Miracle-dz/UniFAR-FTUs huggingface dataset:
The microRNAs, MiR‐31 and MiR‐375, as candidate markers in Barrett's esophageal carcinogenesis

There is a critical need to identify molecular markers that can reliably aid in stratifying esophageal adenocarcinoma (EAC) risk in patients with Barrett's esophagus. MicroRNAs (miRNA/miR) are one such class of biomolecules. In the present cross‐sectional study, we characterized miRNA alterations in progressive stages of neoplastic development, i.e., metaplasia–dysplasia–adenocarcinoma, with an aim to identify candidate miRNAs potentially associated with progression. Using next generation sequencing (NGS) as an agnostic discovery platform, followed by quantitative real‐time PCR (qPCR) validation in a total of 20 EACs, we identified 26 miRNAs that are highly and frequently deregulated in EACs (≥4‐fold in >50% of cases) when compared to paired normal esophageal squamous (nSQ) tissue. We then assessed the 26 EAC‐derived miRNAs in laser microdissected biopsy pairs of Barrett's metaplasia (BM)/nSQ (n = 15), and high‐grade dysplasia (HGD)/nSQ (n = 14) by qPCR, to map the timing of deregulation during progression from BM to HGD and to EAC. We found that 23 of the 26 candidate miRNAs were deregulated at the earliest step, BM, and therefore noninformative as molecular markers of progression. Two miRNAs, miR‐31 and −31*, however, showed frequent downregulation only in HGD and EAC cases suggesting association with transition from BM to HGD. A third miRNA, miR‐375, showed marked downregulation exclusively in EACs and in none of the BM or HGD lesions, suggesting its association with progression to invasive carcinoma. Taken together, we propose miR‐31 and −375 as novel candidate microRNAs specifically associated with early‐ and late‐stage malignant progression, respectively, in Barrett's esophagus. © 2012 Wiley Periodicals, Inc.
Nuclear receptor NR4A1 is a tumor suppressor down-regulated in triple-negative breast cancer

The nuclear receptor (NR) superfamily contains hormone-inducible transcription factors that regulate many physiological and pathological processes through regulating gene expression. NR4A1 is an NR family member that still does not have an identified endogenous ligand, and its role in cancer is also currently unclear and controversial. In this study, we aimed to define the expression profiles and specific role of NR4A1 in the highly malignant triple-negative breast cancer (TNBC), which still lacks available targeted therapies. Bioinformatic analysis revealed a decrease of NR4A1 mRNA expression in human TNBC samples. Semi-quantitative analysis of NR4A1 protein expression by immunohistochemistry also identified a progressive NR4A1 reduction during the development of mouse basal-like mammary tumors and a significant NR4A1 downregulation in human TNBC samples. Furthermore, the expression levels of NR4A1 in human TNBC were negatively associated with tumor stage, lymph node metastasis and disease recurrence. Moreover, ectopic expression of NR4A1 in MDA-MB-231, a TNBC cell line with little endogenous NR4A1, inhibited the proliferation, viability, migration and invasion of these cells, and these inhibitions were associated with an attenuated JNK1–AP-1–cyclin D1 pathway. NR4A1 expression also largely suppressed the growth and metastasis of these cell-derived tumors in mice. These results demonstrate that NR4A1 is downregulated in TNBC and restoration of NR4A1 expression inhibits TNBC growth and metastasis, suggesting that NR4A1 is a tumor suppressor in TNBC.
Addition of testosterone to estrogen replacement therapy in oophorectomized women: effects on sexuality and well-being

