Miracle-dz/UniFAR-FTUs huggingface dataset:
Blockade of Nonhormonal Fibroblast Growth Factors by FP-1039 Inhibits Growth of Multiple Types of Cancer

A soluble FGF receptor trap effectively inhibits tumor growth in the absence of toxicity. Treating Cancer by Design The Renaissance man (or woman) is held up as an ideal of someone with diverse knowledge. Yet, today, it is increasingly difficult to both be broad and have sufficient depth of knowledge to be successful in any one field. Unfortunately, this is also the case for cancer therapies. The most obvious outward signs of some cancers—severe weight loss, tiredness, hair loss, nausea—are actually caused by the nonspecific breadth of the treatments. One pathway that has proved particularly intractable is the fibroblast growth factor (FGF) pathway, which promotes tumor growth and angiogenesis but also contributes key metabolic hormones. Now, Harding et al. have designed a soluble FGF receptor Fc fusion protein (FP-1039) to overcome these difficulties. The authors tested the specificity of FP-1039 both in vitro and in vivo across a wide swath of cancer types. FP-1039 binds to mitogenic FGF ligands, blocking angiogenesis and inhibiting growth of tumors of many different types. Tumors with amplified expression of, or mutations in, FGF receptors (such as certain lung and endometrial cancers) were especially well targeted by this drug. In contrast, FP-1039 did not bind tightly to the hormonal FGFs, and treatment in animal models had minimal toxicity. Although this drug has only been tested in early-stage clinical trial in humans, these data support a specialized inhibition of mitogenic FGFs. Cancer drug design is truly entering the Age of Reason. The fibroblast growth factor (FGF) pathway promotes tumor growth and angiogenesis in many solid tumors. Although there has long been interest in FGF pathway inhibitors, development has been complicated: An effective FGF inhibitor must block the activity of multiple mitogenic FGF ligands but must spare the metabolic hormone FGFs (FGF-19, FGF-21, and FGF-23) to avoid unacceptable toxicity. To achieve these design requirements, we engineered a soluble FGF receptor 1 Fc fusion protein, FP-1039. FP-1039 binds tightly to all of the mitogenic FGF ligands, inhibits FGF-stimulated cell proliferation in vitro, blocks FGF- and vascular endothelial growth factor (VEGF)–induced angiogenesis in vivo, and inhibits in vivo growth of a broad range of tumor types. FP-1039 antitumor response is positively correlated with RNA levels of FGF2, FGF18, FGFR1c, FGFR3c, and ETV4; models with genetic aberrations in the FGF pathway, including FGFR1-amplified lung cancer and FGFR2-mutated endometrial cancer, are particularly sensitive to FP-1039–mediated tumor inhibition. FP-1039 does not appreciably bind the hormonal FGFs, because these ligands require a cell surface co-receptor, klotho or β-klotho, for high-affinity binding and signaling. Serum calcium and phosphate levels, which are regulated by FGF-23, are not altered by administration of FP-1039. By selectively blocking nonhormonal FGFs, FP-1039 treatment confers antitumor efficacy without the toxicities associated with other FGF pathway inhibitors.
Endoscopic Assessment of the Dacryocystorhinostomy Ostium After Endoscopic Surgery

Objectives: Dacryocystorhinostomy (DCR) is currently regarded as the treatment of choice for treatment of epiphora resulting from blockage at the level of the nasolacrimal duct. There has been debate on the effect of healing on the size of the DCR ostium after surgery. The aim of this study is to determine how the size of the surgically created lacrimal ostium changes over time.
Improved field homogenity for microstrip transceiver array for 7T MRI using particle swarm optimization

Microstrip resonators (MSR) show great promise for application to high field magnetic resonance imaging (MRI); however, the conventional MSR produces an inhomogenous field that is strong in the center and weak at the terminating ends. Recent work investigated the application of alternating impedance MSR to improve field homogeneity. Building from these efforts, a new variable impedance MSR configuration is proposed by allowing variation in element size and spacing. Finite difference time domain (FDTD) simulations and particle swarm optimization (PSO) are used to arrive at an optimal design.
Phenformin enhances the therapeutic benefit of BRAFV600E inhibition in melanoma

