Miracle-dz/UniFAR-FTUs huggingface dataset:
Imatinib (STI571) Provides Only Limited Selectivity for CML Cells and Treatment Might Be Complicated by Silent BCR-ABL Genes

Very promising results have been obtained in clinical trials on chronic-phase chronic myeloid leukemia (CP-CML) patients treated with imatinib mesylate (IM; Gleevec®, STI571), a BCR-ABL tyrosine kinase inhibitor. However, we found that IM caused considerable inhibition of normal hematopoietic progenitor cells upon treating control bone marrow (BM) cultures. In vitro IM treatment gave a decrease in the yield and size of colonies from BM of untreated CP-CML patients that was only two to three times that from the normal samples. Moreover, about 30% of myeloid progenitors (CFU-GM) from CML BM still formed colonies in the presence of IM, most of which had BCR-ABL RNA. About half of these treated colonies also displayed methylation of the internal ABL Pa promoter, a CML-specific epigenetic alteration, which was used in this study as a marker for BCR-ABL translocation-containing cells. However, ~5-8% of the treated or the untreated CML BM-derived colonies had no detectable BCR-ABL RNA by two or three rounds of RT-PCR despite being positive for the internal standard RNA and displaying hallmarks of CML, either t(9;22)(q34;q11) or ABL Pa methylation. Our results indicate that IM is only partially specific for CML progenitor cells compared to normal hematopoietic progenitor cells and suggest that some CML cells may have a silent BCR-ABL oncogene that could interfere with therapy.
Evidences of efficacy of allergen immunotherapy in atopic dermatitis: an updated review

Purpose of reviewTo update and assess the quality of the evidence concerning the efficacy of allergen immunotherapy for atopic eczema. Desensitization for eczema as a clinical manifestation of food allergy was not a target of this review. Recent findingsIn the past 5 years, from the last comprehensive systematic review of Bussmann et al., four controlled trials have been published on this topic, two using injection and two sublingual immunotherapy. The active treatment was compared with placebo, pharmacotherapy or different schedules of immunotherapy. The studies variably involved adults and children and showed an improvement of atopic dermatitis severity. Severe eczema seems less responsive to hyposensitization, and a minimal treatment duration of 9–12 months appears necessary. SummaryThe efficacy of immunotherapy in patients with atopic eczema has been poorly investigated in the past 5 years. The available trials have small dimension and some methodological shortcomings, in addition to incomplete reporting. Clinical and methodological interstudy heterogeneity is apparent. Only one study adopted a placebo control. The evidence of efficacy has not critically changed from previous systematic observations. No long-term studies have been conducted to determine the disease-modifying potential of specific immunotherapy in the context of the ‘allergy march’.
Proteasome inhibition by lipofuscin/ceroid during postmitotic aging of fibroblasts

We have studied the effects of hyperoxia and of cell loading with artificial lipofuscin or ceroid pigment on the postmitotic aging of human lung fibroblast cell cultures. Normobaric hyperoxia (40% oxygen) caused an irreversible senescence‐like growth arrest after about 4 wk and shortened postmitotic life span from 1–1/2 years down to 3 months. During the first 8 wk of hyperoxia‐induced ‘aging’, overall protein degradation (breakdown of [35S]methionine metabolically radiolabeled cell proteins) increased somewhat, but by 12 wk and thereafter overall proteolysis was significantly depressed. In contrast, protein synthesis rates were unaffected by 12 wk of hyperoxia. Lysosomal cathepsin‐specific activity (using the fluorogenic substrate z‐FR‐MCA) and cytoplasmic proteasome‐specific activity (measured with suc‐LLVY‐MCA) both declined by 80% or more over 12 wk. Hyperoxia also caused a remarkable increase in lipofuscin/ceroid formation and accumulation over 12 wk, as judged by both fluorescence measurements and FACscan methods. To test whether the association between lipofuscin/ceroid accumulation and decreased proteolysis might be causal, we next exposed cells to lipofuscin/ceroid loading under normoxic conditions. Lipofuscin/ceroid‐loaded cells indeed exhibited a gradual decrease in overall protein degradation over 4 wk of treatment, whereas protein synthesis was unaffected. Proteasome specific activity decreased by 25% over this period, which is important since proteasome is normally responsible for degrading oxidized cell proteins. In contrast, an apparent increase in lysosomal cathepsin activity was actually caused by a large increase in the number of lysosomes per cell. To test whether lipofuscin/ceroid could in fact directly inhibit proteasome activity, thus causing oxidized proteins to accumulate, we incubated purified proteasome with lipofuscin/ceroid preparations in vitro. We found that proteasome is directly inhibited by lipofuscin/ceroid. Our results indicate that an accumulation of oxidized proteins (and lipids) such as lipofuscin/ceroid may actually cause further increases in damage accumulation during aging by inhibiting the proteasome. –Sitte, N. , Huber, M. , Grune, T. , Ladhoff, A. , Doecke, W. ‐D. , von Zglinicki, T. , Davies, K. J. A. Proteasome inhibition by lipofuscin/ceroid during postmitotic aging of fibroblasts. FASEB J. 14, 1490–1498 (2000)
Three-dimensional visualisation and articulating instrumentation: Impact on simulated laparoscopic tasks

