Search

Abstract Prostate cancer treatment resistance is a significant challenge facing the field. Genomic and transcriptomic profiling have partially elucidated the mechanisms through which cancer cells escape treatment, but their relation toward the tumor microenvironment (TME) remains elusive. Here we present a comprehensive transcriptomic landscape of the prostate TME at multiple points in the standard treatment timeline employing single-cell RNA-sequencing and spatial transcriptomics data from 120 patients. We identify club-like cells as a key epithelial cell subtype that acts as an interface between the prostate and the immune system. Tissue areas enriched with club-like cells have depleted androgen signaling and upregulated expression of luminal progenitor cell markers. Club-like cells display a senescence-associated secretory phenotype and their presence is linked to increased polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) activity. Our results indicate that club-like cells are associated with myeloid inflammation previously linked to androgen deprivation therapy resistance, providing a rationale for their therapeutic targeting.

Cryptophytes are a promising source of bioactive compounds that have not been fully explored. This research investigated the antimicrobial activity of total phenolic compounds (TPC) and exopolysaccharides (EPS) extracted from several cryptophytes against a range of harmful foodborne bacteria and fungi. To measure the minimum inhibitory concentration (MIC) value, the broth microdilution method was used. In the antibacterial evaluation of TPC, the MIC ranged between 31.25 and 500 μg/mL, while for the antifungal activity test, it varied from 31.25 to 125 μg/mL. In the antibacterial activity test of EPS, the MIC values ranged from 125 to 1,000 μg/mL, whereas in the antifungal susceptibility test, it ranged between 62.5 and 1,000 μg/mL. The most resistant pathogen against TPC was Escherichia coli, while Campylobacter jejuni was the most susceptible. In the case of EPS, the most resistant pathogen was Salmonella Typhimurium, while Aspergillus versicolor exhibited the highest susceptibility. Overall, in terms of antimicrobial activity, TPC was more effective than EPS. Finally, the tolerance level (TL) for TPC and EPS was ≤4 in all tested samples, indicating their bactericidal/fungicidal mechanism of action. In conclusion, TPC and EPS isolated from cryptophytes demonstrated remarkable antimicrobial properties and ability to fully eradicate pathogens, and could be considered as natural preservatives in the food industry.

A considerable number of antibacterial agents are derived from bacterial metabolites. Similarly, numerous known compounds that impede bacterial virulence stem from bacterial metabolites. Enteropathogenic Escherichia coli (EPEC) is a notable human pathogen causing intestinal infections, particularly affecting infant mortality in developing regions. These infections are characterized by microvilli effacement and intestinal epithelial lesions linked with aberrant actin polymerization. This study aimed to identify potential antivirulence compounds for EPEC infections among bacterial metabolites harvested from marine actinobacteria (Kocuria sp. and Rhodococcus spp.) from the Arctic Sea by the application of virulence-based screening assays. Moreover, we demonstrate the suitability of these antivirulence assays to screen actinobacteria extract fractions for the bioassay-guided identification of metabolites. We discovered a compound in the fifth fraction of a Kocuria strain that interferes with EPEC-induced actin polymerization without affecting growth. Furthermore, a growth-inhibiting compound was identified in the fifth fraction of a Rhodococcus strain. Our findings include the bioassay-guided identification, HPLC-MS-based dereplication, and isolation of a large phospholipid and a likely antimicrobial peptide, demonstrating the usefulness of this approach in screening for compounds capable of inhibiting EPEC virulence.

