Search

Summary: Background: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolonged life in patients with metastatic castration-resistant prostate cancer (mCRPC) in VISION (NCT03511664). However, distinguishing between patients likely and unlikely to respond remains a clinical challenge. We present the first multivariable models of outcomes with 177Lu-PSMA-617 built using data from VISION, a large prospective phase 3 clinical trial powered for overall survival. Methods: Adults with progressive post androgen receptor pathway inhibitor and taxane prostate-specific membrane antigen (PSMA)-positive mCRPC received 177Lu-PSMA-617 plus protocol-permitted standard of care (SoC) or SoC alone. In this post hoc analysis, multivariable Cox proportional hazards models of overall survival (OS) and radiographic progression-free survival (rPFS), and a logistic regression model of prostate-specific antigen response (≥50% decline; PSA50) were constructed and evaluated using C-index or receiver operating characteristic (ROC) analyses with bootstrapping validation. Nomograms were constructed for visualisation. Findings: Patients were randomised between June 2018 and October 2019. Data from all 551 patients in the 177Lu-PSMA-617 arm were analysed in multivariable modelling. The OS nomogram (C-index, 0.73; 95% confidence interval [CI], 0.70–0.76) included whole-body maximum standardised uptake value (SUVmax), time since diagnosis, opioid analgesic use, aspartate aminotransferase, haemoglobin, lymphocyte count, presence of PSMA-positive lesions in lymph nodes, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and neutrophil count. The rPFS nomogram (C-index, 0.68; 0.65–0.72) included SUVmax, time since diagnosis, opioid analgesic use, lymphocyte count, presence of liver metastases by computed tomography, LDH, and ALP. The PSA50 nomogram (area under ROC curve, 0.72; 95% CI, 0.68–0.77) included SUVmax, lymphocyte count and ALP. Performances of the OS and rPFS models were maintained when they were reconstructed excluding SUVmax. Interpretation: These models of outcomes with 177Lu-PSMA-617 are the first built using prospective phase 3 data. They show that a combination of pretreatment laboratory, clinical, and imaging parameters, reflecting both patient and tumour status, influences outcomes. These models are important for aiding treatment selection, patient management, and clinical trial design. Funding: Novartis.

BackgroundMicrovascular invasion is a major histopathological risk factor of postoperative recurrence in patients with hepatocellular carcinoma. This study aimed to develop and validate a digital biopsy model using imaging features to predict microvascular invasion before hepatectomy.MethodsA total of 217 consecutive patients who underwent hepatectomy for resectable hepatocellular carcinoma were enrolled at two tertiary-care reference centers. An imaging-based digital biopsy model was developed and internally validated using logistic regression analysis with adjustments for age, sex, etiology of disease, size and number of lesions.ResultsThree imaging features, i.e., non-smoothness of lesion margin (OR = 16.40), ill-defined pseudocapsula (OR = 4.93), and persistence of intratumoral internal artery (OR = 10.50), were independently associated with microvascular invasion and incorporated into a prediction model. A scoring system with 0 - 3 points was established for the prediction model. Internal validation confirmed an excellent calibration of the model. A cutoff of 2 points indicates a high risk of microvascular invasion (area under the curve 0.87). The overall survival and recurrence-free survival stratified by the risk model was significantly shorter in patients with high risk features of microvascular invasion compared to those patients with low risk of microvascular invasion (overall survival: median 35 vs. 75 months, P = 0.027; recurrence-free survival: median 17 vs. 38 months, P < 0.001)).ConclusionA preoperative assessment of microvascular invasion by digital biopsy is reliable, easily applicable, and might facilitate personalized treatment strategies.

