Novel therapeutic strategies for metastatic prostate cancer in the post-docetaxel setting

Prostate cancer is the most common noncutaneous cancer and the second leading cause of death from cancer in men in most western countries. Advanced prostate cancer is typically sensitive to androgen‐deprivation therapy, but invariably progresses to the castration‐resistant state. Most current prostate cancer treatments are based on cytotoxicity directed against tumor cells via androgen‐deprivation therapy or chemotherapy. Chemotherapy with docetaxel represents the standard first‐line treatment in patients with castration‐resistant prostate cancer (CRPC). Following progression after treatment with docetaxel, cabazitaxel (XRP6258)–prednisone treatment leads to a significantly longer overall survival (OS) time than with mitoxantrone–prednisone. Several other novel agents are currently being evaluated, including sipuleucel‐T, abiraterone acetate, and MDV3100, as well as the radionuclide alpharadin. The cell‐based immunotherapy sipuleucel‐T produces longer OS times in chemotherapy‐naïve patients, whereas the androgen biosynthesis inhibitor abiraterone acetate results in longer OS times following docetaxel. It is envisioned that these agents will change the standard of care for patients with metastatic CRPC. This review focuses on the clinical development of cabazitaxel and abiraterone acetate.     

Palliative Care Consultation Service and Palliative Care Unit: Why Do We Need Both?

Background.

Palliative care (PC) infrastructure has developed differently around the globe. Whereas some institutions consider the palliative care unit (PCU) a valuable component, others report that the sole provision of a state-of-the art palliative care consultation service (PCCS) suffices to adequately care for the severely ill and dying.

Objective.

To aid institutional planning, this study aimed at gathering patient data to distinguish assignments of a concomitantly run PCU and PCCS at a large hospital and academic medical center.

Methods.

Demographics, Eastern Cooperative Oncology Group performance status, symptom/problem burden, discharge modality, and team satisfaction with care for all 601 PCU and 851 PCCS patients treated in 2009 and 2010 were retrospectively analyzed.

Results.

Patients admitted to the PCU versus those consulted by the PCCS: (a) had a significantly worse performance status (odds ratio [OR], 1.48); (b) were significantly more likely to suffer from severe symptoms and psychosocial problems (OR, 2.05), in particular concerning physical suffering and complexity of care; and (c) were significantly much more likely to die during hospital stay (OR, 11.03). For patients who were dying or in other challenging clinical situations (suffering from various severe symptoms), self-rated team satisfaction was significantly higher for the PCU than the PCCS.

Conclusion.

This study presents a direct comparison between patients in a PCU and a PCCS. Results strongly support the hypothesis that the coexistence of both institutions in one hospital contributes to the goal of ensuring optimal high-quality PC for patients in complex and challenging clinical situations.     

Comparing the development of cortex-wide gene expression patterns between two species in a common reference frame

Advances in sequencing techniques have made comparative studies of gene expression a current focus for understanding evolutionary and developmental processes. However, insights into the spatial expression of genes have been limited by a lack of robust methodology. To overcome this obstacle, we developed methods and software tools for quantifying and comparing tissue-wide spatial patterns of gene expression within and between species. Here, we compare cortex-wide expression of RZRβ and Id2 mRNA across early postnatal development in mice and voles. We show that patterns of RZRβ expression in neocortical layer 4 are highly conserved between species but develop rapidly in voles and much more gradually in mice, who show a marked expansion in the relative size of the putative primary visual area across the first postnatal week. Patterns of Id2 expression, by contrast, emerge in a dynamic and layer-specific sequence that is consistent between the two species. We suggest that these differences in the development of neocortical patterning reflect the independent evolution of brains, bodies, and sensory systems in the 35 million years since their last common ancestor.

