Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of Internalizing Human Single-Chain Antibodies Targeting Brain Tumor Sphere Cells

Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain tumor for which there is no curative treatment to date. Resistance to conventional therapies and tumor recurrence pose major challenges to treatment and management of this disease, and therefore new therapeutic strategies need to be developed. Previous studies by other investigators have shown that a subpopulation of GBM cells can grow as neurosphere-like cells when cultured in restrictive medium and exhibits enhanced tumor-initiating ability and resistance to therapy. We report here the identification of internalizing human single-chain antibodies (scFv) targeting GBM tumor sphere cells. We selected a large naive phage antibody display library on the glycosylation-dependent CD133 epitope–positive subpopulation of GBM cells grown as tumor spheres and identified internalizing scFvs that target tumor sphere cells broadly, as well as scFvs that target the CD133-positive subpopulation. These scFvs were found to be efficiently internalized by GBM tumor sphere cells. One scFv GC4 inhibited self-renewal of GBM tumor sphere cells in vitro. We have further developed a full-length human IgG1 based on this scFv, and found that it potently inhibits proliferation of GBM tumor sphere cells and GBM cells grown in regular nonselective medium. Taken together, these results show that internalizing human scFvs targeting brain tumor sphere cells can be readily identified from a phage antibody display library, which could be useful for further development of novel therapies that target subpopulations of GBM cells to combat recurrence and resistance to treatment. Mol Cancer Ther; 9(7); 2131–41. ©2010 AACR.
The Relative Persuasiveness of Gain-Framed Loss-Framed Messages for Encouraging Disease Prevention Behaviors: A Meta-Analytic Review

A meta-analytic review of 93 studies (N = 21,656) finds that in disease prevention messages, gain-framed appeals, which emphasize the advantages of compliance with the communicator's recommendation, are statistically significantly more persuasive than loss-framed appeals, which emphasize the disadvantages of noncompliance. This difference is quite small (corresponding to r = .03), however, and appears attributable to a relatively large (and statistically significant) effect for messages advocating dental hygiene behaviors. Despite very good statistical power, the analysis finds no statistically significant differences in persuasiveness between gain- and loss-framed messages concerning other preventive actions such as safer-sex behaviors, skin cancer prevention behaviors, or diet and nutrition behaviors.
Delay in gastric emptying in patients with chronic renal failure

Background: Gastrointestinal (GI) symptoms are common in patients with chronic renal failure (CRF). Delayed gastric emptying might be a possible pathophysiological mechanism. The aims of this study were to evaluate gastric emptying in patients with CRF and to correlate the findings with GI symptoms and evaluate the impact of Helicobacter pylori infection in CRF patients on gastric emptying. Methods: Thirty‐nine patients with CRF (17 F, 22 M) were compared with 131 healthy subjects (74 F, 57 M). A standardized breakfast was given with 20 spherical, radiopaque markers (ROMs). The emptying was followed by fluoroscopy after 4, 5 and 6 h. Gastric emptying was assessed by calculating the individual mean percentual gastric retention of markers, 4 to 6 h after the meal. The perceived severity of GI symptoms was assessed with a validated questionnaire. Because of gender differences in gastric emptying, men and women were compared separately and a percentile of 95 was chosen as the upper reference value. H. pylori infection was assessed using a serological method. Results: Delayed gastric emptying was found in 14 out of 39 (36%) of the CRF patients. There was no relationship between delayed gastric emptying and age, GI symptoms, H. pylori infection or underlying renal disease. However, a higher proportion of patients in peritoneal dialysis demonstrated delayed gastric emptying compared with predialytic patients (6 of 9 versus 2 of 13, P = 0.026). Men with CRF had a higher gastric retention compared with healthy men (16.6 (0–63.3)% versus 0 (0–2.1)%, P < 0.0001), and 10 men with CRF had delayed gastric emptying (P < 0.0001). There was no significant difference in mean gastric retention between women with CRF and healthy women (13.3 (0–55.4)% versus 10.8 (0–30.0)%, P = 0.93), but 4 women with CRF had delayed gastric emptying (P = 0.02). Eighteen of the CRF patients had GI symptoms (6 F, 12 M) and 21 were asymptomatic (11 F, 10 M). There was no difference in mean gastric retention in patients with CRF with and without GI symptoms (M: 13.3 (0–55.0)% versus 47.5 (5.0–65.0)%, P = 0.51, F: 16.6 (0–63.3)% versus 13.3 (0–59.2)%, P = 0.96). Gastric emptying in CRF patients with and without H. pylori infection showed no difference. Conclusions: Delayed gastric emptying is common in patients with chronic renal failure, particularly in men. The delay was not associated with the presence of GI symptoms, underlying renal disease or H. pylori infection. However, the dialytic status might have an impact on gastric emptying in patients with CRF.
Structural Basis for the ABO Blood-Group Dependence of Plasmodium falciparum Rosetting

