Miracle-dz/UniFAR-FTUs huggingface dataset:
Targeted Therapy for EBV-Associated B-cell Neoplasms

Epstein–Barr virus (EBV) is directly implicated in several B-cell lymphoid malignancies. EBV-associated lymphomas are characterized by prominent activation of the NF-κB pathway and targeting this pathway establishes a rationale for a therapeutic approach. The ubiquitin/proteasome signaling plays an essential role in the regulation of the NF-κB pathway. Ixazomib is an FDA-approved, orally bioavailable proteasome inhibitor. Here we report the first preclinical evaluation of ixazomib-mediated growth-inhibitory effects on EBV-infected B-lymphoblastoid cell lines Raji and Daudi. Ixazomib induced apoptosis in these cell lines in a dose-dependent manner. Cell-cycle analysis demonstrated ixazomib treatment induced cell-cycle arrest at the G2–M phase with a concomitant decrease in G0–G1 and S phases. The results further revealed an increase in p53, p21, and p27 levels and a decrease in survivin and c-Myc protein levels. Mechanistically, ixazomib treatment resulted in the accumulation of polyubiquitinated proteins, including phosphorylated IκBα with a significant reduction of p65 subunit nuclear translocation. Altogether, our preclinical data support the rationale for in vivo testing of ixazomib in EBV-associated B-cell neoplasms. Implications: This preclinical study supports the use of oral proteasome inhibitor ixazomib for targeting NF-κB signaling in the treatment of EBV-associated B-cell neoplasms. Visual Overview: http://mcr.aacrjournals. org/content/molcanres/17/4/839/F1.large. jpg. Visual Overview
Behavior in dogs with spontaneous hypothyroidism during treatment with levothyroxine

Background Thyroid hormone supplementation anecdotally has been described as a valid treatment option for dogs with aggression‐related problems. However, prospective, controlled, and blinded trials evaluating behavior and neurohormonal status in hypothyroid dogs during treatment with levothyroxine are lacking. Objective Levothyroxine supplementation will have a significant influence on the behavior and neurohormonal status of dogs with spontaneous hypothyroidism. Animals Twenty client‐owned dogs diagnosed with spontaneous hypothyroidism. Methods This prospective study was to evaluate the behavior of dogs, which was screened at initial presentation, and after 6 weeks, and 6 months of treatment with levothyroxine (starting dosage 10 μg/kg PO q12h) using the standardized Canine Behavioral Assessment and Research Questionnaire (C‐BARQ). At each time period, circulating serotonin and prolactin (PRL) concentrations were evaluated using a commercially validated ELISA kit and heterologous radioimmunoassay, respectively. Results After 6 weeks of thyroid hormone supplementation, C‐BARQ scores demonstrated a significant increase in activity of hypothyroid dogs (P < .01). No significant change in any of the behavioral signs was observed after 6 months of treatment. No significant difference in circulating concentrations of serotonin (P > .99 and P = .46) and PRL (P = .99 and P = .37) were noted between the 6‐week and 6‐month periods compared with baseline. Conclusions and Clinical Importance The results of this study indicate increased activity of hypothyroid dogs after 6 weeks of thyroid hormone supplementation. None of the hypothyroid dogs in this cohort showed a significant change in any of the evaluated behavioral signs and neurohormonal status after 6 months of thyroid hormone supplementation.
Effect of fructo-oligosaccharide supplementation in soya beverage on the intestinal absorption of calcium and iron in newly weaned rats

Abstract Studies have shown the positive effects of prebiotics on the intestinal absorption of Ca and Fe. The present study evaluated the effect of fructo-oligosaccharide (FOS) supplementation in soya beverage (SB) on absorption mechanisms of Ca and Fe in recently weaned rats. Male Wistar rats were divided into four groups: lactose-free cows’ milk (CM), lactose-free CM with FOS (0·8 g/100 ml) (CMF), SB and soya beverage with FOS (0·8 g/100 ml) (SBF). These rats were euthanised after 1 week of treatment. Organ weight, pH of the caecal content and absorption mechanisms of Ca and Fe were evaluated. The results showed that the weight of the caecal contents increased in the CMF and SBF groups, and the pH of the caecal contents was lower in these groups. The Hb levels of the CMF and SB groups were higher when compared with that of the CM group and lower in relation to the SBF group. The apparent Ca and Fe absorption and apparent Ca retention in the CM group were higher when compared with the SB group, whereas in the CMF group, they were higher in relation to the SBF group. Divalent metal transporter 1 (DMT1) protein expression in the duodenum was higher in the SBF group than in the SB and CMF groups. SB resulted in lower intestinal Ca absorption and higher Hb concentration, despite the lower apparent Fe absorption in relation to CM. Supplementation with FOS provided beneficial effects on Hb and DMT1 protein expression in the duodenum, in addition to improving the absorption process.
Direct Electrophysiological Correlates of Body Ownership in Human Cerebral Cortex

