Miracle-dz/UniFAR-FTUs huggingface dataset:
FLT3 ligand plasma levels in acute myeloid leukemia

This prospective single-center study was designed to assess soluble Fms-like tyrosine kinase 3 ligand concentrations (sFLc) during the treatment of acute myeloid leukemia (AML). Three different kinetic profiles were identified during induction and found to have a significant impact on outcomes, especially survival outcomes. Fms-like tyrosine kinase 3 (FLT3) ligand (FL) is a key regulator of hematopoiesis. sFLc have been shown to correlate with the extent of bone marrow aplasia after radiotherapy or chemotherapy. Interestingly, FL is expressed by leukemic cells and might enhance proliferation through an autocrine process. Moreover, high soluble levels of FL may explain resistance to FLT3 inhibitors. In a previous phase I study, testing a radioimmunotherapy regimen for relapsed/refractory acute lymphoblastic leukemia, we observed that only the responders displayed sustained increased sFLc. Apart from this report, data regarding the prognostic impact of FL levels in leukemia are lacking. We therefore designed a prospective study to investigate the potential prognostic impact of the kinetic profile of sFLc on outcomes in patients with AML. The FLAM/FLAL trial was a prospective single-center, non-interventional study conducted at Nantes University Hospital (Nantes; France). It was planned to include all consecutive adult (≥18 years old) patients with AML (except pro-myelocytic AML) treated intensively with first-line therapy from May 2016 for an 18-month period. Our aim was to assess the impact of sFLc kinetic profile on outcomes. Parameters considered were refractory status after induction, relapse, progression-free survival and overall survival. AML cases were treated according to standard-of-care, first-line therapy (Online Supplementary File). Younger AML patients (<60 years old) with favorable features were treated according to the protocol of the LAM2006CBF trial while other cases were treated within the ongoing BIG study (www.ClinicalTrials.gov NCT02416388). All older AML patients (≥60 years old) were treated according to the protocol of the LAMSA2002 trial. Some older AML patients with favorable features received intensive consolidation with intermediate-dose cytarabine. Allogeneic transplantation was performed according to the criteria of each protocol. sFLc (expressed in pg/mL) was assayed from thawed plasma samples by enzyme-linked immunosorbent assay (DY308, R&D Systems, Minneapolis, MN, USA). These plasma samples had to be collected on days 1, 8, 15 and 22 of induction. All patients provided informed consent to participation in the study. The protocol had been approved by the ethical committee of Nantes University Hospital (GNEDS; ref: RC15_0374), the French Health Ministry (ref: 16-226) and the French National Commission on Informatics and Liberty (CNIL: ref: 2001209v0). The trial was registered at www.ClinicalTrials. gov NCT02693899. The prognostic value of sFLc and sFLc kinetic profile was assessed according to: (i) refractory status after induction (≥5% bone marrow blasts or persistent aplasia >45 days) or (ii) relapse, whether morphological (≥5%
Unexpected High Prevalence of Cardiovascular Disease Risk Factors and Psychiatric Disease Among Young People With Sudden Cardiac Arrest

Background It is believed that most sudden cardiac arrests (SCAs) in young people occur in previously healthy people with rare risk factors for sudden death. Few studies have investigated large populations with complete ascertainment. Our objective was to use multisource records to identify and classify all out‐of‐hospital cardiac arrests in the Greater Toronto Area (population 6.6 million) in people aged 2 to 45 years from 2009 to 2012. Methods and Results Expert reviewers employed a systematic process, with emergency medical services, in‐hospital and coroner records, to adjudicate the cause of death as SCA from cardiac or noncardiac causes. We report the adjudicated etiologies, circumstances, triggers, and characteristics of the SCA cohort. Of 2937 eligible out‐of‐hospital cardiac arrest cases, 608 (20.7%) SCAs had an adjudicated etiology of cardiac cause (120 survivors and 488 nonsurvivors). Two thirds of these SCA patients had a history of cardiovascular disease, and over 50% had been diagnosed with ≥1 cardiovascular disease risk factor. Moreover, 20.1% of SCAs were diagnosed with psychiatric disease and 30% had central nervous system drugs prescribed. Over 30% of SCA patients had central nervous system active drugs, including drugs of abuse detected postmortem, with opioids and ethanol being detected most frequently. Potentially heritable structural cardiac diseases accounted for only 6.9% of SCA events, with acquired cardiac diseases comprising the rest. Conclusions The underlying causes of SCA, in people aged 2 to 45 years, often occur in those with previously diagnosed cardiovascular diseases, and are associated with contributory factors including prescribed medications, recreational drugs, and a concomitant psychiatric history.
ERK and p38 contribute to the regulation of nociceptin and the nociceptin receptor in human peripheral blood leukocytes