Significance Inhibitors of BRAF protein kinase, such as Vemurafenib and Dabrafenib, have shown remarkable antitumor activity in patients with BRAF mutant melanoma. However, most of the patients developed drug resistance during the course of treatment, leading to resumed tumor growth. This drug resistance challenge underscores the need to improve on current BRAF-targeted therapy. In this study, we have shown that phenformin, a biguanide used for treating type 2 diabetes, enhances the antitumor activities of BRAF inhibitors in both cultured melanoma cells and a genetically engineered BRAFV600E-driven mouse model of melanoma. Our preclinical findings suggest that combining phenformin with a BRAF inhibitor may be a more effective treatment than a single-agent BRAF inhibitor for treating patients with melanoma whose tumor harbor BRAF mutations. Biguanides, such as the diabetes therapeutics metformin and phenformin, have demonstrated antitumor activity both in vitro and in vivo. The energy-sensing AMP-activated protein kinase (AMPK) is known to be a major cellular target of biguanides. Based on our discovery of cross-talk between the AMPK and v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) signaling pathways, we investigated the antitumor effects of combining phenformin with a BRAF inhibitor PLX4720 on the proliferation of BRAF-mutated melanoma cells in vitro and on BRAF-driven tumor growth in vivo. Cotreatment of BRAF-mutated melanoma cell lines with phenformin and PLX4720 resulted in synergistic inhibition of cell viability, compared with the effects of the single agent alone. Moreover, treatment with phenformin significantly delayed the development of resistance to PLX4720 in cultured melanoma cells. Biochemical analyses showed that phenformin and PLX4720 exerted cooperative effects on inhibiting mTOR signaling and inducing apoptosis. Noticeably, phenformin selectively targeted subpopulations of cells expressing JARID1B, a marker for slow cycling melanoma cells, whereas PLX4720 selectively targeted JARID1B-negative cells. Finally, in contrast to their use as single agents, the combination of phenformin and PLX4720 induced tumor regression in both nude mice bearing melanoma xenografts and in a genetically engineered BRAFV600E/PTENnull-driven mouse model of melanoma. These results strongly suggest that significant therapeutic advantage may be achieved by combining AMPK activators such as phenformin with BRAF inhbitors for the treatment of melanoma.
Subsidies to Less Favoured Areas in the Czech Republic: Why Do They Matter?

Subsidy to less favoured area (LFA) farms is central to rural development policy in the European Union. Here, three categories of LFA support are assessed: farm competitiveness measures, LFA measures, and agri-environment measures. These categories of measures are complementary to safeguarding land management and delivering ecosystem benefits. Based on historical data for the Czech Republic, this paper endeavours to illustrate potential methods for assessing the LFA subsidies. In sum, rigorous methods to evaluate LFA evidence are still at their very starting point, even as they are necessary in order to ascertain the Community’s capability, alongside the local, regional, or national institutional capability. A positive trend has been identified with regard to stabilizing the available rural development budget for the policy priority “Restoring, preserving and enhancing agroecosystems”.
Processing of a Class I-Restricted Epitope from Tyrosinase Requires Peptide N-Glycanase and the Cooperative Action of Endoplasmic Reticulum Aminopeptidase 1 and Cytosolic Proteases1

Although multiple components of the class I MHC processing pathway have been elucidated, the participation of nonproteasomal cytosolic enzymes has been largely unexplored. In this study, we provide evidence for multiple cytosolic mechanisms in the generation of an HLA-A*0201-associated epitope from tyrosinase. This epitope is presented in two isoforms containing either Asn or Asp, depending on the structure of the tyrosinase precursor. We show that deamidation of Asn to Asp is dependent on glycosylation in the endoplasmic reticulum (ER), and subsequent deglycosylation by peptide-N-glycanase in the cytosol. Epitope precursors with N-terminal extensions undergo a similar process. This is linked to an inability of ER aminopeptidase 1 to efficiently remove N-terminal residues, necessitating processing by nonproteasomal peptidases in the cytosol. Our work demonstrates that processing of this tyrosinase epitope involves recycling between the ER and cytosol, and an obligatory interplay between enzymes involved in proteolysis and glycosylation/deglycosylation located in both compartments.
Ecosystem services approach for sustainable governance in a brackish water lagoon used for aquaculture