Abstract Growing urban population and contemporary urban systems lock-in unsustainable urban development pathways, deteriorating the living quality of urban dwellers. The systemic complexity of these challenges renders it difficult to find solutions using existing planning processes. Alternatively, transformative planning processes are radical, take place on multiple scales, and are often irreversible; therefore, require the integration of local stakeholders’ perspectives, which are often contradictory. We identify perceived levers of urban transformative change using a serious game to facilitate the integration of these perspectives through simulating neighbourhood transformation processes in two European case studies. Building on existing transformation frameworks, we organize, conceptualize, and compare the effectiveness of these levers through demonstrating their interactions with different scales of transformation. Specifically, drawing from close commonalities between large-scale (Three Spheres of Transformation) and place-based (Place-making) transformation frameworks, we show how these interactions can help to develop recommendations to unlock urban transformative change. Results show that access to participation is a key lever enabling urban transformative change. It appears to be mid-level effective to unlock urban transformative change through interactions with the political sphere of transformation and procedural element of Place-making. Ultimately, however, most effective are those levers that interact with all scales of transformation. For example, by engaging a combination of levers including access to participation, public spaces, parking, place-characteristics and place-identity. These findings could be operationalized by self-organized transformation processes focused on repurposing hard infrastructure into public spaces, whilst ensuring continuity of place-based social- and physical features. Local stakeholders could further use such processes to better understand and engage with their individual roles in the transformative process, because interactions with the personal scale, i.e., personal sphere of transformation appear paramount to unlock urban transformative change.

Resumen La intención de este trabajo es analizar si el suicidio siempre es moralmente reprobable. Para ello, se expondrán y evaluarán los argumentos propuestos por Kant, uno de los más fervientes detractores del suicidio. El prusiano consideraba que el suicidio resultaba incondicionalmente reprochable al representar el aniquilamiento de la naturaleza racional y, por tanto, de la dignidad humana. Ahora, condenar de forma absoluta el suicidio es problemático, puesto que se pueden legitimar conductas o estados que contrarían, justamente, la dignidad humana. Por consiguiente, en aras de exponer la viabilidad moral del suicidio, se resaltará la importancia de considerar, antes de juzgar el acto, las circunstancias en que es consumado el suicidio y, asimismo, el posible daño que éste pueda llagar a representar para el individuo y la sociedad. Abstract The purpose of this paper is to analyze whether suicide is always morally reprehensible. In this regard, we will examine the arguments put forth by Kant, one of the most fervent critics of suicide. Kant considered suicide to be unconditionally reprehensible, as it represented the annihilation of rational nature and, consequently, human dignity. However, an absolute condemnation of suicide poses problems, as it may legitimize behaviors contrary to human dignity. Therefore, in order to explore the moral viability of suicide, we will emphasize the importance of considering the circumstances in which the act occurs and the potential harm it may represent for the individual and society.

Abstract Background Bone biopsies in metastatic castrate-resistant prostate cancer (mCRPC) patients can be challenging. This study’s objective was to prospectively validate a multiparametric bone MRI (mpBMRI) algorithm to facilitate target lesion selection in mCRPC patients with sclerotic bone disease for subsequent CT-guided bone biopsies. Methods 20 CT-guided bone biopsies were prospectively performed between 02/2021 and 11/2021 in 17 mCRPC patients with only sclerotic bone disease. Biopsy targets were selected based on MRI, including diffusion-weighted (DWI) and T1-weighted VIBE Dixon MR images, allowing for calculation of the apparent diffusion coefficient (ADC) and the relative fat-fraction (rFF), respectively. Bone marrow with high DWI signal, ADC 0.137). Lesion mean HU was 387 ± 187 HU in NGS feasible and 493 ± 218 HU in non-feasible biopsies (p = 0.521). For targets fulfilling all MRI selection algorithm criteria, 13/14 (93%) biopsies were tumor-positive and 10/12 (83%) provided NGS adequate tissue. Conclusions Multiparametric bone MRI can facilitate target lesion selection for subsequent CT-guided bone biopsy in mCPRC patients with sclerotic metastases. Trial registration Committee for Clinical Research of the Royal Marsden Hospital registration number SE1220.