&NA; Over the past decade, numerous neuroimaging studies based on hemodynamic markers of brain activity have examined the feeling of body ownership using perceptual body‐illusions in humans. However, the direct electrophysiological correlates of body ownership at the cortical level remain unexplored. To address this, we studied the rubber hand illusion in 5 patients (3 males and 2 females) implanted with intracranial electrodes measuring cortical surface potentials. Increased high‐&ggr; (70‐200 Hz) activity, an index of neuronal firing rate, in premotor and intraparietal cortices reflected the feeling of ownership. In both areas, high‐&ggr; increases were intimately coupled with the subjective illusion onset and sustained both during and in‐between touches. However, intraparietal activity was modulated by tactile stimulation to a higher degree than the premotor cortex through effective connectivity with the hand‐somatosensory cortex, which suggests different functional roles. These findings constitute the first intracranial electrophysiological characterization of the rubber hand illusion and extend our understanding of the dynamic mechanisms of body ownership.
Fast track to the neocortex: A memory engram in the posterior parietal cortex

Memories reach the cortex rapidly How fast do learning-induced anatomical changes occur in the brain? The traditional view postulates that neocortical memory representations reflect reinstatement processes initiated by the hippocampus and that a genuine physical trace develops only through reactivation over extended periods. Brodt et al. combined functional magnetic resonance imaging (MRI) with diffusion-weighted MRI during an associative declarative learning task to examine experience-dependent structural brain plasticity in human subjects (see the Perspective by Assaf). This plasticity was rapidly induced after learning, persisted for more than 12 hours, drove behavior, and was localized in areas displaying memory-related functional brain activity. These plastic changes in the posterior parietal cortex, and their fast temporal dynamics, challenge traditional views of systems memory consolidation. Science, this issue p. 1045; see also p. 994 Microstructural plasticity in human brains shows the rapid emergence and long-term persistence of neocortical memory storage. Models of systems memory consolidation postulate a fast-learning hippocampal store and a slowly developing, stable neocortical store. Accordingly, early neocortical contributions to memory are deemed to reflect a hippocampus-driven online reinstatement of encoding activity. In contrast, we found that learning rapidly engenders an enduring memory engram in the human posterior parietal cortex. We assessed microstructural plasticity via diffusion-weighted magnetic resonance imaging as well as functional brain activity in an object–location learning task. We detected neocortical plasticity as early as 1 hour after learning and found that it was learning specific, enabled correct recall, and overlapped with memory-related functional activity. These microstructural changes persisted over 12 hours. Our results suggest that new traces can be rapidly encoded into the parietal cortex, challenging views of a slow-learning neocortex.
Transgenic short-QT syndrome 1 rabbits mimic the human disease phenotype with QT/action potential duration shortening in the atria and ventricles and increased ventricular tachycardia/ventricular fibrillation inducibility

