Miracle-dz/UniFAR-FTUs huggingface dataset:
DrugCombDB: a comprehensive database of drug combinations toward the discovery of combinatorial therapy

Abstract Drug combinations have demonstrated high efficacy and low adverse side effects compared to single drug administration in cancer therapies and thus have drawn intensive attention from researchers and pharmaceutical enterprises. Due to the rapid development of high-throughput screening (HTS), the number of drug combination datasets available has increased tremendously in recent years. Therefore, there is an urgent need for a comprehensive database that is crucial to both experimental and computational screening of synergistic drug combinations. In this paper, we present DrugCombDB, a comprehensive database devoted to the curation of drug combinations from various data sources: (i) HTS assays of drug combinations; (ii) manual curations from the literature; and (iii) FDA Orange Book and external databases. Specifically, DrugCombDB includes 448 555 drug combinations derived from HTS assays, covering 2887 unique drugs and 124 human cancer cell lines. In particular, DrugCombDB has more than 6000 000 quantitative dose responses from which we computed multiple synergy scores to determine the overall synergistic or antagonistic effects of drug combinations. In addition to the combinations extracted from existing databases, we manually curated 457 drug combinations from thousands of PubMed publications. To benefit the further experimental validation and development of computational models, multiple datasets that are ready to train prediction models for classification and regression analysis were constructed and other significant related data were gathered. A website with a user-friendly graphical visualization has been developed for users to access the wealth of data and download prebuilt datasets. Our database is available at http://drugcombdb.denglab. org/.
Effects of three low-volume, high-intensity exercise conditions on affective valence

ABSTRACT A common barrier to exercise is “lack of time”. Accordingly, interest in low-volume, high-intensity training has grown exponentially since this activity is considered time-efficient. However, the high-intensity nature of this exercise may frequently result in feelings of displeasure creating another barrier for many people. The purpose of this study was to compare affective (pleasure-displeasure) responses to three low-volume, high-intensity exercise conditions, including a novel shortened-sprint protocol. Using a within-subjects, randomised crossover experiment, healthy participants (N = 36) undertook a single bout of: 1) traditional reduced-exertion, high-intensity interval training (TREHIT), 2) a novel, shortened-sprint REHIT (SSREHIT) protocol, and 3) sprint continuous training (SCT). Affect and perceived efforts were recorded throughout exercise using the Feeling Scale (FS) and the 15-point Borg Rating of Perceived Exertion (RPE) scale, respectively. Enjoyment was recorded 5 min post-exercise using the Exercise Enjoyment Scale (EES). Differences were found for FS (condition by time interaction: P = 0.01GG, η2 = 0.26), RPE (P = 0.01GG, η2 = 0.23), and enjoyment (P < 0.01) with all outcomes favouring SSREHIT. Shortened-sprint protocols may diminish feelings of displeasure and might be a time-efficient yet tolerable exercise choice to help motivate some people to increase their physical activity and fitness.
Radioembolization Plus Chemotherapy for First-line Treatment of Locally Advanced Intrahepatic Cholangiocarcinoma: A Phase 2 Clinical Trial.

