeper understanding of the dual response of plant and fungal communities in the case of a soil PAH contamination gradient leading to new perspectives on fungal assisted phytoremediation.     

Formulae for determining heterodyne system spurious frequencies that coincide with desired output frequency

In this paper, formulae to determine the lowest order and other higher order spurious frequencies that coincide with desired output signal frequencies of mixers have been derived. The proposed formulae give general expressions that are suitable for any order of heterodyne mixing. The formulae have been verified using a suitable example and compared with the simulation results obtained through the radio frequency simulation software of Advanced Design System. The formulae directly reveal the order of the troublesome spurious frequencies that the designers would encounter in heterodyne systems. In comparison with these direct formulae, the results of existing spurious analysis software are based on the maximum order of simulation carried out. Based on these simulations, the coinciding spurious components have to be manually sorted out. Proposed formulae are quick tools used by the microwave system and circuit designers for choosing and finalizing heterodyne frequencies in their designs without the need for any simulations.     

Supersonic Nozzle Flow Simulations for Particle Coating Applications: Effects of Shockwaves,Nozzle Geometry,Ambient Pressure,and Substrate Location upon Flow Characteristics

Characteristics of supersonic flow are examined with specific regard to nano-particle thin-film coating. Effects of shockwaves, nozzle geometry, chamber pressure, and substrate location were studied computationally. Shockwaves are minimized to reduce fluctuations in flow properties at the discontinuities across diamond shock structures. Nozzle geometry was adjusted to ensure optimal expansion (i.e., P _exit = P _ambient), where shock formation was significantly reduced and flow kinetic energy maximized. When the ambient pressure was reduced from 1 to 0.01316 bar, the nozzle’s diverging angle must be increased to yield the optimum condition of minimized adversed effects. Beyond some critical distance, substrate location did not seem to be a sensitive parameter on flow characteristics when P _amb = 0.01316 bar; however, overly close proximity to the nozzle exit caused flow disturbances inside the nozzle, thereby adversely affecting coating gas flow.     

Influence of clay in limestone fillers for self-compacting cement based composites

High workability together with a good resistance to segregation is needed for cement based composites, specifically fresh self-compacting mortars (SCM); in this prospect, the amount of coarse materials has to be reduced and replaced by fine material. Several limestone fillers are here compared and analysed. These by-products are issued from different industrial sectors, such as the aggregate and lime production industry (quarrying operations) and the ornamental stones industry (sawing operations).Particular attention has been paid to clay content, as consistency of fresh mortars was varying, while other physical characteristics like granulometry remained the same. Relationship between the physico-chemical properties of the fillers and the properties of fresh and hardened mortars are brought forward. Even if it may affect fresh properties of mortars, results clearly show that clay type and content has minor influence than limestone filler itself.     

Neurocognitive signs in prodromal Huntington disease.

Objective: PREDICT-HD is a large-scale international study of people with the Huntington disease (HD) CAG-repeat expansion who are not yet diagnosed with HD. The objective of this study was to determine the stage in the HD prodrome at which cognitive differences from CAG-normal controls can be reliably detected. Method: For each of 738 HD CAG-expanded participants, we computed estimated years to clinical diagnosis and probability of diagnosis in 5 years based on age and CAG-repeat expansion number (Langbehn, Brinkman, Falush, Paulsen, & Hayden, 2004). We then stratified the sample into groups: NEAR, estimated to be ≤9 years; MID, between 9 and 15 years; and FAR, ≥15 years. The control sample included 168 CAG-normal participants. Nineteen cognitive tasks were used to assess attention, working memory, psychomotor functions, episodic memory, language, recognition of facial emotion, sensory–perceptual functions, and executive functions. Results: Compared with the controls, the NEAR group showed significantly poorer performance on nearly all of the cognitive tests and the MID group on about half of the cognitive tests (p = .05, Cohen's d NEAR as large as ?1.17, MID as large as ?0.61). One test even revealed significantly poorer performance in the FAR group (Cohen's d = ?0.26). Individual tasks accounted for 0.2% to 9.7% of the variance in estimated proximity to diagnosis. Overall, the cognitive battery accounted for 34% of the variance; in comparison, the Unified Huntington's Disease Rating Scale motor score accounted for 11.7%. Conclusions: Neurocognitive tests are robust clinical indicators of the disease process prior to reaching criteria for motor diagnosis of HD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)