Long-Term Efficacy and Safety of Enzalutamide Monotherapy in Elderly Patients with Metastatic Castration-Resistant Prostate Cancer: A Case Report.

Introduction: Prostate cancer is one of the most common cancers in men. Despite the sharp rise in incidence, mortality is decreasing. ARTA preparations are preferred options for asymptomatic or mildly symptomatic patients with mCRPC. The use of enzalutamide in elderly patients with mCRPC is risky and depends on a number of factors. An increased risk of falls and fractures has been shown. Case Presentation: We present a case report of an elderly patient with mCRPC treated with enzalutamide with very good long-term tolerance and efficacy. Conclusion: Despite the older age, no reduction of therapy was necessary in the patient due to good tolerance. Administration of enzalutamide in full doses resulted in a very good effect of therapy.

Tolerability of Olaparib Combined with Abiraterone in Patients with Metastatic Castration-resistant Prostate Cancer: Further Results from the Phase 3 PROpel Trial.

BACKGROUND: The PROpel study (NCT03732820) demonstrated a statistically significant progression-free survival benefit with olaparib plus abiraterone versus placebo plus abiraterone in the first-line metastatic castration-resistant prostate cancer (mCRPC) setting, irrespective of homologous recombination repair mutation status. OBJECTIVE: We report additional safety analyses from PROpel to increase clinical understanding of the adverse-event (AE) profiles of olaparib plus abiraterone versus placebo plus abiraterone. DESIGN, SETTING, AND PARTICIPANTS: A randomised (1:1), double-blind, placebo-controlled trial was conducted at 126 centres in 17 countries (October 2018-January 2020). Patients had mCRPC and no prior systemic mCRPC treatment. INTERVENTION: Olaparib (300 mg bid) or placebo with abiraterone (1000 mg od) plus prednisone/prednisolone (5 mg bid). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The data cut-off date was July 30, 2021. Safety was assessed by AE reporting (Common Terminology Criteria for Adverse Events v4.03) and analysed descriptively. RESULTS AND LIMITATIONS: The most common AEs (all grades) for olaparib plus abiraterone versus placebo plus abiraterone were anaemia (46.0% vs 16.4%), nausea (28.1% vs 12.6%), and fatigue (27.9% vs 18.9%). Grade ≥3 anaemia occurred in 15.1% versus 3.3% of patients in the olaparib plus abiraterone versus placebo plus abiraterone arm. The incidences of the most common AEs for olaparib plus abiraterone peaked early, within 2 mo, and were managed typically by dose modifications or standard medical practice. Overall, 13.8% versus 7.8% of patients discontinued treatment with olaparib plus abiraterone versus placebo plus abiraterone because of an AE; 3.8% versus 0.8% of patients discontinued because of anaemia. More venous thromboembolism events were observed in the olaparib plus abiraterone arm (any grade, 7.3%; grade ≥3, 6.8%) than in the placebo plus abiraterone arm (any grade, 3.3%; grade ≥3, 2.0%), most commonly pulmonary embolism (6.5% vs 1.8% for olaparib plus abiraterone vs placebo plus abiraterone). CONCLUSIONS: Olaparib plus abiraterone has a manageable and predictable safety profile. PATIENT SUMMARY: The PROpel trial showed that in patients who had not received any previous treatment for metastatic castration-resistant prostate cancer, olaparib combined with abiraterone was more effective in delaying progression of the disease than abiraterone alone. Most side effects caused by combining olaparib with abiraterone could be managed with supportive care methods, by pausing olaparib administration for a short period of time and/or by reducing the dose of olaparib.

Transport properties of mechanochemically synthesized copper (I) selenide for potential applications in energy conversion and storage.

