Miracle-dz/UniFAR-FTUs huggingface dataset:
EGFR mutation correlates with uninflamed phenotype and weak immunogenicity, causing impaired response to PD-1 blockade in non-small cell lung cancer

ABSTRACT Patients with EGFR mutations showed unfavorable response to programmed cell death-1 (PD-1) blockade immunotherapy in non-small cell lung cancer (NSCLC). Yet the underlying association between EGFR mutation and immune resistance remains largely unclear. We performed an integrated analysis of PD-ligand 1(PD-L1)/CD8 expression and mutation profile based on the repository database and resected early-stage NSCLC in Guangdong Lung Cancer Institute (GLCI). Meanwhile, 2 pool-analyses were set to clarify the correlation between EGFR mutation and PD-L1 expression, and the association of EGFR status with response to anti-PD-1/L1 therapy. Pool-analysis of 15 public studies suggested that patients with EGFR mutations had decreased PD-L1 expression (odds ratio: 1.79, 95% CI: 1.10–2.93; P = 0.02). Analysis of The Cancer Genome Atlas (TCGA) and the GCLI cohort confirmed the inverse correlation between EGFR mutation and PD-L1 expression. Furthermore, patients with EGFR mutation showed a lack of T-cell infiltration and shrinking proportion of PD-L1+/CD8+ TIL (P = 0.034). Importantly, patients with EGFR mutations, especially the sensitive subtype, showed a significantly decreased mutation burden, based on analysis of the discovery and validation sets. Finally, a pool-analysis of 4 randomized control trials confirmed that patients with EGFR mutation did not benefit from PD-1/L1 inhibitors (Hazard ratio [HR] = 1.09, P = 0.51) while patients with EGFR wild-type did (HR = 0.73, P < 0.00001). This study provided evidence of a correlation between EGFR mutations and an uninflamed tumor microenvironment with immunological tolerance and weak immunogenicity, which caused an inferior response to PD-1 blockade in NSCLCs.
Chimerism of the transplanted heart.

BACKGROUND Cases in which a male patient receives a heart from a female donor provide an unusual opportunity to test whether primitive cells translocate from the recipient to the graft and whether cells with the phenotypic characteristics of those of the recipient ultimately reside in the donor heart. The Y chromosome can be used to detect migrated undifferentiated cells expressing stem-cell antigens and to discriminate between primitive cells derived from the recipient and those derived from the donor. METHODS We examined samples from the atria of the recipient and the atria and ventricles of the graft by fluorescence in situ hybridization to determine whether Y chromosomes were present in eight hearts from female donors implanted into male patients. Primitive cells bearing Y chromosomes that expressed c-kit, MDR1, and Sca-1 were also investigated. RESULTS Myocytes, coronary arterioles, and capillaries that had a Y chromosome made up 7 to 10 percent of those in the donor hearts and were highly proliferative. As compared with the ventricles of control hearts, the ventricles of the transplanted hearts had markedly increased numbers of cells that were positive for c-kit, MDR1, or Sca-1. The number of primitive cells was higher in the atria of the hosts and the atria of the donor hearts than in the ventricles of the donor hearts, and 12 to 16 percent of these cells contained a Y chromosome. Undifferentiated cells were negative for markers of bone marrow origin. Progenitor cells expressing MEF2, GATA-4, and nestin (which identify the cells as myocytes) and Flk1 (which identifies the cells as endothelial cells) were identified. CONCLUSIONS Our results show a high level of cardiac chimerism caused by the migration of primitive cells from the recipient to the grafted heart. Putative stem cells and progenitor cells were identified in control myocardium and in increased numbers in transplanted hearts.
Quality of analgesia after lower third molar surgery: A randomised, double-blind study of levobupivacaine, bupivacaine and lidocaine with epinephrine.