Almost everything we know about the human brain comes from comparative studies of other animals: from genes involved in cortical development to system-level networks that generate complex behaviors. Comparative studies of living species provide a robust means by which to understand unknown forms, like humans, and even extinct forms like our early mammalian ancestors. Importantly, these types of studies are critical for identifying features of brain organization that are conserved between species and those that may have been derived in different lineages. They also allow us to determine how developmental programs and timing schedules may vary across species, and to better understand how phenotypic diversity can be generated over shorter and longer timescales. Finally, by making valid comparisons across species, we can begin to understand how complexity emerges in different nervous systems, the rules of brain construction, and the constraints imposed on developing and evolving nervous systems.Despite the importance of comparative studies in biology, most comparisons of anatomically reconstructed data are subjective, and most gene sequencing studies neglect the actual spatial patterns of gene expression across a structure, focusing instead on cell-type expression (1–3). Moreover, many current methods for making comparisons fail to capture the three-dimensional nature of the brain, which is composed of asymmetrical structures that can vary markedly in relative shape, size, and location across species and between developmental time-points. Despite the three-dimensional (3D) nature of the brain, most studies collapse data into two dimensions driven largely by the plane of section at which the brain is cut.As such, neurobiologists are faced with two challenges. First, attempting to understand 3D structures by analyzing two-dimensional (2D) images is inherently problematic because the loss of spatial information is unavoidable, especially in curved structures (4). 2D analysis often involves prespecifying regions of interest (ROIs) to quantify the presence of labeled cells or mRNA expression after in-situ hybridization (ISH), narrowing the focus and potentially missing overall differences across a structure, such as the neocortex. A second challenge, which arises when making comparisons between structures in different species and/or at different developmental time-points, or between different experimental conditions, is determining the extent to which 2D spatial patterning might be invariant to basic transformations in the size and shape of the 3D structure. To this end, it is important for comparisons to be made with respect to a common anatomical reference frame.In the current study, we overcame these challenges by developing a set of algorithms for brain slice registration in 3D, and for incorporating ISH data into a common reference frame to enable point-by-point comparisons between species or experimental conditions (see Materials and Methods). These tools, which we refer to collectively as Stalefish, the Spatial Analysis of Fluorescent (and nonfluorescent) In-Situ Hybridization, allowed for the laminar and spatial patterns of expression of genes involved in cortical development to be quantified and compared in two species of age matched rodents across early postnatal development. Our analysis of Id2 and RZRβ cortical expression patterns in mouse and vole brains reveals both a strong layer-specific conservation of the patterning of these genes, as well as area-specific differences in development that shed new light on the ontogeny and phylogeny of neocortical arealization.     

Void-Induced Ductile Fracture of Metals: Experimental Observations

The paper presents a literature review on the development of microvoids in metals, leading to ductile fracture associated with plastic deformation, without taking into account the cleavage mechanism. Particular emphasis was placed on the results of observations and experimental studies of the characteristics of the phenomenon itself, without in-depth analysis in the field of widely used FEM modelling. The mechanism of void development as a fracture mechanism is presented. Observations of the nucleation of voids in metals from the turn of the 1950s and 1960s to the present day were described. The nucleation mechanisms related to the defects of the crystal lattice as well as those resulting from the presence of second-phase particles were characterised. Observations of the growth and coalescence of voids were presented, along with the basic models of both phenomena. The modern research methods used to analyse changes in the microstructure of the material during plastic deformation are discussed. In summary, it was indicated that understanding the microstructural phenomena occurring in deformed material enables the engineering of the modelling of plastic fracture in metals.     

Host Cell Entry and Neutralization Sensitivity of SARS-CoV-2 Lineages B.1.620 and R.1

The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) facilitates viral entry into host cells and is the key target for neutralizing antibodies. The SARS-CoV-2 lineage B.1.620 carries fifteen mutations in the S protein and is spread in Africa, the US and Europe, while lineage R.1 harbors four mutations in S and infections were observed in several countries, particularly Japan and the US. However, the impact of the mutations in B.1.620 and R.1 S proteins on antibody-mediated neutralization and host cell entry are largely unknown. Here, we report that these mutations are compatible with robust ACE2 binding and entry into cell lines, and they markedly reduce neutralization by vaccine-induced antibodies. Our results reveal evasion of neutralizing antibodies by B.1.620 and R.1, which might have contributed to the spread of these lineages.     

Application of Statistical Methods to Accurately Assess the Effect of Gamma Aluminum Oxide Nanopowder on the Hardness of Composite Materials with Polyester–Glass Recyclate

Polymer composites are materials that are used in many industries. Their wide application has a direct impact on the amount of post-production and post-consumer waste. The global problem with recycling, especially of fiber-reinforced polymeric materials, has prompted research into methods of their use. Previous research on composite materials with polyester–glass recyclate showed a decrease in mechanical properties. The construction material should have the highest mechanical properties. Based on the literature, it was found that the use of nanoadditives may have a positive effect on the parameters of the materials. The use of gamma aluminum nanopowder, in a small amount can significantly increase the mechanical properties of composites with polyester–glass recyclate, and thus can affect the application of these materials to structural elements. The article is devoted to the research on the hardness of composite materials with polyester–glass recyclate and gamma aluminum nanopowder. The main goal is to investigate the possibility of using a nanoadditive as a material, increasing the mechanical properties of composites with polyester–glass recyclate, so as to create a recycled material with the highest possible strength parameters. Hardness tests were performed using the Barcol method. For each composite material, 30 measurements were made in order to subject the results to a statistical analysis. Using parametric statistical tests it was shown that the obtained hardness values at the assumed level of statistical significance p_v = 0.05 for comparisons for the samples of the reference material (B0) do not differ by chance, while for the comparisons in the configurations of the reference material (B0) with the modified materials, (R10, A2, R10A2) they do not differ by accident. Studies have shown that the addition of 2% gamma aluminum nanopowder slightly lowers the hardness of a pure polyester–glass composite, but the same additive allows the hardness of composite materials to be increased with the addition of glass recyclate. This is of particular importance for the development of the optimal composition of polyester–glass composites with the addition of recyclate, which will have good strength properties and at the same time enable the reuse of composite waste.     