Laparoscopy requires the development of technical skills distinct from those used in open procedures. Several factors extending the learning curve of laparoscopy include ergonomic and technical difficulties, such as the fulcrum effect and limited degrees of freedom. This study aimed to establish the impact of four variables on performance of two simulated laparoscopic tasks. Methods: Six subjects including novice (n=2), intermediate (n=2) and expert surgeons completed two tasks: 1) four running sutures, 2) simple suture followed by surgeon's knot plus four square knots. Task variables were suturing angle (left/right), needle holder type (standard/articulating) and visualisation (2D/3D). Each task with a given set of variables was completed twice in random order. The endpoints included suturing task completion time, average and maximum distance from marks and knot tying task completion time. Results: Suturing task completion time was prolonged by 45-degree right angle suturing, articulating needle holder use and lower skill levels (all P < 0.0001). Accuracy also decreased with articulating needle holder use (both P < 0.0001). 3D vision affected only maximum distance (P=0.0108). For the knot tying task, completion time was greater with 45-degree right angle suturing (P=0.0015), articulating needle holder use (P < 0.0001), 3D vision (P=0.0014) and novice skill level (P=0.0003). Participants felt that 3D visualisation offered subjective advantages during training. Conclusions: Results suggest construct validity. A 3D personal head display and articulating needle holder do not immediately improve task completion times or accuracy and may increase the training burden of laparoscopic suturing and knot tying.
Synthesis, cytotoxicity, and antitumor activity of copper(II) and iron(II) complexes of (4)N-azabicyclo[3.2.2]nonane thiosemicarbazones derived from acyl diazines.

A series of thiosemicarbazones (TSCs) (bearing a (4)N-azabicyclo[3.2. 2]nonane moiety) derived from 3-acylpyridazines, 4-acetylpyrimidines, and 2-acetylpyrazines (1-8) were synthesized as potential antitumor agents. TSCs 1-8 exhibited potent cytotoxic activity against human acute lymphoblastic leukemia CCRF-CEM cells (IC(50) = 0.05-0.77 microM) and colon adenocarcinoma HT-29 cells (IC(50) = 0.011-2.22 microM). Copper II complexes of TSCs 1-8 showed significant improvement in cytotoxic activity against HT-29 cells (IC(50) = 0.004-1.51 microM) by a factor of 3. However, complexation of ligands 1, 2, 4, and 6 with Fe(II) results in lowering of cytotoxic activity by a factor of approximately 7. In clonogenic assays involving human tumor cells of different tumor origins, compounds 5, 7, 8, and their copper complexes 5Cu(II), 7Cu(II), and 8Cu(II) exhibited remarkable cytotoxic activities with mean IC(50) values of 6, 0.18, 1, 1, 0.37, and 0.37 nM, respectively. In particular, the compounds were highly effective against human colon carcinoma and large and small cell lung carcinoma cells. The TSC derivative 5 was evaluated in vivo in nude mice bearing LXFL 529 human large cell lung carcinoma cells. With respect to antitumor activity, application of 30 mg/kg/d resulted in moderate inhibition (42%) of tumor growth. No effect on tumor growth was observed at a dose of 10 mg/kg/d. However, a dose of 40 or 60 mg/kg/d resulted in 50 and 75% death, respectively, in the treated mice, indicating the high toxicity of these compounds. Using human liver microsomes, compound 5 was found to be rapidly and highly metabolized in vitro. In actual fact, only 2% of the unmetabolized compound could be detected in the incubation medium after 5 min. The IC(50) for cell proliferation (0.006-0.022 microM) elicited by these compounds is much lower than that of the inhibition of [(14)C]cytidine incorporation into DNA (0.18-3.32 microM). These compounds are also noncell cycle specific agents. Interestingly, compounds 5, 5Cu(II), and 8 were found to be potent inducers of apoptosis in Burkitt's lymphoma cells.
Connected operators on 3D data for human body analysis

