Miracle-dz/UniFAR-FTUs huggingface dataset:
A method for quantification of exportin-1 (XPO1) occupancy by Selective Inhibitor of Nuclear Export (SINE) compounds

Selective Inhibitor of Nuclear Export (SINE) compounds are a family of small-molecules that inhibit nuclear export through covalent binding to cysteine 528 (Cys528) in the cargo-binding pocket of Exportin 1 (XPO1/CRM1) and promote cancer cell death. Selinexor is the lead SINE compound currently in phase I and II clinical trials for advanced solid and hematological malignancies. In an effort to understand selinexor-XPO1 interaction and to establish whether cancer cell response is a function of drug-target engagement, we developed a quantitative XPO1 occupancy assay. Biotinylated leptomycin B (b-LMB) was utilized as a tool compound to measure SINE-free XPO1. Binding to XPO1 was quantitated from SINE compound treated adherent and suspension cells in vitro, dosed ex vivo human peripheral blood mononuclear cells (PBMCs), and PBMCs from mice dosed orally with drug in vivo. Evaluation of a panel of selinexor sensitive and resistant cell lines revealed that resistance was not attributed to XPO1 occupancy by selinexor. Administration of a single dose of selinexor bound XPO1 for minimally 72 hours both in vitro and in vivo. While XPO1 inhibition directly correlates with selinexor pharmacokinetics, the biological outcome of this inhibition depends on modulation of pathways downstream of XPO1, which ultimately determines cancer cell responsiveness.
Comparative study on induced macrocell corrosion phenomenon in repaired ordinary reinforced and self-compacting concrete structures

This paper aimed at an experimental investigation of the comparative corrosion phenomenon in the reinforcing steel of repaired chloride contaminated self-compacting concrete (SCRC) and ordinary concrete (OC) patches. This research is a continuation of a previous study in which macrocell specimens were prepared with OC having different chloride contaminations simulating the actual patch repair in the construction field. Here, in this research, the same specimens were prepared with SCRC to investigate more deeply the macrocell phenomenon in SCRC, which received limited attention in the past. Four prismatic specimens with two sets of 5 and 3% chloride contaminated SCRC at the two ends were prepared respectively, and the middle portion of these specimens was cast after 24 h with uncontaminated SCRC simulating the actual patch repair in the field. After 1 year of experimental observations of corrosion potentials and corrosion rates, interesting and novel results were obtained in comparison with OC and SCRC specimens.
CHARACTERIZATION OF HUMAN CYTOCHROME P450 ENZYMES INVOLVED IN THE METABOLISM OF THE PIPERIDINE-TYPE PHENOTHIAZINE NEUROLEPTIC THIORIDAZINE

The aim of the present study was to identify human cytochrome P450 enzymes (P450s) involved in mono-2-, di-2-, and 5-sulfoxidation, and N-demethylation of the piperidine-type phenothiazine neuroleptic thioridazine in the human liver. The experiments were performed in vitro using cDNA-expressed human P450s (Supersomes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4), liver microsomes from different donors, and P450-selective inhibitors. The results indicate that CYP1A2 and CYP3A4 are the main enzymes responsible for 5-sulfoxidation and N-demethylation (34–52%), whereas CYP2D6 is the basic enzyme that catalyzes mono-2- and di-2-sulfoxidation of thioridazine in human liver (49 and 64%, respectively). Besides CYP2D6, CYP3A4 contributes to a noticeable degree to thioridazine mono-2-sulfoxidation (22%). Therefore, the sulforidazine/mesoridazine ratio may be an additional and more specific marker than the mesoridazine/thioridazine ratio for assessing the activity of CYP2D6. In contrast to promazine and perazine, CYP2C19 insignificantly contributes to the N-demethylation of thioridazine. Considering serious side-effects of thioridazine and its 5-sulfoxide (cardiotoxicity), as well as strong dopaminergic D2 and noradrenergic α1 receptor-blocking properties of mono-2- and di-2-sulfoxides, the obtained results are of pharmacological and clinical importance, in particular, in a combined therapy. Knowledge of the catalysis of thioridazine metabolism helps to choose optimum conditions (a proper coadministered drug and dosage) to avoid undesirable drug interactions.
Assessment of symptoms of urinary incontinence in women with polycystic ovary syndrome

