Miracle-dz/UniFAR-FTUs huggingface dataset:
Ursolic acid promotes apoptosis and mediates transcriptional suppression of CT45A2 gene expression in non‐small‐cell lung carcinoma harbouring EGFR T790M mutations

In non‐small‐cell lung carcinoma (NSCLC) patients, the L858R/T790M mutation of the epithelial growth factor receptor (EGFR) is a major cause of acquired resistance to EGFR‐TKIs treatment that limits their therapeutic efficacy. Identification of drugs that can preferentially kill the NSCLC harbouring L858R/T790M mutation is therefore critical. Here, we have evaluated the effects of ursolic acid, an active component isolated from herbal sources, on erlotinib‐resistant H1975 cells that harbour the L858R/T790M mutation.
The Inclusion of Concentrate with Quebracho Is Advisable in Two Forage-Based Diets of Ewes According to the In Vitro Fermentation Parameters

Simple Summary In dry, mountainous areas, ewes are fed low-quality forages (hay or straw) indoors, although they also graze in high-quality pastures when available. Concentrate supplementation is recommended to cover high nutritional requirements during lactation. Condensed tannins (CT) of quebracho (Schinopsis balansae) can be included in the concentrate to reduce methane (CH4) emissions and ruminal degradation of protein, improving the fermentation’s efficiency. Furthermore, low levels of quebracho can improve some meat and milk quality traits. The effects of the inclusion of concentrate and CT in diets depend on the level of inclusion and the quality of forage. The aim of this study was to evaluate the in vitro fermentation characteristics of diets in order to identify the most suitable one to be fed to ewes under farming conditions. The diets examined differed in quality of the forage available, comparing hay versus fresh forage diets and forage alone versus 70:30 forage:concentrate with (quebracho) or without CT (control) in each type of forage. The fresh-forage-based diets had lower gas and CH4 production and greater in vitro organic matter degradability (IVOMD) than the hay-based diets. The inclusion of quebracho concentrate increased the IVOMD in hay-based diets and reduced ammonia content in fresh-forage-based diets. Abstract Ewes receive hay or graze on fresh pastures supplemented with concentrates to fulfil their lactation requirements. Quebracho (Schinopsis balansae) can be added to change the ruminal fermentation. Fermentation parameters of forages alone and 70:30 forage:concentrate diets with control and quebracho concentrate were compared after 24 h of in vitro incubation. Fresh forage diets produced less gas (p < 0.05) and had greater IVOMD (p < 0.001), ammonia (NH3-N) content, valeric acid, branched-chain volatile fatty acid proportions, and lower propionic acid proportion than the hay diets (p < 0.01). In the hay diets, methane production increased with control concentrate (p < 0.01) and tended to decrease with quebacho concentrate (p < 0.10). The inclusion of both concentrates increased the acetic:propionic ratio (p < 0.01), and only the inclusion of quebracho concentrate increased the IVOMD (p < 0.01). In the fresh forage diets, gas and methane production increased with the inclusion of the control concentrate (p < 0.05), but methane production decreased with quebracho concentrate (p < 0.01). The inclusion of quebracho concentrate reduced the NH3-N content and valeric acid proportion (p < 0.05). In conclusion, the inclusion of quebracho concentrate would be advisable to reduce the CH4 production and NH3-N content in fresh forage diets and to increase the IVOMD in hay diets in comparison with the forages alone.
Digital aripiprazole or digital evergreening? A systematic review of the evidence and its dissemination in the scientific literature and in the media

