Miracle-dz/UniFAR-FTUs huggingface dataset:
Targeting Glycolysis with Epigallocatechin-3-Gallate Enhances the Efficacy of Chemotherapeutics in Pancreatic Cancer Cells and Xenografts

Pancreatic cancer is a complex disease, in need of new therapeutic approaches. In this study, we explored the effect and mechanism of action of epigallocatechin-3-gallate (EGCG), a major polyphenol in green tea, alone and in combination with current chemotherapeutics on pancreatic cancer cell growth, focusing on glycolysis metabolism. Moreover, we investigated whether EGCG’s effect is dependent on its ability to induce reactive oxygen species (ROS). EGCG reduced pancreatic cancer cell growth in a concentration-dependent manner and the growth inhibition effect was further enhanced under glucose deprivation conditions. Mechanistically, EGCG induced ROS levels concentration-dependently. EGCG affected glycolysis by suppressing the extracellular acidification rate through the reduction of the activity and levels of the glycolytic enzymes phosphofructokinase and pyruvate kinase. Cotreatment with catalase abrogated EGCG’s effect on phosphofructokinase and pyruvate kinase. Furthermore, EGCG sensitized gemcitabine to inhibit pancreatic cancer cell growth in vitro and in vivo. EGCG and gemcitabine, given alone, reduced pancreatic tumor xenograft growth by 40% and 52%, respectively, whereas the EGCG/gemcitabine combination reduced tumor growth by 67%. EGCG enhanced gemcitabine’s effect on apoptosis, cell proliferation, cell cycle and further suppressed phosphofructokinase and pyruvate kinase levels. In conclusion, EGCG is a strong combination partner of gemcitabine reducing pancreatic cancer cell growth by suppressing glycolysis.
Probucol, a “non-statin” cholesterol-lowering drug, ameliorates D-galactose induced cognitive deficits by alleviating oxidative stress via Keap1/Nrf2 signaling pathway in mice

Oxidative stress plays a vital role in the initiation and progression of age-related neurodegenerative diseases. Ameliorating oxidative damage is therefore considered as a beneficial strategy for the treatment of age-related neurodegenerative disorders. Probucol (Prob), a lipid-lowering prototype agent, was reported to treat cardiovascular diseases, chronic kidney disease and diabetes mellitus. However, whether Prob has an effect on age-related neurodegenerative diseases remains unknown. In the study, it was found that Prob ameliorated D-galactose (D-gal) induced cognitive deficits and neuronal loss in the hippocampal CA1 region. Moreover, Prob alleviated ROS and MDA levels by elevating SOD, GSH-PX and HO-1 mRNA and protein expressions, and improving plasmic and cerebral SOD and GSH-PX activities in D-gal treated mice. Furthermore, Prob promoted the dissociation of Keap1/Nrf2 complex leading to the accumulation of Nrf2 in nucleus, implying that the improved anti-oxidant property of Prob is mediated by Keap1/Nrf2 pathway. The study firstly demonstrates the favorable effects of Prob against cognitive impairments in a senescent mouse model, rendering this compound a promising agent for the treatment or prevention of age-related neurodegenerative disease.
A2A Receptor Homodimer-Disrupting Sequence Efficiently Delivered by a Protease-Resistant, Cyclic CPP Vector

G-protein-coupled receptors associate into dimers/oligomers whose function is not well understood. One approach to investigate this issue is to challenge oligomerization by peptides replicating transmembrane domains and to study their effect on receptor functionality. The disruptor peptides are typically delivered by means of cell-penetrating vectors such as the human immunodeficiency virus (HIV) transcription trans-activation protein Tat. In this paper we report a cyclic, Tat-like peptide that significantly improves its linear analogue in targeting interreceptor sequences in the transmembrane space. The same cyclic Tat-like vector fused to a transmembrane region not involved in receptor oligomerization was totally ineffective. Besides higher efficacy, the cyclic version has enhanced proteolytic stability, as shown by trypsin digestion experiments.
Retrospective study on transmissible viral proventriculitis and chicken proventricular necrosis virus (CPNV) in the UK

