Miracle-dz/UniFAR-FTUs huggingface dataset:
Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase.

PURPOSE Nilotinib is a second-generation tyrosine kinase inhibitor indicated for the treatment of patients with chronic myeloid leukemia (CML) in chronic phase (CP; CML-CP) and accelerated phase (AP; CML-AP) who are resistant to or intolerant of prior imatinib therapy. In this subanalysis of a phase II study of nilotinib in patients with imatinib-resistant or imatinib-intolerant CML-CP, the occurrence and impact of baseline and newly detectable BCR-ABL mutations were assessed. PATIENTS AND METHODS Baseline mutation data were assessed in 281 (88%) of 321 patients with CML-CP in the phase II nilotinib registration trial. RESULTS Among imatinib-resistant patients, the frequency of mutations at baseline was 55%. After 12 months of therapy, major cytogenetic response (MCyR) was achieved in 60%, complete cytogenetic response (CCyR) in 40%, and major molecular response (MMR) in 29% of patients without baseline mutations versus 49% (P = .145), 32% (P = .285), and 22% (P = .366), respectively, of patients with mutations. Responses in patients who harbored mutations with high in vitro sensitivity to nilotinib (50% inhibitory concentration [IC(50)] <or= 150 nM) or mutations with unknown nilotinib sensitivity were equivalent to those responses for patients without mutations (not significant). Patients with mutations that were less sensitive to nilotinib in vitro (IC(50) > 150 nM; Y253H, E255V/K, F359V/C) had less favorable responses, as 13%, 43%, and 9% of patients with each of these mutations, respectively, achieved MCyR; none achieved CCyR. CONCLUSION For most patients with imatinib resistance and with mutations, nilotinib offers a substantial probability of response. However, mutational status at baseline may influence response. Less sensitive mutations that occurred at three residues defined in this study, as well as the T315I mutation, may be associated with less favorable responses to nilotinib.
The Unrecognized Effects of Phosphodiesterase 4 on Epithelial Cells in Pulmonary Inflammation

Acute pulmonary inflammation is characterized by migration of polymorphonuclear neutrophils (PMNs) into the different compartments of the lung, passing an endothelial and epithelial barrier. Recent studies showed evidence that phosphodiesterase (PDE)4-inhibitors stabilized endothelial cells. PDE4B and PDE4D subtypes play a pivotal role in inflammation, whereas blocking PDE4D is suspected to cause gastrointestinal side effects. We thought to investigate the particular role of the PDE4-inhibitors roflumilast and rolipram on lung epithelium. Acute pulmonary inflammation was induced by inhalation of LPS. PDE4-inhibitors were administered i.p. or nebulized after inflammation. The impact of PDE4-inhibitors on PMN migration was evaluated in vivo and in vitro. Microvascular permeability, cytokine levels, and PDE4B and PDE4D expression were analyzed. In vivo, both PDE4-inhibitors decreased transendothelial and transepithelial migration even when administered after inflammation, whereas roflumilast showed a superior effect compared to rolipram on the epithelium. Both inhibitors decreased TNFα, IL6, and CXCL2/3. CXCL1, the strong PMN chemoattractant secreted by the epithelium, was significantly more reduced by roflumilast. In vitro assays with human epithelium also emphasized the pivotal role of roflumilast on the epithelium. Additionally, LPS-induced stress fibers, an essential requirement for a direct migration of PMNs into the alveolar space, were predominantly reduced by roflumilast. Expression of PDE4B and PDE4D were both increased in the lungs by LPS, PDE4-inhibitors decreased mainly PDE4B. The topical administration of PDE4-inhibitors was also effective in curbing down PMN migration, further highlighting the clinical potential of these compounds. In pulmonary epithelial cells, both subtypes were found coexistent around the nucleus and the cytoplasm. In these epithelial cells, LPS increased PDE4B and, to a lesser extend, PDE4D, whereas the effect of the inhibitors was prominent on the PDE4B subtype. In conclusion, we determined the pivotal role of the PDE4-inhibitor roflumilast on lung epithelium and emphasized its main effect on PDE4B in hyperinflammation.
Applying WHO's 'workforce indicators of staffing need' (WISN) method to calculate the health worker requirements for India's maternal and child health service guarantees in Orissa State.