Background and purposeMobile stroke units (MSU) have been demonstrated to improve prehospital stroke care in metropolitan and rural regions. Due to geographical, social and structural idiosyncrasies of the German city of Mannheim, concepts of established MSU services are not directly applicable to the Mannheim initiative. The aim of the present analysis was to identify major determinants that need to be considered when initially setting up a local MSU service.MethodsLocal stroke statistics from 2015 to 2021 were analyzed and circadian distribution of strokes and local incidence rates were calculated. MSU patient numbers and total program costs were estimated for varying operating modes, daytime coverage models, staffing configurations which included several resource sharing models with the hospital. Additional case-number simulations for expanded catchment areas were performed.ResultsMedian time of symptom onset of ischemic stroke patients was 1:00 p.m. 54.3% of all stroke patients were admitted during a 10-h time window on weekdays. Assuming that MSU is able to reach 53% of stroke patients, the average expected number of ischemic stroke patients admitted to MSU would be 0.64 in a 10-h shift each day, which could potentially be increased by expanding the MSU catchment area. Total estimated MSU costs amounted to € 815,087 per annum. Teleneurological assessment reduced overall costs by 11.7%.ConclusionThis analysis provides a framework of determinants and considerations to be addressed during the design process of a novel MSU program in order to balance stroke care improvements with the sustainable use of scarce resources.

The clinical use of photon-counting CT (PCCT) allows for the generation of virtual non-contrast (VNC) series from contrast-enhanced images. In routine clinical practice, specific issues such as ruling out acute bleeding require non-contrast images. The aim of this study is to evaluate the use of PCCT-derived VNC reconstructions in abdominal imaging. PCCT scans of 17 patients including early arterial, portal venous and native sequences were enrolled. VNC reconstructions have been calculated. In every sequence and VNC reconstruction, 10 ROIs were measured (portal vein, descending aorta, inferior vena cava, liver parenchyma, spleen parenchyma, erector spinae muscle, subcutaneous adipose tissue, first lumbar vertebral body, air, and psoas muscle) and density values were compared. The VNC reconstructions show significant changes in density compared to the contrast-enhanced images. However, there were no significant differences present between the true non-contrast (TNC) and any VNC reconstructions in the observed organs and vessels. Significant differences (p < 0.05) between the measured mean density values in the TNC versus VNC reconstructions were found in fat and bone tissue. The PCCT-derived VNC reconstructions seemed to be comparable to the TNC images, despite some deviations shown in the adipose tissue and bone structures. However, the further benefits in terms of specific clinical issues need to be evaluated.

IntroductionWe previously reported that cholesterol homeostasis in prostate cancer (PC) is regulated by 27-hydroxycholesterol (27HC) and that CYP27A1, the enzyme that converts cholesterol to 27HC, is frequently lost in PCs. We observed that restoring the CYP27A1/27HC axis inhibited PC growth. In this study, we investigated the mechanism of 27HC-mediated anti-PC effects.MethodsWe employed in vitro models and human transcriptomics data to investigate 27HC mechanism of action in PC. LNCaP (AR+) and DU145 (AR-) cells were treated with 27HC or vehicle. Transcriptome profiling was performed using the Affymetrix GeneChip™ microarray system. Differential expression was determined, and gene set enrichment analysis was done using the GSEA software with hallmark gene sets from MSigDB. Key changes were validated at mRNA and protein levels. Human PC transcriptomes from six datasets were analyzed to determine the correlation between CYP27A1 and DNA repair gene expression signatures. DNA damage was assessed via comet assays.ResultsTranscriptome analysis revealed 27HC treatment downregulated Hallmark pathways related to DNA damage repair, decreased expression of FEN1 and RAD51, and induced “BRCAness” by downregulating genes involved in homologous recombination regulation in LNCaP cells. Consistently, we found a correlation between higher CYP27A1 expression (i.e., higher intracellular 27HC) and decreased expression of DNA repair gene signatures in castration-sensitive PC (CSPC) in human PC datasets. However, such correlation was less clear in metastatic castration-resistant PC (mCRPC). 27HC increased expression of DNA damage repair markers in PC cells, notably in AR+ cells, but no consistent effects in AR- cells and decreased expression in non-neoplastic prostate epithelial cells. While testing the clinical implications of this, we noted that 27HC treatment increased DNA damage in LNCaP cells via comet assays. Effects were reversible by adding back cholesterol, but not androgens. Finally, in combination with olaparib, a PARP inhibitor, we showed additive DNA damage effects.DiscussionThese results suggest 27HC induces “BRCAness”, a functional state thought to increase sensitivity to PARP inhibitors, and leads to increased DNA damage, especially in CSPC. Given the emerging appreciation that defective DNA damage repair can drive PC growth, future studies are needed to test whether 27HC creates a synthetic lethality to PARP inhibitors and DNA damaging agents in CSPC.