Jonne Åkerla,1,2 Jaakko Nevalainen,3 Jori S Pesonen,4 Antti Pöyhönen,5 Juha Koskimäki,1 Jukka Häkkinen,6 Teuvo LJ Tammela,1,2 Anssi Auvinen3 1Department of Urology, Tampere University Hospital, Tampere, Finland; 2Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; 3Faculty of Social Sciences, Tampere University, Tampere, Finland; 4Department of Surgery, Päijät-Häme Central Hospital, Lahti, Finland; 5Centre for Military Medicine, The Finnish Defence Forces, Riihimäki, Finland; 6Department of Urology, Länsi-Pohja healthcare District, Kemi, FinlandCorrespondence: Jonne Åkerla, Department of Urology, Tampere University Hospital, Teiskontie 35, Tampere, 33521, Finland, Tel +358 311 611, Fax +358 311 64256, Email jonne.akerla@gmail.comPurpose: To evaluate a random forest (RF) algorithm of lower urinary tract symptoms (LUTS) as a predictor of all-cause mortality in a population-based cohort.Materials and Methods: A population-based cohort of 3143 men born in 1924, 1934, and 1944 was evaluated using a mailed questionnaire including the Danish Prostatic Symptom Score (DAN-PSS-1) to assess LUTS as well as questions on medical conditions and behavioral and sociodemographic factors. Surveys were repeated in 1994, 1999, 2004, 2009 and 2015. The cohort was followed-up for vital status until the end of 2018. RF uses an ensemble of classification trees for prediction with a good flexibility and without overfitting. RF algorithms were developed to predict the five-year mortality using LUTS, demographic, medical, and behavioral factors alone and in combinations.Results: A total of 2663 men were included in the study, of whom 917 (34%) died during follow-up (median follow-up time 15.0 years). The LUTS-based RF algorithm showed an area under the curve (AUC) 0.60 (95% CI 0.52– 0.69) for five-year mortality. An expanded RF algorithm, including LUTS, medical history, and behavioral and sociodemographic factors, yielded an AUC 0.73 (0.65– 0.81), while an algorithm excluding LUTS yielded an AUC 0.71 (0.62– 0.78).Conclusion: An exploratory RF algorithm using LUTS can predict all-cause mortality with acceptable discrimination at the group level. In clinical practice, it is unlikely that LUTS will improve the accuracy to predict death if the patient’s background is well known.Keywords: lower urinary tract symptoms, mortality, machine learning, cohort studies

The digital twin (DT), which involves creating a virtual replica of a physical asset or system, has emerged as a transformative set of tools across various industries. In the oil and gas (O&G) industry, the development of DTs represents a significant evolution in how companies manage complex operations, enhance safety, and optimize decision-making processes. Despite these significant advancements, the underlying tools, technologies, and frameworks for developing DTs in O&G applications remain non-standardized and unfamiliar to many O&G practitioners, highlighting the need for a systematic literature review (SLR) on the topic. Thus, this paper offers an SLR of the existing literature on DT development for O&G from 2018 onwards, utilizing Scopus and Web of Science Core Collection. We provide a comprehensive overview of this field, demonstrate how it is evolving, and highlight standard practices and research opportunities in the area. We perform broad classifications of the 98 studies, categorizing the DTs by their development methodologies, implementation objectives, data acquisition, asset digital development, data integration and preprocessing, data analysis and modeling, evaluation and validation, and deployment tools. We also include a bibliometric analysis of the selected papers, highlighting trends and key contributors. Given the increasing number of new DT developments in O&G and the many new technologies available, we hope to provide guidance on the topic and promote knowledge production and growth concerning the development of DTs for O&G.

Cancer survivorship was recently identified as a prostate cancer (PCa) research priority by PIONEER, a European network of excellence for big data in PCa. Despite being a research priority, cancer survivorship lacks a clear and agreed definition, and there is a distinct paucity of patient-reported outcome (PRO) data available on the subject. Data collection on cancer survivorship depends on the availability and implementation of (validated) routinely collected patient-reported outcome measures (PROMs). There have been recent advances in the availability of such PROMs. For instance, the European Organisation for Research and Treatment of Cancer Quality of Life Group (EORTC QLG) is developing survivorship questionnaires. This provides an excellent first step in improving the data available on cancer survivorship. However, we propose that an agreed, standardised definition of (prostate) cancer survivorship must first be established. Only then can real-world data on survivorship be collected to strengthen our knowledge base. With more men than ever surviving PCa, this type of research is imperative to ensure that the quality of life of these men is considered as much as their quantity of life. Patient summary: As there are more prostate cancer survivors than ever before, research into cancer survivorship is crucial. We highlight the importance of such research and provide recommendations on how to carry it out. The first step should be establishing agreement on a standardised definition of survivorship. From this, patient-reported outcome measures can then be used to collect important survivorship data.

