Miracle-dz/UniFAR-FTUs huggingface dataset:
Expanding the Arsenal of FGFR Inhibitors: A Novel Chloroacetamide Derivative as a New Irreversible Agent With Anti-proliferative Activity Against FGFR1-Amplified Lung Cancer Cell Lines

Fibroblast Growth Factor Receptors (FGFR1–4) have a critical role in the progression of several human cancers, including Squamous Non-Small-Cell Lung Cancer (SQCLC). Both non-selective and selective reversible FGFR inhibitors are under clinical investigation for the treatment of patients with tumors harboring FGFR alterations. Despite their potential efficacy, the clinical development of these drugs has encountered several challenges, including toxicity, and the appearance of drug resistance. Recent efforts have been directed at development of irreversible FGFR inhibitors, which have the potential to exert superior anti-proliferative activity in tumors carrying FGFR alterations. With this in mind, we synthetized, and investigated a set of novel inhibitors possessing a warhead potentially able to covalently bind a cysteine in the P-loop of FGFR. Among them, the chloroacetamide UPR1376 resulted able to irreversible inhibit FGFR1 phosphorylation in FGFR1 over-expressing cells generated from SQCLC SKMES-1 cells. In addition, this compound inhibited cell proliferation in FGFR1-amplified H1581 cells with a potency higher than the reversible inhibitor BGJ398 (infigratinib), while sparing FGFR1 low-expressing cells. The anti-proliferative effects of UPR1376 were demonstrated in both 2D and 3D systems and were associated with the inhibition of MAPK and AKT/mTOR signaling pathways. UPR1376 inhibited cell proliferation also in two BGJ398-resistant cell clones generated from H1581 by chronic exposure to BGJ398, although at concentrations higher than those effective in the parental cells, likely due to the persistent activation of the MAPK pathway associated to NRAS amplification. Combined blockade of FGFR1 and MAPK signaling, by UPR1376 and trametinib respectively, significantly enhanced the efficacy of UPR1376, providing a means of circumventing resistance to FGFR1 inhibition. Our findings suggest that the insertion of a chloroacetamide warhead on a suitable scaffold, as exemplified by UPR1376, is a valuable strategy to develop a novel generation of FGFR inhibitors for the treatment of SQCLC patients with FGFR alterations.
Comparison Between Movement-Based and Task-Based Mirror Therapies on Improving Upper Limb Functions in Patients With Stroke: A Pilot Randomized Controlled Trial

Objective: The aim of this trial was to compare the effect of movement-based mirror therapy (MMT) and task-based mirror therapy (TMT) on improving upper limb functions in patients with stroke. Methods: A total of 34 patients with sub-acute stroke with mildly to moderately impaired upper limb motor functions. The participants were randomly allocated to one of three groups: MMT, TMT, and conventional treatment (CT). The MMT group underwent movement-based mirror therapy for around 30 min/day, 5 days/week, for 4 weeks, whereas the TMT group underwent dose-matched TMT. The CT group underwent only conventional rehabilitation. The MMT and TMT groups underwent CT in addition to their mirror therapy. Blinded assessments were administered at baseline and immediately after the intervention. Upper limb motor functions, measured using Fugl-Meyer Assessment-upper extremity (FMA-UE), Wolf Motor Function Test (WMFT), and hand grip strength; upper limb spasticity, measured using the modified Ashworth scale (MAS); and activities of daily living, measured using the modified Barthel index (MBI). Results: A significant time-by-group interaction effect was noted in FMA-UE. Post-hoc analysis of change scores showed that MMT yielded a better effect on improving FMA-UE than the other two therapies, at a marginally significant level (P = 0.050 and 0.022, respectively). No significant interaction effect was noted in WMFT, hand grip strength, MAS, and MBI. Conclusion: Both MMT and TMT are effective in improving the upper limb function of patients with mild to moderate hemiplegia due to stroke. Nevertheless, MMT seems to be superior to TMT in improving hemiplegic upper extremity impairment. Further studies with larger stroke cohorts are expected to be inspired by this pilot trial. Trial registration number: No. ChiCTR1800019043 (http://www.chictr.org.cn/index.aspx)
Lipopolysaccharide (LPS) Aggravates High Glucose- and Hypoxia/Reoxygenation-Induced Injury through Activating ROS-Dependent NLRP3 Inflammasome-Mediated Pyroptosis in H9C2 Cardiomyocytes