AIMS Short-QT syndrome 1 (SQT1) is an inherited channelopathy with accelerated repolarization due to gain-of-function in HERG/IKr. Patients develop atrial fibrillation, ventricular tachycardia (VT), and sudden cardiac death with pronounced inter-individual variability in phenotype. We generated and characterized transgenic SQT1 rabbits and investigated electrical remodelling. METHODS AND RESULTS Transgenic rabbits were generated by oocyte-microinjection of β-myosin-heavy-chain-promoter-KCNH2/HERG-N588K constructs. Short-QT syndrome 1 and wild type (WT) littermates were subjected to in vivo ECG, electrophysiological studies, magnetic resonance imaging, and ex vivo action potential (AP) measurements. Electrical remodelling was assessed using patch clamp, real-time PCR, and western blot. We generated three SQT1 founders. QT interval was shorter and QT/RR slope was shallower in SQT1 than in WT (QT, 147.8 ± 2 ms vs. 166.4 ± 3, P < 0.0001). Atrial and ventricular refractoriness and AP duration were shortened in SQT1 (vAPD90, 118.6 ± 5 ms vs. 154.4 ± 2, P < 0.0001). Ventricular tachycardia/fibrillation (VT/VF) inducibility was increased in SQT1. Systolic function was unaltered but diastolic relaxation was enhanced in SQT1. IKr-steady was increased with impaired inactivation in SQT1, while IKr-tail was reduced. Quinidine prolonged/normalized QT and action potential duration (APD) in SQT1 rabbits by reducing IKr. Diverse electrical remodelling was observed: in SQT1, IK1 was decreased-partially reversing the phenotype-while a small increase in IKs may partly contribute to an accentuation of the phenotype. CONCLUSION Short-QT syndrome 1 rabbits mimic the human disease phenotype on all levels with shortened QT/APD and increased VT/VF-inducibility and show similar beneficial responses to quinidine, indicating their value for elucidation of arrhythmogenic mechanisms and identification of novel anti-arrhythmic strategies.
Long-term follow-up of intensive chemotherapy followed by reduced-dose and reduced-field irradiation for intracranial germ cell tumor.

OBJECTIVE The authors analyzed the efficacy of intensive chemotherapy followed by reduced-dose and reduced-field irradiation for intracranial germ cell tumors (GCTs) and evaluated the long-term late effects caused by chemoradiotherapy (CRT). METHODS The authors performed a retrospective study. The subjects were 24 patients who received CRT between April 1994 and April 2015. After surgery, intensive chemotherapy followed by reduced-dose and reduced-field irradiation was administered. For those with pure germinoma, who comprised the “good prognosis” group, five courses of conventional-dose chemotherapy (CDC) were administered, and radiotherapy (24 Gy) was applied to the whole ventricle. For all others, defined as the “intermediate and poor prognosis” group, two or three courses of CDC and high-dose chemotherapy were administered with peripheral blood stem cell transplantation and radiotherapy (24–30 Gy) applied to the whole ventricle or a larger field with or without local boost irradiation (20 Gy), which was applied as needed. RESULTS The median period of follow-up was 112.5 months (range 28–261 months), and the 5-/10-year overall and progression-free survival rates were 100%/83.5% and 91.3%/86.5%, respectively. The 5-/10-year overall survival rates determined based on the histological subtypes were 100%/100% for pure germinoma and 93.8%/78.7% for others, respectively. The late toxicities were as follows: endocrine disorder (33% in pure germinoma, 56% in others), involuntary movements (17% in pure germinoma, 39% in others), ear and labyrinth disorders (17% in pure germinoma, 33% in others), and psychiatric disorders (0% in pure germinoma, 33% in others). Nineteen of 24 patients underwent MRI (T2*- or susceptibility-weighted imaging) after radiotherapy, and 16 (84%) of those 19 patients had microbleeds detected, while 2 (10.5%) had radiation-induced cavernous vascular malformations detected. CONCLUSIONS Intensive chemotherapy followed by reduced-dose and reduced-field irradiation for intracranial GCTs had the same outcome as that reported in the literature, but late adverse effects after treatment were observed. Almost all of the complications were relatively mild but had the potential to lead to psychiatric disorders and intracranial hemorrhaging. ABBREVIATIONS AFP = alpha-fetoprotein; CDC = conventional-dose chemotherapy; CMB = cerebral microbleed; CRT = chemoradiotherapy; CSI = craniospinal irradiation; EP = etoposide and cisplatin; GCT = germ cell tumor; HCG = human chorionic gonadotropin; HDC = high-dose chemotherapy; ICE = ifosfamide, cisplatin, and etoposide; NGGCT = nongerminomatous GCT; OS = overall survival; PBSCT = peripheral blood stem cell transplantation; PFS = progression-free survival; RICM = radiation-induced cavernous malformation; STGC = syncytiotrophoblastic giant cell; SWI = susceptibility-weighted imaging.
Comparative Effectiveness and Safety of Standard or Reduced Dose Dabigatran vs. Rivaroxaban in Nonvalvular Atrial Fibrillation

