Miracle-dz/UniFAR-FTUs huggingface dataset:
NRG Oncology CC001: A phase III trial of hippocampal avoidance (HA) in addition to whole-brain radiotherapy (WBRT) plus memantine to preserve neurocognitive function (NCF) in patients with brain metastases (BM).

2009 Background: NRG CC001, a phase III trial of WBRT plus memantine (WBRT+M) with or without HA, sought to evaluate the neuro-protective effects of lowering the hippocampal radiation dose. Methods: Patients (pts) with BM were stratified by RPA class and prior radiosurgery/surgery and randomized to WBRT+M or HA-WBRT+M (30Gy/10 fractions). Standardized NCF tests were performed at baseline, 2, 4, 6, and 12 months (mos). The primary endpoint was NCF failure, defined as decline using the reliable change index on Hopkins Verbal Learning Test-Revised, Trail Making Test, or Controlled Oral Word Association. Cumulative incidence estimated NCF failure (death without NCF failure was competing risk); between-arms differences tested using Gray’s test. Deterioration at each collection time point was tested using a chi-square test. Patient-reported symptoms were assessed using the MD Anderson Symptom Inventory Brain Tumor module and analyzed using mixed effects models and t-tests. Results: From 7/2016 to 3/2018, 518 pts were randomized. Median follow-up was 7.9 mos. HA-WBRT+M was associated with lower NCF failure risk (adjusted hazard ratio (HR) = 0.74, p = 0.02) due to lower risk of deterioration in executive function at 4 mos (p = 0.01) and encoding (p = 0.049) and consolidation (p = 0.02) at 6 mos. Age≤61 predicted lower NCF failure risk (HR = 0.60, p = 0.0002); non-significant test for interaction indicated independent effects of HA and age. Patient-reported fatigue (p = 0.036), difficulty speaking (p = 0.049) and problems remembering things (p = 0.013) at 6 mos favored the HA-WBRT+M arm. Imputation models accounting for missing data also favored the HA-WBRT+M arm for patient-reported cognition (p = 0.011) and symptom interference (p = 0.008) at 6 mos. Treatment arms did not differ in toxicity, overall survival, or intracranial progression. Conclusions: HA during WBRT+M for BM better preserves NCF and patient-reported symptoms, while achieving similar intracranial control and survival. Supported by grants UG1CA189867 (NCORP), U10CA180868 (NRG Oncology Operations), DCP from the National Cancer Institute. Clinical trial information: NCT02360215.
Effect of Certain Quinones, Diquat, and Diuron on Chlorella pyrenoidosa Chick. (Emerson strain)

The effect of 1,4-naphthoquinone, 1,4-benzoquinone, and several CI and NH2-substituted quinones has been studied on growth, chlorophyll concentration, and oxygen evolution in Chlorella pyrenoidosa Chick. (Emerson strain). Drastic decrease of the studied parameters usually was noted after 24 to 48 hr treatment at 3×10–5 M concentration. The effect of the quinones was compared with that of 6,7-dihydrodipyrido [l,2-a:2,l-c-]pyrazidinium salt (diquat) and 3-(3,4-dichlorophenyl)-l,l-dimethylurea (diuron). Diuron inhibited oxygen evolution immediately after addition, but could be washed out and the effect was reversible. Diquat had no inhibitory effect on oxygen evolution and chlorophyll content but caused a slight decrease in cell number. Although some quinones have an almost immediate effect on the oxygen-evolving mechanism, it seems more likely that the overall effect of the quinones is on the total physiological activity of the algal cells. Oxygen evolution seems to affected earlier than chlorophyll destruction, and the observed long-term damage is irreversible. Most of the compounds studied could be classified as algicidal, with the exception of diuron, diquat, and 1,4-benzoquinone which may be considered to be algistatic.
Metabolomic study of alcohol consumption – Investigation of novel candidate biomarkers and their potential clinical use