ABSTRACT Chicken proventricular necrosis virus (CPNV) is a recently described birnavirus, which has been proposed to be the cause of transmissible viral proventriculitis (TVP). The understanding of the epidemiology of both the virus and the disease is very limited. A retrospective investigation on TVP and CPNV in broiler chicken submissions from the UK from between 1994 and 2015 was performed with the aims of assessing the longitudinal temporal evolution of TVP and CPNV, and to review the histological proventricular lesions in the studied chickens. Ninety-nine of the 135 included submissions (73.3%) fulfilled the TVP-diagnostic criteria, while the remaining 36 submissions (26.7%) displayed only lymphocytic proventriculitis (LP). The first detection of CPNV by PCR dated from 2009. Results showed a rise in the number of both TVP and positive CPNV RT–PCR submissions from 2009 with a peak in 2013, suggesting that they may be an emerging or re-emerging disease and pathogen, respectively. Twenty-two out of the 99 submissions displaying TVP lesions (22%) and four out of the 36 (11%) submissions with LP gave positive CPNV RT–PCR results, further supporting the association between CPNV and TVP and confirming that CPNV is present in a low proportion of proventriculi that do not fulfil the TVP-diagnostic criteria. In addition, intranuclear inclusion bodies were observed in 22 of the submissions with TVP. The vast majority of these cases (21 of 22, 96%) gave negative CPNV RT–PCR results, raising the question of whether a virus other than CPNV is responsible for some of these TVP-affected cases. RESEARCH HIGHLIGHTS TVP and CPNV have been present in British broilers since at least 1994 and 2009, respectively. TVP and CPNV seem to be an emerging and re-emerging disease and pathogen, respectively. CPNV was detected in proventriculi with both TVP and LP-lesions. Viruses other than CPNV may be responsible for some TVP-affected cases.
Transgelin, a p53 and PTEN-Upregulated Gene, Inhibits the Cell Proliferation and Invasion of Human Bladder Carcinoma Cells In Vitro and In Vivo

Transgelin (TAGLN/SM22-α) is a regulator of the actin cytoskeleton, affecting the survival, migration, and apoptosis of various cancer cells divergently; however, the roles of TAGLN in bladder carcinoma cells remain inconclusive. We compared expressions of TAGLN in human bladder carcinoma cells to the normal human bladder tissues to determine the potential biological functions and regulatory mechanisms of TAGLN in bladder carcinoma cells. Results of RT-qPCR and immunoblot assays indicated that TAGLN expressions were higher in bladder smooth muscle cells, fibroblast cells, and normal epithelial cells than in carcinoma cells (RT-4, HT1376, TSGH-8301, and T24) in vitro. Besides, the results of RT-qPCR revealed that TAGLN expressions were higher in normal tissues than the paired tumor tissues. In vitro, TAGLN knockdown enhanced cell proliferation and invasion, while overexpression of TAGLN had the inverse effects in bladder carcinoma cells. Meanwhile, ectopic overexpression of TAGLN attenuated tumorigenesis in vivo. Immunofluorescence and immunoblot assays showed that TAGLN was predominantly in the cytosol and colocalized with F-actin. Ectopic overexpression of either p53 or PTEN induced TAGLN expression, while p53 knockdown downregulated TAGLN expression in bladder carcinoma cells. Our results indicate that TAGLN is a p53 and PTEN-upregulated gene, expressing higher levels in normal bladder epithelial cells than carcinoma cells. Further, TAGLN inhibited cell proliferation and invasion in vitro and blocked tumorigenesis in vivo. Collectively, it can be concluded that TAGLN is an antitumor gene in the human bladder.
Evaluating the effectiveness of perceptual treatments on sharp curves: a driving simulator study

Abstract Objective: Speed has been identified as a key risk factor in road crashes, influencing the occurrence of a road crash and its severity. Excessive speeding is particularly dangerous on highway curves, and under critical traffic and environmental conditions. Various measures have been identified to be effective in managing and controlling vehicle speed. Among these, low-cost perceptual measures have been considered to be effective tools, as they generally increase the risks perceived by drivers, or alter speed perception, and consequently lead the drivers to reduce their speeds. The overall aim of this study is 1) to investigate the effectiveness of a set of perceptual treatments in reducing the driver’s speed along a sharp curve of an existing rural road that is characterized by high crash rates, and 2) to identify the most effective measure(s) to implement in the field to counteract the problem of speeding. Methods: A driving simulator study was developed and four speed-reducing measures (white and red peripheral transverse bars (PTB), optical speed bars (OSB) and chevrons) were tested on a sample of forty-two drivers. The driving speeds recorded using the treatments tests were compared to a baseline condition (treatments were not applied). Subjective measures were also collected; these included the driver’s evaluation of the desired speed, risk perception, road legibility, and markings comprehension, as based on screenshot pictures that represented the simulated configurations of the treatments. Results: The outcomes demonstrated an overall effectiveness of the perceptual treatments. Particularly, red PTB were associated with a speed-reduction of up to 12 km/h along the curve under study. An analysis of the questionnaires revealed that drivers did not fully comprehend the relevant message of PTB. Despite that, the drivers did unconsciously reduce their speeds; this confirms the effectiveness of such perceptual treatments based on the optical illusion that entices drivers to reduce their speeds. Conclusions: The findings demonstrated the effectiveness of the perceptual treatments, especially red PTB, in enticing drivers to reduce their speeds whilst approaching the sharp curve under study or driving through the curve.
Regulatory T Cell Development in the Thymus