OBJECTIVES: The pelvic floor muscles are sensitive to androgens, and due to hyperandrogenism, women with polycystic ovary syndrome can have increased mass in these muscles compared to controls. The aim of this study is to compare reports of urine leakage and quality of life between women with and without polycystic ovary syndrome. METHODS: One hundred thirteen 18- to 40-year-old nulliparous women with polycystic ovary syndrome or without the disease (controls) were recruited at the University Hospital of School Medicine of São Paulo University at Ribeirão Preto City, Brazil. The subjects were not taking any hormonal medication, had not undergone previous pelvic surgery and did not exercise their pelvic floor muscles. The women were divided into the following four groups: I- polycystic ovary syndrome with normal body mass index (n = 18), II- polycystic ovary syndrome with body mass index ≥25 (n = 32), III- controls with normal body mass index (n = 29), and IV- controls with Body Mass Index ≥25 (n = 34). Quality of life was evaluated using the SF-36 questionnaire, and the subjects with urinary complaints also completed the International Consultation on Incontinence Questionnaire Short Form to evaluate the severity of their urinary incontinence. RESULTS: The replies to the International Consultation on Incontinence Questionnaire Short Form revealed a significant difference in urinary function between groups, with 24% of the subjects in group IV reporting urinary incontinence. The mean scores for the SF-36 questionnaire revealed that group II had the lowest quality of life. CONCLUSIONS: The control obese group (IV) reported a higher prevalence of urinary incontinence. There was no difference in the reported frequency of urine loss between the polycystic ovary syndrome and control groups with normal body mass index or between the polycystic ovary syndrome and control groups with body mass index ≥25.
Die perforierende Keratoplastik im Kindesalter – das ewige Dilemma

Zusammenfassung Hintergrund: Die perforierende Keratoplastik (PKP) bei Kindern weist im Vergleich zum Erwachsenen besondere Probleme auf. Die schwierige Untersuchbarkeit und Mitteilungsbereitschaft wirkt sich dabei potenzierend auf die ohnehin erhöhte Komplikationsrate (z. B. Fadenlockerung, -infiltrate, Transplantatreaktion) aus. Wie ein Damoklesschwert hängt über den Kindern vor dem 7. Lebensjahr die Gefahr der Amblyopie als potenziell irreversible visuslimitierende Beeinträchtigung. Patienten und Methoden: Die potenziellen Indikationen zur Keratoplastik bei Kindern lassen sich einteilen in (1) kongenitale Trübungen (z. B. Dysgenesien, kongenitale hereditäre Endotheldystrophie [CHED], und Buphthalmus), (2) erworbene traumatische Trübungen, (3) erworbene nicht traumatische Trübungen (z. B. infektiöse Narben, Keratokonus) und (4) Transplantateintrübungen. Wir berichten über unsere Erfahrungen an 126 Keratoplastiken, die zwischen 1980 und 2002 bei Kindern vor dem 16. Lebensjahr durchgeführt wurden, sowie kasuistisch über 5 Kinder, die in Homburg/Saar seit 2006 operiert wurden. Ergebnisse: Wir ziehen bei Kindern eine PTK, lamelläre Keratoplastik oder Autorotationskeratoplastik der PKP zur Verringerung des immunologischen Risikos und des allmählichen Endothelzellverlusts vor. Bei Sklerokornea halten wir aufgrund der Ophthalmopathologie eine PKP für kontraindiziert, bei Petersʼscher Anomalie ist alternativ eine optische Sektoriridektomie zu erwägen. Bei Buphthalmus muss vor einer PKP der intraokuläre Druck reguliert sein (z. B. vorher Trabekulotomie). Bei zentralen perforierenden Hornhaut- und Linsenverletzungen raten wir im amblyopiegefährdeten Alter nach primärer Wundversorgung zur simultanen Kunstlinsenimplantation mit der PKP, um eine rasche optische Rehabilitation zu erreichen. Ein eher kleinerer Transplantatdurchmesser und Einzelknüpfnähte werden bevorzugt, und eine frühe Fadenentfernung – besonders bei neuen Gefäßen – wird angestrebt. Die Indikation zur Narkoseuntersuchung stellen wir im Zweifel großzügig. Schlussfolgerungen: Die Korneatransplantation sollte bei Kindern so früh wie nötig (weniger Amblyopie! ), aber so spät wie möglich (bessere Kooperation! ) erfolgen. Für ein gutes morphologisches und funktionelles Ergebnis der PKP bei Kindern sind, neben der kritischen Indikationsstellung, die ausdrückliche Sensibilisierung der Eltern, die enge Zusammenarbeit mit den Narkoseärzten, und vor allem die exzellente Kooperation mit der Sehschule zur Amblyopieprophylaxe unverzichtbar.
An Escalating Dose Regimen of Pegylated Interferon and Ribavirin in HCV Cirrhotic Patients Referred for Liver Transplant