Importance Patients with unresectable intrahepatic cholangiocarcinoma (ICC) have a poor prognosis. Selective internal radiotherapy (SIRT) is a promising treatment option for hepatic tumors, but no prospective studies of combination SIRT with chemotherapy have been published to our knowledge. Objective To determine the response rate after SIRT combined with chemotherapy in patients with unresectable ICC. Design, Setting, and Participants This phase 2 clinical trial, the Yttrium-90 Microspheres in Cholangiocarcinoma (MISPHEC) trial, included patients with unresectable ICC who have never received chemotherapy or intra-arterial therapy and were treated at 7 centers which had experience with SIRT between November 12, 2013, and June 21, 2016. Statistical analysis was performed from March 31, 2017, to June 17, 2019. Interventions Concomitant first-line chemotherapy with cisplatin, 25 mg/m2, and gemcitabine, 1000 mg/m2 (gemcitabine reduced to 300 mg/m2 for the cycles just before and after SIRT), on days 1 and 8 of a 21-day cycle for 8 cycles. Selective internal radiotherapy was administered during cycle 1 (1 hemiliver disease) or cycles 1 and 3 (disease involving both hemilivers) using glass Y90 microspheres. Main Outcomes and Measures Response rate at 3 months according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary end points were toxic effects, progression-free survival, overall survival, disease control rate, and response rate according to Choi criteria. Results Of 41 patients included in the study, 26 (63%) were male, with a mean (SD) age of 64.0 (10.7) years. Response rate according to RECIST was 39% (90% CI, 26%-53%) at 3 months according to local review and was confirmed at 41% as best response by central review; disease control rate was 98%. According to Choi criteria, the response rate was 93%. After a median follow-up of 36 months (95% CI, 26-52 months), median progression-free survival was 14 months (95% CI, 8-17 months), with progression-free survival rates of 55% at 12 months and 30% at 24 months. Median overall survival was 22 months (95% CI, 14-52 months), with overall survival rates of 75% at 12 months and 45% at 24 months. Of 41 patients, 29 (71%) had grades 3 to 4 toxic effects; 9 patients (22%) could be downstaged to surgical intervention, with 8 (20%) achieving R0 (microscopic-free margins) surgical resection. After a median of 46 months (95% CI, 31 months to not reached) after surgery, median relapse-free survival was not reached among patients who underwent resection. Conclusions and Relevance Combination chemotherapy and SIRT had antitumor activity as first-line treatment of unresectable ICC, and a significant proportion of patients were downstaged to surgical intervention. A phase 3 trial is ongoing.
Cochlear Place of Stimulation Is One Determinant of Cochlear Implant Sound Quality

Objective: Our aim was to determine the effect of acute changes in cochlear place of stimulation on cochlear implant (CI) sound quality. Design: In Experiment 1, 5 single-sided deaf (SSD) listeners fitted with a long (28-mm) electrode array were tested. Basal shifts in place of stimulation were implemented by turning off the most apical electrodes and reassigning the filters to more basal electrodes. In Experiment 2, 2 SSD patients fitted with a shorter (16.5-mm) electrode array were tested. Both basal and apical shifts in place of stimulation were implemented. The apical shifts were accomplished by current steering and creating a virtual place of stimulation more apical that that of the most apical electrode. Results: Listeners matched basal shifts by shifting, in the normal-hearing ear, the overall spectrum up in frequency and/or increasing voice pitch (F0). Listeners matched apical shifts by shifting down the overall frequency spectrum in the normal-hearing ear. Conclusion: One factor determining CI voice quality is the location of stimulation along the cochlear partition.
A Survey of Collaborative UAV–WSN Systems for Efficient Monitoring

Integrated systems based on wireless sensor networks (WSNs) and unmanned aerial vehicles (UAVs) with electric propulsion are emerging as state-of-the-art solutions for large scale monitoring. Main advances stemming both from complex system architectures as well as powerful embedded computing and communication platforms, advanced sensing and networking protocols have been leveraged to prove the viability of this concept. The design of suitable algorithms for data processing, communication and control across previously disparate domains has thus currently become an intensive area of interdisciplinary research. The paper was focused on the collaborative aspects of UAV–WSN systems and the reference papers were analyzed from this point of view, on each functional module. The paper offers a timely review of recent advances in this area of critical interest with focus on a comparative perspective across multiple recent theoretical and applied contributions. A systematic approach is carried out in order to structure a unitary from conceptual design towards key implementation aspects. Focus areas are identified and discussed such as distributed data processing algorithms, hierarchical multi-protocol networking aspects and high level WSN–constrained UAV-control. Application references are highlighted in various domains such as environmental, agriculture, emergency situations and homeland security. Finally, a research agenda is outlined to advance the field towards tangible economic and social impact.
miR‐22‐3p enhances the intrinsic regenerative abilities of primary sensory neurons via the CBL/p‐EGFR/p‐STAT3/GAP43/p‐GAP43 axis