Alcohol intake can significantly affect the health of the individual, and can also cause significant socio-economic damage. Clinical tests for an accurate assessment of alcohol consumption and drinking patterns to early identify potential alcohol-induced disorders are urgently needed in alcohol abuse research and treatment. Ethanol affects a variety of organs, biochemical and signaling pathways, and biological processes, this is why a more holistic biomarker discovery approach which is closer to the phenotype and which gives a more global and direct insight into the development and progression of alcohol-induced toxicity is required. Advancements in tandem mass spectrometry-based metabolomics have made tremendous impact on the identification of candidate biomarker components. Since 1980s only few animal studies have had investigated the relationship between alcohol and metabolic changes. The overall objective of this thesis was to extend the knowledge in the research area of alcohol biomarker discovery. Here, a high-throughput mass spectrometry platform was used on a big European human population cohort to perform a metabolomics study and gain new insights on alcohol-induced metabolic changes in human and their potential underlying biochemical mechanism. According to the current state of knowledge this is the first metabolomics population-based study investigating alcohol-induced metabolic changes in humans. The study bridges the knowledge gap of alcohol and its effects on the metabolic setup. The study identified alcohol-related metabolites and its potential underlying mechanisms which form an additional step in understanding the path between chronic moderate-to-heavy alcohol consumption and its clinical endpoints.
A multifactorial model of T cell expansion and durable clinical benefit in response to a PD-L1 inhibitor

Background Immunotherapies such as checkpoint inhibitors have become a major success in treating patients with late-stage cancers [1], yet the minority of patients benefit [2]. PD-L1 staining and mutation burden are the leading biomarkers associated with response, but each is an imperfect predictor. We seek to address this challenge by developing a multifactorial model for response to anti-PD-L1 therapy. Methods We train a model to predict fine-grained immune response in patients after treatment based on 36 clinical, tumor, and circulating molecular features of each patient collected prior to treatment. Our predicted immune response is then used to anticipate durable clinical benefit (DCB) of treatment. We analyze the bladder cancer patient data of Snyder et al. [3] using the elastic net high-dimensional regression procedure [4] and assess accuracy using leave-one-out cross-validation (LOOCV). Results In held-out patients, the elastic net procedure explains 80% of the variance in immune response as measured by the log number of T cell clones in the tumor that expand in the blood post-therapy. Moreover, if patients are triaged according to held-out predicted expansion, only 34% of non-DCB patients need be treated to ensure that 100% of DCB patients are treated. In contrast, using PD-L1 staining or mutation load alone, one must treat at least 75% of non-DCB patients to ensure that all DCB patients receive treatment. The final elastic net model fit to the entire patient cohort retains 20 of the 36 input features, a mix of clinical, tumor, and circulating patient attributes. In addition, each class of features contributes significantly to the estimated accuracy of the procedure: when tumor features are excluded as inputs, the variance explained in held-out patients drops to 26%; when circulating features are excluded, the explained variance drops to 13%; and when clinical features are excluded, the explained variance drops to 0%. Conclusions In a multifactorial model, tumor, circulating, and clinical features all contribute significantly to the accurate prediction of fine-grained immune response. Moreover, the accurate prediction of this immune response may improve our ability to anticipate clinical benefit.
Computationally efficient electronic-circuit noise calculations

The interreciprocal adjoint network concept is applied to the computer simulation of electronic-circuit noise performance. The method described is extremely efficient, allowing consideration of an arbitrarily large number of uncorrelated noise sources with less effort than for the original small signal a.c. analysis. Because all noise sources may be considered, no a priori assumption need be made as to which noise sources are dominant in a complicated circuit. The method is illustrated with an operational- amplifier example.
Mouse kidney renin is synthesised in precursor form in the wheat germ cell-free protein synthesis system

Translation of total poly(A)-containing RNA from mouse kidney in the wheat germ cell-free protein synthesis system resulted in the production of a form of renin with an apparent molecular weight of around 10,000 greater than that of mature, circulating renin. This is the first direct evidence indicating that kidney renin is synthesised in precursor form. Translation of total poly(A)-containing RNA from mouse sub~ maxillary gland, using the same cell-free system, also resulted in the production of a renin precursor, having the same molecular weight as the kidney species.
Volumetric and End-Tidal Capnography for the Detection of Cardiac Output Changes in Mechanically Ventilated Patients Early after Open Heart Surgery