Little is known about the mechanisms involved in the regulation of nociceptin and its receptor (nociceptin opioid peptide receptor, NOP) in response to inflammation and pain in humans. In this study, specific signaling pathways contributing to the regulation of nociceptin and NOP in human peripheral blood leukocytes were investigated. After approval by the ethics committee, peripheral blood obtained from healthy donors was cultured with or without phorbol-12-myristate-13-acetate (PMA). Prepronociceptin (ppNOC) and NOP mRNA were analyzed by real-time quantitative polymerase chain reaction, and nociceptin concentrations in culture supernatants by fluorescent enzyme immunoassay. Nociceptin and NOP protein levels in blood leukocyte subsets were determined using flow cytometry. To examine the contribution of signaling pathways to ppNOC and NOP regulation, blood was pre-treated with kinase inhibitors specific for ERK, JNK, p38, and NFκB pathways prior to culturing with or without PMA. PMA dose-dependently upregulated ppNOC mRNA but downregulated NOP mRNA in human peripheral blood leukocytes. PMA 10 ng/ml increased ppNOC after 6 h and suppressed NOP after 3 h compared to controls (both P <0.005). Nociceptin concentrations were increased in supernatants of PMA-induced blood samples after 24 h (P <0.005), whereas expression of cell-membrane NOP was decreased by PMA in blood leukocyte subsets (all P <0.05). Blockade of ERK or p38 pathways partially prevented PMA effects on ppNOC and NOP mRNA (all P <0.05). The combination of ERK and p38 inhibitors completely reversed the effects of PMA (P <0.05). ERK and p38 are two major signaling pathways regulating nociceptin and its receptor in human peripheral blood leukocytes under inflammatory conditions.
High Rac1 activity is functionally translated into cytosolic structures with unique nanoscale cytoskeletal architecture

Significance We have correlated signaling behaviors seen with biosensors (conformational changes of Rac1) with the nanoscale resolution of electron cryotomography. The workflow and approaches we describe bridge five orders of magnitude (tens of microns to nanometers) to identify, in the crowded environment within eukaryotic cells, distinct nanoarchitectures induced locally by Rac1 as it mediates cell motility, mechanosensing, and invasion. Our studies reveal a dynamic switching mechanism that generates a nanoscaffold system that can either propagate to highly complex actin filament architectures mandated by biological processes or completely dissipate. The workflow implemented here offers a powerful analytical tool not only for deciphering the function of Rho GTPase molecular switches but for the dynamics of many other macromolecular machines as well. Rac1 activation is at the core of signaling pathways regulating polarized cell migration. So far, it has not been possible to directly explore the structural changes triggered by Rac1 activation at the molecular level. Here, through a multiscale imaging workflow that combines biosensor imaging of Rac1 dynamics with electron cryotomography, we identified, within the crowded environment of eukaryotic cells, a unique nanoscale architecture of a flexible, signal-dependent actin structure. In cell regions with high Rac1 activity, we found a structural regime that spans from the ventral membrane up to a height of ∼60 nm above that membrane, composed of directionally unaligned, densely packed actin filaments, most shorter than 150 nm. This unique Rac1-induced morphology is markedly different from the dendritic network architecture in which relatively short filaments emanate from existing, longer actin filaments. These Rac1-mediated scaffold assemblies are devoid of large macromolecules such as ribosomes or other filament types, which are abundant at the periphery and within the remainder of the imaged volumes. Cessation of Rac1 activity induces a complete and rapid structural transition, leading to the absence of detectable remnants of such structures within 150 s, providing direct structural evidence for rapid actin filament network turnover induced by GTPase signaling events. It is tempting to speculate that this highly dynamical nanoscaffold system is sensitive to local spatial cues, thus serving to support the formation of more complex actin filament architectures—such as those mandated by epithelial−mesenchymal transition, for example—or resetting the region by completely dissipating.
Genetic and epigenetic regulation of cardiomyocytes in development, regeneration and disease