Diabetes aggravates myocardial ischemia-reperfusion (I/R) injury because of the combination effects of changes in glucose and lipid energy metabolism, oxidative stress, and systemic inflammatory response. Studies have indicated that myocardial I/R may coincide and interact with sepsis and inflammation. However, the role of LPS in hypoxia/reoxygenation (H/R) injury in cardiomyocytes under high glucose conditions is still unclear. Our objective was to examine whether lipopolysaccharide (LPS) could aggravate high glucose- (HG-) and hypoxia/reoxygenation- (H/R-) induced injury by upregulating ROS production to activate NLRP3 inflammasome-mediated pyroptosis in H9C2 cardiomyocytes. H9C2 cardiomyocytes were exposed to HG (30 mM) condition with or without LPS, along with caspase-1 inhibitor (Ac-YVAD-CMK), inflammasome inhibitor (BAY11-7082), ROS scavenger N-acetylcysteine (NAC), or not for 24 h, then subjected to 4 h of hypoxia followed by 2 h of reoxygenation (H/R). The cell viability, lactate dehydrogenase (LDH) release, caspase-1 activity, and intracellular ROS production were detected by using assay kits. The incidence of pyroptosis was detected by calcein-AM/propidium iodide (PI) double staining kit. The concentrations of IL-1β and IL-18 in the supernatants were assessed by ELISA. The mRNA levels of NLRP3, ASC, and caspase-1 were detected by qRT-PCR. The protein levels of NF-κB p65, NLRP3, ASC, cleaved caspase-1 (p10), IL-1β, and IL-18 were detected by western blot. The results indicated that pretreatment LPS with 1 μg/ml not 0.1 μg/ml could efficiently aggravate HG and H/R injury by activating NLRP3 inflammasome to mediate pyroptosis in H9C2 cells, as evidenced by increased LDH release and decreased cell viability in the cells, and increased expression of NLRP3, ASC, cleaved caspase-1 (p10), IL-1β, and IL-18. Meanwhile, Ac-YVAD-CMK, BAY11-7082, or NAC attenuated HG- and H/R-induced H9C2 cell injury with LPS stimulated by reversing the activation of NLRP3 inflammasome-mediated pyroptosis. In conclusion, LPS could increase the sensitivity of H9C2 cells to HG and H/R and aggravated HG- and H/R-induced H9C2 cell injury by promoting ROS production to induce NLRP3 inflammasome-mediated pyroptosis.
COLLEGE STUDENTS' ACADEMIC PERFORMANCE AND SELF-REPORTS OF COMPREHENSION STRATEGY USE

Reading for college courses places considerable cognitive-processing demands on students. Drawing on descriptive studies of highly-skilled adult readers, a questionnaire was constructed to determine if the use of reading strategies improved everyday college course performance. Three-hundred and twenty-four college undergraduates responded to an open-ended question about reading goals, an open-ended question about reading comprehension strategy use, and rated 35 reading comprehension strategies for frequency of use. The number of goals and the number of strategies that students gave as answers for the open-ended questions, and the ratings for the 35 strategies as a whole, reliably discriminated between participants with higher and lower grade-point averages. Additional tests with a freshman sample showed that the strategy ratings also discriminated between participants with higher and lower ACT (American College Testing) Reading and English scores. Statistical tests for individual strategies revealed that the strategies that consistently differentiated participants were related to setting and responding to reading goals. Overall the results showed the benefits of comprehension strategy use on college students' academic performance. They contrast with a common characterization of college readers as unsophisticated, inefficient, and ineffective. Future research should focus on developing instructional settings that readily evoke comprehension strategies and encourage students to use them.
Ecosystem Services Related to Carbon Cycling – Modeling Present and Future Impacts in Boreal Forests