Human impacts on deltas often involve reclamation of coastal wetlands, causing a dramatic loss of ecological functions. We propose an Ecosystem Services (ES) approach to promote coordinated governance of aquaculture and environmental conservation in a brackish lagoon of the Po River delta (Italy). Spatiotemporal changes of aquatic vegetated habitats and clam production were evaluated, and experimentally related to ESs: climate regulation, habitat provision for birdlife, and potential for birdwatching. Almost all emergent vegetation was lost during past decades, while aquaculture production increased rapidly. Vegetated habitats sequestered significant amounts of carbon and supported more diverse bird communities than non-vegetated wetlands, including protected species of interest for birdwatching. We demonstrated that sectoral management was ineffective in maintaining ESs, promoting the exploitation of few provisioning services while decreasing many others. We propose an innovative, integrated management that focuses on restoring aquatic vegetation to offset anthropic impacts for the future sustainable governance of deltas.
Under the Rising Wave. How Disaggregated Revenue Sources Can Tell Another Story for Québec’s Top Income Share

Top income investigations usually rely on types of earnings that remain at a tively aggregated level. Using a novel disaggregated dataset for Québec’s top earners, we map the recent evolution of different types of income for the top one percent. Hidden under the steady increase of the top income share, we find that there has been very divergent and sharp rises of different revenue sources at specific moments. When looking at disaggregated data, composition effects and historical counterfactuals in Québec invalidate market-based theories like globalization and skilled biased technical change, but not institution-based theories like financialization, taxation and union strength.
Assessing wetland compensatory mitigation sites to aid in establishing mitigation ratios

Compensatory mitigation has been a keystone of state and federal programs for regulating wetland loss. This study reviewed mitigation performance in Indiana, USA to propose mitigation ratios (area to be mitigated/area permitted for fill) based on the rate of wetland establishment by type. Between 1986 and 1996, the Indiana Department of Environmental Management (IDEM) required 345 mitigation sites. Of these, applicants constructed 214 of the sites; another 70 were not completed. No attempt was made to construct the required mitigation on 49 of the sites. Measurements of both the total wetland area and the area of each vegetation community in the mitigation site were taken at 31 of the sites identified as “constructed. ” IDEM required 34.33 ha to compensate for the 13.73 ha of state waters lost through the permit actions associated with these sites. The mapping effort found that a total of 15.21 ha of wetland and other waters had established, a net gain of 1.48 ha. Vegetation community mapping revealed that palustrine forested areas, which had a failure rate of 71% and wet meadow areas (87% failure) were harder to establish than shallow marsh areas (17% failure) and open water areas (4% failure). These results suggest that federal and state regulatory agencies would have to require minimum mitigation ratios of 3.5∶1 for palustrine forested, 7.6∶1 for wet meadow, 1.2∶1 for shallow marsh, and 1∶1 for open water to compensate for the risk of failure. Additional mitigation may be needed to offset the effects of temporal loss of wetland function.
Gulf Cooperation Council Energy Sectors Governance and Dividend Policy

This study is aims to investigate the governance of the most important sector in the Gulf financial markets, energy sectors. It also looks into the effect of corporate governance on one of the most significant financial polices of in organizations, which is dividend policy. This study involves a sample of eight energy firms in a ten years’ time series, 2008 to 2017. These firms were selected from six Gulf financial markets: Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and United Arab Emirates. The corporate governance was measured by using four indicators. Whereas, the dividend policy was expressed by payout ratio. The findings of the study showed that the outcome hypothesis is adopted in the Gulf Cooperation Council GCC energy sectors; the companies with good governance seek to distribute the profits among shareholders to reduce the conflict of interests and reduce the agency costs. The results also indicated a positive role of public governance in the relationship between corporate governance and the dividend policy.
Research Methods in Management