ABSTRACT Embryonic and postnatal life depend on the uninterrupted function of cardiac muscle cells. These cells, termed cardiomyocytes, display many fascinating behaviors, including complex morphogenic movements, interactions with other cell types of the heart, persistent contractility and quiescence after birth. Each of these behaviors depends on complex interactions between both cardiac-restricted and widely expressed transcription factors, as well as on epigenetic modifications. Here, we review recent advances in our understanding of the genetic and epigenetic control of cardiomyocyte differentiation and proliferation during heart development, regeneration and disease. We focus on those regulators that are required for both heart development and disease, and highlight the regenerative principles that might be manipulated to restore function to the injured adult heart. Summary: This Review discusses the roles of transcription factors, histone modifications and chromatin organization during heart development and repair, highlighting common mechanisms and possible strategies for targeted regeneration.
Are Psychotherapies for Young People Growing Stronger? Tracking Trends Over Time for Youth Anxiety, Depression, Attention-Deficit/Hyperactivity Disorder, and Conduct Problems

With the development of empirically supported treatments over the decades, have youth psychotherapies grown stronger? To investigate, we examined changes over time in treatment effects for four frequently treated youth mental-health problems: anxiety, depression, attention-deficit hyperactivity disorder (ADHD), and conduct disorders. We used PubMed and PsycINFO to search for randomized controlled trials (RCTs) that were published between January 1960 and May 2017 involving youths between the ages of 4 and 18 years. We also searched reviews and meta-analyses of youth psychotherapy research, followed reference trails in the reports we identified, and obtained additional studies identified by therapy researchers whom we contacted. We identified 453 RCTs (31,933 participants) spanning 53 years (1963–2016). Effect sizes for the problem-relevant outcome measures were synthesized via multilevel meta-analysis. We tracked temporal trends for each problem domain and then examined multiple study characteristics that might moderate those trends. Mean effect size increased nonsignificantly for anxiety, decreased nonsignificantly for ADHD, and decreased significantly for depression and conduct problems. Moderator analyses involving multiple study subgroups showed only a few exceptions to these surprising patterns. The findings suggest that new approaches to treatment design and intervention science may be needed, especially for depression and conduct problems. We suggest intensifying the search for mechanisms of change, making treatments more transdiagnostic and personalizable, embedding treatments within youth ecosystems, adapting treatments to the social and technological changes that alter youth dysfunction and treatment needs, and resisting old habits that can make treatments unduly skeuomorphic.
Interferon (IFN)‐α, IFN‐γ, interleukin (IL)‐2, and arachidonic acid metabolites modulate IL‐4‐induced IgE synthesis similarly in healthy persons and in atopic dermatitis patients