This work studied the thermal stability, electrical, and thermoelectrical properties of copper(I) selenide, Cu2Se synthesized by high-energy milling in a planetary ball mill. The phase composition was investigated by X-ray powder diffraction analysis and scanning electron microscopy. The conversion of the precursors during mechanochemical synthesis and the stability of the product was monitored by thermal analysis. The dependence of electrical properties on the product porosity was observed. For the densification of Cu2Se, the method of spark plasma sintering was applied to prepare suitable samples for thermoelectric characterization. High-temperature thermoelectric properties of synthetic Cu2Se were compared to its natural analogue-mineral berzelianite in terms of its potential application in energy conversion. Based on the results a relatively high figure-of-merit, ZT parameter (~ 1.15, T = 770 K) was obtained for undoped Cu2Se, prepared by rapid mechanochemical reaction (5 min). Cyclic voltammetry measurements of Na/NaClO4/Cu2Se cell implied that mechanochemically synthesized Cu2Se could be used as a promising intercalation electrode for sodium-ion batteries.

Circulating tumor cell-derived preclinical models: current status and future perspectives.

Despite the advancements made in the diagnosis and treatment of cancer, the stages associated with metastasis remain largely incurable and represent the primary cause of cancer-related deaths. The dissemination of cancer is facilitated by circulating tumor cells (CTCs), which originate from the primary tumor or metastatic sites and enter the bloodstream, subsequently spreading to distant parts of the body. CTCs have garnered significant attention in research due to their accessibility in peripheral blood, despite their low abundance. They are being extensively studied to gain a deeper understanding of the mechanisms underlying cancer dissemination and to identify effective therapeutic strategies for advanced stages of the disease. Therefore, substantial efforts have been directed towards establishing and characterizing relevant experimental models derived from CTCs, aiming to provide relevant tools for research. In this review, we provide an overview of recent progress in the establishment of preclinical CTC-derived models, such as CTC-derived xenografts (CDX) and cell cultures, which show promise for the study of CTCs. We discuss the advantages and limitations of these models and conclude by summarizing the potential future use of CTCs and CTC-derived models in cancer treatment decisions and their utility as precision medicine tools.

Autophagy modulators influence the content of important signalling molecules in PS-positive extracellular vesicles.

Extracellular vesicles (EVs) are important mediators of intercellular communication in the tumour microenvironment. Many studies suggest that cancer cells release higher amounts of EVs exposing phosphatidylserine (PS) at the surface. There are lots of interconnections between EVs biogenesis and autophagy machinery. Modulation of autophagy can probably affect not only the quantity of EVs but also their content, which can deeply influence the resulting pro-tumourigenic or anticancer effect of autophagy modulators. In this study, we found that autophagy modulators autophinib, CPD18, EACC, bafilomycin A1 (BAFA1), 3-hydroxychloroquine (HCQ), rapamycin, NVP-BEZ235, Torin1, and starvation significantly alter the composition of the protein content of phosphatidylserine-positive EVs (PS-EVs) produced by cancer cells. The greatest impact had HCQ, BAFA1, CPD18, and starvation. The most abundant proteins in PS-EVs were proteins typical for extracellular exosomes, cytosol, cytoplasm, and cell surface involved in cell adhesion and angiogenesis. PS-EVs protein content involved mitochondrial proteins and signalling molecules such as SQSTM1 and TGFß1 pro-protein. Interestingly, PS-EVs contained no commonly determined cytokines, such as IL-6, IL-8, GRO-α, MCP-1, RANTES, and GM-CSF, which indicates that secretion of these cytokines is not predominantly mediated through PS-EVs. Nevertheless, the altered protein content of PS-EVs can still participate in the modulation of the fibroblast metabolism and phenotype as p21 was accumulated in fibroblasts influenced by EVs derived from CPD18-treated FaDu cells. The altered protein content of PS-EVs (data are available via ProteomeXchange with identifier PXD037164) also provides information about the cellular compartments and processes that are affected by the applied autophagy modulators. Video Abstract.

Magnetically Driven Self-Degrading Zinc-Containing Cystine Microrobots for Treatment of Prostate Cancer.

