Miracle-dz/UniFAR-FTUs huggingface dataset:
A Phase I, Dose-Finding Study in Patients with Advanced Solid Malignancies of the Oral γ-Secretase Inhibitor PF-03084014

Purpose: To estimate the maximum tolerated dose (MTD) for continuous oral administration of the γ-secretase inhibitor PF-03084014, determine the recommended phase II dose (RP2D), and evaluate safety and preliminary activity in patients with advanced solid tumors. Experimental Design: This open-label, phase I study consisted of a dose-finding portion based on a 3+3 design, followed by an expansion cohort. PF-03084014 was administered orally, twice daily (BID) for 21 continuous days. Tested doses ranged from 20 to 330 mg BID. In the expansion cohort, patients were to receive the estimated MTD or a lower dose of PF-03084014. Results: A total of 64 patients received treatment. The MTD was estimated to be 220 mg BID. The RP2D was determined to be 150 mg BID, based on the better safety profile versus the 220-mg BID dose, given comparable NOTCH-related target inhibition. The most common treatment-related adverse events were diarrhea, nausea, fatigue, hypophosphatemia, vomiting, rash, and decreased appetite, which were generally mild to moderate in severity. One patient with advanced thyroid cancer had a complete response, and five of seven response-evaluable patients with desmoid tumor achieved a partial response (71.4% objective response rate). Tumor responses were mostly durable, ranging from 1.74+ to 24+ months. PF-03084014 demonstrated a generally dose-dependent pharmacokinetic profile at doses ranging from 20 to 330 mg BID. Consistent downmodulation of NOTCH-related HES4 gene expression was observed in peripheral blood from all evaluable patients. Conclusion: Further development of PF-03084014 for the treatment of patients with advanced solid tumors is warranted and currently under evaluation. Clin Cancer Res; 21(1); 60–67. ©2014 AACR. See related commentary by Hughes et al., p. 7
Intergroup Dialogue Courses on Sexual Orientation: Lesbian, Gay and Bisexual Student Experiences and Outcomes

Intergroup dialogue is a method of social justice education. Most intergroup dialogue research explores race and gender identities. Sexual orientation dialogues are uncommon and not yet examined empirically. This qualitative study explores sexual orientation dialogue courses from the perspective of lesbian, gay, and bisexual (LGB) student participants. Understanding target, or marginalized, group perspective of planned intergroup experiences is important given concerns raised in the literature. We document student motivations for participating in dialogues, core outcomes, and main challenges that arose in dialogue. Core outcomes include learning about and accepting one's sexual identity and empowerment. Challenges include those stemming from invisibility of sexual orientation identity. Recommendations are made for intergroup dialogue practice and research.
Small cell carcinoma of the bladder: a search of the current literature.

PURPOSE Small cell carcinoma of the urinary bladder (SCC-BL) is an extremely rare malignancy, accounting for < 1% of all bladder tumors. Its prognosis is very poor because of its highly aggressive behavior and high metastatic potential. This study aimed to update the management and outcome of SCC-BL by searching the relevant international literature. METHODS Relevant studies were identified by searching MEDLINE and the Cochrane Central Register of Controlled Trials using a combination of terms such as small cell carcinoma, bladder cancer, therapeutic approach, radical cystectomy, radiation therapy and chemotherapy. Additional papers were identified from reviewing references of relevant articles. RESULTS Previously published series have shown that SCC-BL has a significant male predominance, occurs mainly during the 7th and 8th decade of life and macroscopic hematuria is the most common presenting symptom. According to the most important studies, cystectomy alone seems not to be efficient enough for the management of the disease. On the other hand, radiation therapy when combined with chemotherapy is highly effective with increased survival rates. CONCLUSION Poor prognosis and rarity render disease management complicated. A definitive treatment is not yet established but combined therapy with systemic platinum-based chemotherapy and adjuvant local radiotherapy seems to be the most effective therapeutic approach for limited-stage SCC-BL. Further research is required in order to clarify whether prophylactic cranial irradiation (PCI) should be performed on a regular basis.
Computing Teachers' Perspectives on Threshold Concepts: Functions and Procedural Abstraction

