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.     

Nonparallel training for voice conversion based on a parameter adaptation approach

The objective of voice conversion algorithms is to modify the speech by a particular source speaker so that it sounds as if spoken by a different target speaker. Current conversion algorithms employ a training procedure, during which the same utterances spoken by both the source and target speakers are needed for deriving the desired conversion parameters. Such a (parallel) corpus, is often difficult or impossible to collect. Here, we propose an algorithm that relaxes this constraint, i.e., the training corpus does not necessarily contain the same utterances from both speakers. The proposed algorithm is based on speaker adaptation techniques, adapting the conversion parameters derived for a particular pair of speakers to a different pair, for which only a nonparallel corpus is available. We show that adaptation reduces the error obtained when simply applying the conversion parameters of one pair of speakers to another by a factor that can reach 30%. A speaker identification measure is also employed that more insightfully portrays the importance of adaptation, while listening tests confirm the success of our method. Both the objective and subjective tests employed, demonstrate that the proposed algorithm achieves comparable results with the ideal case when a parallel corpus is available.     

SYNTHESIS OF AROMA COMPONENTS DURING THE SPONTANEOUS FERMENTATION OF LAMBIC AND GUEUZE

Lambic is a type of Belgian beer obtained by spontaneous fermentation of wort. The fermentation in casks takes almost two years, and after that period the beer may be re-fermented in bottles and is then called gueuze. To gain insight into the many microbiological transformations occurring during this process, a qualitative and quantitative study of several components formed over a two-year period was undertaken. It was found that lambic and gueuze are characterized by high contents of ethyl acetate, ethyl lactate, lactic acid and acetic acid. Two phases of fermentation may be distinguished: a primary phase lasting for about three months during which almost all the ethanol and higher alcohols are formed and a very long secondary phase during which lactic acid is formed first, followed by ethyl lactate. Some lower fatty acids, including all the acetic acid, are made at the very beginning of the first phase. An important part of the ethyl acetate is made during the first phase but the amounts increase slowly to high levels during the second phase. Unusually low amounts of isoamyl acetate are detected. Several components are above the reported threshold levels of taste and are thus probably involved in the genesis of the typical aroma of lambic and gueuze. These results will allow a further study of the relations between the components found and the microbial populations involved in the spontaneous fermentation inherent in the brewing of lambic and gueuze.     

Automatic detection and validity of the sea-ice edge: an application of enhanced-resolution QuikScat/SeaWinds data

Sea-ice edge detection is an essential task at the different national ice services to secure navigation in ice-covered seas. Comparison between the Remund and Long ice mask image from enhanced-resolution QuikScat/SeaWinds (QS) products and the analyzed ice edge from high-resolution RADARSAT synthetic aperture radar has shown that the automatically determined QS ice mask underestimates the Arctic ice extent. QS data was statistically analyzed by colocating the data with ice charts around Greenland and with the National Aeronautics and Space Administration Team's Special Sensor Microwave/Imager (SSM/I) ice concentration algorithm over the whole Arctic region. All variables, i.e., the backscatter in vertical and horizontal polarization, the active polarization ratio (APR) and the daily standard deviation, are sensitive to ice types and are strongly correlated with ice concentration when the relationship is expressed in exponential form. Our study showed that the APR is especially suitable for ice-ocean separation, and a threshold of -0.02 was determined. An ice edge algorithm based on this APR threshold was developed using the other variables with conservative season-dependent thresholds to eliminate additional ocean noise. Also, the history of the ice cover is considered in order to detect single ice fields that are separated from the main Arctic pack ice. Validation with RADARSAT 1 and with the Advanced Very High Resolution Radiometer showed that the new algorithm successfully detects very low ice concentrations of about 10% during the entire year. The validity of the detected ice edge for near-real-time issues is also discussed in relation to the ice motion in the Marginal Ice Zone and the integration time necessary to produce the enhanced-resolution images. The new algorithm improves the automatic global ice edge resolution by a factor of two when compared to SSM/I products and could be used in both model initialization and data assimilation.     

Localization-limited exciton oscillator strength in colloidal CdSe nanoplatelets revealed by the optically induced stark effect

2D materials are considered for applications that require strong light-matter interaction because of the apparently giant oscillator strength of the exciton tra...     