Prostate cancer is the most commonly diagnosed tumor disease in men, and its treatment is still a big challenge in standard oncology therapy. Magnetically actuated microrobots represent the most promising technology in modern nanomedicine, offering the advantage of wireless guidance, effective cell penetration, and non-invasive actuation. Here, new biodegradable magnetically actuated zinc/cystine-based microrobots for in situ treatment of prostate cancer cells are reported. The microrobots are fabricated via metal-ion-mediated self-assembly of the amino acid cystine encapsulating superparamagnetic Fe3 O4 nanoparticles (NPs) during the synthesis, which allows their precise manipulation by a rotating magnetic field. Inside the cells, the typical enzymatic reducing environment favors the disassembly of the aminoacidic chemical structure due to the cleavage of cystine disulfide bonds and disruption of non-covalent interactions with the metal ions, as demonstrated by in vitro experiments with reduced nicotinamide adenine dinucleotide (NADH). In this way, the cystine microrobots served for site-specific delivery of Zn2+ ions responsible for tumor cell killing via a "Trojan horse effect". This work presents a new concept of cell internalization exploiting robotic systems' self-degradation, proposing a step forward in non-invasive cancer therapy.

Single-cell protein profiling defines cell populations associated with triple-negative breast cancer aggressiveness.

Triple-negative breast cancer (TNBC) is an aggressive and complex subtype of breast cancer that lacks targeted therapy. TNBC manifests characteristic, extensive intratumoral heterogeneity that promotes disease progression and influences drug response. Single-cell techniques in combination with next-generation computation provide an unprecedented opportunity to identify molecular events with therapeutic potential. Here, we describe the generation of a comprehensive mass cytometry panel for multiparametric detection of 23 phenotypic markers and 13 signaling molecules. This single-cell proteomic approach allowed us to explore the landscape of TNBC heterogeneity, with particular emphasis on the tumor microenvironment. We prospectively profiled freshly resected tumors from 26 TNBC patients. These tumors contained phenotypically distinct subpopulations of cancer and stromal cells that were associated with the patient's clinical status at the time of surgery. We further classified the epithelial-mesenchymal plasticity of tumor cells, and molecularly defined phenotypically diverse populations of tumor-associated stroma. Furthermore, in a retrospective tissue-microarray TNBC cohort, we showed that the level of CD97 at the time of surgery has prognostic potential.

Pentamethinium salts suppress key metastatic processes by regulating mitochondrial function and inhibiting dihydroorotate dehydrogenase respiration.

Mitochondria generate energy and building blocks required for cellular growth and function. The notion that mitochondria are not involved in the cancer growth has been challenged in recent years together with the emerging idea of mitochondria as a promising therapeutic target for oncologic diseases. Pentamethinium salts, cyan dyes with positively charged nitrogen on the benzothiazole or indole part of the molecule, were originally designed as mitochondrial probes. In this study, we show that pentamethinium salts have a strong effect on mitochondria, suppressing cancer cell proliferation and migration. This is likely linked to the strong inhibitory effect of the salts on dihydroorotate dehydrogenase (DHODH)-dependent respiration that has a key role in the de novo pyrimidine synthesis pathway. We also show that pentamethinium salts cause oxidative stress, redistribution of mitochondria, and a decrease in mitochondria mass. In conclusion, pentamethinium salts present novel anti-cancer agents worthy of further studies.

mRNA Subtype of Cancer-Associated Fibroblasts Significantly Affects Key Characteristics of Head and Neck Cancer Cells.