Aberrant androgen receptor (AR) signaling drives prostate cancer (PC), and it is a key therapeutic target. Although initially effective, the generation of alternatively spliced AR variants (AR-Vs) compromises efficacy of treatments. In contrast to full-length AR (AR-FL), AR-Vs constitutively activate androgenic signaling and are refractory to the current repertoire of AR-targeting therapies, which together drive disease progression. There is an unmet clinical need, therefore, to develop more durable PC therapies that can attenuate AR-V function. Exploiting the requirement of coregulatory proteins for AR-V function has the capacity to furnish tractable routes for attenuating persistent oncogenic AR signaling in advanced PC. DNA-PKcs regulates AR-FL transcriptional activity and is upregulated in both early and advanced PC. We hypothesized that DNA-PKcs is critical for AR-V function. Using a proximity biotinylation approach, we demonstrated that the DNA-PK holoenzyme is part of the AR-V7 interactome and is a key regulator of AR-V–mediated transcription and cell growth in models of advanced PC. Crucially, we provide evidence that DNA-PKcs controls global splicing and, via RBMX, regulates the maturation of AR-V and AR-FL transcripts. Ultimately, our data indicate that targeting DNA-PKcs attenuates AR-V signaling and provide evidence that DNA-PKcs blockade is an effective therapeutic option in advanced AR-V–positive patients with PC.

Abstract Background Molecular measurements of the genome, the transcriptome, and the epigenome, often termed multi-omics data, provide an in-depth view on biological systems and their integration is crucial for gaining insights in complex regulatory processes. These data can be used to explain disease related genetic variants by linking them to intermediate molecular traits (quantitative trait loci, QTL). Molecular networks regulating cellular processes leave footprints in QTL results as so-called trans-QTL hotspots. Reconstructing these networks is a complex endeavor and use of biological prior information can improve network inference. However, previous efforts were limited in the types of priors used or have only been applied to model systems. In this study, we reconstruct the regulatory networks underlying trans-QTL hotspots using human cohort data and data-driven prior information. Methods We devised a new strategy to integrate QTL with human population scale multi-omics data. State-of-the art network inference methods including BDgraph and glasso were applied to these data. Comprehensive prior information to guide network inference was manually curated from large-scale biological databases. The inference approach was extensively benchmarked using simulated data and cross-cohort replication analyses. Best performing methods were subsequently applied to real-world human cohort data. Results Our benchmarks showed that prior-based strategies outperform methods without prior information in simulated data and show better replication across datasets. Application of our approach to human cohort data highlighted two novel regulatory networks related to schizophrenia and lean body mass for which we generated novel functional hypotheses. Conclusions We demonstrate that existing biological knowledge can improve the integrative analysis of networks underlying trans associations and generate novel hypotheses about regulatory mechanisms.

Outcome research that supports guideline recommendations for primary and secondary preventions largely depends on the data obtained from clinical trials or selected hospital populations. The exponentially growing amount of real-world medical data could enable fundamental improvements in cardiovascular disease (CVD) prediction, prevention, and care. In this review we summarize how data from health insurance claims (HIC) may improve our understanding of current health provision and identify challenges of patient care by implementing the perspective of patients (providing data and contributing to society), physicians (identifying at-risk patients, optimizing diagnosis and therapy), health insurers (preventive education and economic aspects), and policy makers (data-driven legislation). HIC data has the potential to inform relevant aspects of the healthcare systems. Although HIC data inherit limitations, large sample sizes and long-term follow-up provides enormous predictive power. Herein, we highlight the benefits and limitations of HIC data and provide examples from the cardiovascular field, i.e. how HIC data is supporting healthcare, focusing on the demographical and epidemiological differences, pharmacotherapy, healthcare utilization, cost-effectiveness and outcomes of different treatments. As an outlook we discuss the potential of using HIC-based big data and modern artificial intelligence (AI) algorithms to guide patient education and care, which could lead to the development of a learning healthcare system and support a medically relevant legislation in the future.

PARP inhibitor (PARPi) therapy has demonstrated only modest efficacy in advanced breast cancer with BRCA mutations. Here the authors show that, by suppressing PARPi-triggered DNA damage and reducing dsDNA production in BRCA1-deficient breast tumor cells, tumor associated macrophages contribute to PARPi resistance, that can be overcome by STING agonism.