Background Exhaled carbon dioxide (CO2) reflects cardiac output (CO) provided stable ventilation and metabolism. Detecting CO changes may help distinguish hypovolemia or cardiac dysfunction from other causes of haemodynamic instability. We investigated whether CO2 measured as end-tidal concentration (EtCO2) and eliminated volume per breath (VtCO2) reflect sudden changes in cardiac output (CO). Methods We measured changes in CO, VtCO2, and EtCO2 during right ventricular pacing and passive leg raise in 33 ventilated patients after open heart surgery. CO was measured with oesophageal Doppler. Results During right ventricular pacing, CO was reduced by 21% (CI 18–24; p < 0.001), VtCO2 by 11% (CI 7.9–13; p < 0.001), and EtCO2 by 4.9% (CI 3.6–6.1; p < 0.001). During passive leg raise, CO increased by 21% (CI 17–24; p < 0.001), VtCO2 by 10% (CI 7.8–12; p < 0.001), and EtCO2 by 4.2% (CI 3.2–5.1; p < 0.001). Changes in VtCO2 were significantly larger than changes in EtCO2 (ventricular pacing: 11% vs. 4.9% (p < 0.001); passive leg raise: 10% vs. 4.2% (p < 0.001)). Relative changes in CO correlated with changes in VtCO2 (ρ=0.53; p=0.002) and EtCO2 (ρ=0.47; p=0.006) only during reductions in CO. When dichotomising CO changes at 15%, only EtCO2 detected a CO change as judged by area under the receiver operating characteristic curve. Conclusion VtCO2 and EtCO2 reflected reductions in cardiac output, although correlations were modest. The changes in VtCO2 were larger than the changes in EtCO2, but only EtCO2 detected CO reduction as judged by receiver operating characteristic curves. The predictive ability of EtCO2 in this setting was fair. This trial is registered with NCT02070861.
The relationship between sleep time and self-rated health: an analysis based on Italian survey data

Background: a growing and broadly discussed literature has shown that the relationship between sleep duration and health is not linear. Not only are insomnia and insufficient sleep harmful to one’s health, but excessive sleep too is also not beneficial. This study tests the association between selfrated state of health and the duration and pattern of sleep: we discuss the losses and costs in terms of quality of life deriving from excessive sleep time. Methods: we use an ordered probit specification, applied to the Italian Survey on the Use of Time (sample of Italians aged fifteen and over who keep a diary for a working day). Results: we show that greater sleep duration is negatively correlated both with self-reported state of health and with self-reported health satisfaction, while respondents’ subjective perceptions of too much and too little sleep are associated with health conditions in the usual u-shaped way. Conclusions: the negative impact of long sleep on self-reported health is confirmed. However, the effect of short sleep on health conditions is positive, while a measure of decreasing sleep quality - comprising number of interruptions of sleep, insomnia and napping - is correlated to some extent with decreasing health. The public health consequences are still to be explored: the potential gains from sleep restriction are substantial, but little is known about the causal link or the risks. Further research is needed before taking policy decisions.
Three-dimensional connectivity and chromatin environment mediate the activation efficiency of mammalian DNA replication origins