Objective: To evaluate the effect of adding testosterone undecanoate 40 mg daily to estrogen replacement on sexual function, psychological well-being and self-esteem in surgically postmenopausal women. Methods: A letter of invitation to participate in the study was mailed to women who had undergone hysterectomy and bilateral oophorectomy for benign disorders during 1990-98. Fifty women, 45-60 years old, were consecutively recruited and randomly assigned to oral treatment with testosterone undecanoate 40 mg plus estradiol valerate 2 mg daily or placebo plus estradiol valerate 2 mg daily for 24 weeks. A double-blind design was chosen, with cross-over to the other regimen for another 24 weeks of treatment. Forty-four women completed the study. Outcome included scores on McCoy's sex scale questionnaire, the Psychological General Well-Being index and a self-esteem questionnaire, at baseline and after 24 weeks of either treatment. Serum concentrations of total testosterone, sex hormone binding globulin, free testosterone, dihydrotestosterone, androstenedione, estradiol, follicle stimulating hormone and luteinizing hormone were analyzed at baseline and after 24 weeks of both treatment regimens. Results: After 24 weeks, both treatment regimens had significantly improved some of the sexual variables. The addition of testosterone had a significantly better effect on the sex variables 'enjoyment of sex', 'satisfaction with frequency of sexual activity' and 'interest in sex'. The total McCoy score was significantly increased by both treatments, but there was a stronger effect when testosterone was also given. Although both regimens improved psychological well-being and self-esteem, we found no significant differences between testosterone-estrogen or estrogen alone at 24 weeks. Serum levels of all androgens, with considerable individual variation, increased significantly from baseline after 24 weeks of testosterone-estrogen treatment. Supraphysiological levels were achieved in a significant proportion of the women. Increases in estradiol and sex hormone binding globulin were less marked when testosterone was also given. Both treatments reduced gonadotropin levels. Conclusions: The addition of testosterone undecanoate improved specific aspects of sexual function more than treatment with estrogen alone. Improvements in well-being and self-esteem were similar for both treatments. If testosterone undecanoate 40 mg daily should be used for clinical treatment, regular monitoring of androgen serum levels is needed.
How many attempts are required to accomplish out-of-hospital endotracheal intubation?

BACKGROUND An important goal of emergency airway management is to complete endotracheal intubation (ETI) correctly, safely, and quickly, and repeated ETI attempts can increase patient morbidity and mortality. Clinical protocols limiting the number of ETI attempts may minimize harm, but this strategy also may reduce the frequency of successful ETI. OBJECTIVES To characterize the relationship between the number of out-of-hospital ETI attempts and ETI success. METHODS This study used prospective, multicenter data from 42 emergency medical services agencies from an 18-month period. Out-of-hospital rescuers (paramedics, out-of-hospital nurses, and physicians) completed structured, closed-response data forms describing clinical methods, course, and outcomes for all ETIs. An ETI attempt was defined as an insertion of the laryngoscope blade. Rescuers identified ETI outcome (success or failure) for each attempt. The authors defined overall success as ETI outcome (success or failure) on the last attempt, examining cardiac arrest, conventional nonarrest, sedation-facilitated, and rapid-sequence ETI separately. Univariate odds ratios (ORs) were used to identify the number of ETI attempts in which the cumulative ETI success rate approached the overall ETI success rate. RESULTS Complete data were available for 1,941 cases. More than 30% of patients received more than one ETI attempt. For 1,272 cardiac arrest ETIs, cumulative success for the first three attempts were 69.9%, 84.9%, and 89.9%; cumulative success approached overall success (91.8%) after three attempts (OR, 0.79; 95% confidence interval [CI] = 0.61 to 1.04). For 463 conventional non-arrest ETIs, cumulative success for the first three attempts were 57.6%, 69.2%, and 72.7%; cumulative success approached overall success (73.7%) after two attempts (OR, 0.95; 95% CI = 0.71 to 1.28). For 126 sedation-facilitated ETIs, cumulative success for the first three attempts were 44.4%, 62.7%, and 75.4%; cumulative success approached overall success (77.0%) after three attempts (OR, 0.92; 95% CI = 0.51 to 1.64). For 80 rapid-sequence ETI, cumulative ETI success for the first three attempts were 56.3%, 81.3%, and 91.3%; cumulative success approached overall success (96.3%) after three attempts (OR, 0.41; 95% CI = 0.10 to 1.65). CONCLUSIONS Out-of-hospital rescuers often require multiple attempts to accomplish ETI. A protocol limit of three attempts offers reasonable opportunity for accomplishing ETI within the constraints of the out-of-hospital environment.
The Dimer Interfaces of Protease and Extra-Protease Domains Influence the Activation of Protease and the Specificity of GagPol Cleavage