With the introduction of the new computing curriculum in England, teachers are facing many challenges, among them the teaching of computer programming. Literature suggests that the conceptual understanding of this subject contributes to its difficulty and that threshold concepts, as a source of troublesome knowledge, have a significant role in this. This paper explores computing teachers' perspectives on the Threshold Concept framework and suggests potential threshold concepts in the area of Functions and, more generally, in Procedural Abstraction. A study was conducted, using the Delphi method, including both computing teachers with experience teaching at upper secondary/high school and computing teachers with experience practicing programming in a professional environment for more than 7 years. The results indicate that the majority of the participants support that the Threshold Concept framework can explain students' difficulties in programming and agreed on 11 potential threshold concepts in the area of Functions and Procedural Abstraction. The participants focused more on the troublesome characteristic of threshold concepts and less on the transformative and integrative. Most of the participants also specified that they would change the way they teach a concept if they knew that this is a threshold one. Finally, the paper discusses the findings and how these will shape our future research.
Late Onset of Spermatogenesis and Gain of Fertility in POG-Deficient Mice Indicate that POG Is Not Necessary for the Proliferation of Spermatogonia1

Abstract The germ cell-deficient (gcd) mouse mutation is a recessive, transgenic insertional mutation associated with the disruption of two Chr11 genes, Pog (proliferation of germ cells) and Vrk2 (vaccinia virus-related protein kinase 2). We have recently shown that like gcd/gcd mice, targeted Pog−/− males and females show virtually no spermatogenesis or oogenesis at 4–6 wk of age. Because Pog is deleted in gcd/gcd and Pog−/− mice, a comparison of the phenotypes of the two mouse models is appropriate. Here, we report that unlike in POG-deficient females, the germ cells in POG-deficient males eventually populate the seminiferous tubules at 9 wk, and fertility can be achieved by 12 wk. Homozygous gcd/gcd males did not show a similar degree of germ cell population, and most gcd/gcd males remained infertile at 16 and 22 wk of age. A comparison of the degree of germ cell deficiency at 13.5 days postcoitum and 1 day postpartum between Pog−/− and gcd/gcd males revealed that gcd/gcd males had far fewer germ cells than Pog−/− males at both time points. Our data suggest that Pog is essential for proper primordial germ cell proliferation in the embryonic stage but is not needed for spermatogonial proliferation after birth. Thus, the difference in the spermatogenetic potential in adult Pog−/− and gcd/gcd mice may result from the severity of germ cell deficiency rather than from the inability of gcd/gcd spermatogonia to proliferate efficiently. The greater deficiency of germ cells before the onset of spermatogenesis seen in gcd/gcd males compared to Pog−/− mice suggests either that the different background affects the outcome of Pog deletion or that Vrk2 has additional effects on germ cell development.
Exome Sequencing Identifies Potential Risk Variants for Mendelian Disorders at High Prevalence in Qatar

Exome sequencing of families of related individuals has been highly successful in identifying genetic polymorphisms responsible for Mendelian disorders. Here, we demonstrate the value of the reverse approach, where we use exome sequencing of a sample of unrelated individuals to analyze allele frequencies of known causal mutations for Mendelian diseases. We sequenced the exomes of 100 individuals representing the three major genetic subgroups of the Qatari population (Q1 Bedouin, Q2 Persian‐South Asian, Q3 African) and identified 37 variants in 33 genes with effects on 36 clinically significant Mendelian diseases. These include variants not present in 1000 Genomes and variants at high frequency when compared with 1000 Genomes populations. Several of these Mendelian variants were only segregating in one Qatari subpopulation, where the observed subpopulation specificity trends were confirmed in an independent population of 386 Qataris. Premarital genetic screening in Qatar tests for only four out of the 37, such that this study provides a set of Mendelian disease variants with potential impact on the epidemiological profile of the population that could be incorporated into the testing program if further experimental and clinical characterization confirms high penetrance.
Are changes in international accounting standards making them more complex?