Spinal cord injury (SCI) is a devastating disease. Strategies that enhance the intrinsic regenerative ability are very important for the recovery of SCI to radically prevent the occurrence of sensory disorders. Epidermal growth factor (EGF) showed a limited effect on the growth of primary sensory neuron neurites due to the degradation of phosphorylated‐epidermal growth factor receptor (p‐EGFR) in a manner dependent on Casitas B‐lineage lymphoma (CBL) (an E3 ubiquitin‐protein ligase). MiR‐22‐3p predicted from four databases could target CBL to inhibit the expression of CBL, increase p‐EGFR levels and neurites length via STAT3/GAP43 pathway rather than Erk1/2 axis. EGF, EGFR, and miR‐22‐3p were downregulated sharply after injury. In vivo miR‐22‐3p Agomir application could regulate CBL/p‐EGFR/p‐STAT3/GAP43/p‐GAP43 axis, and restore spinal cord sensory conductive function. This study clarified the mechanism of the limited promotion effect of EGF on adult primary sensory neuron neurite and targeting miR‐22‐3p could be a novel strategy to treat sensory dysfunction after SCI.
The Sec1/Munc18‐like proteins TgSec1 and TgVps45 play pivotal roles in assembly of the pellicle and sub‐pellicle network in Toxoplasma gondii

Post‐Golgi vesicle trafficking is indispensable for precise movement of proteins to the pellicle, the sub‐pellicle network and apical secretory organelles in Apicomplexa. However, only a small number of molecular complexes involved in trafficking, tethering and fusion of vesicles have been identified in Toxoplasma gondii. Consequently, it is unclear how complicated vesicle trafficking is accomplished in this parasite. Sec1/Munc18‐like (SM) proteins are essential components of protein complexes involved in vesicle fusion. Here, we found that depletion of the SM protein TgSec1 using an auxin‐inducible degron‐based conditional knockout strategy led to mislocalization of plasma membrane proteins. By contrast, conditional depletion of the SM protein TgVps45 led to morphological changes, asymmetrical loss of the inner membrane complex and defects in nucleation of sub‐pellicular microtubules, polarization and symmetrical assembly of daughter parasites during repeated endodyogeny. TgVps45 interacts with the SNARE protein TgStx16 and TgVAMP4‐1. Conditional ablation of TgStx16 causes the similar growth defect like TgVps45 deficiency suggested they work together for the vesicle fusion at TGN. These findings indicate that these two SM proteins are crucial for assembly of pellicle and sub‐pellicle network in T. gondii respectively.
Vitamin K Antagonists versus Direct Oral Anticoagulants After Transcatheter Aortic Valve Implantation in Atrial Fibrillation.

AIM To examine the risk of arterial thromboembolism, bleeding, and all-cause mortality in AF patients treated with direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) undergoing transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS In this nationwide observational cohort study, 735 patients undergoing TAVI from January 1, 2012 to June 30, 2017 with a history of AF and who were treated with oral anticoagulants were identified using data from Danish nationwide registries. Of these, 219 (29.8%) and 516 (70.2%) patients were treated with DOACs and VKAs, respectively. The DOAC group was characterized by a higher prevalence of previous arterial thromboembolism and a lower prevalence of chronic kidney disease compared with the VKA group. The distribution of age, sex, CHA2DS2-VASc and HAS-BLED-score, and concomitant antiplatelet therapy was similar between groups. Compared with VKA, treatment with DOACs was not associated with a significantly different 3-year absolute risk of arterial thromboembolism (9.6% [95% confidence interval [CI], 4.7%-16.5%] versus 7.4% [95%CI, 4.9%-10.5%] in the DOAC and VKA group, respectively), bleeding (14.3% [95%CI, 7.6%-22.9%] versus 13.3% [95%CI, 9.9%-17.1%]), or all-cause mortality 32.7% [95%CI, 21.8%-44.0%] versus 32.0% [95%CI, 26.8%-37.3%]). In adjusted analyses, treatment with DOACs, as compared with VKAs, was not associated with a significantly different rate of arterial thromboembolism (hazard ratio [HR], 1.23 [95%CI, 0.58-2.59]), bleeding (HR, 1.14 [95%CI, 0.63-2.06]), or all-cause mortality (HR, 0.93 [95%CI, 0.61-1.40]). CONCLUSIONS In patients with AF undergoing TAVI, treatment with DOACs was not associated with a significantly different risk of arterial thromboembolism, bleeding, or all-cause mortality compared with VKA.
TFBSshape: an expanded motif database for DNA shape features of transcription factor binding sites