ABSTRACT Activation of the human immunodeficiency virus type 1 (HIV-1) protease is an essential step in viral replication. As is the case for all retroviral proteases, enzyme activation requires the formation of protease homodimers. However, little is known about the mechanisms by which retroviral proteases become active within their precursors. Using an in vitro expression system, we have examined the determinants of activation efficiency and the order of cleavage site processing for the protease of HIV-1 within the full-length GagPol precursor. Following activation, initial cleavage occurs between the viral p2 and nucleocapsid proteins. This is followed by cleavage of a novel site located in the transframe domain. Mutational analysis of the dimer interface of the protease produced differential effects on activation and specificity. A subset of mutations produced enhanced cleavage at the amino terminus of the protease, suggesting that, in the wild-type precursor, cleavages that liberate the protease are a relatively late event. Replacement of the proline residue at position 1 of the protease dimer interface resulted in altered cleavage of distal sites and suggests that this residue functions as a cis-directed specificity determinant. In summary, our studies indicate that interactions within the protease dimer interface help determine the order of precursor cleavage and contribute to the formation of extended-protease intermediates. Assembly domains within GagPol outside the protease domain also influence enzyme activation.
The role of circulating tumor cells in breast cancer diagnosis and prediction of therapy response.

BACKGROUND Metastatic breast cancer (MBC) is incurable and any treatment is considered palliative. Occult dissemination of tumor cells is responsible for recurrent MBC in patients who have undergone resection of their primary tumor. The presence of circulating tumor cells (CTCs) in patients with MBC predicts progression-free and overall survival. Moreover, this prognostic value is independent of the line of therapy. METHODS to detect and enumerate CTCs vary in sensitivity and specificity, and lack the standardization required for direct comparison between methods. OBJECTIVE To review the methods of detecting CTCs, the prognostic implications of CTCs, and opportunities to exploit the properties of CTCs to develop individualized therapy. METHODS The coupling of antibodies to immunomagnetic beads has facilitated the detection of low-frequency CTCs in peripheral blood of cancer patients. RESULTS/CONCLUSION Standardization of methods will allow for the uniform detection of microscopic disease in the peripheral blood of patients with MBC and provide prognostic information that will allow appropriate risk stratification and modification of the current staging system for advanced disease.
Radioimmunotherapy with 177Lu-DOTA-Rituximab: Final Results of a Phase I/II Study in 31 Patients with Relapsing Follicular, Mantle Cell, and Other Indolent B-Cell Lymphomas

The aim of this study was to determine the maximum tolerated dose (MTD) and to explore the clinical response to 177Lu-DOTA-rituximab in the treatment of patients with relapsed follicular, mantle cell, or other indolent lymphomas such as marginal zone lymphoma. Methods: To evaluate the MTD, we adjusted the dosage of the radiopharmaceutical according to body surface area (BSA). Results: The MTD using 177Lu-DOTA-rituximab was 1,665 MBq/m2 of BSA. Thrombocytopenia and leukopenia were the dose-limiting toxicities. Significant anemia occurred only at dose level 7 (1,850 MBq/m2 of BSA). We observed the nadir of platelets after a median of 36 d from treatment and the nadir of granulocytes after a median of 50 d. Median time to recovery to the next lower grade of toxicity was 7 d. Nonhematologic toxicity was negligible. We observed clinical responses at all dose levels and for all lymphoma entities. Some of the responses were durable; the longest follow-up is currently over 8 y. At present, 11 patients are alive and 8 patients are disease-free. Conclusion: Our results demonstrate the safety and feasibility of 177Lu-DOTA-rituximab treatment for the lymphoma entities tested in this study.
A systemic granulomatous response to Schistosoma mansoni eggs alters responsiveness of bone marrow‐derived macrophages to Toll‐like receptor agonists

