Long-term outcome among men with conservatively treated localised prostate cancer

Optimal management of clinically localised prostate cancer presents unique challenges, because of its highly variable and often indolent natural history. There is an urgent need to predict more accurately its natural history, in order to avoid unnecessary treatment. Medical records of men diagnosed with clinically localised prostate cancer, in the UK, between 1990 and 1996 were reviewed to identify those who were conservatively treated, under age 76 years at the time of pathological diagnosis and had a baseline prostate-specific antigen (PSA) measurement. Diagnostic biopsy specimens were centrally reviewed to assign primary and secondary Gleason grades. The primary end point was death from prostate cancer and multivariate models were constructed to determine its best predictors. A total of 2333 eligible patients were identified. The most important prognostic factors were Gleason score and baseline PSA level. These factors were largely independent and together, contributed substantially more predictive power than either one alone. Clinical stage and extent of disease determined, either from needle biopsy or transurethral resection of the prostate (TURP) chips, provided some additional prognostic information. In conclusion, a model using Gleason score and PSA level identified three subgroups comprising 17, 50, and 33% of the cohort with a 10-year prostate cancer specific mortality of <10, 10–30, and >30%, respectively. This classification is a substantial improvement on previous ones using only Gleason score, but better markers are needed to predict survival more accurately in the intermediate group of patients

Spatial and single-cell profiling of the metabolome, transcriptome and epigenome of the aging mouse liver

Tissues within an organism and even cell types within a tissue can age with different velocities. However, it is unclear whether cells of one type experience different aging trajectories within a tissue depending on their spatial location. Here, we used spatial transcriptomics in combination with single-cell ATAC-seq and RNA-seq, lipidomics and functional assays to address how cells in the male murine liver are affected by age-related changes in the microenvironment. Integration of the datasets revealed zonation-specific and age-related changes in metabolic states, the epigenome and transcriptome. The epigenome changed in a zonation-dependent manner and functionally, periportal hepatocytes were characterized by decreased mitochondrial fitness, whereas pericentral hepatocytes accumulated large lipid droplets. Together, we provide evidence that changing microenvironments within a tissue exert strong influences on their resident cells that can shape epigenetic, metabolic and phenotypic outputs

Wolbachia Bacteria Reside in Host Golgi-Related Vesicles Whose Position Is Regulated by Polarity Proteins

Wolbachia pipientis are intracellular symbiotic bacteria extremely common in various organisms including Drosophila melanogaster, and are known for their ability to induce changes in host reproduction. These bacteria are present in astral microtubule-associated vesicular structures in host cytoplasm, but little is known about the identity of these vesicles. We report here that Wolbachia are restricted only to a group of Golgi-related vesicles concentrated near the site of membrane biogenesis and minus-ends of microtubules. The Wolbachia vesicles were significantly mislocalized in mutant embryos defective in cell/planar polarity genes suggesting that cell/tissue polarity genes are required for apical localization of these Golgi-related vesicles. Furthermore, two of the polarity proteins, Van Gogh/Strabismus and Scribble, appeared to be present in these Golgi-related vesicles. Thus, establishment of polarity may be closely linked to the precise insertion of Golgi vesicles into the new membrane addition site

Who Needs Microtubules? Myogenic Reorganization of MTOC, Golgi Complex and ER Exit Sites Persists Despite Lack of Normal Microtubule Tracks

A wave of structural reorganization involving centrosomes, microtubules, Golgi complex and ER exit sites takes place early during skeletal muscle differentiation and completely remodels the secretory pathway. The mechanism of these changes and their functional implications are still poorly understood, in large part because all changes occur seemingly simultaneously. In an effort to uncouple the reorganizations, we have used taxol, nocodazole, and the specific GSK3-β inhibitor DW12, to disrupt the dynamic microtubule network of differentiating cultures of the mouse skeletal muscle cell line C2. Despite strong effects on microtubules, cell shape and cell fusion, none of the treatments prevented early differentiation. Redistribution of centrosomal proteins, conditional on differentiation, was in fact increased by taxol and nocodazole and normal in DW12. Redistributions of Golgi complex and ER exit sites were incomplete but remained tightly linked under all circumstances, and conditional on centrosomal reorganization. We were therefore able to uncouple microtubule reorganization from the other events and to determine that centrosomal proteins lead the reorganization hierarchy. In addition, we have gained new insight into structural and functional aspects of the reorganization of microtubule nucleation during myogenesis