The role of cytokines and arachidonic acid metabolites in the regulation of IgE production in healthy persons and in atopic dermatitis patients with elevated IgE levels was studied. Interleukin‐4 (IL‐4) induced IgE production in peripheral blood mononuclear cells (PBMCs) of all donors, and no significant difference was found between the amounts of IgE produced by healthy persons and atopic dermatitis patients. Similarly, recombinant interferon (IFN)‐α and IFN‐γ, as well as IL‐2, inhibited IL‐4‐induced IgE production to a similar extent in both study groups. To evaluate the role of arachidonic acid (AA) metabolites in the regulation of IgE production, we added indomethacin, an inhibitor of the cyclooxygenase pathway, or nordihydroguaiaretic acid (NDGA), an inhibitor of the lipoxygenase pathway, to IL‐4‐treated cultures. Both indomethacin and NDGA strongly inhibited IL‐4‐induced IgE production. They also inhibited IL‐4‐induced IgG4 synthesis. No significant difference in the amount of inhibition was found between the two study groups. We were unable to restore the NDGA‐induced inhibition of IgE‐production by adding leukotrienes B4, C4, D4, or 5‐HETE to the NDGA‐treated cultures. PGE2 also failed to restore the indomethacin‐mediated inhibitory effect. Consequently, NDGA‐ and indomethacin‐mediated inhibitory effects do not appear to be mediated by any single factor studied. Collectively, our results show IFNs and IL‐2 to be similar in effect in the modulation of IL‐4‐induced IgE synthesis in healthy and atopic persons. In addition, our results show the importance of AA metabolites in the regulation of IgE and IgG4 synthesis in normal persons as well as in atopic dermatitis patients.
Integration of care for H IV and opioid use disorder

Results: Twenty-nine articles met criteria for inclusion, including 23 unique studies: six took place in HIV care settings, 12 in opioid treatment settings, and five elsewhere. Eight involved screening strategies, 22 involved treatment strategies, and seven involved strategies that encompassed screening and treatment. Randomized controlled studies demonstrated low-to-moderate risk of bias and observational studies demonstrated fair to good quality. Studies in HIV care settings (n1⁄46) identified HIV-related and OUDrelated clinical benefits with the use of buprenorphine/naloxone for OUD. No studies in HIV care settings focused on screening for OUD. Studies in opioid treatment settings (n1⁄412) identified improving HIV screening uptake and clinical benefits with antiretroviral therapy when provided on-site. Counseling intensity for OUD medication adherence or HIV-related risk reduction was not associated with clinical benefits.
Cardioprotective Mechanisms of Cocoa

Abstract Cardiovascular diseases are the main cause of deaths in highly developed countries. Dietetic interventions that involve recommendations for consumption of products with a confirmed health-improving action are an important aspect of prevention of cardiovascular diseases. Cocoa is an alimentary product with significant cardioprotective potential due to its high content of bioactive compounds. The aim of the present study was to review the most recent literature concerning the effectiveness and mechanisms of action of compounds contained in cocoa with regard to selected cardiovascular risk factors and cardiometabolic markers. Study results indicate that cocoa consumption, especially in the form of dark chocolate with high flavonoid content, may be a good strategy to diminish cardiovascular risk due to its beneficial effect on platelet aggregation, decreasing blood pressure, diminishing dyslipidemia, and decreasing blood plasma glucose concentration. Many studies have shown that cocoa-derived flavonoids have antioxidant and anti-inflammatory activity and also play a significant role in preventing insulin resistance. However, in order to completely confirm the potential cardiovascular benefits, it is necessary to conduct larger and longer studies, also with regard to potential dangers associated with long-term consumption of large amounts of flavonoids and determination of a safe and effective dose. Key teaching points Cocoa consumption may be a good strategy in diminishing cardiovascular risk. Beneficial effects on platelet aggregation, blood pressure, dyslipidemia, glycemia, as well as antioxidant and anti-inflammatory activity are observed. There is a need to conduct larger and longer studies to determine a safe and effective dose of cocoa flavonoids.
Sclerosing Angiomatoid Nodular Transformation of the Spleen: Lessons from a Rare Case and Review of the Literature

Sclerosing angiomatoid nodular transformation (SANT) of the spleen is an extremely rare benign lesion. We herein report a case of asymptomatic SANT of the spleen in a middle-aged woman with early breast carcinoma and an undiagnosed splenic mass, which was successfully treated by laparoscopic splenectomy and diagnosed postoperatively. We also review the literature on SANT to help make knowledge more accessible when clinicians encounter a splenic tumor. The present case taught us the following lesson: the presence of a splenic lesion during follow-up for malignancy is not always indicative of metastasis. Therefore, SANT should be considered in the differential diagnosis.
The status of the unaccusative/unergative split in the Croatian-English interlanguage*