Malignant transformation is characterised by aberrant phospholipid metabolism of cancers, associated with the upregulation of choline kinase alpha (CHKα). Due to the metabolic instability of choline radiotracers and the increasing use of late-imaging protocols, we developed a more stable choline radiotracer, [18F]fluoromethyl-[1,2-2H4]choline ([18F]D4-FCH). [18F]D4-FCH has improved protection against choline oxidase, the key choline catabolic enzyme, via a 1H/2D isotope effect, together with fluorine substitution. Due to the promising mechanistic and safety profiles of [18F]D4-FCH in vitro and preclinically, the radiotracer has transitioned to clinical development. [18F]D4-FCH is a safe positron emission tomography (PET) tracer, with a favourable radiation dosimetry profile for clinical imaging. [18F]D4-FCH PET/CT in lung and prostate cancers has shown highly heterogeneous intratumoral distribution and large lesion variability. Treatment with abiraterone or enzalutamide in metastatic castrate-resistant prostate cancer patients elicited mixed responses on PET at 12–16 weeks despite predominantly stable radiological appearances. The sum of the weighted tumour-to-background ratios (TBRs-wsum) was associated with the duration of survival.

Abstract Background Elevated tissue factor (TF) expression, although restricted in normal tissue, has been reported in multiple solid cancers, and expression has been associated with poor prognosis. This manuscript compares TF expression across various solid tumor types via immunohistochemistry in a single study, which has not been performed previously. Aims To increase insight in the prevalence and cellular localization of TF expression across solid cancer types, we performed a detailed and systematic analysis of TF expression in tumor tissue obtained from patients with ovarian, esophageal, bladder, cervical, endometrial, pancreatic, prostate, colon, breast, non‐small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), and glioblastoma. The spatial and temporal variation of TF expression was analyzed over time and upon disease progression in patient‐matched biopsies taken at different timepoints. In addition, TF expression in patient‐matched primary tumor and metastatic lesions was also analyzed. Methods and Results TF expression was detected via immunohistochemistry (IHC) using a validated TF‐specific antibody. TF was expressed in all cancer types tested, with highest prevalence in pancreatic cancer, cervical cancer, colon cancer, glioblastoma, HNSCC, and NSCLC, and lowest in breast cancer. Staining was predominantly membranous in pancreatic, cervical, and HNSCC, and cytoplasmic in glioblastoma and bladder cancer. In general, expression was consistent between biopsies obtained from the same patient over time, although variability was observed for individual patients. NSCLC biopsies of primary tumor and matched lymph node metastases showed no clear difference in TF expression overall, although individual patient changes were observed. Conclusion This study shows that TF is expressed across a broad range of solid cancer types, and expression is present upon tumor dissemination and over the course of treatment.

Introduction: Immune checkpoint inhibitors (ICIs) are increasingly a standard of care for many cancers; these agents can result in immune-related adverse events (irAEs) including fever, which is common but can rarely be associated with systemic immune activation (SIA or acquired HLH). Methods: All consecutive patients receiving ICIs in the Drug Development Unit of the Royal Marsden Hospital between May 2014 and November 2019 were retrospectively reviewed. Patients with fever ≥ 38°C or chills/rigors (without fever) ≤ 6 weeks of commencing ICIs were identified for clinical data collection. Results: Three patients met diagnostic criteria for SIA/HLH with median time to onset of symptoms of 10 days. We describe the clinical evolution, treatment used, and outcomes for these patients. High-dose steroids are used first-line with other treatments, such as tocilizumab, immunoglobulin and therapeutic plasmapheresis can be considered for steroid-refractory SIA/HLH. Conclusion: SIA/HLH post ICI is a rare but a potentially fatal irAE that presents with fever and a constellation of nonspecific symptoms. Early recognition and timely treatment are key to improving outcomes.