Background. To lessen the severity of recurrent hepatitis C virus (HCV) postliver transplantation (post-LT) by treating HCV patients with cirrhosis, we assessed the safety and efficacy of an escalating dose pegylated interferon (PEG-IFN)/ribavirin protocol in pre-LT patients. Methods. Ninety patients were treated with 90 &mgr;g PEG-IFN alpha-2a and 400 mg ribavirin and advanced to 180 &mgr;g and 800 to 1200 mg, respectively, over 8 weeks. Results. Mean age was 55.3 years. Thirty-four percent of patients received prior interferon treatment, 77% had genotype 1 or 4. Mean Child’s score was 6.7 and model for end-stage liver disease 11.2; 49% reached full-dose PEG-IFN and 85% ribavirin, 18% required dose reduction, 33% stopped treatment because of adverse effects, 9% had deterioration of liver function, and 7% died. Follow-up of 9.6 months showed sustained virological response in 13% of patients. The rate of serious complications was 16.3% in Child’s class A, 48% in B, and 100% in C (P=0.005). Serum albumin was a significant predictor for worsening liver function (P=0.007). Conclusions. Using an escalating dose regimen of PEG-IFN alpha-2a and ribavirin, we achieved only a 13% sustained virological response in HCV cirrhotic pre-LT patients with an accompanying 9% risk of worsening liver function and 7% risk of death.
Axial Dependence of Platelet‐Collagen Interactions in Flowing Blood: Upstream Thrombus Growth Impairs Downstream Platelet Adhesion

Vascular subendothelium and collagenous surfaces were exposed to flowing cltrated blood. Platelet interactions with these surfaces were Investigated at various axial distances from the upstream end of the exposed surfaces. A pronounced axial decrease In surface coverage with platelets and in thrombus dimensions was encountered on collagenous surfaces. This phenomenon was observed at shear rates of 200 to 2000 s-1 but was most pronounced at low shear rates (<650 s-1). After 5 minutes of perfusion at a shear rate of 650 s−1 4.6 × 104 platelets were deposited on the most upstream 20 mm2 of the collagen surface, In contrast to 2.2 × 10−6 platelets/ 20 mm2 14 mm farther downstream. Depletion of von Wlllebrand factor and/or thrombospondin from the boundary layer of the blood flow was not responsible for this. Collagen-bound von Wlllebrand factor enhanced the surface coverage with platelets without affecting the axial decrement, while pretreatment of the collagen surface with thrombospondin had no effect at all. However, partial Inhibition of thrombus growth by aspirin reduced the axial decrements, and less thrombogenlc surfaces as human and rabbit subendothelium, which induced only a few small thrombi, produced virtually no axial differences In platelet adhesion. Raising the shear rate to 2600 s-1 also gave no axial differences In platelet-collagen adhesion; It did, however, give an axial Increase In thrombus dimensions. This Increase was neutralized after the addition of antibody against human platelet thrombospondin to the blood. Our data are consistent with the view that platelet-surface Interactions are limited by the arrival of platelets to the surface at shear rates below 650 s-1. Surfaces that Induce rapid-growing upstream thrombi may deplete the boundary layer for platelets, resulting In decreased platelet adhesion and thrombus growth farther downstream. At higher shear rates, when the platelet supply to the surface Is not a limiting factor, thrombospondin released from upstream thrombi appears to enhance downstream thrombus growth and/or thrombus stability.
Geographical Variation in Ribotype Profiles of Escherichia coli Isolates from Humans, Swine, Poultry, Beef, and Dairy Cattle in Florida