This paper presents a novel method for filtering and extraction of human body features from 3D data, either from multi-view images or range sensors. The proposed algorithm consists in processing the geodesic distances on a 3D surface representing the human body in order to find prominent maxima representing salient points of the human body. We introduce a 3D surface graph representation and filtering strategies to enhance robustness to noise and artifacts present in this kind of data. We conduct several experiments on different datasets involving 2 multi-view setups and 2 range data sensors: Kinect and Mesa SR4000. In all of them, the proposed algorithm shows a promising performance towards human body analysis with 3D data.
Extracorporeal life support for 100 adult patients with severe respiratory failure.

OBJECTIVE The authors retrospectively reviewed their experience with extracorporeal life support (ECLS) in 100 adult patients with severe respiratory failure (ARF) to define techniques, characterize its efficacy and utilization, and determine predictors of outcome. SUMMARY BACKGROUND DATA Extracorporeal life support maintains gas exchange during ARF, providing diseased lungs an optimal environment in which to heal. Extracorporeal life support has been successful in the treatment of respiratory failure in infants and children. In 1990, the authors instituted a standardized protocol for treatment of severe ARF in adults, which included ECLS when less invasive methods failed. METHODS From January 1990 to July 1996, the authors used ECLS for 100 adults with severe acute hypoxemic respiratory failure (n = 94): paO2/FiO2 ratio of 55.7+/-15.9, transpulmonary shunt (Qs/Qt) of 52+/-22%, or acute hypercarbic respiratory failure (n = 6): paCO2 84.0+/-31.5 mmHg, despite and after maximal conventional ventilation. The technique included venovenous percutaneous access, lung "rest," transport on ECLS, minimal anticoagulation, hemofiltration, and optimal systemic oxygen delivery. RESULTS Overall hospital survival was 54%. The duration of ECLS was 271.9+/-248.6 hours. Primary diagnoses included pneumonia (49 cases, 53% survived), adult respiratory distress syndrome (45 cases, 51 % survived), and airway support (6 cases, 83% survived). Multivariate logistic regression modeling identified the following pre-ECLS variables significant independent predictors of outcome: 1) pre-ECLS days of mechanical ventilation (p = 0.0003), 2) pre-ECLS paO2/FiO2 ratio (p = 0.002), and 3) age (years) (p = 0.005). Modeling of variables during ECLS showed that no mechanical complications were independent predictors of outcome, and the only patient-related complications associated with outcome were the presence of renal failure (p < 0.0001) and significant surgical site bleeding (p = 0.0005). CONCLUSIONS Extracorporeal life support provides life support for ARF in adults, allowing time for injured lungs to recover. In 100 patients selected for high mortality risk despite and after optimal conventional treatment, 54% survived. Extracorporeal life support is extraordinary but reasonable treatment in severe adult respiratory failure. Predictors of survival exist that may be useful for patient prognostication and design of future prospective studies.
Cardiac-Specific EPI64C Blunts Pressure Overload–Induced Cardiac Hypertrophy