The ABO blood group influences susceptibility to severe Plasmodium falciparum malaria. Recent evidence indicates that the protective effect of group O operates by virtue of reduced rosetting of infected red blood cells (iRBCs) with uninfected RBCs. Rosetting is mediated by a subgroup of PfEMP1 adhesins, with RBC binding being assigned to the N-terminal DBL1α1 domain. Here, we identify the ABO blood group as the main receptor for VarO rosetting, with a marked preference for group A over group B, which in turn is preferred to group O RBCs. We show that recombinant NTS-DBL1α1 and NTS-DBL1α1-CIDR1γ reproduce the VarO-iRBC blood group preference and document direct binding to blood group trisaccharides by surface plasmon resonance. More detailed RBC subgroup analysis showed preferred binding to group A1, weaker binding to groups A2 and B, and least binding to groups Ax and O. The 2.8 Å resolution crystal structure of the PfEMP1-VarO Head region, NTS-DBL1α1-CIDR1γ, reveals extensive contacts between the DBL1α1 and CIDR1γ and shows that the NTS-DBL1α1 hinge region is essential for RBC binding. Computer docking of the blood group trisaccharides and subsequent site-directed mutagenesis localized the RBC-binding site to the face opposite to the heparin-binding site of NTS-DBLα1. RBC binding involves residues that are conserved between rosette-forming PfEMP1 adhesins, opening novel opportunities for intervention against severe malaria. By deciphering the structural basis of blood group preferences in rosetting, we provide a link between ABO blood grouppolymorphisms and rosette-forming adhesins, consistent with the selective role of falciparum malaria on human genetic makeup.
FELINES: a utility for extracting and examining EST-defined introns and exons.

FELINES (Finding and Examining Lots of Intron 'N' Exon Sequences) is a utility written to automate construction and analysis of high quality intron and exon sequence databases produced from EST (expressed sequence tag) to genomic sequence alignments. We demonstrated the various programs of the FELINES utility by creating intron and exon sequence databases for the fungal organism Schizosaccharomyces pombe from alignments of EST to genomic sequences. In addition, we analyzed our constructed S.pombe sequence databases and the well-established Saccharomyces cerevisiae intron database from Manuel Ares' Laboratory for conserved sequence motifs. FELINES was shown to be useful for characterizing branchsites, polypyrimidine tracts and 5' and 3' splice sites in the intron databases and exonic splicing enhancers (ESEs) in S.pombe exons. FELINES is available at http://www.genome. ou.edu/informatics.html.
Suvorexant

Objective: To review the efficacy, safety, and pharmacology data available for suvorexant and determine its role in therapy as compared with other agents available for the treatment of insomnia. Data Sources: A PubMed search using the terms suvorexant and MK-4305 (the original name given to suvorexant during early trials) was conducted in December 2014 to identify initial literature sources. No time frame was used for exclusion of older trials. Study Selection and Data Extraction: Animal studies and trials written in a language other than English were excluded. Abstracts of the remaining trials were evaluated for determination of relevance to this review. References from these studies along with suvorexant prescriber information were used to identify additional literature. Data Synthesis: Three randomized, double-blind, placebo-controlled clinical trials were identified showing suvorexant to be safe, effective, and tolerable for the treatment of insomnia. After 4 weeks of therapy, relative to placebo, the 10- and 20-mg doses improved subjective total sleep time (22.3 and 49.9 minutes, respectively), wake after sleep onset (−21.4 and −28.1 minutes), and latency to persistent sleep (−2.3 and −22.3 minutes). Conclusion: Suvorexant is the first dual orexin receptor antagonist approved for the treatment of insomnia. Clinical trials have shown that it is relatively safe and effective for the treatment of both sleep onset and sleep maintenance at doses of 20 mg or less. Higher doses were studied but not approved because of concerns for next-day somnolence and effects on driving. Further studies are needed to assess this medication in patients with a history of addiction, because they were excluded from clinical trials, as well as to compare suvorexant with other insomnia medications available because no head-to-head studies have yet been conducted. However, its novel mechanism of action and theoretically lower addiction liability make suvorexant an appealing new option.
Windows XP Kernel Crash Analysis

