Miracle-dz/UniFAR-FTUs huggingface dataset:
The artful management of older patients with acute myeloid leukemia

ABSTRACT Acute myeloid leukemia in older patients has historically had a dismal 10-15% long-term survival rate. Although patient frailty plays a role in this disappointing outcome, the primary driver of poor results remains the resistance of disease to current therapies. The optimal management of this difficult-to-treat disease should include a careful consideration of disease, patient and treatment factors. Disease factors include cytogenetic and molecular features and the history of an antecedent hematological disorder. Patient factors include age, performance status, comorbid conditions and individual patient preference. We favor intensive induction in most fit older patients but alternatives such as hypomethylating agents and low-dose cytarabine may be considered in patients with other comorbidities. Enrollment of patients into well designed clinical trials addressing important questions remains of utmost importance in order to advance the understanding and treatment of this disease although the best means of drug development remains a challenging dilemma.
Experimental Evidence for Serial Models of Lexical Access: A Judgment Task

The hypothesis that the lemma and lexeme levels of lexical access are in a feed-forward serial relation is supported. Subjects judge the degree of semantic relatedness of pairs of words. Stimuli are all functionally synonymous; they are pairs of words implicated in natural word blends. Half the stimuli are phonologically related and the other half are not. In one experiment the pairs are presented in a sentential context and in the other no context is provided. In both the experiments the phonologically unrelated pairs are judged closer in meaning than the phonologically related pairs. This is interpreted as support for serial models of lexical access.
Capacidade funcional do idoso: formas de avaliação e tendências

A avaliação da capacidade funcional (CF) dos idosos pode detectar possível risco de dependência futura, estabelecer níveis de morbidade de mortalidade, além de poder balizar intervenções direcionadas aos idosos. Dessa forma, o objetivo desse estudo foi, através de uma pesquisa bibliográfica, identificar os testes mais utilizados e o potencial de cada prova para identificação do nível de CF do idoso. O exame da literatura mostrou que CF tem sido determinada em abordagens gerais, que objetivam traçar o perfil funcional através de um único teste, como as propostas dos testes caminhada e de mobilidade. Por outro lado, pode-se determinar a CF mediante a avaliação de componentes específicos como os testes de equilíbrio, força e marcha. Geralmente, as propostas descritas seguem a idéia de que uma ação funcional, realizada de maneira mais rápida, remete ao potencial funcional do idoso. No entanto, mediante as limitações das quantificações apontadas pelos estudos, observou-se a tendência da avaliação funcional em utilizar analises qualitativas, que objetivam determinar o padrão de movimento, como uma outra via da compreensão da CF do idoso. Além disso, notou-se que a avaliação da CF tem sido indicada e desenvolvida também para aqueles que não apresentam comprometimento funcional aparente e não somente para os idosos evidentemente mais frágeis.
EWS/FLI-1 Silencing and Gene Profiling of Ewing Cells Reveal Downstream Oncogenic Pathways and a Crucial Role for Repression of Insulin-Like Growth Factor Binding Protein 3

ABSTRACT Ewing tumors are characterized by abnormal transcription factors resulting from the oncogenic fusion of EWS with members of the ETS family, most commonly FLI-1. RNA interference targeted to the junction between EWS and FLI-1 sequences was used to inactivate the EWS/FLI-1 fusion gene in Ewing cells and to explore the resulting phenotype and alteration of the gene expression profile. Loss of expression of EWS/FLI-1 resulted in the complete arrest of growth and was associated with a dramatic increase in the number of apoptotic cells. Gene profiling of Ewing cells in which the EWS/FLI-1 fusion gene had been inactivated identified downstream targets which could be grouped in two major functional clusters related to extracellular matrix structure or remodeling and regulation of signal transduction pathways. Among these targets, the insulin-like growth factor binding protein 3 gene (IGFBP-3), a major regulator of insulin-like growth factor 1 (IGF-1) proliferation and survival signaling, was strongly induced upon treating Ewing cells with EWS/FLI-1-specific small interfering RNAs. We show that EWS/FLI-1 can bind the IGFBP-3 promoter in vitro and in vivo and can repress its activity. Moreover, IGFBP-3 silencing can partially rescue the apoptotic phenotype caused by EWS/FLI-1 inactivation. Finally, IGFBP-3-induced Ewing cell apoptosis relies on both IGF-1-dependent and -independent pathways. These findings therefore identify the repression of IGFBP-3 as a key event in the development of Ewing's sarcoma.
Improved Stability and Photoluminescence Yield of Mn2+-Doped CH3NH3PbCl3 Perovskite Nanocrystals