OBJECTIVE In one district of Orissa state, we used the World Health Organization's Workforce Indicators of Staffing Need (WISN) method to calculate the number of health workers required to achieve the maternal and child health 'service guarantees' of India's National Rural Health Mission (NRHM). We measured the difference between this ideal number and current staffing levels. METHODS We collected census data, routine health information data and government reports to calculate demand for maternal and child health services. By conducting 54 interviews with physicians and midwives, and six focus groups, we were able to calculate the time required to perform necessary health care tasks. We also interviewed 10 new mothers to cross-check these estimates at a global level and get assessments of quality of care. FINDINGS For 18 service centres of Ganjam District, we found 357 health workers in our six cadre categories, to serve a population of 1.02 million. Total demand for the MCH services guaranteed under India's NRHM outpaced supply for every category of health worker but one. To properly serve the study population, the health workforce supply should be enhanced by 43 additional physicians, 15 nurses and 80 nurse midwives. Those numbers probably under-estimate the need, as they assume away geographic barriers. CONCLUSIONS Our study established time standards in minutes for each MCH activity promised by the NRHM, which could be applied elsewhere in India by government planners and civil society advocates. Our calculations indicate significant numbers of new health workers are required to deliver the services promised by the NRHM.
Integrating ecosystem services into crop protection and pest management: Case study with the soil fumigant 1,3‐dichloropropene and its use in tomato production in Italy

Ecosystems provide the conditions for producing food, regulating water, and providing wildlife habitats; these, among others, are known as ecosystem services (ESs). Food production is both economically and culturally important to southern European farmers, particularly in Italy where farmers grow flavorsome tomatoes with passion and pride. Growers rely on pesticides for crop protection, the potential environmental impact of which is often questioned by regulators and other stakeholders. The European regulatory system for the approval of pesticides includes a thorough evaluation of risks to the environment and is designed to be protective of ecosystems. The consideration of ESs in environmental decision making is a growing trend, and the present case study provides an example of how ESs evaluation could be used to enhance agricultural practices and regulatory policy for crop protection. By attacking plant roots, nematodes may affect the growth and yield of fruit and vegetable crops, and the income earned by farmers at harvest time. Available solutions include chemical treatments such as 1,3‐dichloropropene (1,3‐D), physical treatments (solarization), and biological treatments (biofumigation). In order to characterize the risks and benefits associated with the use of 1,3‐D in crop protection, ESs and socioeconomic analyses were applied to its use in the control of nematodes in tomato cultivation in southern Italy. The present study confirmed the benefits of 1,3‐D to tomato production in Italy, with significant positive effects on production yields and farm income when compared to limited and transient potential impacts on services such as soil function. It was confirmed that 1,3‐D allows farm income to be maintained and secures tomato production in these regions for the future. Integr Environ Assess Manag 2016;12:801–810. © 2016 SETAC
Resistance of Aphis gossypii (Homoptera: Aphididae) to Fenvalerate and Imidacloprid and Activities of Detoxification Enzymes on Cotton and Cucumber