In mammalian cells, chromosomal replication starts at thousands of origins at which replisomes are assembled and bidirectional DNA synthesis is established. The slowdown of DNA polymerases at endogenous or exogenous obstacles triggers the activation of additional ‘dormant’ origins whose genomic positions and regulation are not well understood. Here we report a comparative study of origin activity in mouse embryonic stem cells growing in control conditions or in the presence of mild replication stress. While stress-responsive origins can be identified, we find that the majority of them are also active, albeit with lower frequency, in the control population. To gain insights into the molecular and structural determinants of origin efficiency, we have analyzed the genetic and epigenetic features of origins stratified according to their frequency of activation. We have also integrated the linear origin maps into three-dimensional (3D) chromatin interaction networks, revealing a hierarchical organization in which clusters of connected origins are brought together by longer-range chromatin contacts. Origin efficiency is proportional to the number of connections established with other origin-containing fragments. Interacting origins tend to be activated with similar efficiency and share their timing of replication even when located in different topologically associated domains. Our results are consistent with a model in which clusters of origins are arranged in 3D in replication factories. Within each factory, ‘main’ and ‘dormant’ origins are functionally defined by a combination of chromatin environment and 3D connectivity.
Follow the Past - A Path Tracking Method Using Recorded Orientation and Steering Commands.

The work presented in this paper is part of the project Autonomous Navigation for Forest Machines (Georgsson et al., 2005) at Umea University, Sweden. The goal of this project is to develop a path-tracking forest vehicle. A human driver drives the path once, while a computer is continuously recording position, velocity, orientation, and steering angle. This information is then used to control the vehicle each time it autonomously travels along the path. If the vehicle gets off course, for example as a result of avoiding an obstacle or because of noise in the positioning sensors, the developed path-tracking algorithm steers like the driver, plus an additional angle, based on the distance to the path and the error in orientation. Traditional algorithms, like Follow the Carrot (Barton, 2001) and Pure Pursuit (Coulter, 1992), use position information only, and sometimes run into problems that can be avoided, by taking into account additional information from the human driver. There are many variations on the basic Pure-Pursuit algorithm. The Adaptive Pure-Pursuit algorithm (Hebert et al., 1997) addresses computational issues and stability at high speeds. The Feedforward Pure-Pursuit algorithm (Hebert et al., 1997) simulates the outcome of various control commands, and selects the most appropriate one. In (Coulter, 1992), the average curvature of the path is used instead of the recorded steering angle in a proportional path-following algorithm. Other researchers, e.g. (Ollero et al., 2001), have approached the problem with a fuzzy-logic controller that uses the same additional information as our suggested algorithm, but has a more complex design. A brief survey of more path-tracking control algorithms can be found in (Makela, 2001).
Lentivirus-mediated RNA interference targeting programmed death receptor ligand 1 increases the immunologic anti-tumor effect of dendritic cell vaccination against pancreatic cancer in SCID-hu mice

Programmed death receptor ligand 1 (PD-L1), which belongs to the B7 family, is overexpressed in a variety of human cancer types and serves a crucial role in immune escape by malignant cells. Programmed death receptor 1 (PD-1) is a specific PD-L1 receptor. PD-1/PD-L1 signaling inhibits the antitumor effects of dendritic cell (DC) immunization for tumor treatment. The aim of the present study was to determine whether inhibiting PD-L1 may increase the immunologic anti-tumor effect of dendritic cells against pancreatic cancer. In the present study, PD-L1 levels in non-cancerous and malignant tissue samples were compared, and the impact of PD-L1 downregulation on human pancreatic cancer PaTu8988 cells was determined by lentivirus-based RNA interference and DC immunotherapy. PD-L1 expression in pancreatic specimens was assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry. PaTu8988 cells expressing reduced levels of PD-L1 were generated by lentivirus-based knockdown to assess the mechanism by which the inhibition of PD-L1 signaling in DC immunization affects therapeutic outcomes in pancreatic cancer-bearing SCID-hu mice. PD-L1 levels were markedly elevated in pancreatic adenocarcinoma samples compared with in non-cancerous tissue. PD-L1 silencing in pancreatic adenocarcinoma cells resulted in improved treatment outcomes of DC immunization in vitro and in vivo compared with traditional DC immunization. PD-L1 silencing enhances the antitumor response of cytotoxic T cells by increasing interferon γ production in vitro. In vivo, this method prevented tumor growth and lung metastasis, and prolonged survival in the SCID-hu model. In conclusion, the results of the present study suggested that suppressing PD-L1 in malignant cells during DC immunization may be a useful tool for immunotherapy in pancreatic adenocarcinoma.
Why did the Tc1-like elements of mollusks acquired the spliceosomal introns?