BACKGROUND/AIM Surgical extraction of lower third molars is followed by mild or severe postoperative pain which peaks at maximal intensity in the first 12 hours and has a significant impact on a patient's postoperative quality of life. The use of long-acting local anaesthetics is a promising strategy to improve postoperative analgesia. The aim of the present study was to investigate analgesic parameters and patient satisfaction after using 0.5% levobupivacaine (Lbup), 0.5% bupivacaine (Bup) and 2% lidocaine with epinephrine 1:80,000 (Lid + Epi) for an inferior alveolar nerve block following lower third molar surgery. METHODS A total of 102 patients (ASA I) were divided into three groups, each of which received either 3 mL of Lbup, Bup or Lid + Epi. The intensity of postoperative analgesia was measured using a verbal rating scale (VRS). The total amounts of rescue analgesics were recorded on the first and during seven postoperative days. Patients satisfaction was noted using a modified verbal scales. RESULTS A significantly higher level of postoperative pain was recorded in Lid + Epi group compared to Bup and Lbup groups. No significant differences were seen between Bup and Lbup, but a significant reduction in the need for rescue analgesics was seen postoperatively in both Lbup and Bup (50%) in comparison with Lid + Epi (80%) in the first 24 hours. The same significant trend in rescue analgesic consumption was recorded for seven postoperative days. Patients' overall satisfaction was significantly lower for Lid + Epi (10%) than for Lbup (56%) and Bup (52%). CONCLUSION The use of a new and long-acting local anaesthetic 0.5% levobupivacaine is clinically relevant and effective for an inferior alveolar nerve block and postoperative pain control after third molar surgery. In our study Lbup and Bup controled postoperative pain more efficiently after lower third molar surgery compared to Lid + Epi.
The Role of Motivation and Leadership in Public Employees’ Job Preferences: Evidence from Two Discrete Choice Experiments

ABSTRACT Two discreet choice experiments investigated how three styles of leadership (i.e., transformational, transactional, and ethical) and three job features aimed at activating different motivational forces (i.e., public service motivation, external regulation, and intrinsic motivation) simultaneously and independently affected the job preferences of a sample of public employees. Subjects displayed a strong preference for jobs that benefit more citizens, that are more interesting, and that require working under ethical leaders rather than unethical ones. Whereas the prospect of a 5% salary increase strengthened participants’ preferences for a given position, offering a 1% salary raise did not significantly change subjects’ job choices. Furthermore, participants did not appear to have any preference for working under a transformational leader rather than a transactional leader.
The Effect of a Short Practical Warm-up Protocol on Repeated Sprint Performance

Abstract Taylor, JM, Weston, M, and Portas, MD. The effect of a short practical warm-up protocol on repeated sprint performance. J Strength Cond Res 27(7): 2034–2038, 2013—The aim of our study was to investigate the effect of a short, practical, 2-phase warm-up on repeated sprint performance when compared with more traditional warm-up protocols that contain stretching activities. Eleven subelite male soccer players completed a warm-up protocol that commenced with 5 minutes jogging at approximately 65% of maximal heart rate, followed by no stretching, static stretching, or dynamic stretching and finishing with a task-specific high-intensity activity. Using a crossover design, the 3 warm-up protocols were performed in a counterbalanced order with at least 48 hours between sessions. Repeated sprint performance was measured using a repeated sprint test that consisted of 6 × 40-m maximal sprints interspersed with a 20-second recovery. There were trivial differences in mean sprint time (0.2%) and posttest blood lactate (3.1%) between the 2-phase warm-up and the 3-phase warm-up that included dynamic stretching, whereas the short warm-up had a possibly detrimental effect on fastest sprint time (0.7%). Fastest (−1.1%) and mean (−1.2%) sprint times were quicker and posttest blood lactates were higher (13.2%) after the 2-phase warm-up when compared with the 3-phase warm-up that included static stretching. Although it is not harmful to complete a traditional 3-phase warm-up that includes dynamic stretching, it appears practical for athletes preparing for activities dependent on repeated sprint ability to complete a 2-phase warm-up consisting of a cardiovascular and specific high-intensity activity.
ABCA transporter gene expression and poor outcome in epithelial ovarian cancer.