Background and purpose: Chemotherapy-induced neutropenia and neutrophil-to-lymphocyte ratio (NLR) are potentially useful prognostic markers in patients with metastatic castration-resistant prostate cancer (mCRPC). This post hoc analysis investigated whether these markers can be utilized for dose considerations and evaluated the prognostic impact of leukocyte subtypes. Patients and methods: PROSELICA assessed the non-inferiority of cabazitaxel 20 mg/m 2 (C20; n = 598) versus 25 mg/m 2 (C25; n = 602) for overall survival (OS) in patients with mCRPC previously treated with docetaxel. The association of grade ⩾ 3 neutropenia, NLR, baseline neutrophilia and lymphopenia with OS, progression-free survival (PFS), and prostate-specific antigen response rate (PSArr) was investigated by an unplanned uni- and multivariate analyses. Results: PROSELICA confirmed the negative prognostic value of increased baseline NLR [⩾3, hazard ratio (HR) 1.40; p

AimsOligoprogression is poorly defined in current literature. Little is known about the natural history and significance of oligoprogression in patients with hormone-resistant prostate cancer on abiraterone or enzalutamide treatment [termed androgen receptor-targeted therapy (ARTT)]. The aim of this study was to determine the prevalence of oligoprogression, describe the characteristics of oligoprogression in a cohort of patients from a single center, and identify the number of patients potentially treatable with stereotactic body radiotherapy (SBRT).MethodsCastration-resistant prostate cancer (CRPC) patients who radiologically progressed while on ARTT were included. Patients with oligoprogressive disease (OPD) (≤3 lesions) on any imaging were identified in a retrospective analysis of electronic patient records. Kaplan–Meier method and log-rank test were used to calculate progression-free and overall survival.ResultsA total of 102 patients with metastatic CRPC on ARTT were included. Thirty (29%) patients presented with oligoprogression (46 lesions in total); 21 (21% of total) patients had lesions suitable for SBRT. The majority of lesions were in the bone (21, 46%) or lymph nodes (15, 33%). Patients with oligoprogression while on ARTT had a significantly better prostate-specific antigen (PSA) response on commencing ARTT as compared to patients who later developed polyprogression. However, PSA doubling time immediately prior to progression did not predict OPD. Median progression-free survival to oligoprogression versus polyprogression was 16.8 vs. 11.7 months. Time to further progression after oligoprogression was 13.6 months in those treated with radiotherapy (RT) for oligoprogression vs. 5.7 months in those treated with the continuation of ARTT alone.ConclusionsIn this study, nearly a third of patients on ARTT for CRPC were found to have OPD. OPD patients had a better PSA response on ART and a longer duration on ARTT before developing OPD as compared to those developing polyprogressive disease (Poly-PD). The majority of patients (70%) with OPD had lesions suitable for SBRT treatment. Prospective randomized control trials are needed to establish if there is a survival benefit of SBRT in oligoprogressive prostate cancer and to determine predictive indicators.

Coronary artery disease (CAD) is a complex, multifactorial disease caused, in particular, by inflammation and cholesterol metabolism. At the molecular level, the role of tissue-specific signaling pathways leading to CAD is still largely unexplored. This study relied on two main resources: (1) genes with impact on atherosclerosis/CAD, and (2) liver-specific transcriptome analyses from human and mouse studies. The transcription factor activating transcription factor 3 (ATF3) was identified as a key regulator of a liver network relevant to atherosclerosis and linked to inflammation and cholesterol metabolism. ATF3 was predicted to be a direct and indirect (via MAF BZIP Transcription Factor F (MAFF)) regulator of low-density lipoprotein receptor (LDLR). Chromatin immunoprecipitation DNA sequencing (ChIP-seq) data from human liver cells revealed an ATF3 binding motif in the promoter regions of MAFF and LDLR. siRNA knockdown of ATF3 in human Hep3B liver cells significantly upregulated LDLR expression (p < 0.01). Inflammation induced by lipopolysaccharide (LPS) stimulation resulted in significant upregulation of ATF3 (p < 0.01) and subsequent downregulation of LDLR (p < 0.001). Liver-specific expression data from human CAD patients undergoing coronary artery bypass grafting (CABG) surgery (STARNET) and mouse models (HMDP) confirmed the regulatory role of ATF3 in the homeostasis of cholesterol metabolism. This study suggests that ATF3 might be a promising treatment candidate for lowering LDL cholesterol and reducing cardiovascular risk.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Non-coding RNAs have already been linked to CVD development and progression. While microRNAs (miRs) have been well studied in blood samples, there is little data on tissue-specific miRs in cardiovascular relevant tissues and their relation to cardiovascular risk factors. Tissue-specific miRs derived from Arteria mammaria interna (IMA) from 192 coronary artery disease (CAD) patients undergoing coronary artery bypass grafting (CABG) were analyzed. The aims of the study were 1) to establish a reference atlas which can be utilized for identification of novel diagnostic biomarkers and potential therapeutic targets, and 2) to relate these miRs to cardiovascular risk factors. Overall, 393 individual miRs showed sufficient expression levels and passed quality control for further analysis. We identified 17 miRs–miR-10b-3p, miR-10-5p, miR-17-3p, miR-21-5p, miR-151a-5p, miR-181a-5p, miR-185-5p, miR-194-5p, miR-199a-3p, miR-199b-3p, miR-212-3p, miR-363-3p, miR-548d-5p, miR-744-5p, miR-3117-3p, miR-5683 and miR-5701–significantly correlated with cardiovascular risk factors (correlation coefficient >0.2 in both directions, p-value (p < 0.006, false discovery rate (FDR)