Abstract TFBSshape (https://tfbsshape.usc.edu) is a motif database for analyzing structural profiles of transcription factor binding sites (TFBSs). The main rationale for this database is to be able to derive mechanistic insights in protein–DNA readout modes from sequencing data without available structures. We extended the quantity and dimensionality of TFBSshape, from mostly in vitro to in vivo binding and from unmethylated to methylated DNA. This new release of TFBSshape improves its functionality and launches a responsive and user-friendly web interface for easy access to the data. The current expansion includes new entries from the most recent collections of transcription factors (TFs) from the JASPAR and UniPROBE databases, methylated TFBSs derived from in vitro high-throughput EpiSELEX-seq binding assays and in vivo methylated TFBSs from the MeDReaders database. TFBSshape content has increased to 2428 structural profiles for 1900 TFs from 39 different species. The structural profiles for each TFBS entry now include 13 shape features and minor groove electrostatic potential for standard DNA and four shape features for methylated DNA. We improved the flexibility and accuracy for the shape-based alignment of TFBSs and designed new tools to compare methylated and unmethylated structural profiles of TFs and methods to derive DNA shape-preserving nucleotide mutations in TFBSs.
Second primary lung cancer following laryngeal cancer: retrospective study of incidence and multivariate analysis of risk factors in 209 patients.

OBJECTIVE To analyse the incidence of second primary lung cancer following treatment for laryngeal cancer and to identify risk factors for its development. METHOD Retrospective case series. RESULTS The five-year actuarial incidence of second primary lung cancer was 8 per cent (1.6 per cent per year). This was associated with a very poor median survival of seven months following diagnosis. Supraglottic tumours were associated with an increased risk of second primary lung cancer compared to glottic tumours in both univariate (hazard ratio = 4.32, p = 0.005) and multivariate analyses (hazard ratio = 4.14, p = 0.03). CONCLUSION Second primary lung cancer occurs at a rate of 1.6 per cent per year following a diagnosis of laryngeal cancer, and this is associated in a statistically significant manner with supraglottic primary tumour. The recent National Lung Cancer Screening Trial suggests a survival advantage of 20 per cent at five years with annual screening using low-dose computed tomography scanning of the chest in a comparable cohort to ours. These findings have the potential to inform post-treatment surveillance protocols in the future.
Sacral neuromodulation in patients with faecal incontinence

Faecal incontinence is very common but complex disorder involving high costs for the patient and the community. Besides a considerable psychological burden it has an enormous socially invalidating aspect that has profound consequences for the patient’s well-being. This dissertation summarizes the usability, safety, feasibility and the possible mechanism of action of sacral neuromodulation (SNM) as a treatment for faecal incontinence. After 10 years of clinical experience with SNM in our hospital, we can conclude that SNM is an effective treatment for functional intestinal disorders, particularly in patients with faecal incontinence.
Lower blood levels of vitamin B12 are related to decreased performance of healthy subjects in the Stroop Color-Word Test

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Detection of amyloid beta peptides in body fluids for the diagnosis of alzheimer’s disease: Where do we stand?