ABSTRACT One of the objectives of International Accounting Standards Board (IASB) is to develop high-quality standards based on clearly articulated principles. However, despite stating that International Financial Reporting Standards (IFRS) are based on principles, IASB continuously revises and amends IFRS. This paper explores the relation between the changes in IFRS and whether the standards have become more complex over time. The sample comprises changes to IFRS between 2005 and 2016. Following Mergenthaler [(2012). Principles-based versus rules-based standards and accounting irregularities (Working paper)] and Donelson, McInnis, and Mergenthaler [(2012). Rules-based accounting standards and litigation. The Accounting Review, 87(4), 1247–1279], this paper scores the rules-based continuum for each standard. The results show that IFRS is becoming more complex because of the changes.
Effect of Larrea tridentata (creosote bush) on cholesterol gallstones and bile secretion in hamsters

Larrea tridentata (Sesse and Moc. ex DC.) Coville is used for the treatment of gallstones in traditional Mexican medicine. The possible prevention or elimination of gallstones by ethanolic and aqueous extracts of the leaves and twigs of L. tridentata was tested in hamsters fed a rich carbohydrate, fat‐free diet. In addition, the effects of the ethanolic extract and its main metabolite, nordihydroguaiaretic acid, on bile secretion in the perfused liver were tested. In the experiment on prevention of gallstones, the dry ethanolic extract at a level of 0.5% of diet completely inhibited gallstone formation, lowered biliary moles percent cholesterol and increased the proportion of chenodeoxycholic acid of hepatic bile. The dry aqueous extract at a level of 1% of diet did not affect gallstone frequency or biliary parameters. In the experiment on elimination of gallstones, the ethanolic extract significantly reduced gallstone frequency, gallbladder bile cholesterol concentration and moles percent cholesterol. Both the ethanolic extract and nordihydroguaiaretic acid had cholestatic effects in the perfused liver, with an EC50 of 34 and 28 mg dL−1, respectively, when perfused for 10 min. This effect was reversible with concentrations up to 40 mg dL−1. The results indicate that L. tridentata could be useful in the treatment of gallstone disease, however care must be taken due to its hepatotoxicity.
Seasonal trends in house dust mite allergen in children’s beds over a 7‐year period

Background: House dust mite (HDM) allergy is closely linked to the expression of asthma and other allergic diseases. Understanding factors influencing variation in allergen may help in controlling allergic disease. The objective of this study was to investigate the effects of seasonal changes in climate, type of bed used in very early childhood and anti‐mite interventions on HDM allergen concentration.
Differences in prevalence of overweight and stunting in 11-year olds across Europe: The Pro Children Study.

OBJECTIVES To assess country differences in prevalence of overweight, obesity, underweight and stunting in the Pro Children Survey. METHODS A cross-sectional study conducted in a random sample of schools in nine European countries in 2003. The subjects were 8317 11-year-old children from Austria, Belgium, Denmark, Iceland, The Netherlands, Norway, Portugal, Spain and Sweden. Parents reported height and weight of the children, and BMI values were analysed using the US Centers of Disease Control and Prevention and the International Obesity Task Force reference populations. Continuous variables were compared with one-way analysis of variance (ANOVA) with Games-Howell post hoc tests. Categorical variables were analysed using chi-square tests. RESULTS The prevalence of overweight + obesity varied between the countries from 8.6% to 30.6% and 5.9% to 26.5%, respectively, depending on the reference population, with the lowest prevalence in Dutch girls, the highest in Portuguese boys. Obesity prevalence varied from 1.1% (Dutch and Danish girls) to 10.7% (Portuguese boys) and from 0.3% (Dutch girls) to 6.2% (Portuguese boys), respectively. Portugal and Spain had the highest prevalence of overweight and obesity for both genders. The ranking of the countries according to overweight and obesity prevalence was roughly the same, independent of reference population. The prevalence of underweight varied from 2.3% (Swedish boys) to 12.3% (Belgian boys), using the American reference population. The proportion of stunted children was highest in Portugal, Spain and Belgium. CONCLUSIONS The highest levels of overweight, obesity and stunting in the pro children material are found in Portugal and Spain.
Facilitation of adrenergic transmission in the canine heart by intracoronary infusion of angiotensin II: effect of prostaglandin synthesis inhibition.