By employing the two types of errors well-documented in the literature on the L2 acquisition of English unaccusatives, namely passive morphology and postverbal subjects, this study investigates the status of the unaccusative/unergative split in the Croatian-English interlanguage and the issue of UG involvement in L2 acquisition. Despite being unable to provide a full and unified account of the common response pattern obtained from native and non-native speakers, the study demonstrates that unaccusatives and unergatives are represented as distinct verb classes in the Croatian-English interlanguage and argues that such representations could not have been acquired without access to UG.
Global Transcriptomic Profile of Dorsal Root Ganglion and Physiological Correlates of Cisplatin-Induced Peripheral Neuropathy

Background Multiple cell signaling pathways are implicated in the development, progression, and persistence of cisplatin-induced peripheral neuropathy. Although advances have been made in terms of understanding specific neurotoxic mechanisms, there are few predictive factors identified that can help inform the clinician approach to symptom prevention or management. Objective We investigate the differential sensitivity to cisplatin-induced peripheral neuropathy and examine the contribution of dorsal root ganglion (DRG) transcriptional profiles across two inbred strains of mice. Methods Cisplatin (4 mg/kg intraperitoneal or vehicle control) was administered twice a week for 4 weeks to adult female C57BL/6J and A/J mice—the C57BL/6J strain of mice characterized by a robust mechanical allodynia and the A/J with a mild largely resistant allodynia phenotype. Peripheral nerve conduction velocities (NCVs), electrophysiological evaluation of wide dynamic range (WDR) neurons, morphological examination of DRG neurons, and microarray analysis of spinal cord tissues were compared across the 4 weeks. Results The A/J strain presents with an early, mild nocifensive response to cisplatin with reduced neuronal activity in WDR neurons and small changes in cross-sectional nucleus size in DRG neurons at 4 weeks. The more nocifensive-sensitive C57BL/6J strain presents with no early changes in WDR neuron responsiveness; however, there were significant changes in DRG size. Both strains demonstrate a drop in NCV after 4 weeks of treatment, with the greatest reduction present in the A/J strain. Transcriptome data implicate neuroimmune modulation in the differential response to cisplatin in the DRGs of A/J and C57BL/6J mice. Discussion Nocifensive responses in both strains implicate involvement of small myelinated and unmyelinated fibers in neurotoxic cisplatin response, whereas reductions in NCV reflect involvement of the largest myelinated fibers in the peripheral nerves. Microarray data analysis identifies neuropathy-relevant gene sets with differential activation of pathways, suggesting a role for antigen presentation in the differential neurotoxic response to cisplatin across strains. Further research is indicated to determine the relative contributions of each of these potential pathological mechanisms to both the neurotoxic response to cisplatin and to the potential for targeted therapy.
Exploitation of Three Non-Conventional Yeast Species in the Brewing Process

Consumers require high-quality beers with specific enhanced flavor profiles and non-conventional yeasts could represent a large source of bioflavoring diversity to obtain new beer styles. In this work, we investigated the use of three different non-conventional yeasts belonging to Lachancea thermotolerans, Wickerhamomyces anomalus, and Zygotorulaspora florentina species in pure and mixed fermentation with the Saccharomyces cerevisiae commercial starter US-05. All three non-conventional yeasts were competitive in co-cultures with the S. cerevisiae, and they dominated fermentations with 1:20 ratio (S. cerevisiae/non-conventional yeasts ratios). Pure non-conventional yeasts and co-cultures affected significantly the beer aroma. A general reduction in acetaldehyde content in all mixed fermentations was found. L. thermotolerans and Z. florentina in mixed and W. anomalus in pure cultures increased higher alcohols. L. thermotolerans led to a large reduction in pH value, producing, in pure culture, a large amount of lactic acid (1.83 g/L) while showing an enhancement of ethyl butyrate and ethyl acetate in all pure and mixed fermentations. W. anomalus decreased the main aroma compounds in comparison with the S. cerevisiae but showed a significant increase in ethyl butyrate and ethyl acetate. Beers produced with Z. florentina were characterized by an increase in the isoamyl acetate and α-terpineol content.