The calcium-responsive molecule, calcineurin, has been well characterized to play a causal role in pathological cardiac hypertrophy over the past decade. However, the intrinsic negative regulation of calcineurin signaling during the progression of cardiomyocyte hypertrophy remains enigmatic. Herein, we explored the role of EPI64C, a dual inhibitor of both Ras and calcineurin signaling during T-cell activation, in pressure overload–induced cardiac hypertrophy. We generated a cardiac-specific Epi64c conditional knockout mouse strain and showed that loss of Epi64c remarkably exacerbates pressure overload–induced cardiac hypertrophy. In contrast, EPI64C gain-of-function in cardiomyocyte-specific Epi64c transgenic mice exerts potent protective effects against cardiac hypertrophy. Mechanistically, the cardioprotective effects of EPI64C are largely attributed to the disrupted calcineurin signaling but are independent of its Ras suppressive capability. Molecular studies have indicated that the 406 to 446 C-terminal amino acids in EPI64C directly bind to the 287 to 337 amino acids in the catalytic domain of calcineurin, which is responsible for the EPI64C-mediated suppressive effects. We further extrapolated our studies to cynomolgus monkeys and showed that gene therapy based on lentivirus-mediated EPI64C overexpression in the monkey hearts blunted pressure overload–induced cardiac hypertrophy. Our study thus identified EPI64C as a novel negative regulator in cardiac hypertrophy by targeting calcineurin signaling and demonstrated the potential of gene therapy and drug development for treating cardiac hypertrophy.
Superheroes, Safety, and Social Policy: Induced Levels of Physical Security may Produce Greater Liberal Policy Preferences

Preferences for conservative policies are thought to be, at least in part, the result of experiencing a more threatening world, and consequentially preferring to avoid, rather than approach, new information or situations (Hibbing, Alford & Smith, 2014; Jost, Federico, & Napier, 2013; Shook & Fazio 2009). In addition to explaining how policy attitudes may be formed, this recent research has helped to explain why attitudes may be more responsive to external influences (or manipulations) than previously thought, especially in regard to political attitudes such as ideology and partisanship. Therefore, as feelings of safety are increased, and feelings of threat are decreased, individuals' policy preferences may become less conservative. This study examines the relationship between economic & social policy attitudes, ideology, and feelings of safety. In order to explore this, we replicated Study 1 conducted by Napier and colleagues (2017), which demonstrated that when conservative individuals imagined a scenario in which they were invincible, and consequently felt physically safe, this increased their liberalism on social policy preferences. We find that while the manipulation successfully increased feelings of physical safety, this resulted in no significant effect on political attitudes for either Republicans or Democrats. This research demonstrates the importance of further exploration into the relationship of safety, rather than threat, and political attitudes.
Is Androgenetic Alopecia a Photoaggravated Dermatosis?

Progressive thinning of the scalp hair in androgenetic alopecia (AGA) results in a gradual decline in natural protection of the scalp from ultraviolet radiation (UVR). A number of pathologic conditions of the scalp are evidently related to UVR, particularly photosensitive diseases and disorders of the chronically photodamaged bald scalp. The most important chronic effects of UVR are photocarcinogenesis and solar elastosis. Besides these, erosive pustular dermatosis and ‘red scalp’ are distinct disorders peculiar to the balding scalp. While the consequences of sustained UVR on the unprotected scalp are well appreciated, the effects of UVR on hair loss have widely been ignored. However, clinical observations and theoretical considerations suggest that UVR may have negative effects: acute telogen effluvium from UVR has been described, and the production of porphyrins by Propionibacterium sp. in the pilosebaceous duct, with photoactivation of porphyrins leading to oxidative tissue injury, has been implicated in follicular microinflammation. Alternatively, keratinocytes themselves may respond to physicochemical stress from UVR, besides irritants and pollutants, by producing radical oxygen species and nitric oxide and by releasing proinflammatory cytokines, eventually leading to injury of the putative site of follicular stem cells in the superficial portion of the hair follicle. Since all of these processes involved in hair loss share the common feature that they are induced or exacerbated by exposure to sunlight, it is proposed that AGA is a photoaggravated dermatosis that requires photoprotection.
A new approach to traffic sign recognition through primary visual characteristics