Enapotamab Vedotin,an AXL-Specific Antibody-Drug Conjugate,Demonstrates Antitumor Efficacy in Patient-Derived Xenograft Models of Soft Tissue Sarcoma

Doxorubicin (doxo) remains the standard of care for patients with advanced soft tissue sarcoma (STS), even though response rates to doxo are only around 14% to 18%. We evaluated enapotamab vedotin (EnaV), an AXL-specific antibody-drug conjugate (ADC), in a panel of STS patient-derived xenografts (PDX). Eight models representing multiple STS subtypes were selected from our STS PDX platform (n = 45) by AXL immunostaining on archived passages. Models were expanded by unilateral transplantation of tumor tissue into the left flank of 20 NMRI nu/nu mice. Once tumors were established, mice were randomized into an EnaV treatment group, or a group treated with isotype control ADC. Treatment efficacy was assessed by tumor volume evaluation, survival analysis, and histological evaluation of tumors, and associated with AXL expression. EnaV demonstrated significant tumor growth delay, regression, and/or prolonged survival compared to isotype control ADC in 5/8 STS PDX models investigated. Experimental passages of responding models were all found positive for AXL at varying levels, but no linear relationship could be identified between the level of expression and level of response to EnaV. One model was found negative for AXL on experimental passage and did not respond to EnaV. This study provides a preclinical rationale for the evaluation of AXL-targeting ADCs in the treatment of AXL-expressing sarcomas.     

Association of Ligamentum Flavum Hypertrophy with Adolescent Idiopathic Scoliosis Progression—Comparative Microarray Gene Expression Analysis

The role of the ligamentum flavum (LF) in the pathogenesis of adolescent idiopathic scoliosis (AIS) is not well understood. Using magnetic resonance imaging (MRI), we investigated the degrees of LF hypertrophy in 18 patients without scoliosis and on the convex and concave sides of the apex of the curvature in 22 patients with AIS. Next, gene expression was compared among neutral vertebral LF and LF on the convex and concave sides of the apex of the curvature in patients with AIS. Histological and microarray analyses of the LF were compared among neutral vertebrae (control) and the LF on the apex of the curvatures. The mean area of LF in the without scoliosis, apical concave, and convex with scoliosis groups was 10.5, 13.5, and 20.3 mm², respectively. There were significant differences among the three groups (p < 0.05). Histological analysis showed that the ratio of fibers (Collagen/Elastic) was significantly increased on the convex side compared to the concave side (p < 0.05). Microarray analysis showed that ERC2 and MAFB showed significantly increased gene expression on the convex side compared with those of the concave side and the neutral vertebral LF cells. These genes were significantly associated with increased expression of collagen by LF cells (p < 0.05). LF hypertrophy was identified in scoliosis patients, and the convex side was significantly more hypertrophic than that of the concave side. ERC2 and MAFB genes were associated with LF hypertrophy in patients with AIS. These phenomena are likely to be associated with the progression of scoliosis.     

Use of topographic correction in Landsat TM-based forest interpretation in Nepal

The land use of two districts in western Nepal was classified into forest and non-forest by satellite imagery with different topographical corrections. The accuracy of the forest biomass and timber volume estimates was also tested. The forest areas were interpretated correctly, with an accuracy of 82-88%. The best result was derived when the Minnaert constants of forest were separated from those of other land uses which were combined. The timber volume and biomass estimates were computed using the weighted nearest neighbour method. The coefficients of determination were 0.06 for timber volume and 0.09 for biomass. The use of the existing land use data seems to have potential for improving the results of topographic normalization. Because the reflectance in mountainous areas depends on many vegetative and terrain features, the simple non-Lambertian correction over broad categories did not significantly improve the results.     

An emergent approach to systems of physical agents

For the past ten years the author has been involved in industrial research on applications of agent architectures to manufacturing, and is presently technical advisor to an industrial consortium that is fielding pilot tests of shop-floor agents. The specific problem addressed by most of their work is the management of material flow and resource utilization on the factory floor. Classically, these problems have been considered under the rubrics of ‘scheduling’ and ‘shop-floor control’, and have been addressed with top-down control that does not offer the robustness and agility required in modern competitive environments. The approach has been to reify parts and equipment as agents, and seek architectures that permit the overall shop schedule to emerge dynamically from their interaction, rather than being imposed top-down.