1) You will learn how to ask original research questions. 2) You will learn how to collect, assimilate, and critically review literature on a given topic. 3) You will learn about the different paradigms in management research, strategies of research design and how to do methodologically appropriate work 4) You will learn about best practice in management research and how to prepare scholarly work for publication 5) You will learn about ethics in the research process and how to do ethical management research
Clinical features of microscopic colitis in a nation-wide follow-up study in Iceland

Objective. The long-term natural history of collagenous colitis (CC) and lymphocytic colitis (LC) is not well known. The few reports available that address these issues have a limited follow-up. The aims of this study were to evaluate the natural history of microscopic colitis (MC), to describe the treatment medications prescribed and to assess the use of non-steroidal anti-inflammatory drugs (NSAIDs) in MC. Material and methods. This study is based on an earlier epidemiological study conducted in Iceland where 125 patients with MC (71 with CC and 54 with LC) were diagnosed in the period 1995–99. All patients still alive and available were questioned about symptoms, treatment and NSAID use in the 3 months preceding the interview. Results. In a mean follow-up time of 6.4 years from diagnosis, 15% of the patients had diarrhoeal symptoms more than once a week, 30% less than once a week and 55% had no diarrhoea. Abdominal pain was reported in 18% of the patients. There was no statistically significant difference in symptoms of CC and LC patients. Forty-eight patients (50%) were receiving medication for MC, 16% used aminosalicylates and 14% corticosteroids. Patients using medication for MC had significantly more diarrhoeal symptoms compared with those who did not (p=0.002). Patients using NSAIDs regularly or as required, statistically did not have more symptoms related to MC than non-NSAID users. Conclusions. Only a minority of patients with MC had diarrhoea more than once a week in a long-term follow-up and the symptom pattern was similar between CC and LC patients. The use of NSAIDs was not associated with more diarrhoeal symptoms.
Stress proteins in oligodendrocytes: differential effects of heat shock and oxidative stress

Heat shock proteins (HSP) or stress proteins serve as biomarkers to identify the contribution of stress situations underlying the pathogenesis of degenerative diseases of the CNS. We have analyzed by immunoblot technique the constitutive and inducible occurance of stress proteins in cultured rat brain oligodendrocytes subjected to heat shock or oxidative stress exerted by hydrogen peroxide, or a combination of both. The data demonstrate that oligodendrocytes constitutively express HSP32, HSP60 and the cognate form of the HSP70 family of proteins, HSC70. After heat shock, HSP25, αB‐crystallin and HSP70 were up‐regulated, while after oxidative stress the specific induction of HSP32 and αB‐crystallin was observed. HSP32 represents heme oxygenase 1 (HO‐1), a small stress protein with enzymatic activity involved in the oxidative degradation of heme which participates in iron metabolism. The presence of the iron chelators phenanthroline or deferoxamine (DFO), which previously has been shown to protect oligodendrocytes from oxidative stress‐induced onset of apoptosis, caused a marked stimulation of HSP32 without affecting HSP70. This indicates that DFO possibly exerts its protective role by directly influencing the antioxidant capacity of HO‐1. In summary, HSP in oligodendrocytes are differentially stimulated by heat stress and oxidative stress. Heme oxygenase‐1 has been linked to inflammatory processes and oxidative stress, its specific up‐regulation after oxidative stress in oligodendrocytes suggests that it is an ideal candidate to investigate the involvement of oxidative stress in demyelinating diseases.
The African Indigenous Vegetables Value Chain Governance in Kenya