ABSTRACT Waters impacted by fecal pollution can exact high risks to human health and can result in financial losses due to closures of water systems used for recreation and for harvesting seafood. Identifying the sources of fecal pollution in water is paramount in assessing the potential human health risks involved as well as in assessing necessary remedial action. Recently, various researchers have used the ribotyping method to identify sources of bacterial indicators (Escherichia coli and enterococci) in environmental waters. While these studies have identified genotypic differences between human- and animal-derived indicators that are capable of differentiating organisms isolated from humans and various animal hosts, most have focused on organisms collected from a confined geographic area and have not addressed the question of whether these ribotype profiles are watershed specific or if they can be applied universally to organisms from other geographic locations. In this study, E. coli isolates were obtained from humans, beef cattle, dairy cattle, swine, and poultry from locations in northern, central, and southern Florida and were subjected to ribotyping analysis. The intent was to determine (i) if ribotype profiles are capable of discriminating the source of E. coli at the host species level and (ii) if the resulting fingerprints are uniform over an extended geographic area or if they can be applied only to a specific watershed. Our research indicated that, using a single restriction enzyme (HindIII), the ribotyping procedure is not capable of differentiating E. coli isolates from the different animal species sampled in this study. Results indicate, however, that this procedure can still be used effectively to differentiate E. coli as being either human or animal derived when applied to organisms isolated from a large geographic region.
Dynamic connectivity modulates local activity in the core regions of the default-mode network

Significance When a person is at wakeful rest, not paying particular attention to the environment, his/her brain activity will not drift into random noise. Instead, it maintains robust dynamical structures to support ongoing cognition. Previous studies on the resting state have focused on either connectivity features across brain regions or local activity features within regions. Here, we show that the interactions between regions are dynamic and covary with local activity. This covariation provides insights into the neural underpinnings of ongoing cognition that is driven by the brain’s intrinsic network interactions. Segregation and integration are distinctive features of large-scale brain activity. Although neuroimaging studies have been unraveling their neural correlates, how integration takes place over segregated modules remains elusive. Central to this problem is the mechanism by which a brain region adjusts its activity according to the influence it receives from other regions. In this study, we explore how dynamic connectivity between two regions affects the neural activity within a participating region. Combining functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) in the same group of subjects, we analyzed resting-state data from the core of the default-mode network. We observed directed influence from the posterior cingulate cortex (PCC) to the anterior cingulate cortex (ACC) in the 10-Hz range. This time-varying influence was associated with the power alteration in the ACC: strong influence corresponded with a decrease of power around 13–16 Hz and an increase of power in the lower (1–7 Hz) and higher (30–55 Hz) ends of the spectrum. We also found that the amplitude of the 30- to 55-Hz activity was coupled to the phase of the 3- to 4-Hz activity in the ACC. These results characterized the local spectral changes associated with network interactions. The specific spectral information both highlights the functional roles of PCC–ACC connectivity in the resting state and provides insights into the dynamic relationship between local activity and coupling dynamics of a network.
Characteristics of Salmonella Contamination of Broilers and Slaughterhouses in the Region of Constantine (Algeria)

The present study provides the first data about the prevalence of Salmonella contamination of broilers and slaughterhouses in the region of Constantine, Algeria. The serotypes and anti‐microbial resistance phenotypes of the isolates were determined, and risk factors contributing to the contamination were evaluated. A total of 2490 samples, 1800 originating from 30 broiler farms and 690 from 15 slaughterhouses, were taken during two periods: March 2005–June 2006 and September 2006–March 2007. Salmonella contamination concerned 37% of the broiler farms and 53% of the slaughterhouses. Among the 55 isolates recovered, 10 different serotypes were identified. The most frequently recovered serotypes in both slaughterhouses and breeder farms were S. Hadar (36%, n = 20), S. Virchow (16%, n = 9), S. Infantis (10.9%, n = 6), S. Albany (11%, n = 6) and S. Carnac (7%, n = 4). Isolates belonging to S. Heidelberg (2%, n = 1) and S. Rissen (2%, n = 1) were found only in farms, while those belonging to S. Typhimurium (9%, n = 5), S. Enteritidis (4%, n = 2) and S. Montevideo (2%, n = 1) were recovered only from slaughterhouses. Thirty‐nine isolates (80%) were resistant to at least one anti‐microbial and 51% were multi‐resistant, i.e. resistant to two or more anti‐microbial molecules. About 58% (n = 32) were resistant to streptomycin, 36% (n = 20) to tetracyclines, 27% (n = 15) to nalidixic acid, 13% (n = 7) to ofloxacin and one isolate to enrofloxacin. Finally, seven distinct anti‐microbial resistance profiles were identified. In parallel, four risk factors were found to be significantly associated with Salmonella contamination. Together with the huge spread of Salmonella in the broiler production chain in Constantine, Algeria, these risk factors highlight the hazards of the broiler channels, particularly linked to poor technical and hygiene practices.
Current Evidence on Auricular Therapy for Chemotherapy-Induced Nausea and Vomiting in Cancer Patients: A Systematic Review of Randomized Controlled Trials