Abstract Alzheimer’s disease (AD) is an incurable neurodegenerative disease characterized by progressive decline of cognitive abilities. Amyloid beta peptides (Aβ), Tau proteins and the phosphorylated form of the Tau protein, p-Tau, are the core pathological biomarkers of the disease, and their detection for the diagnosis of patients is progressively being implemented. However, to date, their quantification is mostly performed on cerebrospinal fluid (CSF), the collection of which requires an invasive lumbar puncture. Early diagnosis has been shown to be important for disease-modifying treatment, which is currently in development, to limit the progression of the disease. Nevertheless, the diagnosis is often delayed to the point where the disease has already progressed, and the tools currently available do not allow for a systematic follow-up of patients. Thus, the search for a molecular signature of AD in a body fluid such as blood or saliva that can be collected in a minimally invasive way offers hope. A number of methods have been developed for the quantification of core biomarkers, especially in easily accessible fluids such as the blood, that improve their accuracy, specificity and sensitivity. This review summarizes and compares these approaches, focusing in particular on their use for Aβ detection, the earliest biomarker to be modified in the course of AD. The review also discusses biomarker quantification in CSF, blood and saliva and their clinical applications.
Patterns of narrative discourse in early recovery following severe Traumatic Brain Injury

ABSTRACT Primary Objective: To investigate the nature and patterns of narrative discourse impairment in people with severe Traumatic Brain Injury (TBI) during early recovery. Methods and Procedures: A single image picture description task was administered to 42 participants with severe TBI at 3 and 6-months post-injury. The same task was administered to 37 control participants. Discourse samples were analyzed with measures of productivity, informativeness and story organization. The performance of people with TBI was compared with the control group at both 3 and 6 months, and the performance of the participants with TBI was also compared across the two time points. Individual patterns of performance were also examined. Results: Inferential analyses revealed significant differences between the control group and the group with TBI on informativeness at both time points and number of complete episodes at 3 months, but no significant differences for productivity measures. There was no significant change for the group with TBI between 3 and 6 months. However, individual improvement over time was observed. Conclusions: People with TBI have discourse difficulties early post TBI that are also present at 6-months post-injury. In order to understand longer-term discourse recovery, it is necessary to examine participant patterns over further time points on this narrative task.
Synergistic effects of apelin and leptin on isolated rat pulmonary arteries

Apelin (AP) and leptin (LEP) are adipokines with vasomotor actions. Taking into account the published data on the role of obesity in the development of pulmonary hypertension, we studied the implications of apelin on leptin relaxing effects on isolated rat pulmonary arteries. LEP had vasodilatatory effects on phenylephrine-precontracted rat pulmonary arteries from normal and ovalbumin-sensitized rats, but not on rats with monocrotaline-induced pulmonary hypertension. AP13 pretreatment increased LEP effects by one-half. Our studies revealed the existence of synergistic favorable effects of these adipokines on pulmonary vessels.
A luminal EF-hand mutation in STIM1 in mice causes the clinical hallmarks of tubular aggregate myopathy

ABSTRACT STIM and ORAI proteins play a fundamental role in calcium signaling, allowing for calcium influx through the plasma membrane upon depletion of intracellular stores, in a process known as store-operated Ca2+ entry. Point mutations that lead to gain-of-function activity of either STIM1 or ORAI1 are responsible for a cluster of ultra-rare syndromes characterized by motor disturbances and platelet dysfunction. The prevalence of these disorders is at present unknown. In this study, we describe the generation and characterization of a knock-in mouse model (KI-STIM1I115F) that bears a clinically relevant mutation located in one of the two calcium-sensing EF-hand motifs of STIM1. The mouse colony is viable and fertile. Myotubes from these mice show an increased store-operated Ca2+ entry, as predicted. This most likely causes the dystrophic muscle phenotype observed, which worsens with age. Such histological features are not accompanied by a significant increase in creatine kinase. However, animals have significantly worse performance in rotarod and treadmill tests, showing increased susceptibility to fatigue, in analogy to the human disease. The mice also show increased bleeding time and thrombocytopenia, as well as an unexpected defect in the myeloid lineage and in natural killer cells. The present model, together with recently described models bearing the R304W mutation (located on the coiled-coil domain in the cytosolic side of STIM1), represents an ideal platform to characterize the disorder and test therapeutic strategies for patients with STIM1 mutations, currently without therapeutic solutions. This article has an associated First Person interview with Celia Cordero-Sanchez, co-first author of the paper. Summary: We describe a mouse model (KI-STIM1I115F) that displays the clinical hallmarks of tubular aggregate myopathy. This model provides a new opportunity to characterize the disorder and test novel therapeutic strategies.