Imaging biomarkers in prostate cancer: role of PET/CT and MRI

Prostate-specific antigen (PSA) is currently the most widely used biomarker of prostate cancer (PCa). PSA suggests the presence of primary tumour and disease relapse after treatment, but it is not able to provide a clear distinction between locoregional and distant disease. Molecular and functional imaging, that are able to provide a detailed and comprehensive overview of PCa extension, are more reliable tools for primary tumour detection and disease extension assessment both in staging and restaging. In the present review we evaluate the role of PET/CT and MRI in the diagnosis, staging and restaging of PCa, and the use of these imaging modalities in prognosis, treatment planning and response assessment. Innovative imaging strategies including new radiotracers and hybrid scanners such as PET/MRI are also discussed

DAF-16/FOXO employs the chromatin remodeller SWI/SNF to promote stress resistance and longevity

Organisms are constantly challenged by stresses and privations and require adaptive responses for their survival. The transcription factor DAF-16/FOXO is central nexus in these responses, but despite its importance little is known about how it regulates its target genes. Proteomic identification of DAF-16/FOXO binding partners in Caenorhabditis elegans and their subsequent functional evaluation by RNA interference (RNAi) revealed several candidate DAF-16/FOXO cofactors, most notably the chromatin remodeller SWI/SNF. DAF-16/FOXO and SWI/SNF form a complex and globally colocalize at DAF-16/FOXO target promoters. We show that specifically for gene-activation, DAF-16/FOXO depends on SWI/SNF, facilitating SWI/SNF recruitment to target promoters, in order to activate transcription by presumed remodelling of local chromatin. For the animal, this translates into an essential role of SWI/SNF for DAF-16/FOXO-mediated processes, i.e. dauer formation, stress resistance, and the promotion of longevity. Thus we give insight into the mechanisms of DAF-16/FOXO-mediated transcriptional regulation and establish a critical link between ATP-dependent chromatin remodelling and lifespan regulation

WormBase 2007

WormBase (www.wormbase.org) is the major publicly available database of information about Caenorhabditis elegans, an important system for basic biological and biomedical research. Derived from the initial ACeDB database of C. elegans genetic and sequence information, WormBase now includes the genomic, anatomical and functional information about C. elegans, other Caenorhabditis species and other nematodes. As such, it is a crucial resource not only for C. elegans biologists but the larger biomedical and bioinformatics communities. Coverage of core areas of C. elegans biology will allow the biomedical community to make full use of the results of intensive molecular genetic analysis and functional genomic studies of this organism. Improved search and display tools, wider cross-species comparisons and extended ontologies are some of the features that will help scientists extend their research and take advantage of other nematode species genome sequences

The pharmacological regulation of cellular mitophagy

Small molecules are pharmacological tools of considerable value for dissecting complex biological processes and identifying potential therapeutic interventions. Recently, the cellular quality-control process of mitophagy has attracted considerable research interest; however, the limited availability of suitable chemical probes has restricted our understanding of the molecular mechanisms involved. Current approaches to initiate mitophagy include acute dissipation of the mitochondrial membrane potential (ΔΨm) by mitochondrial uncouplers (for example, FCCP/CCCP) and the use of antimycin A and oligomycin to impair respiration. Both approaches impair mitochondrial homeostasis and therefore limit the scope for dissection of subtle, bioenergy-related regulatory phenomena. Recently, novel mitophagy activators acting independently of the respiration collapse have been reported, offering new opportunities to understand the process and potential for therapeutic exploitation. We have summarized the current status of mitophagy modulators and analyzed the available chemical tools, commenting on their advantages, limitations and current applications

Prevalence of interstitial pneumonia suggestive of COVID-19 at 18F-FDG PET/CT in oncological asymptomatic patients in a high prevalence country during pandemic period: a national multi-centric retrospective study

Purpose: To assess the presence and pattern of incidental interstitial lung alterations suspicious of COVID-19 on fluorine-18-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) ([18F]FDG PET/CT) in asymptomatic oncological patients during the period of active COVID-19 in a country with high prevalence of the virus. Methods: This is a multi-center retrospective observational study involving 59 Italian centers. We retrospectively reviewed the prevalence of interstitial pneumonia detected during the COVID period (between March 16 and 27, 2020) and compared to a pre-COVID period (January\u2013February 2020) and a control time (in 2019). The diagnosis of interstitial pneumonia was done considering lung alterations of CT of PET. Results: Overall, [18F]FDG PET/CT was performed on 4008 patients in the COVID period, 19,267 in the pre-COVID period, and 5513 in the control period. The rate of interstitial pneumonia suspicious for COVID-19 was significantly higher during the COVID period (7.1%) compared with that found in the pre-COVID (5.35%) and control periods (5.15%) (p < 0.001). Instead, no significant difference among pre-COVID and control periods was present. The prevalence of interstitial pneumonia detected at PET/CT was directly associated with geographic virus diffusion, with the higher rate in Northern Italy. Among 284 interstitial pneumonia detected during COVID period, 169 (59%) were FDG-avid (average SUVmax of 4.1). Conclusions: A significant increase of interstitial pneumonia incidentally detected with [18F]FDG PET/CT has been demonstrated during the COVID-19 pandemic. A majority of interstitial pneumonia were FDG-avid. Our results underlined the importance of paying attention to incidental CT findings of pneumonia detected at PET/CT, and these reports might help to recognize early COVID-19 cases guiding the subsequent management