20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years

The administration of endocrine therapy for 5 years substantially reduces recurrence rates during and after treatment in women with early-stage, estrogen-receptor (ER)-positive breast cancer. Extending such therapy beyond 5 years offers further protection but has additional side effects. Obtaining data on the absolute risk of subsequent distant recurrence if therapy stops at 5 years could help determine whether to extend treatment

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field

Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials

Background Neoadjuvant chemotherapy (NACT) for early breast cancer can make breast-conserving surgery more feasible and might be more likely to eradicate micrometastatic disease than might the same chemotherapy given after surgery. We investigated the long-term benefits and risks of NACT and the influence of tumour characteristics on outcome with a collaborative meta-analysis of individual patient data from relevant randomised trials. Methods We obtained information about prerandomisation tumour characteristics, clinical tumour response, surgery, recurrence, and mortality for 4756 women in ten randomised trials in early breast cancer that began before 2005 and compared NACT with the same chemotherapy given postoperatively. Primary outcomes were tumour response, extent of local therapy, local and distant recurrence, breast cancer death, and overall mortality. Analyses by intention-to-treat used standard regression (for response and frequency of breast-conserving therapy) and log-rank methods (for recurrence and mortality). Findings Patients entered the trials from 1983 to 2002 and median follow-up was 9 years (IQR 5–14), with the last follow-up in 2013. Most chemotherapy was anthracycline based (3838 [81%] of 4756 women). More than two thirds (1349 [69%] of 1947) of women allocated NACT had a complete or partial clinical response. Patients allocated NACT had an increased frequency of breast-conserving therapy (1504 [65%] of 2320 treated with NACT vs 1135 [49%] of 2318 treated with adjuvant chemotherapy). NACT was associated with more frequent local recurrence than was adjuvant chemotherapy: the 15 year local recurrence was 21·4% for NACT versus 15·9% for adjuvant chemotherapy (5·5% increase [95% CI 2·4–8·6]; rate ratio 1·37 [95% CI 1·17–1·61]; p=0·0001). No significant difference between NACT and adjuvant chemotherapy was noted for distant recurrence (15 year risk 38·2% for NACT vs 38·0% for adjuvant chemotherapy; rate ratio 1·02 [95% CI 0·92–1·14]; p=0·66), breast cancer mortality (34·4% vs 33·7%; 1·06 [0·95–1·18]; p=0·31), or death from any cause (40·9% vs 41·2%; 1·04 [0·94–1·15]; p=0·45). Interpretation Tumours downsized by NACT might have higher local recurrence after breast-conserving therapy than might tumours of the same dimensions in women who have not received NACT. Strategies to mitigate the increased local recurrence after breast-conserving therapy in tumours downsized by NACT should be considered—eg, careful tumour localisation, detailed pathological assessment, and appropriate radiotherapy

Πλήρης αντικατάσταση των πετρελαϊκών μονάδων ηλεκτροπαραγωγής της Αμοργού με εγκαταστάσεις Ανανεώσιμων Πηγών Ενέργειας