Auricular therapy (AT) has been historically viewed as a convenient approach adjunct to pharmacological therapy for cancer patients with chemotherapy-induced nausea and vomiting (CINV). The aim of this study was to assess the evidence of the therapeutic effect of AT for CINV management in cancer patients. Relevant randomized controlled trials were retrieved from 12 electronic databases without language restrictions. Meanwhile, manual search was conducted for Chinese journals on complementary medicine published within the last five years, and the reference lists of included studies were also checked to identify any possible eligible studies. Twenty-one studies with 1713 participants were included. The effect rate of AT for managing acute CINV ranged from 44.44% to 93.33% in the intervention groups and 15% to 91.67% in the control groups. For delayed CINV, it was 62.96% to 100% and 25% to 100%, respectively. AT seems to be a promising approach in managing CINV. However, the level of evidence was low and the definite effect cannot be concluded as there were significant methodological flaws identified in the analyzed studies. The implications drawn from the 21 studies put some clues for future practice in this area including the need to conduct more rigorously designed randomized controlled trials.
Fibroblast activating protein-α expression in squamous cell carcinoma of the esophagus in primary and irradiated tumors: the use of archival FFPE material for molecular techniques

There are numerous reports suggesting that fibroblast activating protein-α (FAP-α) plays an important role in invasion of various tumor types. We studied the expression pattern of FAP-α in esophageal squamous cell carcinoma (ESCC) patients who had not been treated primarily and those who had received neoadjuvant radiochemotherapy. Our goal was to establish whether readily available tissue specimens fixed in formalin and stored in paraffin blocks for years might still be a source of FAP-α RNA for PCR analysis. The study included 20 patients divided into two groups, 10 patients in each group. We evaluated the expression of FAP- α by PCR techniques in fresh frozen and in paraffin-embedded tissues, and compared it to the expression in non-cancer tissues. To detect the protein expression level of FAP-α in paraffin-embedded tissues we used chromogenic immunohistochemical (IHC) staining. Data were analyzed by t-test or the nonparametric Wilcoxon matched pair test using Statistica 12.5 software. We observed an increased level of the FAP-α gene and protein expression in cancer tissues when compared with their corresponding normal tissues. However, statistically significant differences were found only in the group of patients untreated before surgery. RNA extracted from paraffin-embedded tissue sections had very low quality, especially in the context of degradation. FAP-α remains a highly altered participant of a complex microenvironment in esophageal squamous cell carcinoma, and its role in cell signaling requires further study. In this paper, we conclude that the use of a regular RT-PCR method for diagnostic purposes, which we have presented in an earlier paper, can be as good as qRT-PCR. Also, immunohistochemistry proved to be very useful and the only reliable method that can be used on longterm stored formalin-fixed, paraffin-embedded tissues.
Financial Development, Growth, and Regional Disparity in Post-Reform China

Deepening financial development and rapid economic growth in China have been accompanied by widening income disparity between the coastal and inland regions. In this paper, by employing panel dataset for 29 Chinese provinces over the period of 1990-2001 and applying the generalized method of moment (GMM) techniques, we examine the impacts of financial development on China’s growth performance. Our empirical results show that financial development significantly promotes economic growth in coastal regions but not in the inland regions; the weak finance-growth nexus in inland provinces may aggravate China’s regional disparities.
roX RNAs Are Required for Increased Expression of X-Linked Genes in Drosophila melanogaster Males

The male-specific lethal (MSL) ribonucleoprotein complex is necessary for equalization of X:A expression levels in Drosophila males, which have a single X chromosome. It binds selectively to the male X chromosome and directs acetylation of histone H4 at lysine 16 (H4Ac16), a modification linked to elevated transcription. roX1 and roX2 noncoding RNAs are essential but redundant components of this complex. Simultaneous removal of both roX RNAs reduces X localization of the MSL proteins and permits their ectopic binding to autosomal sites and the chromocenter. However, the MSL proteins still colocalize, and low levels of H4Ac16 are detected at ectopic sites of MSL binding and residual sites on the X chromosome of roX1− roX2− males. Microarray analysis was performed to reveal the effect of roX1 and roX2 elimination on X-linked and autosomal gene expression. Expression of the X chromosome is decreased by 26% in roX1− roX2− male larvae. Enhanced expression could not be detected at autosomal sites of MSL binding in roX1− roX2− males. These results implicate failure to compensate X-linked genes, rather than inappropriate upregulation of autosomal genes at ectopic sites of MSL binding, as the primary cause of male lethality upon loss of roX RNAs.