Интраоперационные и онкологические результаты лечения пациентов с почечно-клеточным раком и распространением опухолевого тромба по венозной системе

Background. The general characteristic of renal cell cancer is metastatic invasion of tumor thrombus in the inferior vena cava (IVC). Objective is the evaluation of the results of surgical treatment of patients with renal cell carcinoma and venous tumor thrombus.Materials and methods. During the period from 2011 to April 2017  in the Clinic of Urology at the N.I. Pirogov City Clinical Hospital No. 1 26  radical/cytoreductive nephrectomies with thrombectomy were conducted. Men predominated (n = 20 (76.9 %)) over women (n = 6 (23.1 %)) among the patients. Median age – 64 years (47–82 years). 14 (53.8 %) patients were diagnosed with disease of the right kidney and 12 (46.2 %) of the left kidney. Level I (n = 12 (46.2 %)) – renal vein, perirenal part of the IVC. Level II (n = 8 (30.8 %)) – infrahepatic part of the IVC. Level III (n = 5 (19.2 %)) – retrohepatic part of the IVC. Level IV (n = 1 (3.8 %)) – supradiaphragmatic (intrapericardial, intra-atrial) part of the IVC. Enlarged retroperitoneal lymph nodes were detected in 11 (42.3 %) cases based on the data received from computed tomography scan. 6 (23.1 %) patients were diagnosed with distant metastases at the time of operation: solitary in 4 (15.4 %) cases, multiple in 2 (7.7 %) cases.Results. All interventions ocurred without intraoperative lethality. Median operative time – 212 minutes (140–335 minutes). Blood loss median 300 ml (50–5000 ml). Blood salvage (Cell-Saver) was used on 4 (15.4 %) patients due to major blood loss. In 4 (15.4 %) cases one of single-plane operations was performed (cholecystectomy, atypical hepatic resection, prosthetic repair of abdominal region of aorta, resection of the IV liver segment, left hemicolectomy (T4, malignant invasion in descending colon)). Postoperative complications were registered  in 8 (30.8 %) cases. Lethality in the early (30 days) postoperative period equaled 7.7 % (n = 2).Conclusion. Radical/cytoreductive nephrectomies with thrombectomy from the IVC is a technically complex surgery. It should be performed in expert centers with material and technical resources for such operations.Введение. Особенностью рака почки является метастатическая инвазия опухолевого тромба в нижнюю полую вену (НПВ). Цель исследования – оценка результатов хирургического лечения пациентов с почечно-клеточным раком и распространением опухолевого тромба по венозной системе.Материалы и методы. В период с 2011 г. по апрель 2017 г. в клинике урологии ГКБ № 1 им. Н. И. Пирогова выполнены 26 радикальных / циторедуктивных нефрэктомии с тромбэктомией. Среди пациентов были 20 (76,9 %) мужчин и 6 (23,1 %) женщин. Медиана возраста – 64 года (47–82 года). Заболевание правой почки выявлено у 14 (53,8 %) пациентов, левой – у 12 (46,2 %). Опухолевый тромбоз был классифицирован на 4 уровня: I (n = 12 (46,2 %)) – почечная вена, периренальный отдел НПВ; II (n = 8 (30,8 %)) – подпеченочный отдел НПВ; III (n = 5 (19,2 %)) – внутрипеченочный отдел НПВ; IV (n = 1 (3,8 %)) – наддиафрагмальный (внутриперикардиальный, внутрипредсердный) отдел НПВ. Увеличенные забрюшинные лимфатические узлы по данным компьютерной томографии определялись в 11 (42,3 %) случаях. Отдаленные метастазы на момент операции диагностированы у 6 (23,1 %) пациентов: солитарные – у 4 (15,4 %), множественные – у 2 (7,7 %).Результаты. Все 26 вмешательств были без интраоперационной летальности. Медиана продолжительности операции – 212 мин (140–335 мин). Медиана кровопотери – 300 мл (50–5000 мл). В связи с кровопотерей аппаратную реинфузию (Cell-Saver) крови проводили 4 (15,4 %) пациентам. В 4 (15,4 %) случаях выполнена одна из симультанных операций (холецистэктомия, атипичная резекция печени, протезирование брюшного отдела аорты, резекция IV сегмента печени, СВЧ-абляция метастатического очага VII сегмента печени, гемиколэктомия слева (стадия T4, прорастание опухоли в нисходящую кишку)). Послеоперационные осложнения зарегистрированы у 8 (30,8 %) пациентов. Летальность в раннем послеоперационном периоде (30 дней) составила 7,7 %  (n = 2).Заключение. Радикальная / циторедуктивная нефрэктомия с тромбэктомией из НПВ является технически сложной операцией. Ее необходимо выполнять в экспертных центрах, имеющих материально-техническую базу для подобных вмешательств