Development of a comprehensive regulatory T (Treg) cell compartment in the thymus is required to maintain immune homeostasis and prevent autoimmunity. In this study, we review cellular and molecular determinants of Treg cell development in the thymus. We focus on the evidence for a self-antigen–focused Treg cell repertoire as well as the APCs responsible for presenting self-antigens to developing thymocytes. We also cover the contribution of different cytokines to thymic Treg development and the cellular populations that produce these cytokines. Finally, we update the originally proposed “two-step” model of thymic Treg differentiation by incorporating new evidence demonstrating that Treg cells develop from two Treg progenitor populations and discuss the functional importance of Treg cells generated via either progenitor pathway.
Detection of 8-Hydroxy-2′-Deoxyguanosine Biomarker with a Screen-Printed Electrode Modified with Graphene

In this work we present the preparation of graphene material by exfoliation of graphite rods via pulses of current in electrolyte, containing a mixture of boric acid (0.05 M) and sodium chloride (0.05 M). The material was morphologically and structurally characterized by SEM/TEM/HR-TEM, XRD and FTIR techniques. TEM investigation of graphene flakes deposited onto carbon-coated grids allowed the visualization of thin and transparent regions, attributed to few-layer graphene (FLG), as well as thick and dark regions attributed to multi-layer graphene (MLG). The mixed composition of the material was additionally confirmed by XRD, which further indicated that the amount of FLG within the sample was around 83%, while MLG was around 17%. The performance of a screen-printed electrode (SPE) modified with graphene (SPE-Gr) was tested for 8-hydroxy-2'-deoxyguanosine detection. The graphene-modified electrode had a higher sensitivity in comparison with that of SPE, both in standard laboratory solutions (phosphate buffered saline-PBS) and in human saliva.
40-Hz auditory steady-state responses and the complex information processing: An exploratory study in healthy young males

Electroencephalographic (EEG) activity in the gamma (30–80 Hz) range is related to a variety of sensory and cognitive processes which are frequently impaired in schizophrenia. Auditory steady-state response at 40-Hz (40-Hz ASSR) is utilized as an index of gamma activity and is proposed as a biomarker of schizophrenia. Nevertheless, the link between ASSRs and cognitive functions is not clear. This study explores a possible relationship between the performance on cognitive tasks and the 40-Hz ASSRs in a controlled uniform sample of young healthy males, as age and sex may have complex influence on ASSRs. Twenty-eight young healthy male volunteers participated (mean age ± SD 25.8±3.3) in the study. The 40-Hz click trains (500 ms) were presented 150 times with an inter-stimulus interval set at 700–1000 ms. The phase-locking index (PLI) and event-related power perturbation (ERSP) of the ASSR were calculated in the 200–500 ms latency range, which corresponds to the steady part of the response. The Psychology Experiment Building Language (PEBL) task battery was used to assess five cognitive subdomains: the Choice response time task, the Stroop test, the Tower of London test, the Lexical decision task and the Semantic categorisation task. Pearson‘s correlation coefficients were calculated to access the relationships; no multiple-test correction was applied as the tests were explorative in nature. A significant positive correlation was observed for the late-latency gamma and the mean number of steps in the Tower of London task reflecting planning and problem-solving abilities. These findings support the concept that 40-Hz ASSR might highlight top-down mechanisms which are related to cognitive functioning. Therefore, 40-Hz ASSRs can be used to explore the relationship between cognitive functioning and neurophysiological indices of brain activity.
Does Early Chemotherapy Improve Survival in Advanced Endometrial Cancer?