Background In November 2017, the Food and Drug Administration (FDA) approved a version of a second-generation antipsychotic, aripiprazole, embedded with a sensor (Abilify MyCite). Objective To systematically review the evidence supporting the FDA’s approval of digital aripiprazole and how that evidence was disseminated in the scientific literature and news reports. Study selection Prospective, double-blind, randomised controlled trials (RCTs), non-randomised and non-comparative studies were included if they focused on the use of digital aripiprazole. All scientific publications citing the trials were included if written in English. For the news reports, all languages were included if an English translation was available, and all records that were published after FDA approval were included. Findings In the primary evidence search, no RCT comparing digital aripiprazole with a non-digital formulation, other active comparators or placebo was found. Only three non-comparative uncontrolled cohorts were found. No study provided data on remission, quality of life or any efficacy outcome. Fourteen scientific papers were identified that cited the trials and 70 news stories met the inclusion criteria. Almost 80% (11/14) of the scientific papers and three-fourths (52/70) of the news stories conveyed an unsupported impression of benefit. Conclusions Regulatory approval for this first-ever digital drug was based on weak evidence, and there was no evidence of better adherence with the digital version of aripiprazole compared with the non-digital version. The possibilities afforded by this technology make room for a new type of evergreening (ie, patenting of older drugs with a sensor as a ‘new invention’). Both the scientific literature and news reports conveyed an unsupported impression of benefit. Trial registration number CRD42018089515.
Neuromuscular Function and Blood Flow Occlusion with Dynamic Arm Flexor Contractions.

INTRODUCTION Blood flow restricted or occlusion exercise enhances muscle hypertrophy and strength during resistance training. The acute effects on voluntary and electrically evoked muscle contractile characteristics with impaired blood flow at low and high contraction forces has not been explored. METHODS On separate days, nine males completed two different protocols of concentric elbow flexor contractions. A repetitive low-force (~25% of isometric maximum voluntary contraction, MVC) with blood flow occlusion (BFO; 300mmHg) protocol was compared to a high-force (~80% MVC) free blood flow protocol (HF), until range of motion (0-90°) was impaired. Torque, velocity and power were compared to baseline and between protocols. MVC and voluntary activation (VA) were assessed during and following each protocol. Muscle twitch, low (20Hz) and high (50 Hz) tetanus, and compound muscle action potential (Mmax) area were measured at 0, 2, 5, 10, and 20min of recovery. RESULTS Repetitions to failure (FP) were lower for HF (~16) versus BFO (~21), and MVC at FP was reduced more during BFO (~77%) compared to HF (~23%), with no difference in VA (~10% loss) between protocols. At FP, velocities for BFO and HF were similarly reduced by ~63% and ~56%, respectively, however peak power decreased more during BFO (~90%) compared with HF (~67%). Total work for BFO was ~40% lower than for HF. Peak power for HF was recovered by 2mins, whereas BFO required 20mins. Low-frequency fatigue (20Hz/50Hz) was greater following BFO (~70% decrease versus ~29% decrease following HF), while Mmax area was unaffected. CONCLUSION Concentric elbow flexions at low-force with BFO causes greater impairments in strength and power than HF and therefore may be a replacement for high-force exercise used in chronic training.
The Sex–Gender Effects in the Road to Tailored Botanicals

Phenols are a wide family of phytochemicals that are characterized by large chemical diversity and are considered to bioactive molecules of foods, beverages, and botanicals. Although they have a multitude of biological actions, their beneficial effects are rarely evidenced in clinical research with high scientific rigor. This may occur due to the presence of numerous confounders, such as the modulation of phenol bioavailability, which can be regulated by microbiota, age, sex-gender. Sex-gender is an important determinant of health and well-being, and has an impact on environmental and occupational risks, access to health care, disease prevalence, and treatment outcomes. In addition, xenobiotic responses may be strongly influenced by sex-gender. This review describes how sex–gender differentially influences the activities of phenols also in some critical periods of women life such as pregnancy and lactation, considering also the sex of fetuses and infants. Thus, sex–gender is a variable that must be carefully considered and should be used to propose directions for future research on the road to tailored medicine and nutrition.
Real-world effectiveness and tolerability of small-cell lung cancer (SCLC) treatments: A systematic literature review (SLR)