Head and neck squamous cell carcinomas (HNSCC) belong among severe and highly complex malignant diseases showing a high level of heterogeneity and consequently also a variance in therapeutic response, regardless of clinical stage. Our study implies that the progression of HNSCC may be supported by cancer-associated fibroblasts (CAFs) in the tumour microenvironment (TME) and the heterogeneity of this disease may lie in the level of cooperation between CAFs and epithelial cancer cells, as communication between CAFs and epithelial cancer cells seems to be a key factor for the sustained growth of the tumour mass. In this study, we investigated how CAFs derived from tumours of different mRNA subtypes influence the proliferation of cancer cells and their metabolic and biomechanical reprogramming. We also investigated the clinicopathological significance of the expression of these metabolism-related genes in tissue samples of HNSCC patients to identify a possible gene signature typical for HNSCC progression. We found that the right kind of cooperation between cancer cells and CAFs is needed for tumour growth and progression, and only specific mRNA subtypes can support the growth of primary cancer cells or metastases. Specifically, during coculture, cancer cell colony supporting effect and effect of CAFs on cell stiffness of cancer cells are driven by the mRNA subtype of the tumour from which the CAFs are derived. The degree of colony-forming support is reflected in cancer cell glycolysis levels and lactate shuttle-related transporters.

Cancer cell viscoelasticity measurement by quantitative phase and flow stress induction.

Cell viscoelastic properties are affected by the cell cycle, differentiation, and pathological processes such as malignant transformation. Therefore, evaluation of the mechanical properties of the cells proved to be an approach to obtaining information on the functional state of the cells. Most of the currently used methods for cell mechanophenotyping are limited by low robustness or the need for highly expert operation. In this paper, the system and method for viscoelasticity measurement using shear stress induction by fluid flow is described and tested. Quantitative phase imaging (QPI) is used for image acquisition because this technique enables one to quantify optical path length delays introduced by the sample, thus providing a label-free objective measure of morphology and dynamics. Viscosity and elasticity determination were refined using a new approach based on the linear system model and parametric deconvolution. The proposed method allows high-throughput measurements during live-cell experiments and even through a time lapse, whereby we demonstrated the possibility of simultaneous extraction of shear modulus, viscosity, cell morphology, and QPI-derived cell parameters such as circularity or cell mass. Additionally, the proposed method provides a simple approach to measure cell refractive index with the same setup, which is required for reliable cell height measurement with QPI, an essential parameter for viscoelasticity calculation. Reliability of the proposed viscoelasticity measurement system was tested in several experiments including cell types of different Young/shear modulus and treatment with cytochalasin D or docetaxel, and an agreement with atomic force microscopy was observed. The applicability of the proposed approach was also confirmed by a time-lapse experiment with cytochalasin D washout, whereby an increase of stiffness corresponded to actin repolymerization in time.

Metabolic tricks of cancer cells.

One of the characteristics of cancer cells important for tumorigenesis is their metabolic plasticity. Indeed, in various stress conditions, cancer cells can reshape their metabolic pathways to support the increased energy request due to continuous growth and rapid proliferation. Moreover, selective pressures in the tumor microenvironment, such as hypoxia, acidosis, and competition for resources, force cancer cells to adapt by complete reorganization of their metabolism. In this review, we highlight the characteristics of cancer metabolism and discuss its clinical significance, since overcoming metabolic plasticity of cancer cells is a key objective of modern cancer therapeutics and a better understanding of metabolic reprogramming may lead to the identification of possible targets for cancer therapy.

Abiraterone and Olaparib for Metastatic Castration-Resistant Prostate Cancer.

Abiraterone and Olaparib for Metastatic Prostate CancerPatients with metastatic castration-resistant prostate cancer, regardless of homologous recombination repair gene mutation status, received either abiraterone and olaparib or abiraterone and placebo in the first-line setting. Imaging-based progression-free survival was 24.8 months for patients treated with abiraterone and olaparib versus 16.6 months for those receiving abiraterone alone.

Parametric Deconvolution for Cancer Cells Viscoelasticity Measurements from Quantitative Phase Images.

In this contribution, we focused on optimising a dynamic flow-based shear stress system to achieve a reliable platform for cell shear modulus (stiffness) and viscosity assessment using quantitative phase imaging. The estimation of cell viscoelastic properties is influenced by distortion of the shear stress waveform, which is caused by the properties of the flow system components (i.e., syringe, flow chamber and tubing). We observed that these components have a significant influence on the measured cell viscoelastic characteristics. To suppress this effect, we applied a correction method utilizing parametric deconvolution of the flow system's optimized impulse response. Achieved results were compared with the direct fitting of the Kelvin-Voigt viscoelastic model and the basic steady-state model. The results showed that our novel parametric deconvolution approach is more robust and provides a more reliable estimation of viscosity with respect to changes in the syringe's compliance compared to Kelvin-Voigt model.