Introduction Evidence on the effectiveness of prostate cancer screening based on prostate-specific antigen is inconclusive and suggests a questionable balance between benefits and harms due to overdiagnosis, and complications from biopsies and overtreatment. However, diagnostic accuracy studies have shown that detection of clinically insignificant prostate cancer can be reduced by MRI combined with targeted biopsies.The aim of the paper is to describe the analysis of the ProScreen randomised trial to assess the performance of the novel screening algorithm in terms of the primary outcome, prostate cancer mortality and secondary outcomes as intermediate indicators of screening benefits and harms of screening.Methods The trial aims to recruit at least 111 000 men to achieve sufficient statistical power for the primary outcome. Men will be allocated in a 1:3 ratio to the screening and control arms. Interim analysis is planned at 10 years of follow-up, and the final analysis at 15 years. Difference between the trial arms in prostate cancer mortality will be assessed by Gray’s test using intention-to-screen analysis of randomised men. Secondary outcomes will be the incidence of prostate cancer by disease aggressiveness, progression to advanced prostate cancer, death due to any cause and cost-effectiveness of screening.Ethics and dissemination The trial protocol was reviewed by the ethical committee of the Helsinki University Hospital (2910/2017). Results will be disseminated through publications in international peer-reviewed journals and at scientific meetings.Trial registration number NCT03423303

In this work, we describe an improved series of N-phenylpyrrolamide inhibitors that exhibit potent activity against DNA gyrase and are highly effective against high-priority gram-positive bacteria. The most potent compounds show low nanomolar IC 50 values against Escherichia coli DNA gyrase, and in addition, compound 7c also inhibits E. coli topoisomerase IV in the nanomolar concentration range, making it a promising candidate for the development of potent dual inhibitors for these enzymes. All tested compounds show high selectivity towards the human isoform DNA topoisomerase IIα. Compounds 6a, 6d, 6e and 6f show MIC values between 0.031 and 0.0625 μg/mL against vancomycin-intermediate S. aureus (VISA) and Enterococcus faecalis strains. Compound 6g shows an inhibitory effect against the methicillin-resistant S. aureus strain (MRSA) with a MIC of 0.0625 μg/mL and against the E. faecalis strain with a MIC of 0.125 μg/mL. In a time-kill assay, compound 6d showed a dose-dependent bactericidal effect on the MRSA strain and achieved bactericidal activity at 8 × MIC after 8 h. The duration of the post-antibiotic effect (PAE) on the MRSA strain for compound 6d was 2 h, which corresponds to the PAE duration for ciprofloxacin. The compounds were not cytotoxic at effective concentrations, as determined in an MTS assay on the MCF-7 breast cancer cell line., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nace Zidar reports financial support was provided by Slovenian Research Agency. Cristina D. Cruz, Paivi Tammela reports financial support was provided by Research Council of Finland. Marton Simon Czikkely reports financial support was provided by Hungarian Ministry of Culture and Innovation. Nace Zidar has patent New N-phenylpyrrolamide inhibitors of DNA gyrase and topoisomerase IV with antibacterial activity pending to University of Ljubljana. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The development of new therapies is hampered by the lack of predictive, and patient-relevant in vitro models. Organ-on-chip (OOC) technologies can potentially recreate physiological features and hold great promise for tissue and disease modeling. However, the non-standardized design of these chips and perfusion control systems has been a barrier to quantitative high-throughput screening (HTS). Here we present a scalable OOC microfluidic platform for applied kinetic in vitro assays (AKITA) that is applicable for high, medium, and low throughput. Its standard 96-well plate and 384-well plate layouts ensure compatibility with existing laboratory workflows and high-throughput data collection and analysis tools. The AKITA plate is optimized for the modeling of vascularized biological barriers, primarily the blood-brain barrier, skin, and lung, with precise flow control on a custom rocker. The integration of trans-epithelial electrical resistance (TEER) sensors allows rapid and repeated monitoring of barrier integrity over long time periods. Together with automated liquid handling and compound permeability testing analyses, we demonstrate the flexibility of the AKITA platform for establishing human-relevant models for preclinical drug and precision medicine's efficacy, toxicity, and permeability under near-physiological conditions.