BACKGROUND ATP-binding cassette (ABC) transporters play various roles in cancer biology and drug resistance, but their association with outcomes in serous epithelial ovarian cancer (EOC) is unknown. METHODS The relationship between clinical outcomes and ABC transporter gene expression in two independent cohorts of high-grade serous EOC tumors was assessed with real-time quantitative polymerase chain reaction, analysis of expression microarray data, and immunohistochemistry. Associations between clinical outcomes and ABCA transporter gene single nucleotide polymorphisms were tested in a genome-wide association study. Impact of short interfering RNA-mediated gene suppression was determined by colony forming and migration assays. Association with survival was assessed with Kaplan-Meier analysis and log-rank tests. All statistical tests were two-sided. RESULTS Associations with outcome were observed with ABC transporters of the "A" subfamily, but not with multidrug transporters. High-level expression of ABCA1, ABCA6, ABCA8, and ABCA9 in primary tumors was statistically significantly associated with reduced survival in serous ovarian cancer patients. Low levels of ABCA5 and the C-allele of rs536009 were associated with shorter overall survival (hazard ratio for death = 1.50; 95% confidence interval [CI] =1.26 to 1.79; P = 6.5e-6). The combined expression pattern of ABCA1, ABCA5, and either ABCA8 or ABCA9 was associated with particularly poor outcome (mean overall survival in group with adverse ABCA1, ABCA5 and ABCA9 gene expression = 33.2 months, 95% CI = 26.4 to 40.1; vs 55.3 months in the group with favorable ABCA gene expression, 95% CI = 49.8 to 60.8; P = .001), independently of tumor stage or surgical debulking status. Suppression of cholesterol transporter ABCA1 inhibited ovarian cancer cell growth and migration in vitro, and statin treatment reduced ovarian cancer cell migration. CONCLUSIONS Expression of ABCA transporters was associated with poor outcome in serous ovarian cancer, implicating lipid trafficking as a potentially important process in EOC.
Psychological characteristics of patients with myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM1) is the most common adult‐onset muscular dystrophy. It is associated with motor symptoms but patients also display non‐motor symptoms such as particular personality traits. Studies have reported mixed results about personality characteristics which may be attributable to small sample sizes, different disease severity of groups studied, and use of different questionnaires or method. This study aimed to describe the psychological characteristics of a large cohort of patients with DM1, to characterize those at risk of developing a psychiatric disorder, and to compare characteristics between two DM1 phenotypes, a mild and more severe adult‐onset phenotype.
Frames and Grids in Unconstrained and Linearly Constrained Optimization: A Nonsmooth Approach

This paper describes a class of frame-based direct search methods for unconstrained and linearly constrained optimization. A template is described and analyzed using Clarke's\break nonsmooth calculus. This provides a unified and simple approach to earlier results for grid- and frame-based methods, and also provides partial convergence results when the objective function is not smooth, undefined in some places, or both. The template also covers many new methods which combine elements of previous ideas using frames and grids. These new methods include grid-based simple descent algorithms which allow moving to points off the grid at every iteration and can automatically control the grid size, provided function values are available. The concept of a grid is also generalized to that of an admissible set, which allows sets, for example, with circular symmetries. The method is applied to linearly constrained problems using a simple barrier approach.
The endangered Iris atropurpurea (Iridaceae) in Israel: honey-bees, night-sheltering male bees and female solitary bees as pollinators.

BACKGROUND AND AIMS The coastal plain of Israel hosts the last few remaining populations of the endemic Iris atropurpurea (Iridaceae), a Red List species of high conservation priority. The flowers offer no nectar reward. Here the role of night-sheltering male solitary bees, honey-bees and female solitary bees as pollinators of I. atropurpurea is documented. METHODS Breeding system, floral longevity, stigma receptivity, visitation rates, pollen loads, pollen deposition and removal and fruit- and seed-set were investigated. KEY RESULTS The main wild pollinators of this plant are male eucerine bees, and to a lesser extent, but with the potential to transfer pollen, female solitary bees. Honey-bees were found to be frequent diurnal visitors; they removed large quantities of pollen and were as effective as male sheltering bees at pollinating this species. The low density of pollen carried by male solitary bees was attributed to grooming activities, pollen displacement when bees aggregated together in flowers and pollen depletion by honey-bees. In the population free of honey-bee hives, male bees carried significantly more pollen grains on their bodies. Results from pollen analysis and pollen deposited on stigmas suggest that inadequate pollination may be an important factor limiting fruit-set. In the presence of honey-bees, eucerine bees were low removal-low deposition pollinators, whereas honey-bees were high removal-low deposition pollinators, because they removed large amounts into corbiculae and deposited relatively little onto receptive stigmas. CONCLUSIONS Even though overall, both bee taxa were equally effective pollinators, we suggest that honey-bees have the potential to reduce the amount of pollen available for plant reproduction, and to reduce the amount of resources available to solitary bee communities. The results of this study have potential implications for the conservation of this highly endangered plant species if hives are permitted inside reserves, where the bulk of Oncocyclus iris species are protected.
Genre-Based Writing Classrooms and Learner Beliefs in East Asian EAP Contexts