Mechanobiology of cancerogenesis.

BACKGROUND: Within the tumour microenvironment, tumour cells are exposed to different mechanical stimuli such as compression stress, cell-cell and cell-extracellular matrix traction forces, interstitial fluid pressure, and shear stress. Cells actively sense and process this information by the mechanism of mechanotransduction to make decisions about their growth, motility, and differentiation. Indeed, the mechanical properties of the tumour microenvironment can deeply influence the behaviour of cancer cells and promote cancerogenesis. During tumour progression, desmoplasia arises and a positive feedback loop between the stiffening extracellular matrix and the properties enabling tumour expansion is established. Tumour cells can use mechanic stimuli to promote proliferation, increase their migratory and invasive potential, and induce therapeutic resistance. Mechanobio-logy is a progressive multidisciplinary field which studies how mechanical forces influence the behaviour of cells or tissues and may provide some interesting targets for cancer therapy. PURPOSE: In this review, we discuss the mechanical properties of cancer cells and describe the tumour promoting effect of the transformed extracellular matrix. We propose that the differences in the mechanobio-logy of cells and extracellular matrix are significant enough to facilitate tumorigenesis and may provide interesting targets for cancer therapy.

Mechanochemistry for Energy Materials: Impact of High-Energy Milling on Chemical, Electric and Thermal Transport Properties of Chalcopyrite CuFeS2 Nanoparticles.

Chalcopyrite CuFeS2 , a semiconductor with applications in chemical sector and energy conversion engineering, was synthetized in a planetary mill from elemental precursors. The synthesis is environmentally friendly, waste-free and inexpensive. The synthesized nano-powders were characterized by XRD, SEM, EDX, BET and UV/Vis techniques, tests of chemical reactivity and, namely, thermoelectric performance of sintered ceramics followed. The crystallite size of ∼13 nm and the strain of ∼17 were calculated for CuFeS2 powders milled for 60, 120, 180 and 240 min, respectively. The evolution of characteristic band gaps, Eg, and the rate constant of leaching, k, of nano-powders are corroborated by the universal evolution of the parameter SBET /X (SBET -specific surface area, X-crystallinity) introduced for complex characterization of mechanochemically activated solids in various fields such as chemical engineering and/or energy conversion. The focus on non-doped semiconducting CuFeS2 enabled to assess the role of impurities, which critically and often negatively influence the thermoelectric properties.

An Electrochemical Amperometric Ethylene Sensor with Solid Polymer Electrolyte Based on Ionic Liquid.

An electrochemical amperometric ethylene sensor with solid polymer electrolyte (SPE) and semi-planar three electrode topology involving a working, pseudoreference, and counter electrode is presented. The polymer electrolyte is based on the ionic liquid 1-butyl 3-methylimidazolium bis(trifluoromethylsulfonyl)imide [BMIM][NTf2] immobilized in a poly(vinylidene fluoride) matrix. An innovative aerosol-jet printing technique was used to deposit the gold working electrode (WE) on the solid polymer electrolyte layer to make a unique electrochemical active SPE/WE interface. The analyte, gaseous ethylene, was detected by oxidation at 800 mV vs. the platinum pseudoreference electrode. The sensor parameters such as sensitivity, response/recovery time, repeatability, hysteresis, and limits of detection and quantification were determined and their relation to the morphology and microstructure of the SPE/WE interface examined. The use of additive printing techniques for sensor preparation demonstrates the potential of polymer electrolytes with respect to the mass production of printed electrochemical gas sensors.

Kelvin probe force microscopy of the nanoscale electrical surface potential barrier of metal/semiconductor interfaces in ambient atmosphere.