Abstract Resistance of two strains of cotton aphid, Aphis gossypii Glover, to fenvalerate and imidacloprid were determined on cotton (Gossypium hirsutum L.) and cucumber (Cucumis sativa L.) after resistance selection of one strain to fenvalerate for 16 consecutive generations, and of a second strain to imidacloprid for 12 consecutive generations on cotton in greenhouses. Dose–response and activities of detoxication enzymes of the fenvalerate-resistant strain (R-fenvalerate), the imidacloprid-resistant strain (R-imidacloprid), and a susceptible strain (S) were determined. After 16 consecutive generations of selection, resistance of A. gossypii to fenvalerate increased >29,000-fold and to imidacloprid 8.1-fold. On cucumber, resistance of the R-fenvalerate strain to fenvalerate increased 700-fold and to imidacloprid 3.6-fold. However, the most significant finding in this study was that the R-imidacloprid strain exhibited cross-resistance to fenvalerate, with a resistance ratio of 108.9-fold on cotton and 33.5-fold on cucumber, whereas the R-fenvalerate strain did not show significant cross-resistance to imidacloprid on either plant species. Both resistant strains of A. gossypii were more resistant to fenvalerate on cotton than on cucumber, whereas their susceptibility to imidacloprid on cotton and cucumber were not significantly different. The response of the S strain to fenvalerate and imidacloprid were similar on cotton and cucumber. Activities of acetylcholinesterase (AChE) and α-naphthylacetate (α-NA) esterases of A. gossypii were significantly different among the three strains, with the R-fenvalerate strain having the highest, followed by the R-imidacloprid strain, and the S strain the lowest. The activities of the AChE and α-NA esterases for all three strains were also significantly higher on cotton than on cucumber. The resistance mechanism and resistance management strategies for the R-fenvalerate and R-imidacloprid strains of A. gossypii to fenvalerate and imidacloprid on cotton and cucumber are discussed.
Autopathogenic T Helper Cell Type 1 (Th1) and Protective Th2 Clones Differ in Their Recognition of the Autoantigenic Peptide of Myelin Proteolipid Protein

We previously generated a panel of T helper cell 1 (Th1) clones specific for an encephalitogenic peptide of myelin proteolipid protein (PLP) peptide 139–151 (HSLGKWLGHPDKF) that induces experimental autoimmune encephalomyelitis (EAE) upon adoptive transfer. In spite of the differences in their T cell receptor (TCR) gene usage, all these Th1 clones required W144 as the primary and most critical TCR contact residue for the activation. In this study, we determined the TCR contact residues of a panel of Th2/Th0 clones specific for the PLP peptide 139–151 generated either by immunization with the PLP 139–151 peptide with anti– B7-1 antibody or by immunization with an altered peptide Q144. Using alanine-substituted peptide analogues of the native PLP peptide, we show that the Th2 clones have shifted their primary contact residue to the NH2-terminal end of the peptide. These Th2 cells do not show any dependence on the W144, but show a critical requirement for L141/G142 as their major TCR contact residue. Thus, in contrast with the Th1 clones that did not proliferate to A144-substituted peptide, the Th2 clones tolerated a substitution at position 144 and proliferated to A144 peptide. This alternative A144 reactive repertoire appears to have a critical role in the regulation of autoimmune response to PLP 139–151 because preimmunization with A144 to expand the L141/G142-reactive repertoire protects mice from developing EAE induced with the native PLP 139–151 peptide. These data suggest that a balance between two different T cell repertoires specific for same autoantigenic epitope can determine disease phenotype, i.e., resistance or susceptibility to an autoimmune disease.
Hierarchical Ordering of Reticular Networks

The structure of hierarchical networks in biological and physical systems has long been characterized using the Horton-Strahler ordering scheme. The scheme assigns an integer order to each edge in the network based on the topology of branching such that the order increases from distal parts of the network (e.g., mountain streams or capillaries) to the “root” of the network (e.g., the river outlet or the aorta). However, Horton-Strahler ordering cannot be applied to networks with loops because they they create a contradiction in the edge ordering in terms of which edge precedes another in the hierarchy. Here, we present a generalization of the Horton-Strahler order to weighted planar reticular networks, where weights are assumed to correlate with the importance of network edges, e.g., weights estimated from edge widths may correlate to flow capacity. Our method assigns hierarchical levels not only to edges of the network, but also to its loops, and classifies the edges into reticular edges, which are responsible for loop formation, and tree edges. In addition, we perform a detailed and rigorous theoretical analysis of the sensitivity of the hierarchical levels to weight perturbations. In doing so, we show that the ordering of the reticular edges is more robust to noise in weight estimation than is the ordering of the tree edges. We discuss applications of this generalized Horton-Strahler ordering to the study of leaf venation and other biological networks.
The influence of layer-interface geometry on single-layer folding