Objectives: In endometrial cancer, the appropriate sequence of adjuvant chemotherapy (aCT) and adjuvant radiation therapy (aRT) is unclear. We aim evaluated whether early chemotherapy is associated with improved overall survival (OS) and cancer-specific survival (CSS). Methods: Endometrial cancer patients that received aCT and aRT were selected from the SEER-Medicare database. Early chemotherapy was defined as receiving aCT before aRT, with or without additional aCT (“sandwich” regimens). All other patients received a full course of aRT before chemotherapy with or without concurrent chemotherapy. Univariate and multivariate Cox proportional hazards regression was utilized to assess the impact of clinical and demographic factors on OS. Results: We selected 597 patients for analysis. Median age and was 72 years; 85% of patients were white. Overall, 68% of women had FIGO (International Federation of Gynecology and Obstetrics) stage III disease and 77% received 4 to 6 cycles of chemotherapy. Five-year OS (66.6% vs. 62.4%, P=0.46) and 5-year CSS (71.1% vs. 71.2%, P=0.88) was not significantly improved among those receiving early chemotherapy. In addition, early chemotherapy did not improve OS (hazard ratio [HR]=0.87; 95% confidence interval [CI]: 0.56-1.34, P=0.53) or CSS (HR=1.21; 95% CI: 0.82-1.79, P=0.34) on multivariate analysis. Compared with 1 to 3 cycles, receiving 4 to 6 (HR=0.48, 95% CI: 0.26-0.87, P=0.02), and ≥7 cycles (HR=0.42, 95% CI: 0.20-0.89, P=0.02) of chemotherapy was associated with improved OS. Conclusion: No differences in OS or CSS were noted among endometrial patients receiving early chemotherapy. However, the number of chemotherapy cycles was associated with prolonged survival.
Binding of FAD and tryptophan to the tryptophan 6‐halogenase Thal is negatively coupled

Flavin‐dependent halogenases require reduced flavin adenine dinucleotide (FADH2), O2, and halide salts to halogenate their substrates. We describe the crystal structures of the tryptophan 6‐halogenase Thal in complex with FAD or with both tryptophan and FAD. If tryptophan and FAD were soaked simultaneously, both ligands showed impaired binding and in some cases only the adenosine monophosphate or the adenosine moiety of FAD was resolved, suggesting that tryptophan binding increases the mobility mainly of the flavin mononucleotide moiety. This confirms a negative cooperativity between the binding of substrate and cofactor that was previously described for other tryptophan halogenases. Binding of substrate to tryptophan halogenases reduces the affinity for the oxidized cofactor FAD presumably to facilitate the regeneration of FADH2 by flavin reductases.
Perturbed development of cranial neural crest cells in association with reduced sonic hedgehog signaling underlies the pathogenesis of retinoic-acid-induced cleft palate

ABSTRACT Cleft palate (CP) is one of the most common congenital craniofacial anomalies in humans and can be caused by either single or multiple genetic and environmental factor(s). With respect to environmental factors, excessive intake of vitamin A during early pregnancy is associated with increased incidence of CP in offspring both in humans and in animal models. Vitamin A is metabolized to retinoic acid (RA); however, the pathogenetic mechanism of CP caused by altered RA signaling during early embryogenesis is not fully understood. To investigate the detailed cellular and molecular mechanism of RA-induced CP, we administered all-trans RA to pregnant mice at embryonic day (E)8.5. In the RA-treated group, we observed altered expression of Sox10, which marks cranial neural crest cells (CNCCs). Disruption of Sox10 expression was also observed at E10.5 in the maxillary component of the first branchial arch, which gives rise to secondary palatal shelves. Moreover, we found significant elevation of CNCC apoptosis in RA-treated embryos. RNA-sequencing comparisons of RA-treated embryos compared to controls revealed alterations in Sonic hedgehog (Shh) signaling. More specifically, the expression of Shh and its downstream genes Ptch1 and Gli1 was spatiotemporally downregulated in the developing face of RA-treated embryos. Consistent with these findings, the incidence of CP in association with excessive RA signaling was reduced by administration of the Shh signaling agonist SAG (Smoothened agonist). Altogether, our results uncovered a novel mechanistic association between RA-induced CP with decreased Shh signaling and elevated CNCC apoptosis. Editor's choice: The RA-Shh signaling pathway is revealed to be critical during cranial neural crest development, which impacts secondary palate development.
European Medicines Agency’s Priority Medicines Scheme at 2 Years: An Evaluation of Clinical Studies Supporting Eligible Drugs