Transposable elements are the DNA sequences capable of transpositions within the genome and, thus, exerting a considerable influence on the genome functioning and structure and providing the source of new genes. Transposable elements are classified into retrotransposons and the DNA transposons. IS630/Tc1/mariner superfamily of DNA transposons is one of the most diverse groups broadly represented among the eukaryotes. We identified a new group of Tc1-like elements in the mollusks, which we named TLEWI. These DNA transposons are characterized by the low copy number, the lack of terminal inverted repeats and the presence of DD36E signature and the spliceosomal introns in transposase sequence. Their prevalence among the mollusks is limited to subclass Pteriomorpha (Bivalvia). Since TLEWI possess the features of domesticated TE and the structure similar to the eukaryotic genes, which is not typical for the DNA transposons, we consider the hypothesis of co-optation of TLEWI gene by the bivalves.
Growth promoter alternatives after the ban on antibiotics.

Feed additives are used world-wide for many different reasons. Some help to cover the needs for essential nutrients and others to increase animal performance, feed intake and thereby optimize feed utilization. They can positively affect technological properties and quality of feed as well as animal products. In many countries the use of feed additives is more and more questioned by the consumers: substances such as antibiotics, hormones and ß-agonists with perceived high risks are banned in animal diets. The trend in consumer demand is for safer and more organic food. Environmental aspects and animal management conditions become essential in intensive animal production systems. Therefore, the feed industry is eagerly looking for effective alternatives which are acceptable to the consumer and environmentally sound. Organic acids, enzymes, probiotics, prebiotics and highly available minerals as well as herbs or botanicals can be seen as potential alternatives to metabolic modifiers and antibiotics. The best results can be achieved by the use of these feed additives under good environmental conditions.
SP0122 OPTIMIZING HOLLISTIC TREATMENTS: THE CHALLENGE OF IMPLEMENTATION

International guidelines present recommendations for holistic care for RMDs, building upon best evidence. However, there is still a gap between what we know about best care and what we do to implement best care in our clinical services. Having EULAR guidelines alone (and multiple updates and revisions) is not enough to change complex systems. European funders are now investing in projects to accelerate the uptake of best care across multiple European partners. Using one example of a completed EIT-Health funded implementation project, JIGSAW-E (Joint Implementation of Guidelines for oSteoArthritis in Western Europe), this presentation will highlight some of the challenges of implementation such as: understanding the context; competing priorities; lack of time and funding; stability of the workforce; and differing health care systems. It will describe the use of Knowledge Mobilization and Communities of Practice as methods for overcoming these challenges and optimizing holistic treatments. The presentation will offer some of the key factors for implementation such as ‘leading from the middle” and brokering across silos; working with patients and the public ‘Patients are the most under- used resource in any health care system”; using theories, models and frameworks to plan, understand and evaluate implementation; using pilot sites to build momentum with dedicated Communities of Practice; and agreeing what success should look like. Disclosure of Interests: None declared
Mice deficient of Myc super-enhancer region reveal a differential control mechanism between normal and pathological growth

The gene desert upstream of the Myc oncogene on chromosome 8q24 contains susceptibility loci for several major forms of human cancer, including cancers of breast, prostate, and colon. The region shows high conservation between human and mouse and contains multiple MYC enhancers that are activated in tumor cells. However, the role of this region in normal development has not been addressed. Here we show that a 538 kb deletion of the entire MYC upstream super-enhancer region in mice results in 50 to 80% decrease in MYC expression in multiple tissues. The mice are viable and show no overt phenotype. However, they are resistant to tumorigenesis, and most normal cells isolated from them grow slowly in culture. Consistently, deletion of the 8q24 super-enhancer region perturbs Myc targets only in cultured cells, but not in vivo. These results reveal that only cells whose Myc activity is increased by serum or oncogenic driver mutations depend on the 8q24 super-enhancer region, and indicate that targeting the activity of this element is a promising strategy of cancer chemoprevention and therapy.