Objectives SCLC makes up approximately 15% of all lung carcinomas and is characterized by relatively aggressive spread and poorer prognosis compared to other lung cancers. Treatment options are limited, and their efficacy in randomized trials is poor, whilst outcomes in clinical practice remain unclear. The aim of this study was to assess the real-world effectiveness and tolerability of SCLC treatments. Methods An SLR was conducted across nine databases accessed through OVID, capturing observational, non-randomized studies published between 01/2006–11/2018. In total, 554 abstracts were retrieved and systematically screened for eligibility. The eligible publications included effectiveness and tolerability data from adult SCLC patients (at any line of therapy). Additional grey literature searches were conducted. Results Forty-three publications were included in this review—data from first-line therapies were captured most often (n = 32), while data from second (n = 14) and third line (n = 7) and beyond (n = 7) were less frequent. The publications reported primarily on chemotherapy/radiotherapy. The majority of publications lacked robustness and only 14/43 conducted statistical analyses or controlled for bias. Median OS for the largest SCLC populations were 9.6 months at first line (n = 23,535) and 4.9 months at second line (n = 254) for treatment with chemotherapy, and 4.7 months at third line (n = 120) for predominantly platinum-based chemotherapy or cyclophosphamide/adriamycin/vincristine. Hematologic toxicities (such as neutropenia, thrombocytopenia and anemia) were the most frequently reported TRAEs (n = 9). Conclusions Real-world treatment effectiveness and tolerability data were fragmented and inconsistently reported, and available publications were primarily of poor quality and lacked statistical analyses. This SLR showed limited treatment options and poor OS in SCLC, with no treatment option being clearly superior. TRAEs additionally increased the burden of this already challenging disease. Recent data suggest real-world outcomes are even poorer that those reported in clinical trials, and that novel therapies are needed to offer new treatment options for patients.
Effects of Anserine/Carnosine Supplementation on Mild Cognitive Impairment with APOE4

Background: Oral supplementation of anserine/carnosine helps preserve cognitive functions in healthy older adults. Mild cognitive impairment (MCI) is a transition between cognitive-normal and dementia. Therefore, it needs to investigate whether anserine/carnosine supplementation (ACS) has effects on subjects with MCI. Methods: A randomized, double-blind, placebo-controlled 12-week trial was performed. Fifty-four subjects with MCI were randomized to an active group ingesting 750 mg of anserine and 250 mg of carnosine per day or a placebo (1:1). Evaluation of cognitive change was conducted utilizing a psychometric test battery. Results: The score improvement in the global Clinical Dementia Rating (gloCDR) was superior in the active group than placebo (p = 0.023). No beneficial effect in the active group was detected in the other psychometric tests including the Mini-Mental State Examination (MMSE), the Wechsler Memory Scale, and the Alzheimer’s Disease Assessment Scale (ADAS). When APOE4 positive (APOE4 (+)) or negative (APOE4 (-)) subjects were separately analyzed, beneficial change in the APOE4 (+) subjects was observed in MMSE (p = 0.025) as well as in gloCDR (p = 0.026). Conclusions: The present study might suggest that protective effects against cognitive decline in APOE4 (+) MCI subjects exist.
Predictors of high hospital care and medication costs and cost trajectories in community-dwellers with Alzheimer’s disease

Abstract Objectives We studied the determinants of high healthcare costs (highest decile of hospital care and medication costs) and cost trajectories among all community-dwellers with clinically verified Alzheimer’s disease (AD), diagnosed during 2005–2011 in Finland (N = 70,531). Methods The analyses were done separately for hospital care costs, medication costs and total healthcare costs that were calculated for each 6-month period from 5 years before to 3 years after AD diagnosis. Results Total healthcare costs were driven mainly by hospital care costs. The definition of “high-cost person” was time-dependent as 63% belonged to the highest 10% at some timepoint during the study period and six distinct cost trajectories were identified. Strokes, cardiovascular diseases, fractures and mental and behavioural disorders were most strongly associated with high hospital care costs. Conclusions Although persons with AD are often collectively considered as expensive patient group, there is large temporal and inter-individual variation in belonging to the highest decile of hospitalization and/or medication costs. It would be important to assess whether hospitalization rate could be decreased by, e.g., comprehensive outpatient care with more efficient management of comorbidities. In addition, other interventions that could decrease hospitalization rate in persons with dementia should be studied further in this context. Key messages Persons with AD had large individual fluctuation in hospital care costs and medication costs over time. Hospital care costs were considerably larger than medication costs, with fractures, cardiovascular diseases and mental and behavioural disorders being the key predictors. Antidementia medication was associated with lower hospital care costs.
Stepwise functional connectivity reveals altered sensory‐multimodal integration in medication‐naïve adults with attention deficit hyperactivity disorder