Abdominal aortic aneurysms (AAA) may remain clinically silent until they enlarge and patients present with a potentially lethal rupture. This necessitates early detection and elective treatment. The goal of this study was to develop an easy-to-train algorithm which is capable of automated AAA screening in CT scans and can be applied to an intra-hospital environment. Three deep convolutional neural networks (ResNet, VGG-16 and AlexNet) were adapted for 3D classification and applied to a dataset consisting of 187 heterogenous CT scans. The 3D ResNet outperformed both other networks. Across the five folds of the first training dataset it achieved an accuracy of 0.856 and an area under the curve (AUC) of 0.926. Subsequently, the algorithms performance was verified on a second data set containing 106 scans, where it ran fully automated and resulted in an accuracy of 0.953 and an AUC of 0.971. A layer-wise relevance propagation (LRP) made the decision process interpretable and showed that the network correctly focused on the aortic lumen. In conclusion, the deep learning-based screening proved to be robust and showed high performance even on a heterogeneous multi-center data set. Integration into hospital workflow and its effect on aneurysm management would be an exciting topic of future research.

A major goal in systems biology is a comprehensive description of the entirety of all complex interactions between different types of biomolecules—also referred to as the interactome—and how these interactions give rise to higher, cellular and organism level functions or diseases. Numerous efforts have been undertaken to define such interactomes experimentally, for example yeast-two-hybrid based protein-protein interaction networks or ChIP-seq based protein-DNA interactions for individual proteins. To complement these direct measurements, genome-scale quantitative multi-omics data (transcriptomics, proteomics, metabolomics, etc.) enable researchers to predict novel functional interactions between molecular species. Moreover, these data allow to distinguish relevant functional from non-functional interactions in specific biological contexts. However, integration of multi-omics data is not straight forward due to their heterogeneity. Numerous methods for the inference of interaction networks from homogeneous functional data exist, but with the advent of large-scale paired multi-omics data a new class of methods for inferring comprehensive networks across different molecular species began to emerge. Here we review state-of-the-art techniques for inferring the topology of interaction networks from functional multi-omics data, encompassing graphical models with multiple node types and quantitative-trait-loci (QTL) based approaches. In addition, we will discuss Bayesian aspects of network inference, which allow for leveraging already established biological information such as known protein-protein or protein-DNA interactions, to guide the inference process.

Sugarcane root systems are poorly studied and understood due to the perennial nature, tall stature, and the long cropping cycle. Whilst some field studies gave insights into sugarcane root traits, there is no detailed description of root and root system traits available. The objectives of our work were to establish a baseline of sugarcane root trait values that will serve for future studies, and to characterize the degree of root system resilience when restricting tiller number. We first conducted an initial screening for root trait diversity on a collection of twenty cultivars representative of sugarcane breeding from 1930 to now. Then we investigated the effect of reduced tillering, via manual de-tillering, on the plant root and root system traits of five varieties grown under optimal conditions in a glasshouse for 1700°Cd. In addition to establishing baseline means and variation for sugarcane root trait values that could serve as a reference for crop models, we demonstrated that the sugarcane root mass fraction was extremely resilient to drastic reduction in tiller number. Restricted plants were effectively maintaining their root system configuration (opening angle) by dramatically increasing the number of nodal roots produced per tiller as well as maximizing total root length by increasing the specific root length. Using this knowledge of sugarcane root traits in combination with the specific agronomic constraints for sugarcane will now underpin the development of a root system ideotype for sugarcane to enable targeted root trait selection for improving crop productivity.