As far as the safety of a driver is concerned, more focus should be put on correct interpretation and information which is conveyed by a traffic sign, while driving a vehicle along the road. A sign board can be thought of as an emblem which disseminates important and meaningful information regarding the potential hazards prevailing among road users comprising roadways cladded with snowfall, construction worksites or repairing of roads taking place and telling the people to follow an alternative route. It alerts the person who is passing through the road about the maximum possible extremity that his vehicle is trying to achieve indicating slowing down the speed of vehicle since chances of having collision cannot be ruled out. With constant increasing of the training database size, not only the recognition accuracy, but also the computation complexity should be considered in designing a feasible recognition approach. The traffic sign images were acquired from the image database and were subjected to some pre-processing techniques such as conversion of original into gray scale images, filtering the images with the help of Averaging Filter, Wiener Filter, carrying out the operation of Unsharp Mask Filtering which consists of performing the conventional method of Unsharp Mask Filtering as well as controlling the amount of sharpness with the help of certain parameters. In the future, we will concentrate on detecting, recognizing as well as classifying a particular sign board.
Exploring the Use of Large Clinical Data to Inform Patients for Shared Decision Making

Barriers to patient participation in the shared decision making process prevent patients from fully participating in evaluating treatment options and treatment selection. Patients who use a decision aid are more informed and engaged in the shared decision making process. Patient decision aids do not use real clinical data for patient information and may not represent the data well. We designed an interface, for a shared decision making aid, that leverages clinical data to inform risk ratios and create patient stories, or vignettes, and present a visual representation of quantified treatment outcomes data. Usability testing was conducted with experts to evaluate the interface and the utility of using real clinical information that patients can explore. The experts' comments were transcribed and coded for themes. Themes were quantified and comments were interpreted for refinement and modification to the patient decision aid interface and data visualization.
Viral quasi-species evolution during hepatitis Be antigen seroconversion.

BACKGROUND & AIMS Although viral quasi-species evolution may be related to pathogenesis of disease, little is known about this in hepatitis B virus (HBV); consequently, we aimed to evaluate the evolution of HBV quasi-species in patients with well-characterized clinical phenotypes of chronic hepatitis B. METHODS Four cohorts of well-defined clinical phenotypes of chronic hepatitis B, hepatitis Be antigen (HBeAg) seroconverters (spontaneous seroconverters and interferon-induced seroconverters) and nonseroconverters (controls and interferon nonresponders) were followed during 60 months on average. Serum from 4 to 5 time points was used for nested polymerase chain reaction, cloning, and sequencing of the precore/core gene (20 clones/sample). Only patients with genotype B were used. Sequences were aligned using Clustal X, then serial-sample unweighted pair grouping method with arithmetic means phylogenetic trees were constructed using Pebble 1.0 after which maximum likelihood estimates of pairwise distances under a GTR + I + G model was assessed. Viral diversity and substitution rates were then estimated. RESULTS Analysis of 3386 sequences showed that HBeAg seroconverters had 2.4-fold higher preseroconversion viral sequence diversity (P = .0183), and 10-fold higher substitution rate (P < .0001) than did nonseroconverters, who had persistently low viral diversity (3.6 x 10(-3) substitutions/site) and substitution rate (2.2 x 10(-5) substitutions x site(-1) x month(-1)). After seroconversion, there was a striking increase in viral diversity. Most seroconverters had viral variants that showed evidence of positive selection, which was seen mainly after seroconversion. CONCLUSIONS The high viral diversity before a reduction in HBV DNA and before HBeAg seroconversion could either be related to occurrence of stochastic mutations that lead to a break in immune tolerance or to increased immune reactivity that drives escape mutations.
Longitudinal studies of effects of divorce on children in Great Britain and the United States.

National, longitudinal surveys from Great Britain and the United States were used to investigate the effects of divorce on children. In both studies, a subsample of children who were in two-parent families during the initial interview (at age 7 in the British data and at ages 7 to 11 in the U.S. data) were followed through the next interview (at age 11 and ages 11 to 16, respectively). At both time points in the British data, parents and teachers independently rated the children's behavior problems, and the children were given reading and mathematics achievement tests. At both time points in the U.S. data, parents rated the children's behavior problems. Children whose parents divorced or separated between the two time points were compared to children whose families remained intact. For boys, the apparent effect of separation or divorce on behavior problems and achievement at the later time point was sharply reduced by considering behavior problems, achievement levels, and family difficulties that were present at the earlier time point, before any of the families had broken up. For girls, the reduction in the apparent effect of divorce occurred to a lesser but still noticeable extent once preexisting conditions were considered.