Neuroimaging studies indicate that children with attention‐deficit/hyperactivity disorder (ADHD) present alterations in several functional networks of the sensation‐to‐cognition spectrum. These alterations include functional overconnectivity within sensory regions and underconnectivity between sensory regions and neural hubs supporting higher order cognitive functions. Today, it is unknown whether this same pattern of alterations persists in adult patients with ADHD who had never been medicated for their condition. The aim of the present study was to assess whether medication‐naïve adults with ADHD presented alterations in functional networks of the sensation‐to‐cognition spectrum. Thirty‐one medication‐naïve adults with ADHD and twenty‐two healthy adults underwent resting‐state functional magnetic resonance imaging (rs‐fMRI). Stepwise functional connectivity (SFC) was used to characterize the pattern of functional connectivity between sensory seed regions and the rest of the brain at direct, short, intermediate, and long functional connectivity distances, thus covering the continuum from the sensory input to the neural hubs supporting higher order cognitive functions. As compared to controls, adults with ADHD presented increased SFC degree within primary sensory regions and decreased SFC degree between sensory seeds and higher order integration nodes. In addition, they exhibited decreased connectivity degree between sensory seeds and regions of the default‐mode network. Consistently, the higher the score in clinical severity scales the lower connectivity degree between seed regions and the default mode network.
Response of the Green Alga Chlamydomonas reinhardtii to the DNA Damaging Agent Zeocin

DNA damage is a ubiquitous threat endangering DNA integrity in all living organisms. Responses to DNA damage include, among others, induction of DNA repair and blocking of cell cycle progression in order to prevent transmission of damaged DNA to daughter cells. Here, we tested the effect of the antibiotic zeocin, inducing double stranded DNA breaks, on the cell cycle of synchronized cultures of the green alga Chlamydomonas reinhardtii. After zeocin application, DNA replication partially occurred but nuclear and cellular divisions were completely blocked. Application of zeocin combined with caffeine, known to alleviate DNA checkpoints, decreased cell viability significantly. This was probably caused by a partial overcoming of the cell cycle progression block in such cells, leading to aberrant cell divisions. The cell cycle block was accompanied by high steady state levels of mitotic cyclin-dependent kinase activity. The data indicate that DNA damage response in C. reinhardtii is connected to the cell cycle block, accompanied by increased and stabilized mitotic cyclin-dependent kinase activity.
Determinants of caregiver burden in heart failure: does caregiver contribution to heart failure patient self-care increase caregiver burden?

Background: The burden is high in caregivers of heart failure patients, but the literature on patient and caregiver predictors of caregiver burden is inconsistent. Also, it is unknown if caregiver contribution to heart failure self-care maintenance (i.e. helping patients to maintain heart failure stable) and self-care management (i.e. helping patients to act in case of heart failure worsening) increases caregiver burden. Aims: To identify caregiver and patient predictors of caregiver burden in heart failure; and to evaluate if caregiver contribution to heart failure self-care maintenance and management increases caregiver burden. Methods: A cross-sectional study with the enrolment of 505 caregivers of heart failure patients. We used the caregiver burden inventory and the caregiver contribution to self-care of heart failure index. We analysed the data using hierarchical regression. Results: Heart failure caregivers, mostly women (52.5%), with a mean age 56.5 (±14.9) years, cared for heart failure patients, mostly men (55.2%), with a mean age of 75.9 (±10.4) years. Caregiver predictors of higher caregiver burden were older age, female gender, fewer caregiving hours and poor social support. Patient predictors of higher caregiver burden were older age, better education, taking fewer medications and higher quality of life. Caregiver contribution to self-care maintenance and management were not significant predictors of caregiver burden. Conclusions: Our results could help providers to identify heart failure caregivers who are more exposed to burden. As caregiver contribution to heart failure self-care improves patient outcomes and seems not burdensome for caregivers, providers may consider educating caregivers about self-care as a viable option for improving patient outcomes without increasing caregiver burden.
Prognostic Impact of Melatonin Receptors MT1 and MT2 in Non-Small Cell Lung Cancer (NSCLC)