Abstract:This empirical study examines how English for Academic Purposes (EAP) university classes in Japan and South Korea approach second language (L2), genre-based writing studies and how students (n=71) perceive their studies in light of recent trends in genre theory pedagogy and methodology. A questionnaire and semi-structured interviews were used to collect data on learner perceptions, while interviews with instructors (n=2) and a review of their teaching materials revealed classroom teaching practices. The results demonstrate that current genre-based teaching methods in Japan and South Korea are not entirely congruent with (a) learners' perceptions of teaching practices that can facilitate academic writing development, (b) genre-based pedagogies in other learning contexts, and (c) what the literature suggests are principles of best practice. The participants call for a more integrated, form- and functionbased approach to genre-based studies. This study argues for more integrated genre pedagogies in Japan and South Korea and provides EAP instructors concerned with best practice a foundation for change regarding genre-based teaching methods. This research also contributes to a better understanding of L2 writing studies in East Asian contexts and advances understandings of learner metacognition as a tool for informing localized L2 writing pedagogies.
Vascular endothelial growth factor system in the cow oviduct: A possible involvement in the regulation of oviductal motility and embryo transport

Vascular endothelial growth factor (VEGF) is a potent angiogenic and permeability enhancing factor, which shows the highest activity in the oviduct during the periovulatory period of the estrous cycle in cattle. It has also been shown that the contraction activity of oviduct is highest during the periovulatory period. The present study therefore focused on the possible involvement of VEGF in the regulation of biosynthesis and secretion of contraction‐relaxation‐related substances in the cow oviduct. Possible autonomous VEGF system in the oviduct as well as its endocrine control was also studied. Bovine oviductal epithelial cells (BOEC) in the second passage were cultured with VEGF (1 ng/ml) alone or with luteinizing hormone (LH; 10 ng/ml), estradiol 17‐β (E2; 1 ng/ml), and/or progesterone (P4; 1 ng/ml). The levels of prostaglandins (PGs), endothelin‐1 (ET‐1), and angiotensin II (Ang II) in the medium were measured using second antibody enzymeimmunoassay (EIA). The mRNA expressions for cycloxygenase‐2 (Cox‐2), prostaglandin F synthase (PGFS), prostaglandin E synthase (PGES), prepro‐ET‐1, endothelin converting enzyme‐1 (Ece‐1), angiotensin converting enzyme‐1 (Ace‐1), VEGF and its receptors were investigated using real‐time RT‐PCR. The results indicate that, (1) VEGF dose‐dependently stimulated the release of prostaglandin E2 (PGE2), prostaglandin F2α (PGF2α), and ET‐1, but not Ang II. VEGF and VEGF with LH, E2, and P4 upregulated mRNA expression for biosynthesis cascade of PG, ET‐1 as well as their release. However, only the combination of VEGF with LH, E2, and P4 upregulated mRNA for Ace‐1 and Ang II release, but not VEGF alone. (2) Treatments of LH, with E2 and/or P4 increased the mRNA expression for VEGF, Flk‐1 and Flt‐1, and (3) VEGF itself downregulated the expression of mRNA for VEGF, and LH, E2, and P4 enhanced this downregulatory effect. The results of the present study provide the first evidence that (1) VEGF directly stimulates the biosynthesis and release of PGE2, PGF2α, and ET‐1 in the bovine oviduct, (2) LH stimulates the oviductal VEGF system, and (3) VEGF downregulates the oviductal VEGF system and this downregulation was further intensified in the presence of LH. The data suggest that the preovulatory LH‐surge, together with increasing E2 secretion from the Graffian follicle and basal P4 levels from the regressing corpus luteum (CL), upregulates the oviductal VEGF system, inducing the maximum oviductal production of contraction–relaxation‐related substances for active oviduct contraction and rapid transport of gametes to the fertilization site. However, the oviductal VEGF elevation caused by the LH‐surge, appears to downregulate the oviductal VEGF system immediately after ovulation thereby may contribute to suppress oviductal contraction to secure slow transport of the embryo to the uterus at the optimal time. Mol. Reprod. Dev. © 2005 Wiley‐Liss, Inc.
Alteration of the insulin‐like growth factor axis during in vitro differentiation of the human osteosarcoma cell line HOS 58