Dabigatran and rivaroxaban at standard or reduced doses have been compared to warfarin in nonvalvular atrial fibrillation (NVAF), but not to each other. This was a new user study of standard dose and reduced dose dabigatran or rivaroxaban for NVAF in the French healthcare database, matched on gender, age, date of first dispensing, and high‐dimensional propensity score, followed 2 years. Hazard ratios (HRs; 95% confidence intervals (CI)) of stroke or systemic embolism (SSE), major bleeding (MB), or death were computed. In matched standard‐dose patients (8,290 per arm), mean age 67 years, HRs for dabigatran vs. rivaroxaban were SSE 0.92 (95% CI = 0.67–1.26), MB 0.59 (95% CI = 0.39–0.90), and death 0.84 (95% CI = 0.65–1.11). In reduced‐dose patients (7,639 per arm), mean age 80 years, HRs for dabigatran vs. rivaroxaban were SSE 0.73 (95% CI = 0.59–0.94), MB 0.74 (95% CI = 0.57–0.96), and death 0.95 (95% CI = 0.83–1.09). In conclusion, at either dose, dabigatran had similar or better effectiveness than rivaroxaban but lower bleeding risk. Death rates were not different.
Activated T cells induce proliferation of oligodendrocyte progenitor cells via release of vascular endothelial cell growth factor‐A

Neuroinflammatory diseases such as multiple sclerosis are characterized by infiltration of lymphocytes into the central nervous system followed by demyelination and axonal degeneration. While evidence suggests that activated T lymphocytes induce neurotoxicity and impair function of neural stem cells, the effect of T cells on oligodendrocyte progenitor cells (OPCs) is still uncertain, partly due to the difficulty in obtaining human OPCs. Here we studied the effect of activated T cells on OPCs using OPCs derived from human hematopoietic stem cells or from human fetal brain. OPCs were exposed to supernatants (sups) from activated T cells. Cell proliferation was determined by EdU incorporation and CellQuanti‐Blue assays. Surprisingly, we found that sups from activated T cells induced OPC proliferation by regulating cell cycle progression. Vascular endothelial growth factor A (VEGF‐A) transcripts were increased in T cells after activation. Immunodepletion of VEGF‐A from activated T cell sups significantly attenuated its effect on OPC proliferation. Furthermore, VEGF receptor 2 (VEGFR2) was expressed on OPCs and its inhibition also attenuated activated T cell‐induced OPC proliferation. Thus, activated T cells have a trophic role by promoting OPC proliferation via the VEGFR2 pathway.
Questionnaire showed that Swedish paediatric clinics complied well with the revised European guidelines for diagnosing coeliac disease

In 2012, revised criteria for diagnosing childhood coeliac disease were published by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition and incorporated into the revised Swedish guidelines the same year. These made it possible, in certain cases, to diagnose coeliac disease without taking small bowel biopsies. This survey assessed the extent to which the new guidelines were implemented by Swedish paediatric clinics two years after their introduction.
Are acceptance and mindfulness‐based interventions ‘value for money’? Evidence from a systematic literature review

Objectives Acceptance and mindfulness‐based interventions (A/MBIs) are recommended for people with mental health conditions. Although there is a growing evidence base supporting the effectiveness of different A/MBIs for mental health conditions, the economic case for these interventions has not been fully explored. The aim of this systematic review was to identify and appraise all available economic evidence of A/MBIs for the management of mental health conditions. Methods Eight electronic bibliographic databases (MEDLINE, MEDLINE In‐Process & Other Non‐Indexed Citations, EMBASE, Web of Science, NHS Economic Evaluation Database (EED), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA) database, and EconLit) were searched for relevant economic evaluations published from each database's inception date until November 2017. Study selection, quality assessment, and data extraction were carried out according to published guidelines. Results Ten relevant economic evaluations presented in 11 papers were identified. Seven of the included studies were full economic evaluations (i.e., costs and effects assessed), and three studies were partial economic evaluations (i.e., only costs were considered in the analysis). The A/MBIs that had been subjected to economic evaluation were acceptance and commitment therapy (ACT), dialectical behaviour therapy (DBT), mindfulness‐based cognitive therapy (MBCT), and mindfulness‐based stress reduction (MBSR). In terms of clinical presentations, the evaluation of cost‐effectiveness of A/MBIs has been more focused on depression and emotional unstable personality disorder with three and four economic evaluations, respectively. Three out of seven full economic evaluations observed that A/MBIs were cost‐effective for the management of mental health conditions. Nevertheless, the heterogeneity of included populations, interventions, and economic evaluation study types limits the extent to which firm conclusions can currently be made. Conclusion This first substantive review of economic evaluations of A/MBIs indicates that more research is needed before firm conclusions can be reached on the cost‐effectiveness of A/MBIs for mental health conditions. Practitioner points The findings of the review provide information that may be relevant to mental health service commissioners and decision‐makers as all economic evidence available on acceptance and mindfulness‐based interventions for mental health conditions is summarized. Evidence relating to the cost‐effectiveness and cost‐saving potential of acceptance and mindfulness‐based interventions is focused mainly on depression and emotional unstable personality disorder to date. Heterogeneity in the specific forms of acceptance and mindfulness‐based interventions may limit generalizability of the findings. The number of health economic evaluations relating to acceptance and mindfulness‐based interventions remains relatively small. Further research in this area is required.
Impact of empirical treatment with antifungal agents on survival of patients with candidemia