Background: Several studies have investigated the inhibitory effect of melatonin on lung cancer cells. There are no data available on the prognostic impact of melatonin receptors MT1 and MT2 in non-small cell lung cancer (NSCLC). Materials and Methods: Immunohistochemical studies of MT1 and MT2 were conducted on NSCLC (N = 786) and non-malignant lung tissue (NMLT) (N = 120) using tissue microarrays. Molecular studies were performed on frozen fragments of NSCLC (N = 62; real time PCR), NMLT (N = 24) and lung cancer cell lines NCI-H1703, A549 and IMR-90 (real time PCR, western blot). Results: The expression of both receptors was higher in NSCLC than in NMLT. Higher MT1 and MT2 expression levels (at protein and mRNA) were noted in squamous cell carcinomas (SCC) compared to adenocarcinomas (AC). MT1 immunoexpression decreased as both the tumour size and the cancer stage increased in the whole cohort, while MT2 decreased as the cancer stage increased, with lymph node involvement (in the whole study group) and increasing malignancy grade (in SCC). Higher expression of MT2 was associated with a favorable prognosis. MT2 was an independent prognostic factor for overall survival (OS) in all analyzed NSCLC and in smoking patients. Conclusions: Our observations may point to the potential prognostic significance of MT2 in NSCLC.
GABAergic cell transplants in the anterior cingulate cortex reduce neuropathic pain aversiveness

Peripheral nerve injury-induced neuropathic pain has both sensory discriminative and affective features. Juarez-Salinas et al. report that transplanting embryonic GABAergic progenitor cells from the medial ganglionic eminence into the rostral anterior cingulate cortex reduces ongoing pain aversiveness in a mouse model of chemotherapy (paclitaxel)-induced neuropathic pain.
The relationship between adolescent sport participation and lifelong participation in physical activity in Norway

In this paper, the relationship between adolescent sport participation and lifelong participation in physical activity (LLP) is scrutinized, in order to explain why people are active later in life. Literature treating the relationship between sport participation during adolescence was compared to literature into characteristics of Norwegian adolescent sport. Organized and competitive sport does not facilitate lifelong continuation in physical activity, due to its characteristics of sport: adolescents often drop out from sport, adolescents specializes in one sport instead of keeping or developing a broad repertoire for physical activity, and adolescents do not feel autonomous and free in a sport setting as it is adult controlled. Assisted by Bourdieu’s theory of field and habitus, the analysis indi cates that habitus (including characteristics of social class) better explains LLP than does adolescent sport participation. It is proposed that habitus can be seen as the intermediate mechanism that explains both adolescent sport participation and LLP (instead of seeing the former explaining the latter).
Suradnja gospodarstva i znanosti u Hrvatskoj: stajalište znanstvenika

Industry-science relationship is considered to be a very important part of the innovation system and it represents one of the crucial factors in national innovation capacity. Extant studies show that a significant proportion of the products and processes that are currently sold and used could not have been developed without academic research. Both industry and academia can benefit from this relationship. Research focus in this paper is on interactions between science and the industry from the researchers’ point of view based on field study in Croatia. This paper seeks to develop understanding of determinants of collaboration intensity with industry and scientists satisfaction in this relationship. It explores scientists’ motivations to collaborate and perceptions of barriers for collaboration as well as how they perceive the other side in this relationship. Research findings show strong scientist interest in the collaboration with industry. Significant motives that can explain their interest are intellectual challenge and additional income. Scientists find more powerful obstacles in their internal organizations than in external relationship with industry. They are persuaded that industry is not as interested in collaboration as they are. Less critical are those group of scientists who have already built closer working ties with industry.