PC users have started viewing crashes as a fact of life rather than a problem. To improve operating system dependability, systems designers and programmers must analyze and understand failure data. In this paper, we analyze Windows XP kernel crash data collected from a population of volunteers who contribute to the Berkeley Open Infrastructure for Network Computing (BOINC) project. We found that OS crashes are predominantly caused by poorly-written device driver code. Users as well as product developers will benefit from understanding the crash behaviors elaborated in this paper.
Palpable lingual cysts, a possible indicator of porcine cysticercosis, in Teso District, Western Kenya

Methods: During a cross-sectional survey, 316 randomly selected small-scale farms were visited, from which a case-control study of 31 case farms and 93 randomly selected control farms was constructed. Information on potential risk factors for Taenia solium cysticercosis-taeniosis was obtained using questionnaires administered via personal interviews. Results: Farm prevalence of palpable lingual cysts was estimated at 9.8% (31 of 316) (95% confidence interval [CI], 6.5%-13.1%). Total number of pigs testing positive was 33, resulting in a pig prevalence of 6.5% (95% CI, 4%-9%). Pigs were kept as a source of income (98%) and for home consumption (2%). Sources of pigs included local purchases (94%; 117 of 124), and purchases from Uganda (6%; seven of 124). Most farmers (95%; 118 of 124) kept their pigs on free range. Pork was sourced from local butcheries (85%) and home slaughtering (15%). Most households slaughtering pigs at home had their pork “inspected” by household friends (five of nine). Absence of latrines was more common in case households (42%; 13 of 31) than in controls (18%; 17 of 93) (P = .01; OR = 3.2; 95% CI, 1.2%-8.55).
Effects of Low-Dose Diethylstilbestrol Exposure on DNA Methylation in Mouse Spermatocytes

Evidence from previous studies suggests that the male reproductive system can be disrupted by fetal or neonatal exposure to diethylstilbestrol (DES). However, the molecular basis for this effect remains unclear. To evaluate the effects of DES on mouse spermatocytes and to explore its potential mechanism of action, the levels of DNA methyltransferases (DNMTs) and DNA methylation induced by DES were detected. The results showed that low doses of DES inhibited cell proliferation and cell cycle progression and induced apoptosis in GC-2 cells, an immortalized mouse pachytene spermatocyte-derived cell line, which reproduces primary cells responses to E2. Furthermore, global DNA methylation levels were increased and the expression levels of DNMTs were altered in DES-treated GC-2 cells. A total of 141 differentially methylated DNA sites were detected by microarray analysis. Rxra, an important component of the retinoic acid signaling pathway, and mybph, a RhoA pathway-related protein, were found to be hypermethylated, and Prkcd, an apoptosis-related protein, was hypomethylated. These results showed that low-dose DES was toxic to spermatocytes and that DNMT expression and DNA methylation were altered in DES-exposed cells. Taken together, these data demonstrate that DNA methylation likely plays an important role in mediating DES-induced spermatocyte toxicity in vitro.
Phase I Expansion and Pharmacodynamic Study of the Oral MEK Inhibitor RO4987655 (CH4987655) in Selected Patients with Advanced Cancer with RAS–RAF Mutations