ABSTRACT Introduction The objective of this study was to evaluate the impact of echinocandins and fluconazole) on mortality 7 and 30 days after candidemia onset and overall in-hospital mortality), in patients with candidemia at a Spanish tertiary hospital. Methods A retrospective study was conducted that enrolled all non-neutropenic adult patients diagnosed with candidemia at Hospital Clínico Universitario de Valladolid between 2007 and 2016. A total of 179 patients were evaluated, they were divided into two sub-groups: surviving patients (n = 92) and non-surviving patients (n = 87). Results The 7-day mortality was 25,1% (45), 30-day mortality was 46,9% (84), and overall in-hospital mortality was 48,6% (87). 40.8% of patients received no antifungal treatment (43.8% of surviving patients and 37.8% of non-surviving patients; p=0.15). A total of 106 (59.2%) patients were treated, of which 90 patients (50.3%) received empiric treatment. 19.6% and 47.8% of surviving patients were treated with echinocandins and fluconazole, respectively. By contrast, of non-surviving patients, 31.0% were treated with echinocandins and 47.1% received fluconazole. Survival for the first 7 days was significantly higher in treated with antifungal agents (log-rank = 0.029), however, there were not significant differences in 30-day survival. Factors linked to a significant increase in overall in-hospital mortality were age (OR 1.040), septic shock (OR 2.694) and need for mechanical ventilation > 48 h (OR 2.812). Conclusion Patients who received antifungal treatment, regardless of whether they received fluconazole or echinocandins, had a significantly lower mortality rate after 7 days than untreated patients, although no significant differences in 30-day mortality were seen.
Preoperative sarcopenia is a predictor of poor prognosis of esophageal cancer after esophagectomy: a comprehensive systematic review and meta-analysis.

The impact of preoperative sarcopenia on long-term survival of esophageal cancer patients after esophagectomy remains unclear. We conducted an updated meta-analysis focusing on current topic comprehensively. We systematically searched relevant studies investigating the impact of preoperative sarcopenia on survival of patients with surgically treated esophageal cancer in PubMed, Embase, and Web of Science up to July 20, 2018. Data of 3-year and 5-year overall survival (OS) rates as well as hazard ratio (HR) of OS and disease-free survival (DFS) were collected for analysis by using the STATA 12.0 package. Finally, a total of 11 cohort studies consisting of 1520 patients (795 sarcopenic patients and 725 nonsarcopenic patients) were included for analysis. Our meta-analysis showed that patients with sarcopenia had a significantly lower 3-year (51.6% vs. 65.4%, P < 0.001) and 5-year OS rate (41.2% vs. 52.2%, P = 0.018) than those without sarcopenia. Sarcopenia was found to be an independent predictor of poor OS (HR = 1.58; 95% confidence interval (CI) = [1.35, 1.85]; P < 0.001) and DFS (HR = 1.46; 95% CI = [1.12, 1.90]; P = 0.005) in esophageal cancer patients after esophagectomy. No obvious heterogeneities or publication bias were observed during analysis. Therefore, patients with sarcopenia had a significantly worse prognosis than those without after surgical resection of esophageal cancer. Preoperative sarcopenia is an independent unfavorable prognostic factor for esophageal cancer patients after esophagectomy. However, high-quality studies with appropriate adjustments for confounding factors are needed to confirm our conclusions.