Forests regulate climate, as carbon, water and nutrient fluxes are modified by physiological processes of vegetation and soil. Forests also provide renewable raw material, food, and recreational possibilities. Rapid climate warming projected for the boreal zone may change the provision of these ecosystem services. We demonstrate model based estimates of present and future ecosystem services related to carbon cycling of boreal forests. The services were derived from biophysical variables calculated by two dynamic models. Future changes in the biophysical variables were driven by climate change scenarios obtained as results of a sample of global climate models downscaled for Finland, assuming three future pathways of radiative forcing. We introduce continuous monitoring on phenology to be used in model parametrization through a webcam network with automated image processing features. In our analysis, climate change impacts on key boreal forest ecosystem services are both beneficial and detrimental. Our results indicate an increase in annual forest growth of about 60% and an increase in annual carbon sink of roughly 40% from the reference period (1981–2010) to the end of the century. The vegetation active period was projected to start about 3 weeks earlier and end ten days later by the end of the century compared to currently. We found a risk for increasing drought, and a decrease in the number of soil frost days. Our results show a considerable uncertainty in future provision of boreal forest ecosystem services.
Taking Action or Thinking About It? State Orientation and Rumination Are Correlated in Athletes

Athletic performance in competitive sports relies heavily on the ability to cope effectively with stressful situations. In contrast, some athletes report that their thoughts revolve around the future or past and not around the actual demands during competitions. In those specific stressful situations, the lack of focus like an unintended fixation on repetitive cognitions can have fatal consequences with regard to the performance. Especially when competitors are close in their athletic capabilities, differences in effectively coping with stress and mental stability may decide about winning and losing. One established factor of performing effectively under pressure is the individual tendency to either focus on taking action (i.e., action orientation) or on focusing on the own emotions (i.e., state orientation). It is widely acknowledged that state-oriented athletes have disadvantages in performing under stress. Moreover, the action control theory claims that state orientation is related to ruminative cognitions, which itself is assumed to impair performance in the long term. We tested this hypothesis in 157 competitive athletes from different sports (including individual and team sports). Regression analysis demonstrates a substantial correlation of failure-related action orientation (i.e., state orientation) with different measures of rumination (including general, clinically relevant, and competition-related rumination). In addition, general (i.e., content independent) rumination also correlated substantially with a rumination scale adapted specifically to sports-related competition. These results suggest (1) that a sports and competition-related ruminative mechanism exists and (2) that ruminative cognitions are related to the cognitive basis of state orientation. While our study does not allow for a causal interpretation, it provides an additional approach to investigate mental factors underlying inter-individual differences in athletic performance under stress and pressure.
Construction of Potential Glioblastoma Multiforme-Related miRNA-mRNA Regulatory Network

Background: Glioblastoma multiforme (GBM), the most common and aggressive human malignant brain tumor, is notorious for its limited treatment options and poor prognosis. MicroRNAs (miRNAs) are found to be involved in tumorigenesis of GBM. However, a comprehensive miRNA-mRNA regulatory network has still not been established. Methods: A miRNA microarray dataset (GSE90603) was obtained from GEO database. Then, we employed GEO2R tool to perform differential expression analysis. Potential transcription factors and target genes of screened differentially expressed miRNAs (DE-miRNAs) were predicted. The GBM mRNA dataset were downloaded from TCGA database for identifying differentially expressed genes (DEGs). Next, GO annotation and KEGG pathway enrichment analysis was conducted. PPI network was then established, and hub genes were identified via Cytoscape software. The expression and prognostic roles of hub genes was further evaluated. Results: Total 33 DE-miRNAs, consisting of 10 upregulated DE-miRNAs and 23 downregulated DE-miRNAs, were screened. SP1 was predicted to potentially regulate most of screened DE-miRNAs. Three thousand and twenty seven and 3,879 predicted target genes were obtained for upregulated and downregulated DE-miRNAs, respectively. Subsequently, 1,715 upregulated DEGs and 1,259 downregulated DEGs were identified. Then, 149 and 295 potential downregulated and upregulated genes commonly appeared in target genes of DE-miRNAs and DEGs were selected for GO annotation and KEGG pathway enrichment analysis. The downregulated genes were significantly enriched in cGMP-PKG signaling pathway and calcium signaling pathway whereas the upregulated genes were enriched in pathways in cancer and PI3K-Akt signaling pathway. Construction and analysis of PPI network showed that STXBP1 and TP53 were recognized as hub genes with the highest connectivity degrees. Expression analytic result of the top 20 hub genes in GBM using GEPIA database was generally identical with previous differential expression analysis for TCGA data. EGFR, PPP3CB, and MYO5A expression was significantly associated with patients' OS. Conclusions: In this study, we established a potential GBM-related miRNA-mRNA regulatory network, which explores a comprehensive understanding of the molecular mechanisms and provides key clues in seeking novel therapeutic targets for GBM. In the future, more experiments need to be performed to validate our current findings.
The Level of Serum Albumin Is Associated with Renal Prognosis in Patients with Diabetic Nephropathy