Abstract Geometrical heterogeneities along layer interfaces play a key role in determining the geometries of folds developed during shortening of competent layers. We present a series of numerical simulations to investigate the influence of initial sinusoidal perturbations on the folding of single layers. Models consist of a competent viscous single layer embedded in a softer matrix, with the layer orientated parallel to the shortening direction. We first generalize the wide spectrum of sinusoidal perturbations accounting for asymmetries along and across a competent single layer, using two parameters: transversal asymmetry (A′) and longitudinal asymmetry (φ). These two parameters allow the transition between classical fold shapes and pinch and swell geometries to be studied. The parameter A′ describes the development of fold hinges with different geometries between the upper and lower layer interfaces, and abnormal curvatures between the outer and inner arcs of fold hinges. The parameter φ induces a strong polarity on the folds, with a systematic preferred orientation of the pinch and swell regions of the layer, even if there is no shear component parallel to the layer. Our results demonstrate the importance of structural inheritance on the resulting fold geometries, and suggest that caution must be taken when using certain types of asymmetrical folds as strain markers and kinematic indicators.
Globally optimal spinal cord segmentation using a minimal path in high dimensions

Spinal cord segmentation is an important step to empirically quantify spinal cord atrophy that can occur in neurological diseases such as multiple sclerosis (MS). In this work, we propose a novel method to find the globally optimal segmentation of the spinal cord using a high dimensional minimal path search. The spinal cord cross-sectional shapes are represented using principal component analysis (in the probability simplex) which captures most of spinal cord's axial cross-sectional variation and partial volume effects. We propose modifications to the A* minimal path search algorithm that drastically reduce the required memory and run-time to make our high dimensional minimal path optimization computationally feasible. Finally, we validate our results over five vertebrae levels of both healthy and MS clinical MR volumes (20 volumes total) and show improvements on volume agreement with expert segmentations and less user interaction when compared to current state-of-the-art methods.
Distinct Expression Profiles and Different Functions of Odorant Binding Proteins in Nilaparvata lugens Stål

Background Odorant binding proteins (OBPs) play important roles in insect olfaction. The brown planthopper (BPH), Nilaparvata lugens Stål (Delphacidae, Auchenorrhyncha, Hemiptera) is one of the most important rice pests. Its monophagy (only feeding on rice), wing form (long and short wing) variation, and annual long distance migration (seeking for rice plants of high nutrition) imply that the olfaction would play a central role in BPH behavior. However, the olfaction related proteins have not been characterized in this insect. Methodology/Principal Findings Full length cDNA of three OBPs were obtained and distinct expression profiles were revealed regarding to tissue, developmental stage, wing form and gender for the first time for the species. The results provide important clues in functional differentiation of these genes. Binding assays with 41 compounds demonstrated that NlugOBP3 had markedly higher binding ability and wider binding spectrum than the other two OBPs. Terpenes and Ketones displayed higher binding while Alkanes showed no binding to the three OBPs. Focused on NlugOBP3, RNA interference experiments showed that NlugOBP3 not only involved in nymph olfaction on rice seedlings, but also had non-olfactory functions, as it was closely related to nymph survival. Conclusions NlugOBP3 plays important roles in both olfaction and survival of BPH. It may serve as a potential target for developing behavioral disruptant and/or lethal agent in N. lugens.
Malignant tumors of the liver in children.

This article aims to give an overview of pediatric liver tumors; in particular of the two most frequently occurring groups of hepatoblastomas and hepatocellular carcinomas. Focus lays on achievements gained through worldwide collaboration. We present recent advances in insight, treatment results, and future questions to be asked. Increasing international collaboration between the four major Pediatric Liver Tumor Study Groups (SIOPEL/GPOH, COG, and JPLT) may serve as a paradigm to approach rare tumors. This international effort has been catalyzed by the Children's Hepatic tumor International Collaboration (CHIC) formation of a large collaborative database. Interrogation of this database has led to a new universal risk stratification system for hepatoblastoma using PRETEXT/POSTTEXT staging as a backbone. Pathologists in this international collaboration have established a new histopathological consensus classification for pediatric liver tumors. Concomitantly there have been advances in chemotherapy options, an increased role of liver transplantation for unresectable tumors, and a web portal system developed at www.siopel. org for international education, consultation, and collaboration. These achievements will be further tested and validated in the upcoming Paediatric Hepatic International Tumour Trial (PHITT).
Large-Eddy Simulations of the 26 November 1991 FIRE II Cirrus Case