Cryptophytes are a promising source of bioactive compounds that have not been fully explored. This research investigated the antimicrobial activity of total phenolic compounds (TPC) and exopolysaccharides (EPS) extracted from several cryptophytes against a range of harmful foodborne bacteria and fungi. To measure the minimum inhibitory concentration (MIC) value, the broth microdilution method was used. In the antibacterial evaluation of TPC, the MIC ranged between 31.25 and 500 μg/mL, while for the antifungal activity test, it varied from 31.25 to 125 μg/mL. In the antibacterial activity test of EPS, the MIC values ranged from 125 to 1,000 μg/mL, whereas in the antifungal susceptibility test, it ranged between 62.5 and 1,000 μg/mL. The most resistant pathogen against TPC was Escherichia coli , while Campylobacter jejuni was the most susceptible. In the case of EPS, the most resistant pathogen was Salmonella Typhimurium, while Aspergillus versicolor exhibited the highest susceptibility. Overall, in terms of antimicrobial activity, TPC was more effective than EPS. Finally, the tolerance level (TL) for TPC and EPS was ≤4 in all tested samples, indicating their bactericidal/fungicidal mechanism of action. In conclusion, TPC and EPS isolated from cryptophytes demonstrated remarkable antimicrobial properties and ability to fully eradicate pathogens, and could be considered as natural preservatives in the food industry., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Abidizadegan, Peltomaa, Ilina, Tammela and Blomster.)

This study presents the discovery of a new series of N -phenylpyrrolamide inhibitors of bacterial DNA gyrase with improved antibacterial activity. The most potent inhibitors had low nanomolar IC 50 values against Escherichia coli DNA gyrase (IC 50 ; 2-20 nM) and E. coli topoisomerase IV (22i, IC 50 = 143 nM). Importantly, none of the compounds showed activity against human DNA topoisomerase IIα, indicating selectivity for bacterial targets. Among the tested compounds, 22e emerged as the most effective against Gram-positive bacteria with minimum inhibitory concentration (MIC) values of 0.25 μg mL -1 against Staphylococcus aureus ATCC 29213 and MRSA, and 0.125 μg mL -1 against Enterococcus faecalis ATCC 29212. For Gram-negative bacteria, compounds 23b and 23c showed the greatest efficacy with MIC values ranging from 4 to 32 μg mL -1 against E. coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Acinetobacter baumannii ATCC 17978 and A. baumannii ATCC 19606. Notably, compound 23b showed promising activity against the clinically relevant Gram-negative pathogen Klebsiella pneumoniae ATCC 10031, with an MIC of 0.0625 μg mL -1 . Furthermore, compounds 23a and 23c exhibited significantly lower susceptibility to resistance development compared to novobiocin in S. aureus ATCC 29213 and K. pneumoniae ATCC 10031. Overall, the most promising compounds of this series showed excellent on-target potency, marking a significant improvement over previous N -phenylpyrrolamide inhibitors., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

A considerable number of antibacterial agents are derived from bacterial metabolites. Similarly, numerous known compounds that impede bacterial virulence stem from bacterial metabolites. Enteropathogenic Escherichia coli (EPEC) is a notable human pathogen causing intestinal infections, particularly affecting infant mortality in developing regions. These infections are characterized by microvilli effacement and intestinal epithelial lesions linked with aberrant actin polymerization. This study aimed to identify potential antivirulence compounds for EPEC infections among bacterial metabolites harvested from marine actinobacteria ( Kocuria sp. and Rhodococcus spp.) from the Arctic Sea by the application of virulence-based screening assays. Moreover, we demonstrate the suitability of these antivirulence assays to screen actinobacteria extract fractions for the bioassay-guided identification of metabolites. We discovered a compound in the fifth fraction of a Kocuria strain that interferes with EPEC-induced actin polymerization without affecting growth. Furthermore, a growth-inhibiting compound was identified in the fifth fraction of a Rhodococcus strain. Our findings include the bioassay-guided identification, HPLC-MS-based dereplication, and isolation of a large phospholipid and a likely antimicrobial peptide, demonstrating the usefulness of this approach in screening for compounds capable of inhibiting EPEC virulence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Pylkkö, Schneider, Rämä, Andersen and Tammela.)