The cupric ion (Cu2+) plays a dual role as both nutrient and toxicant to freshwater and marine phytoplankton, functioning in multiple photochemical processes, as well as reactive oxygen species (ROS) production. This duality has been investigated through a variety of methods to determine the consequences of natural and anthropogenic copper introduction to algal ecosystem composition. Studies conducted over the past few decades have described the growth responses of many unique organisms to copper availability. Such observations are critical for describing the global distributions of major phytoplankton species in terms of global trace metal abundance; however, highly variable experimental practices impede direct inter-study comparison. The aim of this systematic review is to summarize the available data regarding the effects of copper concentration on diverse marine phytoplankton growth rates. Through extensive literary comparison, 143 studies were systematically reviewed, and data on copper concentrations and growth rates reported were extracted. From the data available, we conclude that trends in phytoplankton sensitivity to copper are mainly driven by a single study. We discuss the obstacles to inter-study comparison and detail both the concurring and conflicting results to date, with an emphasis on taxonomic trends and methodologies employed. Finally, we present the first copper sensitivity measurements for marine unicellular diazotrophs using three representative strains of the unicellular nitrogen-fixing cyanobacterium, Crocosphaera watsonii.

Targeting the activation function-1 (AF-1) domain located in the N-terminus of the androgen receptor (AR) is an attractive therapeutic alternative to the current approaches to inhibit AR action in prostate cancer (PCa). Here we show that the AR AF-1 is bound by the cochaperone Bag-1L. Mutations in the AR interaction domain or loss of Bag-1L abrogate AR signaling and reduce PCa growth. Clinically, Bag-1L protein levels increase with progression to castration-resistant PCa (CRPC) and high levels of Bag-1L in primary PCa associate with a reduced clinical benefit from abiraterone when these tumors progress. Intriguingly, residues in Bag-1L important for its interaction with the AR AF-1 are within a potentially druggable pocket, implicating Bag-1L as a potential therapeutic target in PCa.

A novel post-processing methodology able to assess whole-body tumor heterogeneity in patients with metastatic disease is proposed. The method is demonstrated on paired pre- and post-treatment data sets obtained from an initial cohort of six patients with metastatic disease from primary prostate or ovarian cancers. Whole-body diffusion-weighted imaging and T 1 -weighted contrast-enhanced imaging data were acquired covering the chest, abdomen, and pelvis. Joint histograms of Apparent Diffusion Coefficient and Fractional Enhancement values were calculated within volumes of interest and were modeled as a Gaussian mixture of two classes. Probability maps and volumetric estimates of the magnetic resonance data-derived classes providing visualization of pre- and post-treatment data are shown in three patient examples. This technique provided spatially heterogeneous characterization of regions following treatment as defined by the combined analysis of apparent diffusion coefficient and fractional enhancement. A new whole-body magnetic resonance data analysis has been demonstrated enabling visualization of intra-patient response heterogeneity in patients with metastatic cancer. Changes in the parameters of each subpopulation derived from this technique (apparent diffusion coefficient and fractional enhancement) reflect changes in the tissue properties of each subpopulation following treatment. Furthermore, the volume change of each population can be quantified. Such techniques may be essential for personalized anti-cancer therapy where there is a need to detect early drug-resistance and monitor heterogeneous response.

En este ensayo se afirma que las investigaciones desarrolladas en Chile sobre la enseñanza del derecho no han reparado suficientemente en las cuestiones referidas al cambio de modelo universitario y su influencia en la enseñanza y aprendizaje del derecho. Esto, a su vez, ha impedido a los teóricos nacionales ejercer una mayor influencia en los procesos de reforma al sistema universitario en general y a las modificaciones y proyecciones de la enseñanza del derecho en particular.