Abstract Large-eddy simulations (LESs) were performed to study the dynamical, microphysical, and radiative processes in the 26 November 1991 FIRE II cirrus event. The LES model inherits the framework of the RAMS version 3b, developed at Colorado State University. It includes a new two-stream radiation model developed by Harrington and a new subgrid-scale model developed by Kosovic. The LES model successfully simulated a single thin cloud layer for LES-1 and a deep cloud structure for LES-2. The simulations demonstrated that latent heat release can play a significant role in the evolution of thick cirrus clouds. For the thin cirrus in LES-1, the latent heat release was insufficient for the cirrus clouds to become positively buoyant. However, in some special cases such as LES-2, positively buoyant cells can be embedded within the cirrus layers. The updrafts from these cells induced its own pressure perturbations that affected the cloud evolution. Vertical profiles of the total radiative and latent heating r.
1-1-2006 Cost-Benefit Analysis : New Foundations on Shifting Sand

New Foundations of Cost–Benefit Analysis, by Matthew Adler and Eric Posner, represents the most ambitious and credible effort to date to build a solid theoretical defense of the use of cost–benefit analysis (CBA) in evaluating government regulation. In this review, three cost–benefit “skeptics” offer their reactions to this ambitious and important book. We note its virtues – its humility, its scrupulousness, its open-mindedness. We also explore its vices. If preferences are to be “laundered,” is it intellectually defensible to remove the bad but not consider adding the good? Does Adler’s and Posner’s welfarism really play the limited role they suppose, or does it risk “crowding out” other important deontological and distributional values? If CBA is merely a decision procedure that provides an imperfect proxy of welfare – the moral criterion we really care about – how do we know that the proxy it provides in practice will actually be accurate enough to be useful? Isn’t this at bottom an empirical question that cannot be answered by this thoroughly theoretical book? If CBA is no more than an imperfect proxy for welfare, then alternative imperfect decision procedures may perform better in the real world.
A Faster, Better Approximation Algorithm for the Minimum Latency Problem

We give a 7.18-approximation algorithm for the minimum latency problem that uses only $O(n \log n)$ calls to the prize-collecting Steiner tree (PCST) subroutine of Goemans and Williamson. This improves the previous best algorithms in both performance guarantee and running time. A previous algorithm of Goemans and Kleinberg for the minimum latency problem requires an approximation algorithm for the $k$-minimum spanning tree ($k$-MST) problem which is called as a black box for each value of $k$. Their algorithm can achieve an approximation factor of 10.77 while making $O(n (n+\log C) \log n)$ PCST calls, a factor of 8.98 using $O(n^3(n+\log C) \log n)$ PCST calls, or a factor of $7.18+\epsilon$ using $n^{O(1/\epsilon)}\log C$ PCST calls, via the $k$-MST algorithms of Garg, Arya and Ramesh, and Arora and Karakostas, respectively. Here $n$ denotes the number of nodes in the instance, and $C$ is the largest edge cost in the input. In all cases, the running time is dominated by the PCST calls. Since the PCST subroutine can be implemented to run in $O(n^2)$ time, the overall running time of our algorithm is $O(n^3 \log n)$. We also give a faster randomized version of our algorithm that achieves the same approximation guarantee in expectation, but uses only $O(\log^2 n)$ PCST calls, and derandomize it to obtain a deterministic algorithm with factor $7.18+\epsilon$, using $O(\frac{1}{\epsilon} \log^2 n)$ PCST calls. The basic idea for our improvement is that we do not treat the $k$-MST algorithm as a black box. This allows us to take advantage of some special situations in which the PCST subroutine delivers a 2-approximate $k$-MST. We are able to obtain the same approximation ratio that would be given by Goemans and Kleinberg if we had access to 2-approximate $k$-MSTs for all values of $k$, even though we have them only for some values of $k$ that we are not able to specify in advance. We also extend our algorithm to a weighted version of the minimum latency problem.