We studied the effect of intracoronary angiotensin II (AII) infusion on the coronary sinus output of norepinephrine (NE) elicited by left cardiac sympathetic nerve stimulation in pentobarbital-anesthetized dogs pretreated with a prostaglandin synthesis inhibitor (indomethacin) or its vehicle. The NE output from the heart was determined from the NE levels in coronary sinus blood before and during cardiac sympathetic nerve stimulation. In both indomethacin- and vehicle-pretreated animals, infusion of AII (30 ng kg-1 min-1) into the left coronary artery augmented the coronary sinus output of NE elicited by sympathetic nerve stimulation, but had no effect on the basal output of NE from the heart. In both groups of animals, the AII-induced increase in NE output was associated with an increase in the effect of cardiac sympathetic nerve stimulation on left ventricular contractility (LVdP/dt max). All did not alter the removal of exogenous NE by the heart and moreover the AII-induced increase in the output of NE elicited by cardiac sympathetic nerve stimulation was also observed during blockade of neuronal and extraneuronal uptake with cocaine and normetanephrine, respectively. Therefore, the All-induced increase in the coronary sinus output of NE and LVdPl dt max elicited by cardiac sympathetic nerve stimulation is most likely due to enhanced NE release from adrenergic nerve terminals in the heart. The ability of All to increase the coronary sinus output of NE and the positive inotropic response elicited by cardiac sympathetic nerve stimulation was enhanced in animals pretreated with the cyclooxygenase inhibitor, indomethacin. (ABSTRACT TRUNCATED AT 250 WORDS)
Activation of Rheumatoid Factor–Specific B Cells Is Antigen Dependent and Occurs Preferentially Outside of Germinal Centers in the Lupus-Prone NZM2410 Mouse Model

AM14 rheumatoid factor (RF) B cells in the MRL/lpr mice are activated by dual BCR and TLR7/9 ligation and differentiate into plasmablasts via an extrafollicular (EF) route. It was not known whether this mechanism of activation of RF B cells applied to other lupus-prone mouse models. We investigated the mechanisms by which RF B cells break tolerance in the NZM2410-derived B6.Sle1. Sle2.Sle3 (TC) strain in comparison with C57BL/6 (B6) controls, each expressing the AM14 H chain transgene in the presence or absence of the IgG2aa autoantigen. The TC, but not B6, genetic background promotes the differentiation of RF B cells into Ab-forming cells (AFCs) in the presence of the autoantigen. Activated RF B cells preferentially differentiated into plasmablasts in EF zones. Contrary to the MRL/lpr strain, TC RF B cells were also located within germinal centers, but only the formation of EF foci was positively correlated with the production of RF AFCs. Immunization of young TC.AM14 H chain transgenic mice with IgG2aa anti-chromatin immune complexes (ICs) activated RF B cells in a BCR- and TLR9-dependent manner. However, these IC immunizations did not result in the production of RF AFCs. These results show that RF B cells break tolerance with the same general mechanisms in the TC and the MRL/lpr lupus-prone genetic backgrounds, namely the dual activation of the BCR and TLR9 pathways. There are also distinct differences, such as the presence of RF B cells in GCs and the requirement of chronic IgG2aa anti-chromatin ICs for full differentiation of RF AFCs.
The coevolution of innovation and technical intelligence in primates