Objective Although hypoalbuminemia is frequently found in most patients with diabetic nephropathy (DN), its relationship to the severity and progression of DN remains largely unknown. Our aim was to investigate the association between the serum albumin levels and clinicopathological features and renal outcomes in patients with type 2 diabetes mellitus (T2DM) and biopsy-proven DN. Materials and Methods A total of 188 patients with T2DM and biopsy-proven DN followed up for at least one year were enrolled. The patients were divided into four groups based on the albumin levels: normal group: ≥35 g/L (n = 87); mild group: 30-35 g/L (n = 34); moderate group: 25-30 g/L (n = 36); and severe group: <25 g/L (n = 31). The renal outcome was defined by progression to end-stage renal disease. The impact of the serum albumin level on renal survival was estimated using Cox regression analysis. Results Among the cases, the serum albumin level had a significant correlation with proteinuria, renal function, and glomerular lesions. A multivariate Cox regression analysis indicated that the severity of hypoalbuminemia remained significantly associated with an adverse renal outcome, independent of clinical and histopathological features. In reference to the normal group, the risk of progression to ESRD increased such that the hazard ratio (HR) for the mild group was 2.09 (95% CI, 0.67-6.56, p = 0.205), 6.20 (95% CI, 1.95-19.76, p = 0.002) for the moderate group, and 7.37 (95% CI, 1.24-43.83, p = 0.028) for the severe group. Conclusions These findings suggested that hypoalbuminemia was associated with a poorer renal prognosis in patients with T2DM and DN.
Correlation of tumor necrosis factor alpha, interleukin 6 and interleukin 10 with blood pressure, risk of preeclampsia and low birth weight in gestational diabetes.

Several pathophysiological mechanisms have been proposed in the development of pregnancy complications, including endothelial dysfunction, an inflammatory pathway and oxidative stress. The aim of the present study was to evaluate the correlation between proinflammatory cytokines TNF-alpha, IL-6 and dual cytokine IL-10 in the mother's peripheral blood and blood pressure, risk of preeclampsia and low birth weight in gestational diabetes (GDM). We observed 40 women with GDM divided into a gestational hypertension group (n=20) and comparison group (n=20) with normal blood pressure. We found a significant positive correlation between TNF-alpha; IL-6; IL-10 levels and systolic blood pressure (SBP) in the second trimester (p<0.001; p<0.001; p<0.001); the third trimester (p<0.001; p<0.001; p<0.05). We also proved correlations for diastolic blood pressure (DBP) during the second; third trimester (p<0.001; p<0.001; p<0.001); (p<0.001; p<0.001; p<0.0015). We demonstrated a statistically significant positive association between high TNF-alpha group and preeclampsia risk in the third trimester (p=0.04). We also determined the negative correlation in the second trimester between birth weight and TNF-alpha; IL-6, IL-10 levels (p<0.05; p<0.001; p<0.001). To conclude, our data highlight the importance of cytokines TNF-alpha, IL-6 and IL-10 in blood pressure regulation. In addition high levels of TNF-alpha have been associated with increased risk of preeclampsia. We found a significant negative correlation between levels of TNF-alpha, IL-6, IL-10 and birth weight.
Effects of ischaemic postconditioning on outcomes of patients with ST-segment elevation myocardial infarction who underwent primary percutaneous coronary intervention: a meta-analysis