A wide array of carbon materials finds extensive utility across various industrial applications today. Nonetheless, the production processes for these materials continue to entail elevated temperatures, necessitate the use of inert atmospheres, and often involve the handling of aggressive and toxic chemicals. The prevalent method for large-scale carbon material production, namely the pyrolysis of waste biomass and polymers, typically unfolds within the temperature range of 500-700 °C under a nitrogen (N 2 ) atmosphere. Unfortunately, this approach suffers from significant energy inefficiency due to substantial heat loss over extended processing durations. In this work, we propose an interesting alternative: the carbonization of photothermal nanocellulose/polypyrrole composite films through CO 2 laser irradiation in the presence of air. This innovative technique offers a swift and energy-efficient means of preparing carbon materials. The unique interaction between nanocellulose and polypyrrole imparts the film with sufficient stability to retain its structural integrity post-carbonization. This breakthrough opens up new avenues for producing binder-free electrodes using a rapid and straightforward approach. Furthermore, the irradiated film demonstrates specific and areal capacitances of 159 F g -1 and 62 μF cm -2 , respectively, when immersed in a 2 M NaOH electrolyte. These values significantly surpass those achieved by current commercial activated carbons. Together, these attributes render CO 2 -laser carbonization an environmentally sustainable and ecologically friendly method for carbon material production., (© 2024 The Authors. ChemSusChem published by Wiley-VCH GmbH.)

The coronavirus disease 2019 (COVID-19) pandemic has heavily challenged the global healthcare system. Despite the vaccination programs, the new virus variants are circulating. Further research is required for understanding of the biology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and for discovery of therapeutic agents against the virus. Here, we took advantage of drug repurposing to identify if existing drugs could inhibit SARS-CoV-2 infection. We established an open high throughput platform for in vitro screening of drugs against SARS-CoV-2 infection. We screened ∼1000 drugs for their ability to inhibit SARS-CoV-2-induced cell death in the African green monkey kidney cell line (Vero-E6), analyzed how the hit compounds affect the viral N (nucleocapsid) protein expression in human cell lines using high-content microscopic imaging and analysis, determined the hit drug targets in silico, and assessed their ability to cause phospholipidosis, which can interfere with the viral replication. Duvelisib was found by in silico interaction assay as a potential drug targeting virus-host protein interactions. The predicted interaction between PARP1 and S protein, affected by Duvelisib, was further validated by immunoprecipitation. Our results represent a rapidly applicable platform for drug repurposing and evaluation of the new emerging viruses' responses to the drugs. Further in silico studies help us to discover the druggable host pathways involved in the infectious cycle of SARS-CoV-2., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Benzothiazole-based bacterial DNA gyrase and topoisomerase IV inhibitors are promising new antibacterial agents with potent activity against Gram-positive and Gram-negative bacterial strains. The aim of this study was to improve the uptake of these inhibitors into the cytoplasm of Gram-negative bacteria by conjugating them to the small siderophore mimics. The best conjugate 18b displayed potent Escherichia coli DNA gyrase and topoisomerase IV inhibition. The interaction analysis of molecular dynamics simulation trajectory showed the important contribution of the siderophore mimic moiety to binding affinity. By NMR spectroscopy, we demonstrated that the hydroxypyridinone moiety alone was responsible for the chelation of iron(iii). Moreover, 18b showed an enhancement of antibacterial activity against E. coli JW5503 in an iron-depleted medium, clearly indicating an increased uptake of 18b in this bacterial strain., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

This study aimed to identify inhibitors of the translocated intimin receptor (Tir) of enteropathogenic Escherichia coli (EPEC). EPEC is an intestinal pathogen that causes diarrhea and is a major health concern worldwide. Because Tir is a key virulence factor involved in EPEC pathogenesis, inhibiting its function is a potential strategy for controlling EPEC infections. Virtual screening was applied to chemical libraries to search for compounds that inhibit Tir-mediated bacterial adherence to host cells. Three sites were targeted using the cocrystal structure published earlier. A selection of compounds was then assessed in a cell-based infection model and fluorescence microscopy assay. The results of this study provide a basis for further optimization and testing of Tir inhibitors as potential therapeutic agents for EPEC infections., (© 2023 The Authors. ChemBioChem published by Wiley-VCH GmbH.)