Macrophages play a pivotal role in innate and acquired immune responses to Schistosoma mansoni. Classical (M1) or alternative (M2) activation states of these cells further delineate their roles in tissue damage through innate immunity or fibrotic remodeling, respectively. In the present study, we addressed the following question: Does systemic Th2‐type cytokine polarization evoked by S. mansoni affect macrophage differentiation and activation? To this end, we analyzed bone marrow‐derived macrophages from mice with S. mansoni egg‐induced pulmonary granulomas and unchallenged (or naïve) mice to determine their activation state and their response to specific TLR agonists, including S. mansoni egg antigens. Unlike naïve macrophages, macrophages from Th2‐polarized mice constitutively expressed significantly higher “found in inflammatory zone‐1” (FIZZ1) and ST2 (M2 markers) and significantly lower NO synthase 2, CCL3, MIP‐2, TNF‐α, and IL‐12 (M1 markers). Also, compared with naïve macrophages, Th2‐polarized macrophages exhibited enhanced responses to the presence of specific TLR agonists, which consistently induced significantly higher levels of gene and protein levels for M2 and M1 markers in these cells. Together, these data show that signals received by bone marrow precursors during S. mansoni egg‐induced granuloma responses dynamically alter the development of macrophages and enhance the TLR responsiveness of these cells, which may ultimately have a significant effect on the pulmonary granulomatous response.
Binary Phase Diagrams and Thermodynamic Properties of Silicon and Essential Doping Elements (Al, As, B, Bi, Ga, In, N, P, Sb and Tl)

Fabrication of solar and electronic silicon wafers involves direct contact between solid, liquid and gas phases at near equilibrium conditions. Understanding of the phase diagrams and thermochemical properties of the Si-dopant binary systems is essential for providing processing conditions and for understanding the phase formation and transformation. In this work, ten Si-based binary phase diagrams, including Si with group IIIA elements (Al, B, Ga, In and Tl) and with group VA elements (As, Bi, N, P and Sb), have been reviewed. Each of these systems has been critically discussed on both aspects of phase diagram and thermodynamic properties. The available experimental data and thermodynamic parameters in the literature have been summarized and assessed thoroughly to provide consistent understanding of each system. Some systems were re-calculated to obtain a combination of the best evaluated phase diagram and a set of optimized thermodynamic parameters. As doping levels of solar and electronic silicon are of high technological importance, diffusion data has been presented to serve as a useful reference on the properties, behavior and quantities of metal impurities in silicon. This paper is meant to bridge the theoretical understanding of phase diagrams with the research and development of solar-grade silicon production, relying on the available information in the literature and our own analysis.
[Prevalence and risk factors of age-related macular degeneration (AMD) in a Tunisian hospital population].

PURPOSE To describe the prevalence and the risk factors for the age related macular degeneration (AMD) in a Tunisian hospital population. PATIENTS AND METHODS A total of 2204 subjects 50 years of age and older were enrolled in a prospective study conducted between august 2004 and February 2009. Medical history was reviewed. Subjects underwent a complete ophthalmic examination, including best corrected visual acuity and slit lamp biomicroscopy with fundus examination. Fundus photography and fluorescein angiography were performed if clinical features of AMD were observed on fundus examination. Cases were classified in early and late stages of AMD. RESULTS The prevalence of late AMD was higher than early AMD. Significant risk factors are age, male gender, smoking, excessive sunlight exposure and poor consumption of fish. Cardiovascular disease, diabetes and dyslipimia were not significantly associated to a high prevalence of AMD. CONCLUSION AMD is a multifactorial disease. In our Tunisian hospital population, the prevalence of AMD was higher than in the Europeen population. It can be explained by genetic differences or risk factors. Age, cigarette smoking and sunlight exposure were associated with increasing prevalence of AMD in Tunisia.
Alzheimer's disease

Alzheimer's disease, the commonest cause of dementia, is a growing global health concern with huge implications for individuals and society. In this review, current understanding of the epidemiology, genetics, pathology and pathogenesis of Alzheimer's disease is outlined, before its clinical presentation and current treatment strategies are discussed. Finally, the review discusses how our enhanced understanding of Alzheimer pathogenesis, including the recognition of a protracted preclinical phase, is informing new therapeutic strategies with the aim of moving from treatment to prevention.
Neurocognitive and personality factors in homo- and heterosexual pedophiles and controls.