Organic–inorganic CH3NH3PbCl3 perovskite nanocrystals (PNCs) doped with Mn2+, CH3NH3PbxMn1−xCl3, have been successfully prepared using a reprecipitation method at room temperature. Structural and morphological characterizations reveal that the CH3NH3PbxMn1−xCl3 PNCs with cubic phase transforms from particles to cubes and increases in size from 16.2 ± 4.4 nm in average diameter to 25.3 ± 7.2 nm in cubic length after the addition of Mn2+ precursor. The CH3NH3PbxMn1−xCl3 PNCs exhibit a weak exciton emission at ~405 nm with a low absolute quantum yield (QY) of around 0.4%, but a strong Mn2+ dopant emission at ~610 nm with a high QY of around 15.2%, resulting from efficient energy transfer from the PNC host to the Mn2+ dopant via the 4T1→6A1 transition. In addition, the thermal and air stability of CH3NH3PbxMn1−xCl3 PNCs are improved due to the passivation with (3-aminopropyl) triethoxysilane (APTES), which is important for applications such as light emitting diodes (LEDs).
MHC Polymorphism Can Enrich the T Cell Repertoire of the Species by Shifts in Intrathymic Selection

The murine class I molecule H-2Kb and its natural gene conversion variant, H-2Kbm8, which differs from H-2Kb solely at 4 aa at the bottom of the peptide-binding B pocket, are expressed in coisogenic mouse strains C57BL/6 (B6) and B6.C-H-2bm8 (bm8). These two strains provide an excellent opportunity to study the effects of Mhc class I polymorphism on the T cell repertoire. We recently discovered a gain in the antiviral CTL repertoire in bm8 mice as a consequence of the emergence of the Mhc class I allele H-2Kbm8. In this report we sought to determine the mechanism behind the generation of this increased CTL diversity. Our results demonstrate that repertoire diversification occurred by a gain in intrathymic positive selection. As previously shown, the emergence of the same Mhc allele also caused a loss in positive selection of T cell repertoire specific for another Ag, OVA-8. This indicates that a reciprocal loss-and-gain pattern of intrathymic selection exists between H-2Kb and H-2Kbm8. Therefore, in the thymus of an individual, a new Mhc allele can select new T cell specificities, while abandoning some T cell specificities selected by the wild-type allele. A byproduct of this repertoire shift is a net gain of T cell repertoire of the species, which is likely to improve its survival fitness.
Elicitation of natural killer cells in beige mice by infection with vesicular stomatitis virus

Vesicular stomatitis virus (VSV) infection of beige (bg/bg) mice induced levels of natural killer cytolytic activity comparable to that of uninfected normal bg/+ controls, but considerably less than natural killer activity in VSV-infected bg/+ mice. In contrast, VSV-infected bg/bg and bg/+ mice had essentially equivalent amounts of anti-VSV cytotoxic T-lymphocyte and antibody activity. VSV infection induced comparable levels of interferon in both bg/bg and bg/+ mice. Therefore, the decreased natural killer activity in bg/bg mice could not be attributed to an inability to produce interferon.
Differences in the interactions of Nocardia asteroides with macrophage, endothelial, and astrocytoma cell lines

An in vitro model for studying host cell interactions with Nocardia asteroides was developed. Thus, macrophage cell lines J774A.1 and P388D1, pulmonary artery endothelium cell line CPAE, rat glial tumor cell line C6, and human astrocytoma cell lines CCF-STTG1 and U-373 MG were infected with either log- or stationary-phase cells of N. asteroides GUH-2, and the host cell-nocardia interactions were determined by light microscopy and electron microscopy. Polyclonal antinocardial antibody did not enhance uptake of nocardiae by any of these cell lines; however, log-phase cells of GUH-2 infected a higher percentage of J774A.1 and P388D1 than did stationary-phase organisms. When cells infected with stationary-phase GUH-2 were incubated for 6 h, filaments developed, which indicated that nocardial growth had occurred. In J774A.1 and P388D1, only 31 to 57% of the total stationary-phase coccobacillary cells that were phagocytized formed filaments within 6 h. This indicated that there was some inhibition of growth of the phagocytized nocardiae within these macrophage cell lines; however, the nocardiae grew within the endothelial (> 87% filaments) and astrocytoma (100% filaments) cell lines. Microfilament inhibitor cytochalasin B inhibited uptake of GUH-2 by macrophages and other cell lines, except that there was no effect on uptake of nocardial cells by astrocytoma cell line U-373 MG. Scanning and transmission electron microscopy showed phagocytosis of GUH-2 by the different cell lines. In cytochalasin B-treated cells, nocardiae were shown to penetrate through the cell surface and become internalized in a manner distinct from typical phagocytosis, suggesting that filamentous forms of this organism have a phagocytosis-independent invasion factor. The extent of this cytochalasin-resistant cellular penetration by the nocardiae differed in the different cell lines.
Molecular characterization of fowl adenoviruses isolated from inclusion body hepatitis outbreaks in commercial broiler chickens in Malaysia

Fowl adenoviruses (FAdVs), belonging to the Aviadenovirus genus of the family Adenoviridae, have been classified into five species (A to E) and further divided into 12 serotypes. The objective of this study was to identify the serotype classification of five Malaysian FAdV isolates obtained from field outbreaks of IBH in commercial broiler chickens. Hexon-based polymerase chain reactions (PCR), combined with restriction enzyme analysis (REA), were applied. Viral DNA reacted positively with H1/H2 and H3/ H4 primer pairs which hybridised to highly conserved regions of the hexon genes. The restriction enzyme profiles of the H1/H2 fragment digested with HaeII and the H3/H4 fragment digested with HpaII revealed that all five isolates shared identical patterns and are characterised as being FAdV-8b, species E. Meanwhile, sequence analysis of the L1 loop region of the hexon gene revealed 98.1% identity with FAdV-8b strain 764. High bootstrap values in phylogenetic analysis supported the clustering of the Malaysian FAdV isolates into FAdV species E. The present study has provided a very useful reference for further studies of FAdVs in Malaysia. Vaccination strategies should be developed against FAdVs infection in commercial broiler chickens to prevent IBH outbreaks in the country.
Functional SNPs in Genes Encoding the 5-HT2A Receptor Modify the Affinity and Potency of Several Atypical Antipsychotic Drugs

Atypical antipsychotic drugs (AADs) are the standard treatment for both the acute and long-term management of schizophrenia and an augmentation to mood stabilizers for bipolar disorder (BD). Yet many individuals who take AADs do not fully respond to them, while others experience side effects that include weight gain and metabolic disorder. This in vitro pharmacogenetic study examined whether allelic variants in the 5-hydroxytryptamine (HT)2A receptor alter the in vitro pharmacology of six AADs (clozapine, olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole). We selected 4 functional single-nucleotide polymorphisms (SNPs) for investigation (Thr25Asn, Ile197Val, Ala447Val, and His452Tyr), conducted site-directed mutagenesis studies to induce variants into human HEK-293 cell lines, and screened allelic variants for their effects on 5-HT 2A receptors in the cell lines. We conducted numerous binding assays and fluorescence-based assay system (FLEX station) experiments using the six AADs. Our results indicated that three polymorphic 5-HT2A receptors (Ile197Val, Ala447Val, and His452Tyr) exhibited statistically significant, though modest, changes in atypical antipsychotic affinity. In addition, three polymorphic receptors (Thr25Asn, Ile197Val, and His452Try) altered AAD potency. Our findings support in vivo evidence that functional SNPs in genes encoding neuroreceptor drug targets could explain interindividual differences in AAD drug response and tolerability. We suggest that more in vivo pharmacogenetic studies of well-characterized patients who are prescribed AADs be indicated. Future pharmacogenetic studies of well-characterized patients will likely involve tagging SNPs and the use of haplotypes related to other genes encoding neuroreceptor drug targets.
Protective Role of Anakinra Against Transthyretin-Mediated Axonal Loss and Cell Death in a Mouse Model of Familial Amyloidotic Polyneuropathy

Abstract Familial amyloidotic polyneuropathy (FAP) is characterized by a length-dependent axonal loss in the peripheral nervous system that results from deposition of extracellular prefibrillar transthyretin (TTR) and amyloid fibrils. We have previously shown that an inflammatory stimulus in the peripheral nerve in a mouse model of FAP triggers local TTR expression and deposition, leading to poor regeneration. We also demonstrated that blocking interleukin-1 (IL-1) signaling by the IL-1 receptor antagonist anakinra is beneficial in preventing nerve TTR deposition and associated toxicity. Here, we investigated whether IL-1 signaling influences TTR biology after an injury stimulus in a V30M FAP mouse model. Animals were treated with anakinra 48 hours before sciatic nerve ligation; the nerves were analyzed 7 days postlesion. Anakinra decreased TTR expression by Schwann cells and TTR extracellular deposition after nerve injury, which resulted in improved regeneration. Moreover, treated mice had less apoptotic cell death. In wild-type mice, inflammation is important for regeneration but, in the FAP model mice, an altered threshold of the inflammatory response differentially regulates TTR. Taken together, our results show that anakinra administration before injury can modulate TTR-induced peripheral nervous system pathology, thereby corroborating the protective interference of this drug in a FAP preclinical model.
Cross-border e-signature implementation experience

This paper describes the experience of ongoing project 'Increasing capacity of local governments in providing e-services in Ida-Virumaa-Leningrad oblast cross-border areas' (ELRII-470), implemented under Cross Border Cooperation Program of the ENPI Estonia-Latvia-Russia 2007--2013. Lessons learned from this project seem interesting to learn and use in similar projects.
Characterization of the role of IL‐6 in the progression of prostate cancer

We recently identified IL‐6, a pleiotropic cytokine implicated in the neoplastic process of a variety of neoplasms, as a mediator of prostate cancer morbidity. In the present study, we investigated the expression of members of the IL‐6 supergene family and related cytokines and the potential role of IL‐6 in prostate cancer growth regulation.
Measurement of the plasma boundary shift and approximation of the magnetic surfaces on the IR-T1 Tokamak

In this research we measured the plasma boundary shift using array of magnetic pick- up coils on the IR- T1 tokamak. Also we approximated the magnetic surfaces by an equilibrium calculation. Firstly, four magnetic probes were designed, constructed, and installed on outer surface of the IR- T1 tokamak chamber and then plasma boundary displacement measured from them. On the other hand, magnetic surfaces approximated by equilibrium calculation of the Grad- Shafranov equation based on expansion of free functions as quadratic in flux function.
Intratumoral Injection of HSV1716, an Oncolytic Herpes Virus, Is Safe and Shows Evidence of Immune Response and Viral Replication in Young Cancer Patients

Purpose: HSV1716 is an oncolytic herpes simplex virus-1 (HSV-1) studied in adults via injection into the brain and superficial tumors. To determine the safety of administering HSV1716 to pediatric patients with cancer, we conducted a phase I trial of image-guided injection in young patients with relapsed or refractory extracranial cancers. Experimental Design: We delivered a single dose of 105 to 107 infectious units of HSV1716 via computed tomography–guided intratumoral injection and measured tumor responses by imaging. Patients were eligible for up to three more doses if they achieved stable disease. We monitored HSV-1 serum titers and shedding by PCR and culture. Results: We administered a single dose of HSV1716 to eight patients and two doses to one patient. We did not observe any dose-limiting toxicities. Adverse events attributed to virus included low-grade fever, chills, and mild cytopenias. Six of eight HSV-1 seronegative patients at baseline showed seroconversion on day 28. Six of nine patients had detectable HSV-1 genomes by PCR in peripheral blood appearing on day +4 consistent with de novo virus replication. Two patients had transient focal increases in metabolic activity on 18fluorine-deoxyglucose PET, consistent with inflammatory reactions. In one case, the same geographic region that flared later appeared necrotic on imaging. No patient had an objective response to HSV1716. Conclusions: Intratumoral HSV1716 is safe and well-tolerated without shedding in children and young adults with late-stage, aggressive cancer. Viremia consistent with virus replication and transient inflammatory reactions hold promise for future HSV1716 studies. Clin Cancer Res; 23(14); 3566–74. ©2017 AACR.
Hypoxia, Angiogenesis and Atherogenesis

The balance between vascular oxygen supply and metabolic demand for oxygen within the vasculature is normally tightly regulated. An imbalance leads to hypoxia and a consequential cascade of cellular signals that attempt to offset the effects of hypoxia. Hypoxia is invariably associated with atherosclerosis, wound repair, inflammation and vascular disease. The anoxaemia hypothesis proposes that an imbalance between the demand for and supply of oxygen in the arterial wall is a key factor in the development of atherosclerosis and plaque angiogenesis. There is now substantial evidence that hypoxia plays an essential role in angiogenesis as well as plaque angiogenesis. It controls the metabolism, and responses of many of the cell types found within the developing plaque and whether the plaque will evolve into a stable or unstable phenotype. Hypoxia is characterized in molecular terms by the stabilization of hypoxia-inducible factor (HIF) 1a, a subunit of the heterodimeric nuclear transcriptional factor HIF-1 and a master regulator of oxygen homeostasis. The expression of HIF-1 is localized to perivascular tissues, inflammatory macrophages and smooth muscle cells where it regulates several genes that are important to vascular function including vascular endothelial growth factor, nitric oxide synthase, endothelin-1 and erythropoietin. This chapter summarizes the effects of hypoxia on the functions of cells involved in angiogenesis as well as atherogenesis (plaque angiogenesis) and the evidence for its potential importance from experimental models and clinical studies.
Relaxation effects in MOS devices due to tunnel exchange with near-interface oxide traps

Transif Jrs and capacitors in reany types of analog MOS circuits such as chargeredistribution AID converters, switched-capacitor filters and sample-and-holds, are routinely subjected to momentary large-signal stress conditions during the course of their normal operation. During these transients, charge can be captured by oxide traps close to the Si-Si0 2 interface by tunneling. When the stress is removed, the emission of this trapped charge peL'sists for periods which greatly exceed the capture time, leading to dielectric relaxation in capacitors and transient threshold voltage shifts in MOSFETs. While the amount of trapped charge is too small to be of interest in most digital circuits where the resulting threshold voltage shifts fall comfortably within noise margins, in analog circuits it can lead to hysteresis effects, charge redistribution errors and long-tail components in the settling time of comparators and operational amplifiers with MOS input stages. As analog integrated circuits are pushed towards higher levels of speed and accuracy, these trapping-induced relaxation effects will impose increasingly important performance limitations . Previous experimental studies of charge trapping by near-interface oxide traps have neglected the voltage and time ranges relevant to analog circuits, while existing theories do not provide a complete description of the various mechanisms by which traps can be charged and discharged. This thesis undertakes a detailed characterization of trapping-induced relaxation effects in MOSFETs and capacitors as a function of bias, time, temperature and geometry, under cOllditions relevant to analog circuit operation. A theoretical description of various relaxation mechanisms is presented and it is shown that the dominant charging/discharging mechanism under the bias conditions of interest is by the elastic tunneling of charge carriers to and from oxide traps. Tunneling occurs directly between the silicon band edges and an oxide trap, or in conjuction with either lattice relaxation multiphonon emission. in the insulator or the assistance of fast surface states at the interface. Experimental data from transistors with conventional and nitrided dielectrics are presented and explained using
Blood transfusion from antiquity to the discovery of the Rh factor.

Use of blood as a therapeutic agent by drinking it as “Elixir Vitae” goes back before Biblical time. Despite the opposition of Celsus (25 BC – AD 50), drinking blood continued; it was routine to drink the blood of fallen gladiators as a remedy for various ailments, including epilepsy. Rational thinking about blood transfusion was prevented by the beliefs of Aristotle (384–322 BC) and Galen (130–200 AD), who taught that the blood was made in the heart or the liver and flowed until it was used up. These views remained undisputed for >1400 years, until the discovery in 1616 of the blood circulation by William Harvey (1578–1657). Harvey’s discovery gave a sudden impetus to transfer blood from animals to humans and from one person to another. The first blood transfusion was carried out in 1628 by an Italian physician, Giovanni Francisco Colle (1558–1631) [1]. In 1665, Richard Lower (1631–1691) in England successfully transfused dogs with blood [2]. In 1666, blood transfusion into a human was performed in Paris by the mathematician, philosopher, and teacher, Jean Baptiste Denis (1625– 1704) [3]. He transfused lamb’s blood into 3 men with great success to cure their diseases, but the fourth patient died as the result of the transfusion. Denis, a target of opposition and jealousy of the medical and religious communities, was sued for wrongful death by the widow. Although Denis was found not negligent, the Paris court ordered him to stop further transfusions. Subsequently, the Medical Faculty of Paris petitioned the Parliament to outlaw blood transfusion throughout France. The Parliament agreed with the petitioners; transfusions fell into disrepute until the early 1800s. Exceptions were Fig. 1. The first illustration of the transfusion of blood [5]. Note that the seated man is receiving a transfusion from a dog into the left arm, while he simultaneously is being bled from the right arm by blood letting.