In birds and primates, the frequency of behavioural innovation has been shown to covary with absolute and relative brain size, leading to the suggestion that large brains allow animals to innovate, and/or that selection for innovativeness, together with social learning, may have driven brain enlargement. We examined the relationship between primate brain size and both technical (i.e. tool using) and non-technical innovation, deploying a combination of phylogenetically informed regression and exploratory causal graph analyses. Regression analyses revealed that absolute and relative brain size correlated positively with technical innovation, and exhibited consistently weaker, but still positive, relationships with non-technical innovation. These findings mirror similar results in birds. Our exploratory causal graph analyses suggested that technical innovation shares strong direct relationships with brain size, body size, social learning rate and social group size, whereas non-technical innovation did not exhibit a direct relationship with brain size. Nonetheless, non-technical innovation was linked to brain size indirectly via diet and life-history variables. Our findings support ‘technical intelligence’ hypotheses in linking technical innovation to encephalization in the restricted set of primate lineages where technical innovation has been reported. Our findings also provide support for a broad co-evolving complex of brain, behaviour, life-history, social and dietary variables, providing secondary support for social and ecological intelligence hypotheses. The ability to gain access to difficult-to-extract, but potentially nutrient-rich, resources through tool use may have conferred on some primates adaptive advantages, leading to selection for brain circuitry that underlies technical proficiency.
Heterogeneous time zone effects and exports

The negative effect of time zone differences on trade flows due to an increase in trade costs across country-pairs has been well established in the literature. Recent studies also find trade cost elasticity to be heterogeneous across country-pairs and across the distribution of trade flows. We use a quantile estimation to examine whether time zone differences have heterogeneous effects along the conditional distribution of exports. This estimation enables us to identify the log-linear gravity model with zero trade flows. We find that the negative between time zone differences and trade is driven mainly by country-pairs that trade the least. Specifically, we find that while time zone differences negatively impact trade in general, these differences affect countries at the low end of the trade distribution (10th percentile) more compared to higher end of the trade distribution (90th percentile). Our results further demonstrate the potentially large fixed costs associated with trade, especially for country-pairs that trade the least.
The effect of vaccination on the epidemiology of varicella zoster virus.

Varicella zoster virus (VZV) causes chickenpox (varicella) on primary exposure and can reactivate later in life to cause shingles (zoster). As primary infection is more serious in adults than children, and exposure to the virus might boost the immune response to both chickenpox and shingles, there are two main concerns regarding infant VZV vaccination: that it could lead to an increase in adult disease; and/or that it could lead to a temporary increase in the incidence of shingles. This paper reviews the evidence for such outcomes. The consensus view of mathematical modelling studies is that the overall varicella associated burden is likely to decrease in the long term, regardless of the level of vaccine coverage. On the other hand, recent evidence suggests that an increase in zoster incidence appears likely, and the more effective vaccination is at preventing varicella, the larger the increase in zoster incidence. Targeted vaccination of susceptible adolescents and/or the contacts of high-risk individuals can be effective at preventing disease in these individuals with minimal risk to the community. However, targeted strategies would not prevent most disease (including most severe disease), and will not lead to a long-term reduction in the incidence of zoster. Understanding the mechanisms for maintaining immunity against varicella and zoster is critical for predicting the long-term effects of vaccination. Meanwhile sensitive surveillance of both chickenpox and shingles is essential in countries that have implemented, or are about to implement, varicella vaccination.
An Examination of Influences Leading to Americans’ Endorsement of the Policy of Free Trade

The authors explore influences on Americans’ endorsement of free trade in general, the North American Free Trade Agreement (NAFTA) in particular. Work in the behavioral sciences suggests the value of using constructs that express the nature of persons’ orientation toward their own and other countries to explain their willingness to endorse these concepts. On this basis, the authors created a model that features paths of influence leading to the two Endorsement constructs. They subjected survey data from 240 respondents to structural equation analysis to test the model. The results, using total effects, show that Endorsement of free trade in general and NAFTA in particular are related negatively to Ethnocentrism, Nationalism, Prejudice, and Image of Mexicans, and positively related to Education. These findings hold implications for policymakers who seek to sway public opinion about international trade; they also suggest implications for further research into the subject.
Neutrophil‐Derived Metalloproteinase‐9 Predicts Healing Quality after Sinus Surgery

Background: In a recent study, we have shown that gelatinase‐B (metalloproteinase [MMP]‐9) in nasal secretions can have both monitoring and predictive value on the healing outcome after functional endoscopic sinus surgery (FESS) to treat chronic rhinosinusitis (CRS) and nasal polyposis (NP). In this work, we aimed to explore the source of MMP‐9 and the influence of inflammation on MMP‐9 expression and release in nasal tissue and secretions during airway remodelling after surgery.