Objective The aim of this meta-analysis was to evaluate the effects of ischaemic postconditioning (IPC) therapy on hard clinical endpoints in ST-segment elevation myocardial infarction (STEMI) patients who underwent primary percutaneous coronary intervention (PPCI). Design Systematic review and meta-analysis to evaluate the effects of IPC on the outcomes of patients with STEMI. Data sources PubMed, Embase and the Cochrane Library were systematically searched for relevant articles published prior to May 1, 2018. Eligibility criteria for selecting studies Randomised trials comparing conventional PPCI to PPCI combined with IPC in STEMI patients were included. The primary endpoint was heart failure. Secondary endpoints were all-cause mortality and major adverse cardiac events (MACE), including cardiac death, heart failure and MI. The Cochrane Reviewer’s Handbook 4.2 was used to assess the risk of bias. Data extraction and synthesis Relevant data were extracted by two independent investigators. We derived pooled risk ratios (RRs) with random effects models. Sensitivity and subgroup analyses were performed. Results Ten studies that had enrolled 3137 patients were included. PPCI combined with IPC failed to reduce heart failure (RR: 0.88, 95% CI: 0.61 to 1.26, p=0.47; absolute risk: 3.64% in the IPC group and 4.11% in the PPCI only group), all-cause mortality (RR: 0.94, 95% CI: 0.69 to 1.27, p=0.68; absolute risk: 5.07% in the IPC group and 5.27% in the PPCI onlygroup), MACE (RR: 1.05, 95% CI: 0.83 to 1.32, p=0.69; absolute risk: 9.37% in the IPC group and 8.93% in the PPCI only group), cardiac death (RR: 1.28, 95% CI: 0.85 to 1.93, p=0.24; absolute risk: 4.28% in the IPC group and 3.25% in the PPCI only group) and MI (RR: 1.08, 95% CI: 0.38 to 3.12, p=0.88; absolute risk: 3.61% in the IPC group and 3.44% in the PPCI only group). Conclusions IPC combined with PPCI does not reduce heart failure, MACE and all-cause mortality compared with traditional PPCI in patients with STEMI. Trial registration number CRD42017063959
The impact of the market portfolio on the valuation, incentives and optimality of executive stock options

This paper examines the effect on valuation and incentives of allowing executives receiving options to trade on the market portfolio. We propose a continuous time utility maximization model to value stock and option compensation from the executive's perspective. The executive may invest non-option wealth in the market and riskless asset but not in the company stock itself, leaving them subject to firm-specific risk for incentive purposes. Since the executive is risk averse, this unhedgeable firm risk leads them to place less value on the options than their cost to the company. Hay Group Study 2002 cited in Skapinker (2003). By distinguishing between these two types of risks, we are able to examine the effect of stock volatility, firm-specific risk and market risk on the value to the executive. In particular, options do not give incentive to increase total risk, but rather to increase the proportion of market relative to firm-specific risk, so executives prefer high beta companies. The paper also examines the relationship between risk and incentives, and finds firm-specific risk decreases incentives whilst market risk may decrease incentives depending on other parameters. The model supports the use of stock rather than options if the company can adjust cash pay when granting stock-based compensation.
Haematological adverse events associated with tyrosine kinase inhibitors in chronic myeloid leukaemia: A network meta‐analysis

Despite their overall favourable safety profile, tyrosine kinase inhibitors (TKIs) are related to severe adverse events including haematological toxicities such as anaemia, leucopenia, neutropenia and thrombocytopenia. We designed a systematic review and network meta‐analysis of randomised controlled trials to compare safety among TKIs (bosutinib, dasatinib, imatinib, nilotinib, ponatinib and radotinib) used by patients diagnosed with chronic myeloid leukaemia.
Evaluation of the acceptability and clinical utility of an Arabic-language mindfulness CD in an Australian community setting

The cultural, linguistic, and religious diversity of Australia's population presents challenges for mental health service delivery. Arabic-speaking communities in Australia underutilise mental health services despite high levels of trauma and psychological distress. Clinicians who work with this population lack linguistically and culturally appropriate clinical resources. The aim of this study was to explore the acceptability and clinical utility of a Mindfulness Skills CD translated into formal Arabic. The 70 participants were Arabic-speaking adults, mostly Lebanese-born Muslim women, who enrolled in a 5-week mindfulness program using the CD and agreed to follow-up at 12 weeks. Both recruitment and data collection were undertaken by a female project officer who is a widely respected member of the Arabic community in south-east Sydney. Compliance with the program protocol was high and all but 4 participants continued to use the CD beyond the 5 weeks. Overall, participants reported that mindfulness techniques fitted well with their way of life and were compatible with their cultural and religious practices. Most found mindfulness complementary to their regular reflective prayer. Using the Mindfulness Skills CD was associated with statistically significant reductions in psychological distress as measured by the Kessler Scale (K10) and the Depression, Anxiety, and Stress Scale (DASS21) postprogram (K10; DASS21 Depression and Stress subscales) and at follow-up (all measures). The evaluation showed that the Arabic Mindfulness Skills CD is an effective and culturally appropriate mental health resource for this population group. This low-cost, easily distributed resource is suitable for use in individual self-management and as an adjunct to primary and specialist mental health care.