190 σ.Όπως δείχνουν πολυάριθμες έρευνες, οι εκπομπές αερίων του θερμοκηπίου στην ατμόσφαιρα είναι ήδη πάρα πολύ υψηλές, και αναμένεται να αυξηθούν ακόμα περισσότερο τα επόμενα χρόνια. Έτσι, ο πλανήτης δεν μπορεί να απορροφήσει όλη αυτή τη ρύπανση, με αποτέλεσμα να αυξάνεται η μέση θερμοκρασία, με όλες τις δυσμενείς επιπτώσεις που προκαλεί αυτό. Η ηλεκτροπαραγωγή έχει μεγάλο μερίδιο ευθύνης για την υπερβολική εκπομπή αερίων του θερμοκηπίου. Είναι, λοιπόν, αναγκαίο να προσπαθήσουμε να υποκαταστήσουμε τις ρυπογόνες μονάδες που βασίζονται στα ορυκτά καύσιμα με μονάδες ανανεώσιμων πηγών ενέργειας, ώστε να μετριάσουμε την κλιματική αλλαγή. Ιδανικό μέρος για να δοκιμασθεί μία τέτοια μετάβαση είναι τα αυτόνομα νησιωτικά συστήματα των Ελληνικών νησιών. Η εργασία αυτή μελετά την πλήρη υποκατάσταση των πετρελαϊκών μονάδων της Αμοργού με μονάδες ανανεώσιμων πηγών ενέργειας. Για να επιτευχθεί μία αξιόπιστη ενεργειακή μελέτη σε ένα σύστημα όπου η ηλεκτροπαραγωγή βασίζεται αποκλειστικά σε μονάδες ΑΠΕ, είναι απαραίτητη η ύπαρξη ωριαίων χρονοσειρών για την ταχύτητα του ανέμου καθώς και για την ηλιακή ακτινοβολία στο νησί. Δυστυχώς, τέτοια δεδομένα δεν είναι διαθέσιμα. Συνεπώς, είναι αναγκαία η παραγωγή συνθετικών ωριαίων χρονοσειρών, μέσω στοχαστικών μεθόδων, από τα λιγοστά δεδομένα που υπάρχουν για την Αμοργό. Στη συνέχεια πραγματοποιείται μία ενεργειακή μελέτη όπου αναλύονται τα χαρακτηριστικά του φορτίου του νησιού καθώς και η υπάρχουσα δομή της ηλεκτροπαραγωγής, όπου διαπιστώνεται πως σήμερα η ηλεκτρική ενέργεια στην Αμοργό είναι πολύ ακριβή και ρυπογόνος. Έπειτα, παρουσιάζονται δύο εναλλακτικές για την πλήρη υποκατάσταση των πετρελαϊκών μονάδων από μονάδες ΑΠΕ: Μία υβριδική περίπτωση φωτοβολταϊκών-αιολικών-αποθήκευσης χωρίς τη χρήση βιομάζας και μία άλλη υβριδική περίπτωση φωτοβολταϊκών-αιολικών-αποθήκευσης με χρήση βιομάζας. Οι δύο αυτές εναλλακτικές συγκρίνονται μεταξύ τους ως προς το κόστος της ενέργειας και ως προς άλλες παραμέτρους και σχολιάζεται η συμμετοχή της βιομάζας στην ηλεκτροπαραγωγή. Τέλος, πραγματοποιείται μια μελέτη πραγματοποίησης-εγκατάστασης ενός υβριδικού συστήματος αιολικού πάρκου-αποθήκευσης το οποίο αναλαμβάνει από μόνο του να τροφοδοτήσει το σύνολο του φορτίου της Αμοργού. Απαντώνται θεμελιώδεις ερωτήσεις που αφορούν τον έλεγχο της τάσης και της συχνότητας καθώς και την ποιότητα της ισχύος στο φορτίο. Εξηγείται αν είναι δυνατή η εγκατάσταση ενός τέτοιου συστήματος σήμερα, καθώς και το πόσο κοντά είμαστε στην πλήρη ηλεκτροδότηση από ανανεώσιμες πηγές ενέργειας.As proved by numerous studies, greenhouse gas emissions are already dangerously high and are expected to rise even more in the next few years. Consequently, our planet would not be able to absorb this pollution, which is likely to worsen global warming, with all the negative implications that will follow. Unfortunately, electricity generation has the lion share in the excessive emission of air pollutants. Thus, it is necessary to try to substitute the units that depend on fossil fuels with units that operate with renewable energy sources. Ideal places for trying this transition are the autonomous island systems of the Aegean Islands. This study aims to the complete substitution of diesel generators in Amorgos island, with renewable energy sources. In order to achieve a reliable energy study in a system where the electricity production depends only on renewable energy sources, it is necessary to obtain hourly time-series for wind speed and solar radiation. Unfortunately, such data are not available for Amorgos island. As a consequence, it is necessary to generate synthetic time series through stochastic methods from the poor data available for the island. Then, a pre-feasibility energy study is conducted where load characteristics and current coverage are analyzed. Then, two alternatives for the complete substitution of diesel units from renewable energy sources are presented: One hybrid PV-Wind-Storage case without the use of biomass and one other hybrid PV-Wind-Storage case which includes biomass. The two alternatives are compared between them regarding the cost of energy and the participation of biomass in the electricity generation is commented. Then, the new, renewable, system is compared with the current one in the fields of energy cost and emissions. Finally, a feasibility study of a hybrid wind-storage system which would cover the whole load by itself is conducted. Several fundamental questions are answered, regarding voltage and frequency control as well as load’s power quality. Then, it is explained whether the installation of such a system today is feasible or how close we are regarding electricity generation only from renewable sources.Γεώργιος Π. Κονδύλη