INTRODUCTION Several neuropsychological studies have suggested an association between pedophilia, neurocognitive disturbances, and specific personality profiles. However, inconsistencies in the findings have not been explained sufficiently, because many studies did not control for possible confounding factors, such as age, education level, or gender orientation. AIM Therefore, the present investigation examined neurocognitive performance and personality profiles in pedophiles in dependence of sexual gender preferences and sexual deviance, as well as with regard to age and education level. MAIN OUTCOME MEASURES Scores on the different neurocognitive tests, personality questionnaires, and Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV (SCID) interviews. METHODS An extensive neurocognitive test battery (including a reduced version of the German Wechsler Adult Intelligence Scale, the Wisconsin card-sorting test, d2 Attention-Deficit Test, and the Corsi block-tapping test) as well as two personality questionnaires (Minnessota Multiphasic Personality Inventory [MMPI-2] and the Multiphasic Sex Inventory [MSI]) were used to examine a consecutive sample of 20 psychiatrically assessed (SCID I and II) pedophile inpatients (nine exclusively attracted to females and 11 to males) from two high security forensic hospitals and 28 healthy controls (14 heterosexual, 14 homosexual). RESULTS Compared with controls, pedophiles showed neurocognitive impairments and personality specifics in the majority of tests and questionnaires, such as reduced values on the intelligence scale and weaker performances in information processing, together with high scores for psychopathy and paranoia, and signs of sexual obsessiveness and sexual dysfunction. In contrast to previous reports, some of these alterations were at least partly explained by factors other than pedophilia, such as education level or age. CONCLUSION These alterations may be seen to be in line with the hypothesis of a perturbation of neurodevelopment in early life. These results enhance our knowledge about pedophilia-associated impairment in neurocognitive functioning and personality structure insofar as they allow a more detailed description of, and insight into, modulatory factors.
Nutrient Amendments in Soil DNA Stable Isotope Probing Experiments Reduce the Observed Methanotroph Diversity

ABSTRACT Stable isotope probing (SIP) can be used to analyze the active bacterial populations involved in a process by incorporating 13C-labeled substrate into cellular components such as DNA. Relatively long incubation times are often used with laboratory microcosms in order to incorporate sufficient 13C into the DNA of the target organisms. Addition of nutrients can be used to accelerate the processes. However, unnatural concentrations of nutrients may artificially change bacterial diversity and activity. In this study, methanotroph activity and diversity in soil was examined during the consumption of 13CH4 with three DNA-SIP experiments, using microcosms with natural field soil water conditions, the addition of water, and the addition of mineral salts solution. Methanotroph population diversity was studied by targeting 16S rRNA and pmoA genes. Clone library analyses, denaturing gradient gel electrophoresis fingerprinting, and pmoA microarray hybridization analyses were carried out. Most methanotroph diversity (type I and type II methanotrophs) was observed in nonamended SIP microcosms. Although this treatment probably best reflected the in situ environmental conditions, one major disadvantage of this incubation was that the incorporation of 13CH4 was slow and some cross-feeding of 13C occurred, thereby leading to labeling of nonmethanotroph microorganisms. Conversely, microcosms supplemented with mineral salts medium exhibited rapid consumption of 13CH4, resulting in the labeling of a less diverse population of only type I methanotrophs. DNA-SIP incubations using water-amended microcosms yielded faster incorporation of 13C into active methanotrophs while avoiding the cross-feeding of 13C.