Neurophysiological Markers for Monitoring Exercise and Recovery Cycles in Endurance Sports

The current study analyzes the suitability and reliability of selected neurophysiological and vegetative nervous system markers as biomarkers for exercise and recovery in endurance sport. Sixty-two healthy men and women, endurance trained and moderately trained, performed two identical acute endurance tests (running trial 1 and running trial 2) followed by a washout period of four weeks. Exercise protocol consisted of an acute running trial lasting 60 minutes. An intensity corresponding to 95% of the heart rate at individual anaerobic threshold for 40 minutes was followed by 20 minutes at 110%. At pre-exercise, post-exercise, three hours post-exercise and 24 hours post-exercise, experimental diagnostics on Brain-derived neurotrophic factor (BDNF), heart rate variability (HRV), Stroop Color and Word Test (SCWT), and Short-Form McGill Pain Questionnaire (SF-MPQ) were performed. Significant changes over time were found for all parameters (p < .05). Furthermore, there was an approached statistical significance in the interaction between gender and training status in BDNF regulation (F₍₃₎ = 2.43; p = 0.06), while gender differences were found only for LF/HF-ratio (3hPoEx, F₍₃₎ = 3.40; p = 0.002). Regarding the reliability, poor ICC-values (< 0.5) were found for BDNF, Stroop sensitivity and pNN50, while all other parameters showed moderate ICC-values (0.5-0.75). Plasma-BDNF, SCWT performance, pain perception and all HRV parameters are suitable exercise-sensitive markers after an acute endurance exercise. Moreover, pain perception, SCWT reaction time and all HRV parameters show a moderate reliability, others rather poor. In summary, a selected neurophysiological and vegetative marker panel can be used to determine exercise load and recovery in endurance sports, but its repeatability is limited due to its vaguely reliability. Key points

• Pain perception and the Stroop test have moderate reliability in the use of exercise and recovery markers after two identical exercise loads in endurance sports
• Markers of heart rate variability also show moderate reliability as biomarkers after intense endurance exercise under identical conditions.
• There are associations between neurophysiological markers and inflammatory blood markers after endurance exercise that are partially associated with gender and training status

Key words: NNervous system, monitoring training, biomarkers, reliability, executive function, heart rate variability     

A Multipathogen Bile Sample-based PCR Assay Can Guide Empirical Antimicrobial Strategies in Cholestatic Liver Diseases

Background and objectivesPolymerase chain reaction (PCR) techniques provide rapid detection of pathogens. This pilot study evaluated the diagnostic utility and clinical impact of multiplex real-time PCR (mRT-PCR, SeptiFast) vs. conventional microbial culture (CMC) in bile samples of patients with chronic cholestatic liver diseases (cCLDs), endoscopic retrograde cholangio-pancreatography (ERCP), and peri-interventional-antimicrobial-prophylaxis (pAP).MethodsWe prospectively collected bile samples from 26 patients for microbiological analysis by CMC and mRT-PCR. Concordance of the results of both methods was determined by Krippendorff''s alpha (α) for inter-rater reliability and the Jaccard index of similarity.ResultsmRT-PCR_bile and CMC_bile results were concordant for only Candida albicans (α=0.8406; Jaccard index=0.8181). mRT-PCR_bile detected pathogens in 8/8 cases (100%), CMC_bile in 7/8 (87.5%), and CMC_blood in 5/8 (62.5%) with clinical signs of infection. mRT-PCR_bile, CMC_bile, and CMC_blood had identical detection results in 3/8 (37.5%) with clinical signs of infection (two Klebsiella spp. and one Enterococcus faecium). The total pathogen count was significantly higher with mRT-PCR_bile than with CMC_bile (62 vs. 31; χ²=30.031, p<0.001). However, pathogens detected by mRT-PCR_bile were more often susceptible to pAP according to the patient infection/colonization history (PI/CH) and surveillance data for antibiotic resistance in our clinic (DARC). Pathogens identified by mRT-PCR_bile and resistant to pAP by PI/CH and DARC were likely to be clinically relevant.ConclusionsmRT-PCR in conjunction with CMCs for bile analysis increased diagnostic sensitivity and may benefit infection management in patients with cholestatic diseases. Implementation of mRT-PCR in a bile sample-based diagnostic routine can support more rapid and targeted use of antimicrobial agents in cCLD-patients undergoing ERCP and reduce the rate/length of unnecessary administration of broad-spectrum antibiotics.