Increasingly, food security interventions in developing economies are adapting value chain approaches to facilitate the integration of smallholders into high margin value chains. In Kenya, the resurgence of African Indigenous Vegetables due to their medicinal value and rich micronutrients is a case in point. The vegetables are cultivated by smallholders, and the supply has not matched the demand in the high margin markets among urban consumers. Access to such high margin markets necessitates that smallholders gain entry or upgrade into the networks of those buyers who possess considerable control of these value chains. There is limited value chain scholarship on chain governance and its implication for smallholder participation in Kenya. This study investigated how value chain governance influences farmer participation in vegetable markets and food security in Kenya. This study employed exploratory case study design to provide chain architecture, isolate primary actors, their roles, relations, constraints and opportunities for upgrading by smallholders. A mixed method approach involving a multistage sampling technique of 339 respondents was employed to bring to the surface insights on chain architecture, market margins and governance structures and their implications as regards upgrading trajectories for small-scale farmers in Kenya. Thematic analysis was used for data analysis. Spot market relations were found to dominate traditional value chains in rural areas while peri-urban areas exhibited both traditional and coordinated value chains. The value chains are characterised by very weak linkages between upstream actors and downstream partners, where wholesalers and supermarkets play the role of leading firms in traditional and coordinated value chains, respectively. The study recommends the inclusion of famers in market management committees and the establishment of binding contractual arrangements with supermarkets.
Evaluation of an experimental patch test model for the detection of irritant skin reactions to moisturisers

Background/aims: Moisturisers are used daily by a large number of people to prevent dryness of the skin. Irritant skin reactions to moisturisers are, however, known to occur. In order to prevent such irritant reactions reliable test methods for irritancy testing of moisturisers are needed. This study was undertaken to evaluate a non‐invasive patch test model for the detection of irritant skin reactions to moisturisers.
A Fast Discriminative Training Algorithm for Minimum Classification Error

In this paper a new algorithm is proposed for fast discriminative training of hidden Markov models (HMMs) based on minimum classification error (MCE). The algorithm is able to train acoustic models in a few iterations, thus overcoming the slow training speed typical of discriminative training methods based on gradient-descendent. The algorithm tries to cancel the gradient of the objective function in every iteration. Re-estimation expressions of the HMM parameters are derived. Experiments with triphone and word models show that the proposed algorithm always achieves much better results in a single iteration than MCE, MMI or MPE do over several iterations.
Joseon Funerary Texts Tested Using Ancient DNA Analysis of a Korean Mummy

In Korea, ancient DNA (aDNA) analysis has been applied to investigations into the genetic affiliations of mummies found in Joseon Dynasty tombs (1392–1910 CE), becoming now indispensable tool for researches studying human remains from archaeological sites. In the course of our recent examinations on a Korean mummy of Joseon Dynasty, we discovered many teeth contained in a pouch. And in fact, the historical literature on the topic of Joseon funerals contain general accounts of pouches in which an individual's lost teeth were collected over the course of a lifetime and, after death, placed in the coffin with the body. To test the veracity of the historical texts, the present study undertook aDNA analyses and compared the results between specifically questioned (Q) samples (teeth) and known (K) samples (brain and bone) from the mummy to ensure that they came from the same individual. Although the Q‐K comparison of autosomal short tandem repeat results did not show full concordance due to allelic drop‐outs in some loci, our statistical calculation indicated that the teeth in the pouch are highly likely those of the mummy. Additionally, Q‐K comparison of mitochondrial DNA sequence results showed 100% matches between samples. There results, in short, could not gainsay the conjecture that the teeth samples originated from the person buried in the tomb; and if so, he must have kept his teeth for a long time after their loss. As the application of aDNA analysis to Korean mummy studies develops, there will be other opportunities to test historical documents, particularly those referring to funerary rites. Anat Rec, 298:1191–1207, 2015. © 2015 Wiley Periodicals, Inc.
Sustainable innovation behavior in restaurants

ABSTRACT Although a major contributor to environmental degradation and global climate change, most city administrators, policymakers and regulators do not hold restaurants accountable for their adverse impacts. New policies with incentives are urgently needed that leverage existing drivers of sustainable innovation. Using innovation adoption and planned behavior theories, a path analysis model is developed to evaluate the current level of sustainability in the restaurant industry and reveal the predictors of future sustainability behavioral intention. The results show that three predictors ‒ past experience, perceived behavioral control, and perceived innovation characteristics ‒ largely determine whether restaurants engage in sustainable innovation in the future.