Purpose: This phase I expansion study assessed safety, pharmacodynamic effects, and antitumor activity of RO4987655, a pure MEK inhibitor, in selected patients with advanced solid tumor. Experimental Design: We undertook a multicenter phase I two-part study (dose escalation and cohort expansion). Here, we present the part 2 expansion that included melanoma, non–small cell lung cancer (NSCLC), and colorectal cancer with oral RO4987655 administered continuously at recommended doses of 8.5 mg twice daily until progressive disease (PD). Sequential tumor sampling investigated multiple markers of pathway activation/tumor effects, including ERK phosphorylation and Ki-67 expression. BRAF and KRAS testing were implemented as selection criteria and broader tumor mutational analysis added. Results: Ninety-five patients received RO4987655, including 18 BRAF-mutant melanoma, 23 BRAF wild-type melanoma, 24 KRAS-mutant NSCLC, and 30 KRAS-mutant colorectal cancer. Most frequent adverse events were rash, acneiform dermatitis, and gastrointestinal disorders, mostly grade 1/2. Four (24%) of 17 BRAF-mutated melanoma had partial response as did four (20%) of 20 BRAF wild-type melanoma and two (11%) of 18 KRAS-mutant NSCLC. All KRAS-mutant colorectal cancer developed PD. Paired tumor biopsies demonstrated reduced ERK phosphorylation among all cohorts but significant differences among cohorts in Ki-67 modulation. Sixty-nine percent showed a decrease in fluorodeoxyglucose uptake between baseline and day 15. Detailed mutational profiling confirmed RAS/RAF screening and identified additional aberrations (NRAS/non-BRAF melanomas; PIK3CA/KRAS colorectal cancer) without therapeutic implications. Conclusions: Safety profile of RO4987655 was comparable with other MEK inhibitors. Single-agent activity was observed in all entities except colorectal cancer. Evidence of target modulation and early biologic activity was shown among all indications independent of mutational status. Clin Cancer Res; 20(16); 4251–61. ©2014 AACR.
Steady-state Function of the Ubiquitous Mammalian Na/H Exchanger (NHE1) in Relation to Dimer Coupling Models with 2Na/2H Stoichiometry

We describe the steady-state function of the ubiquitous mammalian Na/H exchanger (NHE)1 isoform in voltage-clamped Chinese hamster ovary cells, as well as other cells, using oscillating pH-sensitive microelectrodes to quantify proton fluxes via extracellular pH gradients. Giant excised patches could not be used as gigaseal formation disrupts NHE activity within the patch. We first analyzed forward transport at an extracellular pH of 8.2 with no cytoplasmic Na (i.e., nearly zero-trans). The extracellular Na concentration dependence is sigmoidal at a cytoplasmic pH of 6.8 with a Hill coefficient of 1.8. In contrast, at a cytoplasmic pH of 6.0, the Hill coefficient is <1, and Na dependence often appears biphasic. Results are similar for mouse skin fibroblasts and for an opossum kidney cell line that expresses the NHE3 isoform, whereas NHE1−/− skin fibroblasts generate no proton fluxes in equivalent experiments. As proton flux is decreased by increasing cytoplasmic pH, the half-maximal concentration (K1/2) of extracellular Na decreases less than expected for simple consecutive ion exchange models. The K1/2 for cytoplasmic protons decreases with increasing extracellular Na, opposite to predictions of consecutive exchange models. For reverse transport, which is robust at a cytoplasmic pH of 7.6, the K1/2 for extracellular protons decreases only a factor of 0.4 when maximal activity is decreased fivefold by reducing cytoplasmic Na. With 140 mM of extracellular Na and no cytoplasmic Na, the K1/2 for cytoplasmic protons is 50 nM (pH 7.3; Hill coefficient, 1.5), and activity decreases only 25% with extracellular acidification from 8.5 to 7.2. Most data can be reconstructed with two very different coupled dimer models. In one model, monomers operate independently at low cytoplasmic pH but couple to translocate two ions in “parallel” at alkaline pH. In the second “serial” model, each monomer transports two ions, and translocation by one monomer allosterically promotes translocation by the paired monomer in opposite direction. We conclude that a large fraction of mammalian Na/H activity may occur with a 2Na/2H stoichiometry.
Bullying among nursing staff: Relationship with psychological/behavioral responses of nurses and medical errors