The Priority Medicines (PRIME) scheme was launched by the European Medicines Agency (EMA) in 2016 to expedite the development and approval of promising products targeting conditions with high unmet medical need. Manufacturers of PRIME drugs receive extensive regulatory advice on their trial designs. Until June 2018, the EMA granted PRIME status to 39 agents, evaluated in 138 studies (102 initiated before and 36 after PRIME eligibility). A third of the studies forming the basis of PRIME designation were randomized controlled trials, and a quarter of the studies were blinded. There was no statistically significant difference between trials initiated before and after PRIME designation in terms of randomized design and use of blinding. However, significantly more efficacy studies included a clinical end point after PRIME designation than before, and significantly fewer included surrogate measures alone. There were no statistically significant differences between the trial designs of PRIME and non‐PRIME‐designated products.
SOD2 acetylation on lysine 68 promotes stem cell reprogramming in breast cancer

Significance Mitochondrial superoxide dismutase (SOD2) has been established as a suppressor of tumor initiation. However, late-stage solid tumors display high levels of SOD2 expression. Here, we report that overexpression of SOD2 causes its accumulation in an acetylated form that increases mitochondrial reactive oxygen species as well as HIF2α activity. HIF2α is a potent promoter of cancer stem cell formation, which is largely responsible for treatment failure and metastatic recurrence of breast cancer. In agreement, we found increased SOD2 and HIF2α in metastatic lesions compared with primary tumors from the same patients. Taken together, our results indicate that the accumulation of acetylated SOD2 observed in late-stage cancer may drive cancer stem cell formation, contributing to tumor aggressiveness and poorer outcomes. Mitochondrial superoxide dismutase (SOD2) suppresses tumor initiation but promotes invasion and dissemination of tumor cells at later stages of the disease. The mechanism of this functional switch remains poorly defined. Our results indicate that as SOD2 expression increases acetylation of lysine 68 ensues. Acetylated SOD2 promotes hypoxic signaling via increased mitochondrial reactive oxygen species (mtROS). mtROS, in turn, stabilize hypoxia-induced factor 2α (HIF2α), a transcription factor upstream of “stemness” genes such as Oct4, Sox2, and Nanog. In this sense, our findings indicate that SOD2K68Ac and mtROS are linked to stemness reprogramming in breast cancer cells via HIF2α signaling. Based on these findings we propose that, as tumors evolve, the accumulation of SOD2K68Ac turns on a mitochondrial pathway to stemness that depends on HIF2α and may be relevant for the progression of breast cancer toward poor outcomes.
Type 2 myocardial infarction in general medical wards

Abstract Type 2 myocardial infarction (MI) is defined as myocardial necrosis due to imbalance between myocardial oxygen supply and demand. The objective of this study was to assess the features, treatments, and outcomes of patients with type 2 MI in comparison with patients with type 1 MI hospitalized in general medical wards. A retrospective review was performed on patients admitted to general medicine wards diagnosed with MI in Sheba Medical Center between January 1, 2016 and December 31, 2016. Comparative analysis between patients with type 1 and type 2 MI was performed. The study included 349 patients with type 1 MI and 206 patients with type 2 MI. The main provoking factors for type 2 MI were sepsis (38.1%), anemia (29.1%), and hypoxia (23.8%). Patients with type 2 MI were older (79.1 ± 11.9 vs 75.2 ± 11.7, P < .001) and had a lower rate of prior MI (23.3% vs 38.1%, P < .001) and percutaneous coronary intervention (PCI) (34% vs 48.7%, P = .023) compared with patients with type 1 MI. Patients with type 2 MI were significantly less prescribed antiplatelet therapy (79.1% vs 96%, P < .001) and statins (60.7% vs 80.2%, P < .001), and were less referred to coronary angiography (10.7% vs 54.4%, P < .001). Type 2 MI was associated with a significantly higher 1-year mortality rate compared with type 1 MI (38.8% vs 26.6%, P = .004), but after accounting for age and sex differences, this association lacked statistical significance. In conclusion, type 2 MI patients were older and had similar comorbidities compared with those with type 1 MI. These patients were less prescribed medical therapy and coronary intervention, and had a higher 1-year mortality rate. Establishing a clear therapeutic approach for type 2 MI is required.