This study deals with the preparation and characterization of metallic nanoinclusions on the surface of semiconducting Bi2Se3 that could be used for an enhancement of the efficiency of thermoelectric materials. We used Au forming a 1D alloy through diffusion (point nanoinclusion) and Mo forming thermodynamically stable layered MoSe2 nanosheets through the reaction with the Bi2Se3. The Schottky barrier formed by the 1D and 2D nanoinclusions was characterized by means of atomic force microscopy (AFM). We used Kelvin probe force microscopy (KPFM) in ambient atmosphere at the nanoscale and compared the results to those of ultraviolet photoelectron spectroscopy (UPS) in UHV at the macroscale. The existence of the Schottky barrier was demonstrated at +120 meV for the Mo layer and -80 meV for the Au layer reflecting the formation of MoSe2 and Au/Bi2Se3 alloy, respectively. The results of both methods (KPFM and UPS) were in good agreement. We revealed that long-time exposure (tens of seconds) to the electrical field leads to deep oxidation and the formation of perturbations greater than 1 µm in height, which hinder the I-V measurements.

Accelerating Physics-Based Simulations Using End-to-End Neural Network Proxies: An Application in Oil Reservoir Modeling.

We develop a proxy model based on deep learning methods to accelerate the simulations of oil reservoirs-by three orders of magnitude-compared to industry-strength physics-based PDE solvers. This paper describes a new architectural approach to this task modeling a simulator as an end-to-end black box, accompanied by a thorough experimental evaluation on a publicly available reservoir model. We demonstrate that in a practical setting a speedup of more than 2000X can be achieved with an average sequence error of about 10% relative to the simulator. The task involves varying well locations and varying geological realizations. The end-to-end proxy model is contrasted with several baselines, including upscaling, and is shown to outperform these by two orders of magnitude. We believe the outcomes presented here are extremely promising and offer a valuable benchmark for continuing research in oil field development optimization. Due to its domain-agnostic architecture, the presented approach can be extended to many applications beyond the field of oil and gas exploration.

Queue management systems are not a necessary measure for the protection of personal data.

The new legislation, in particular the General Regulation on Personal Data Protection (GDPR), constitutes relatively demanding criteria on healthcare. However, the institute of medical secrets, which is an ancient medical practice and is part of various legal and professional regulations, contains many elements of today's protection of personal data and is not new among the professional medical public. Under the GDPR, however, there are steps that can be labelled as at least controversial. Such disputable measures have recently been to introduce electronic queue management systems, as we know from post offices. They are not a necessary measure for the protection of personal data in the waiting rooms of ambulances, they are not required by law, even with regard to GDPR and from the point of view of medical ethics are even at least problematic. If GDPR is applied in a similar way, it does not really benefit from the protection of personal data, and a useful tool like GDPR will be undoubtedly discredited. Keywords: electronic queue management systems, GDPR, medical ethics, personal data protection, patient.

Plasticity and intratumoural heterogeneity of cell surface antigen expression in breast cancer.

Background:The intratumoural heterogeneity, often driven by epithelial-to-mesenchymal transition (EMT), significantly contributes to chemoresistance and disease progression in adenocarcinomas. Methods:We introduced a high-throughput screening platform to identify surface antigens that associate with epithelial­mesenchymal plasticity in well-defined pairs of epithelial cell lines and their mesenchymal counterparts. Using multicolour flow cytometry, we then analysed the expression of 10 most robustly changed antigens and identified a 10-molecule surface signature, in pan-cytokeratin-positive/EpCAM-positive and -negative fractions of dissociated breast tumours. Results:We found that surface CD9, CD29, CD49c, and integrin ß5 are lost in breast cancer cells that underwent EMT in vivo. The tetraspanin family member CD9 was concordantly downregulated both in vitro and in vivo and associated with epithelial phenotype and favourable prognosis. Conclusions:We propose that overall landscape of 10-molecule surface signature expression reflects the epithelial­mesenchymal plasticity in breast cancer.