The insulin‐like growth factors I and II (IGF‐I, IGF‐II), their receptors, and high affinity binding proteins (IGFBPs) represent a family of cellular modulators that play essential roles in the development and differentiation of cells and tissues including the skeleton. Recently, the human osteosarcoma cell line HOS 58 cells were used as an in vitro model of osteoblast differentiation characterized by (i) a rapid proliferation rate in low‐density cells that decreased continuously with time of culture and (ii) an increasing secretion of matrix proteins during their in vitro differentiation. In the present paper, HOS 58 cells with low cell density at early time points of the in vitro differentiation (i) displayed a low expression of IGF‐I and ‐II; (ii) synthesized low levels of IGFBP‐2, ‐3, ‐4, and ‐5, but (iii) showed high expression levels of both the type I and II IGF receptors. During the in vitro differentiation of HOS 58 cells, IGF‐I and ‐II expressions increased continuously in parallel with an upregulation of IGFBP‐2, ‐3, ‐4, and ‐5 whereas the IGF‐I receptor and IGF‐II/M6P receptor mRNA were downregulated. In conclusion, the high proliferative activity in low cell density HOS 58 cells was associated with high mRNA levels of the IGF‐IR, but low concentrations of IGFBP‐2. The rate of proliferation of HOS 58 cells continuously decreased during cultivation in parallel with a decline in IGF‐IR expression, but increase of mitoinhibitory IGFBP‐2. These data are indicative for a role of the IGF axis during the in vitro differentiation of HOS 58 cells. J. Cell. Biochem. 102: 28–40, 2007. © 2007 Wiley‐Liss, Inc.
Mutation analysis of NR0B2 among 1545 Danish men identifies a novel c.278G>A (p.G93D) variant with reduced functional activity

Variations of the small heterodimer partner (SHP, NR0B2) gene, an atypical nuclear receptor that inhibits transactivation by hepatocyte nuclear factor (HNF)‐4α, are associated with obesity among Japanese. The purpose of the study was to evaluate the prevalence of SHP variants among obese Danish men. Using combined SSCP and heteroduplex analysis, we analyzed the entire coding region of SHP for variants in a cohort of 750 Danish men with early‐onset obesity and genotyped a cohort of 795 nonobese control subjects using PCR‐RFLP. Functional analyses of the identified coding region variants were performed in both MIN6‐m9 and HepG2 cell lines. A total of five novel variants, including three missense variants (c.100C>G [p.R34G], c.278G>A [p.G93D], and c.415C>A [p.P139H]) and two silent variants (c.65C>T [p.Y22Y] and c.339G>A [p.P113P]) were identified. Moreover, the previously reported c.512G>C [p.G171A] polymorphism was identified. The 171A allele was not associated with obesity (p = 0.07). The 34G, 93D, and 139H‐alleles were rare variants, which were found only among obese subjects. Among the four coding region variants, the 93D‐allele showed a reduced in vitro inhibition of the HNF‐4α transactivation of the HNF‐1α promoter expression when expressed in MIN6‐m9 and HepG2 cell lines (p<0.01). In contrast to reported findings among obese Japanese, functional variants are rare among Danish men. A functional 93D variant of SHP was identified in 1 out of 750 obese and in none of 795 nonobese control subjects. Further large‐scale population studies are necessary to assess the clinical impact of this rare variant on obesity risk among European subjects. Hum Mutat 24:381–387, 2004. © 2004 Wiley‐Liss, Inc.