Aim: The aim of this article is to examine the relationship between three types of bullying (person-related, work-related, and physically intimidating) with two types of outcomes (psychological/behavioral responses of nurses and medical errors). In addition, it investigates if the three types of bullying behaviors vary with age or gender of nurses and if the extent of bullying varies across different facilities in an institution. Background: Nurses play an integral role in achieving safe and effective health care. To ensure nurses are functioning at their optimal level, health care organizations need to reduce negative components that impact nurses’ job performance and their mental and physical health. Mitigating bullying from the workplace may be necessary to create and maintain a high-performing, caring, and safe hospital culture. Methods: Using an internal e-mail system, an e-mail requesting the participants to complete the questionnaire on Survey Monkey was sent to a sample of 1,078 nurses employed across three facilities at a university hospital system in the Midwest. Two hundred forty-one completed questionnaires were received with a response rate of 23%. Bullying was measured utilizing the Negative Acts Questionnaire-Revised (NAQ-R). Outcomes (psychological/behavioral responses of nurses and medical errors) were measured using Rosenstein and O’Daniel’s (2008) modified scales. Results: Person-related bullying showed significant positive relationships with psychological/behavioral responses and medical errors. Work-related bullying showed a significant positive relationship with psychological/behavioral responses, but not with medical errors. Physically intimidating bullying did not show a significant relationship to either outcome. Whereas person-related bullying was found to be negatively associated with age of nurses, physically intimidating bullying was positively associated with age. Male nurses experienced higher work-related bullying than female nurses. Conclusion: Findings from this study suggest that bullying behaviors exist and affect psychological/behavioral responses of nurses such as stress and anxiety and medical errors. Health care organizations should identify bullying behaviors and implement bullying prevention strategies to reduce those behaviors and the adverse effects that they may have on psychological/behavioral responses of nurses and medical errors.
Peritoneal Dialysis in the USA

416 Peritoneal Dialysis (PD) has had a difficult decade in the United States. The country with the largest number of dialysis patients, and arguably the greatest influence on dialysis practice, has seen a significant decline in PD utilization. In 1995, 14% of prevalent dialysis patients in the US were on PD, but now the number is closer to 8% (1,2). The proposed explanations underlying this trend have included changes in the patient population, with increased aging and comorbidity, proliferation of hemodialysis (HD) units, consolidation in the dialysis provider industry, hidden economic incentives for providers and physicians to do HD, inadequate training of nephrology fellows in PD, suboptimal predialysis education for patients, and unduly onerous clearance guidelines. In this edition of Peritoneal Dialysis International (PDI), we focus on PD in the US and on many of these issues. In an Original Article, Troidle et al. review barriers to PD utilization in their network in New England. They use data from a survey of medical directors to show that perceived patient factors are a central issue in low PD utilization. What is striking here is that misconceptions appear to underlie patient and physician concerns about doing PD. In an associated Commentary reviewing the decline in PD use, Mehrotra focuses on inadequate training of nephrologists and insufficient numbers of predialysis clinics. He makes an eloquent plea to bring PD into the “mainstream” of US academic nephrology. Pulliam et al. review the data on consolidation of large chain dialysis providers in the US. They argue strongly that this has not been a key factor in the decline of PD and that large chains are no more responsible for the falloff in utilization than other providers. Other possible contributors to the falloff in PD utilization, including economic factors, have been reviewed in recent editions of PDI and other journals (3–7). Others may argue that the falloff in PD in the US has been driven by concerns about patient outcomes on the EDITOR’S INTRODUCTION
Transition to Entrepreneurship from the Public Sector: Predispositional and Contextual Effects

Studies of career dynamics implicitly claim that government employees are not entrepreneurial. Utilizing longitudinal data from the U.S. Panel Study for Income Dynamics, we investigate the reasons for the low rate of entrepreneurship from the public sector. We conjecture that it is due to labor market matching processes and the bureaucratic nature of public organizations and bureaucratization of individuals. Our life-course analysis identifies labor market matching as a major determinant: nonentrepreneurial types choose public sector employment. We also uncover tenure and context effects, which decrease and increase the hazard rate of entrepreneurial exit, respectively. Whereas the former effect points toward adaptation and internal labor market sorting, the latter draws attention to exits due to frustration.