Functional Conservation of Cis-Regulatory Elements of Heat-Shock Genes over Long Evolutionary Distances

Transcriptional control of gene regulation is an intricate process that requires precise orchestration of a number of molecular components. Studying its evolution can serve as a useful model for understanding how complex molecular machines evolve. One way to investigate evolution of transcriptional regulation is to test the functions of cis-elements from one species in a distant relative. Previous results suggested that few, if any, tissue-specific promoters from Drosophila are faithfully expressed in C. elegans. Here we show that, in contrast, promoters of fly and human heat-shock genes are upregulated in C. elegans upon exposure to heat. Inducibility under conditions of heat shock may represent a relatively simple “on-off” response, whereas complex expression patterns require integration of multiple signals. Our results suggest that simpler aspects of regulatory logic may be retained over longer periods of evolutionary time, while more complex ones may be diverging more rapidly

Comparative Developmental Expression Profiling of Two C. elegans Isolates

Gene expression is known to change during development and to vary among genetically diverse strains. Previous studies of temporal patterns of gene expression during C. elegans development were incomplete, and little is known about how these patterns change as a function of genetic background. We used microarrays that comprehensively cover known and predicted worm genes to compare the landscape of genetic variation over developmental time between two isolates of C. elegans. We show that most genes vary in expression during development from egg to young adult, many genes vary in expression between the two isolates, and a subset of these genes exhibit isolate-specific changes during some developmental stages. This subset is strongly enriched for genes with roles in innate immunity. We identify several novel motifs that appear to play a role in regulating gene expression during development, and we propose functional annotations for many previously unannotated genes. These results improve our understanding of gene expression and function during worm development and lay the foundation for linkage studies of the genetic basis of developmental variation in gene expression in this important model organism

Chromosome-Biased Binding and Gene Regulation by the Caenorhabditis elegans DRM Complex

DRM is a conserved transcription factor complex that includes E2F/DP and pRB family proteins and plays important roles in development and cancer. Here we describe new aspects of DRM binding and function revealed through genome-wide analyses of the Caenorhabditis elegans DRM subunit LIN-54. We show that LIN-54 DNA-binding activity recruits DRM to promoters enriched for adjacent putative E2F/DP and LIN-54 binding sites, suggesting that these two DNA–binding moieties together direct DRM to its target genes. Chromatin immunoprecipitation and gene expression profiling reveals conserved roles for DRM in regulating genes involved in cell division, development, and reproduction. We find that LIN-54 promotes expression of reproduction genes in the germline, but prevents ectopic activation of germline-specific genes in embryonic soma. Strikingly, C. elegans DRM does not act uniformly throughout the genome: the DRM recruitment motif, DRM binding, and DRM-regulated embryonic genes are all under-represented on the X chromosome. However, germline genes down-regulated in lin-54 mutants are over-represented on the X chromosome. We discuss models for how loss of autosome-bound DRM may enhance germline X chromosome silencing. We propose that autosome-enriched binding of DRM arose in C. elegans as a consequence of germline X chromosome silencing and the evolutionary redistribution of germline-expressed and essential target genes to autosomes. Sex chromosome gene regulation may thus have profound evolutionary effects on genome organization and transcriptional regulatory networks.National Institutes of Health (U.S.) (grant GM24663)National Institutes of Health (U.S.) (grant DK068429)National Institutes of Health (U.S.) (grant GM082971)National Institutes of Health (U.S.) (grant GM076378

Drug discovery: Insights from the invertebrate Caenorhabditis elegans

Therapeutic drug development is a long, expensive, and complex process that usually takes 12–15 years. In the early phases of drug discovery, in particular, there is a growing need for animal models that ensure the reduction in both cost and time. Caenorhabditis elegans has been traditionally used to address fundamental aspects of key biological processes, such as apoptosis, aging, and gene expression regulation. During the last decade, with the advent of large-scale platforms for screenings, this invertebrate has also emerged as an essential tool in the pharmaceutical research industry to identify novel drugs and drug targets. In this review, we discuss the reasons why C. elegans has been positioned as an outstanding cost-effective option for drug discovery, highlighting both the advantages and drawbacks of this model. Particular attention is paid to the suitability of this nematode in large-scale genetic and pharmacological screenings. High-throughput screenings in C. elegans have indeed contributed to the breakthrough of a wide variety of candidate compounds involved in extensive fields including neurodegeneration, pathogen infections and metabolic disorders. The versatility of this nematode, which enables its instrumentation as a model of human diseases, is another attribute also herein underscored. As illustrative examples, we discuss the utility of C. elegans models of both human neurodegenerative diseases and parasitic nematodes in the drug discovery industry. Summing up, this review aims to demonstrate the impact of C. elegans models on the drug discovery pipeline.Fil: Giunti, Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Andersen, Natalia Denise. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Rayes, Diego Hernán. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: de Rosa, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentin