Miracle-dz/UniFAR-FTUs huggingface dataset:
Drugs targeting the bone microenvironment: new therapeutic tools in Ewing's sarcoma?

Introduction: Ewing's sarcoma (ES) is the second most frequent malignant primary bone tumour in children, adolescents and young adults. The overall survival is 60 – 70% at 5 years but still very poor for patients with metastases, disease relapse or for those not responding to chemotherapy. For these high risk patients, new therapeutic approaches are needed beyond conventional therapies (chemotherapy, surgery and radiation) such as targeted therapies. Areas covered: Transcriptomic and genomic analyses in ES have revealed alterations in genes that control signalling pathways involved in many other cancer types. To set up more specific approaches, it is reasonable to think that the particular microenvironment of these bone tumours is essential for their initiation and progression, including in ES. To support this hypothesis, preclinical studies using drugs targeting bone cells (bisphosphonate zoledronate, anti-receptor activator of NF-κB ligand strategies) showed promising results in animal models. This review will discuss the new targeted therapeutic options in ES, focusing more particularly on the ones modulating the bone microenvironment. Expert opinion: Targeting the microenvironment represents a new option for patients with ES. The proof-of-concept has been demonstrated in preclinical studies using relevant animal models, especially for zoledronate, which induced a strong inhibition of tumour progression in an orthotopic bone model.
End of the scaling theory and Moore's law

The progress of the electronics has been conducted until today by the downsizing of devices for more than 100 year since its beginning in early 20th century. However, it is believed now that the downsizing will reach its limit in several years because of several sure reasons. After reaching the limit, we cannot expect such a big progress as the past for electron devices in terms of cost, performance and energy consumption. Then, the effort will be focused to develop various kind of electron devices such as new memory, sensors, power, photovoltaic, battery and MEMS devices which are demanded for IoT era. In a long term, our research and development will shift to how to use the existing bio system more efficiently rather than developing only solid-state devices only.
Brain‐derived neurotrophic factor gene Val66Met polymorphism and cognitive function in obsessive–compulsive disorder

In the present study, we have tested the hypothesis that brain‐derived neurotrophic factor (BDNF) gene Val66Met polymorphism is associated with obsessive–compulsive disorder (OCD) and also investigated the association between the BDNF Val66Met polymorphism and the performance on tests measuring executive functions in a sample of patients with OCD. A total of 100 patients diagnosed with OCD according to DSM‐IV criteria and 110 control subjects were included in this study. Single nucleotide polymorphism (G/A) leading to Val to Met substitution at codon 66 in BDNF was screened in the DNA samples of all participants. The genotype frequencies of BDNF Val66Met polymorphism were compared in OCD patients and healthy controls. The four subgroups of OCD and healthy control subjects, determined according to being Val homozygous or carrying a Met allele, were also compared according to their performance in a battery of neuropsychological tests of executive functions and verbal memory. There was no significant difference for the allele and genotype distributions of BDNF Val66Met polymorphism between the OCD and healthy control groups. Compared to the other three subgroups, OCD‐Met carriers were slower on Trail‐Making Test part A (TMT A), part B (TMT B) score and its speed‐corrected score (TMT B‐A). OCD‐Met carriers had also poor performance on verbal fluency tasks and several CVLT measures compared only to the healthy control‐Met carriers. These results demonstrate that the BDNF Val66Met polymorphism does not appear to be a risk factor for OCD. However, the presence of a BDNF Met allele, which is a known attenuator of BDNF activity, may be associated with a poorer executive functioning in OCD. © 2012 Wiley Periodicals, Inc.
In Vitro Phosphorylation by cAMP-dependent Protein Kinase Up-regulates Recombinant Saccharomyces cerevisiae Mannosylphosphodolichol Synthase*

DPM1 is the structural gene for mannosylphosphodolichol synthase (i.e. Dol-P-Man synthase, DPMS) in Saccharomyces cerevisiae. Earlier studies with cDNA cloning and sequence analysis have established that 31-kDa DPMS of S. cerevisiae contains a consensus sequence (YRRVIS141) that can be phosphorylated by cAMP-dependent protein kinase (PKA). We have been studying the up-regulation of DPMS activity by protein kinase A-mediated phosphorylation in higher eukaryotes, and used the recombinant DPMS from S. cerevisiae in this study to advance our knowledge further. DPMS catalytic activity was indeed enhanced severalfold when the recombinant protein was phosphorylated in vitro. The rate as well as the magnitude of catalysis was higher with the phosphorylated enzyme. A similar increase in the catalytic activity was also observed when the in vitro phosphorylated recombinant DPMS was assayed as a function of increasing concentrations of exogenous dolichylmonophosphate (Dol-P). Kinetic studies indicated that there was no change in the Km for GDP-mannose between the in vitro phosphorylated and control recombinant DPMS, but the Vmax was increased by 6-fold with the phosphorylated enzyme. In vitro phosphorylated recombinant DPMS also exhibited higher enzyme turnover (kcat) and enzyme efficiency (kcat/Km). SDS-PAGE followed by autoradiography of the 32P-labeled DPMS detected a 31-kDa phosphoprotein, and immunoblotting with anti-phosphoserine antibody established the presence of a phosphoserine residue in in vitro phosphorylated recombinant DPMS. To confirm the phosphorylation activation of recombinant DPMS, serine 141 in the consensus sequence was replaced with alanine by PCR site-directed mutagenesis. The S141A DPMS mutant exhibited more than half-a-fold reduction in catalytic activity compared with the wild type when both were analyzed after in vitro phosphorylation. Thus, confirming that S. cerevisiae DPMS activity is indeed regulated by the cAMP-dependent protein phosphorylation signal, and the phosphorylation target is serine 141.
The influence of therapeutic alliance and insight on medication adherence in schizophrenia

Background: Poor adherence is one of the leading problems affecting the effectiveness of treatment in schizophrenia. It is an identified factor for relapse and hospitalizations with major social and economic consequences. Various determinants of poor adherence have been identified but few studies investigate the role of therapeutic alliance on medication adherence in routine mental healthcare. Aims: To investigate links between therapeutic alliance insight and medication adherence in routine care and community psychiatry. Methods: In this cross-sectional study, 38 inpatients that met ICD-10 criteria for schizophrenia or schizoaffective disorder were recruited and independently interviewed just before discharge. Various rating scales were used: the self-reported 4-Point ordinal Alliance Scale (4PAS), the Medication Adherence Rating Scale (MARS) and the Scale to assess Unawareness of Mental Disorder (SUMD). In addition, we investigated the relationships between medication adherence and clinical variables through uni- and multivariate analysis. Results: Therapeutic alliance was significantly correlated with adherence (r = 0.663, P < 0.0001) and insight (r =−0.664, P < 0.0001). Poor adherence was associated in patients with substance or alcohol use disorders (5.4 vs. 2.9, P = 0.0075, t = 2.83). No significant difference was found between the demographic characteristics of the sample, the characteristics of the treatments and adherence. Conclusions: A weak therapeutic alliance and low insight are associated with poor adherence in patients with schizophrenia or schizoaffective disorder who were hospitalized. Specific psycho-educational programs to improve therapeutic alliance and insight should be implemented to achieve better therapeutic adherence and outcome.
Use and Impact of eHealth System by Low-income Women With Breast Cancer

ABSTRACT This article is the second of a two-part series reporting on a population-based study intended to use an eHealth system to examine the feasibility of reaching underserved women with breast cancer (Gustafson, McTavish et al., Reducing the digital divide for low-income women with breast cancer, 2004; Madison Center for Health Systems Research and Analysis, University of Wisconsin; Comprehensive Health Enhancement Support System [CHESS]) and determine how they use the system and what impact it had on them. Participants included women recently diagnosed with breast cancer whose income was at or below 250% of poverty level and were living in rural Wisconsin (n = 144; all Caucasian) or Detroit (n = 85; all African American). Because this was a population-based study all 229 participants received CHESS. A comparison group of patients (n = 51) with similar demographics was drawn from a separate recently completed randomized clinical trial. Use rates (e.g., frequency and length of use as well as type of use) as well as impact on several dimensions of quality of life and participation in health care are reported. Low-income subjects in this study logged on and spent more time on CHESS than more affluent women in a previous study. Urban African Americans used information and analysis services more and communication services less than rural Caucasians. When all low-income women from this study are combined and compared with a low-income control group from another study, the CHESS group was superior to that control group in 4 of 8 outcome variables at both statistically and practically significant levels (social support, negative emotions, participation in health care, and information competence). When African Americans and Caucasians are separated the control group's sample size becomes 30 and 21 thus reducing power. Statistical significance is retained, however, in all four outcomes for Caucasians and in two of four for African Americans. Practical significance is retained for all four outcomes. We conclude that an eHealth system like CHESS will be used extensively and have a positive impact on low-income women with breast cancer.
Synapsin II Regulation of GABAergic Synaptic Transmission Is Dependent on Interneuron Subtype

Synapsins are epilepsy susceptibility genes that encode phosphoproteins reversibly associated with synaptic vesicles. Synapsin II (SynII) gene deletion produces a deficit in inhibitory synaptic transmission, and this defect is thought to cause epileptic activity. We systematically investigated how SynII affects synchronous and asynchronous release components of inhibitory transmission in the CA1 region of the mouse hippocampus. We found that the asynchronous GABAergic release component is diminished in SynII-deleted (SynII(−)) slices. To investigate this defect at different interneuron subtypes, we selectively blocked either N-type or P/Q-type Ca2+ channels. SynII deletion suppressed the asynchronous release component at synapses dependent on N-type Ca2+ channels but not at synapses dependent on P/Q-type Ca2+ channels. We then performed paired double-patch recordings from inhibitory basket interneurons connected to pyramidal neurons and used cluster analysis to classify interneurons according to their spiking and synaptic parameters. We identified two cell subtypes, presumably parvalbumin (PV) and cholecystokinin (CCK) expressing basket interneurons. To validate our interneuron classification, we took advantage of transgenic animals with fluorescently labeled PV interneurons and confirmed that their spiking and synaptic parameters matched the parameters of presumed PV cells identified by the cluster analysis. The analysis of the release time course at the two interneuron subtypes demonstrated that the asynchronous release component was selectively reduced at SynII(−) CCK interneurons. In contrast, the transmission was desynchronized at SynII(−) PV interneurons. Together, our results demonstrate that SynII regulates the time course of GABAergic release, and that this SynII function is dependent on the interneuron subtype. SIGNIFICANCE STATEMENT Deletion of the neuronal protein synapsin II (SynII) leads to the development of epilepsy, probably due to impairments in inhibitory synaptic transmission. We systematically investigated SynII function at different subtypes of inhibitory neurons in the hippocampus. We discovered that SynII affects the time course of GABA release, and that this effect is interneuron subtype specific. Within one of the subtypes, SynII deficiency synchronizes the release and suppresses the asynchronous release component, while at the other subtype SynII deficiency suppresses the synchronous release component. These results reveal a new SynII function in the regulation of the time course of GABA release and demonstrate that this function is dependent on the interneuron subtype.
Histone H3 lysine 36 methyltransferase Hypb/Setd2 is required for embryonic vascular remodeling

HYPB is a human histone H3 lysine 36 (H3K36)–specific methyltransferase and acts as the ortholog of yeast Set2. This study explored the physiological function of mammalian HYPB using knockout mice. Homozygous disruption of Hypb impaired H3K36 trimethylation but not mono- or dimethylation, and resulted in embryonic lethality at E10.5-E11.5. Severe vascular defects were observed in the Hypb −/− embryo, yolk sac, and placenta. The abnormally dilated capillaries in mutant embryos and yolk sacs could not be remodeled into large blood vessels or intricate networks, and the aberrantly rounded mesodermal cells exhibited weakened interaction with endothelial cells. The embryonic vessels failed to invade the labyrinthine layer of placenta, which impaired the embryonic–maternal vascular connection. These defects could not be rescued by wild-type tetraploid blastocysts, excluding the possibility that they were caused by the extraembryonic tissues. Consistent with these phenotypes, gene expression profiling in wild-type and Hypb −/− yolk sacs revealed that the Hypb disruption altered the expression of some genes involved in vascular remodeling. At the cellular level, Hypb −/− embryonic stem cell–derived embryonic bodies, as well as in vitro–cultured human endothelial cells with siRNA-mediated suppression of HYPB, showed obvious defects in cell migration and invasion during vessel formation, suggesting an intrinsic role of Hypb in vascular development. Taken together, these results indicate that Hypb is required for embryonic vascular remodeling and provide a tool to study the function of H3K36 methylation in vasculogenesis/angiogenesis.
A 127‐kDa Protein (UV‐DDB) Binds to the Cytoplasmic Domain of the Alzheimer's Amyloid Precursor Protein

Abstract : Alzheimer amyloid precursor protein (APP) is an integral membrane protein with a short cytoplasmic domain of 47 amino acids. It is hoped that identification of proteins that interact with the cytoplasmic domain will provide new insights into the physiological function of APP and, in turn, into the pathogenesis of Alzheimer's disease. To identify proteins that interact with the cytoplasmic domain of APP, we employed affinity chromatography using an immobilized synthetic peptide corresponding to residues 645‐694 of APP695 and identified a protein of ~130 kDa in rat brain cytosol. Amino acid sequencing of the protein revealed the protein to be a rat homologue of monkey UV‐DDB (UV‐damaged DNA‐binding protein, calculated molecular mass of 127 kDa). UV‐DDB/p127 co‐immunoprecipitated with APP using an anti‐APP antibody from PC12 cell lysates. APP also co‐immunoprecipitated with UV‐DDB/p127 using an anti‐UV‐DDB/p127 antibody. These results indicate that UV‐DDB/p127, which is present in the cytosolic fraction, forms a complex with APP through its cytoplasmic domain. In vitro binding experiments using a glutathione S‐transferase‐APP cytoplasmic domain fusion protein and several mutants indicated that the YENPTY motif within the APP cytoplasmic domain, which is important in the internalization of APP and amyloid β protein secretion, may be involved in the interaction between UV‐DDB/p127 and APP.
Rhino-9J (hrrh9J ): A New Allele at the Hairless Locus

A spontaneous mutation arose in the MRL/MpJ-Faslpr/Faslpr colony in which mice lost hair after completion of the first hair cycle. Hair loss was progressive from head to tail. As these mice aged, they developed wrinkled skin and long curved nails. Histologically, affected skin developed comedones (pilary cysts), deep dermal cysts, and dermal foreign body granulomas associated with rupture of the follicles. The alopecic epidermis was acanthotic. The mutation was autosomal recessive. Crosses with RHJ/Le +/hrrhJ (rhino-J) mutant mice yielded affected offspring with the same phenotype, verifying the presence of a new allele of rhino, a mutation at the hairless (hr) locus on mouse chromosome 14.
Effect of fetal thyroid hormone (RT3) on sarcoma cells in culture

Fetal thyroid hormone (RT3) is considered metabolically inactive and is present in high concentration in fetuses and in some patients with end‐stage malignant disease. In a virus‐induced erythroleukemia cell model, RT3 was found to stimulate the growth of the erythroleukemia cells in culture. The focus of this research was to test the effect of RT3, at several concentrations, on the growth of naturally occurring human sarcomas in cell culture. Cloned cell lines of Ewing sarcoma, rhabdomyosarcoma, and osteogenic sarcoma were grown in multiple flasks of serum‐free medium containing varying concentrations of RT3, ranging from 10−8 and 10−5 M. Cells grown in serum‐free medium containing no RT3 were used as a control. RT3 significantly increased the growth (total protein) of the rhabdomyosarcoma cell line in culture at concentrations between 10−8 and 10−6 M, with the maximum effect at 10−7 M. The growth of one cell line of Ewing sarcoma was not affected by RT3 for any of the concentrations tested. The growth of two Ewing sarcomas and one osteogenic sarcoma was significantly stimulated by RT3 but only at the highest concentration of 10−5 M. The growth of the other osteogenic sarcoma cell line was significantly increased at concentrations of 10−6 and 10−7 M. The stimulatory effect of RT3 on several sarcoma cell lines in culture suggests the presence of a specific receptor in the neoplastic cells and the possibility that RT3 may be useful as a model for new chemotherapeutic agents.
Far field's starting distance

The far field of an antenna is generally considered to be the region where the outgoing wavefront is planar and the antenna radiation pattern has a polar variation and is independent of the distance from the antenna. Hence, to generate a locally plane wave in the far field the radial component of the electric field must be negligible compared to the transverse component. Also, the ratio of the electric and the magnetic far fields should equal the intrinsic impedance of the medium. These two requirements must hold in all angular directions from the antenna. The radial and the transverse components of the fields are space dependent so to determine the starting distance of the far field we need to examine the simultaneous satisfaction of these two properties for all θ and φ angular directions, where θ is the angle measured from z-axis and φ is the angle measured from the x-axis. The objective of this paper can be summarized in three points: First, this paper intends to illustrate that 2D2 / λ formula, where D is the maximum dimension of the antenna and λ is the operating wavelength, is not universally valid, it is only valid for antennas where D ≫ λ. Second, this paper intends to compute a more specific constraint so instead of D ≫ λ we compute a threshold for D after which the 2D2 / λ formula applies. Third, this paper intends to properly interpret D in the formula 2D2 / λ when the antenna is operating over an imperfect ground plane. In this paper, we do not use 2D2 / λ for antennas operating over an imperfect ground instead we use a formula which depends on the transmitting and receiving antenna's heights over the air-Earth interface.
Cytotoxicity of syringin and 4-methoxycinnamyl alcohol isolated from Foeniculum vulgare on selected human cell lines

This study was carried out to determine the cytotoxic effect of seven plant extracts and the isolated compounds – syringin and 4-methoxycinnamyl alcohol – on cancerous and non-cancerous cells. The ethanol extract of Foeniculum vulgare was found to exhibit the most significant toxicity with an IC50 value of 19.97 μg/mL on HeLa cells. Bioassay-guided fractionation led to the isolation of two compounds, syringin (1) and 4-methoxycinnamyl alcohol (2). Both compounds showed toxicity against MCF-7, HeLa and DU145 cancer cell line. The results showed that compound 2 showed high toxicity against all the cancer cell lines with IC50 values of 14.24, 7.82 and 22.10 μg/mL, respectively. 4-Methoxycinnamyl alcohol also showed no apoptotic effect in cell cycle analysis after 48 h at a concentration of 10 μg/mL. However, DNA fragmentation study revealed that necrosis took place at a concentration of 10 μg/mL after 48 h exposure.
Imbalance between soluble tumour necrosis factor receptors type 1 and 2 in chronic periodontitis.

BACKGROUND Soluble types of tumour necrosis factor (TNF) receptors type 1 and 2 modulate the TNF-alpha-mediated inflammatory responses in chronic periodontitis (CP). OBJECTIVES This study investigated the levels of TNF-alpha, soluble TNF receptor type 1 and 2 in gingival crevicular fluid (GCF) and serum of healthy subjects and CP patients. MATERIALS AND METHODS Thirty-eight sera and 73 GCF samples were collected from 16 healthy subjects and 22 CP patients. GCF was collected from probing pocket depth (PPD)< or =3 mm sites of healthy subjects, PPD< or =3, 4-6 and > or =7 mm sites of CP patients. The levels of TNF-alpha, soluble TNF receptor type 1 and 2 in the serum and GCF were quantified by enzyme-linked immunosorbant assay. RESULTS The total amounts of TNF-alpha, soluble TNF receptor type 1 and 2 in GCF significantly elevated with increasing PPD in both site-based (p<0.05) and subject-based (p<0.05) analyses. However, their levels progressively diverged as the pocket depths increased, with the soluble TNF receptor type 2 level being comparatively lower than type 1. On the other hand, soluble TNF receptor type 2/type 1 ratios in GCF decreased as the severity of periodontitis increased (p<0.0001). CONCLUSION The imbalance between soluble TNF receptor type 1 and 2 levels in GCF could be related to CP severity.