Miracle-dz/UniFAR-FTUs huggingface dataset:
Preclinical Development Hsp 90 Inhibitor – Mediated Disruption of Chaperone Association of ATR with Hsp 90 Sensitizes Cancer Cells to DNA Damage

Following DNA damage that results in stalled replication fork, activation of ATR-CHK1 signaling induces the DNA damage response (DDR) in transformed cells. In the present studies on human cervical and breast cancer cells, we determined the effects of hsp90 inhibition on the levels and accumulation of DNA damage/ repair–associated proteins following exposure to g-ionizing radiation (IR; 4 Gy). We show that hsp90 inhibition with 17-allylamino-demehoxygeldanamycin or the novel, nongeldanamycin analogue AUY922 (resorcinylic isoxazole amide; Novartis Pharma) dose-dependently reduced the levels of ATR and CHK1 without affecting ATM levels. AUY922-mediated depletion of ATR and CHK1 was associated with an increase in their polyubiquitylation and decreased binding to hsp90. Cotreatment with bortezomib partially restored AUY922-mediated depletion of ATR and CHK1 levels. Additionally, treatment with AUY922 reduced the accumulation of ATR, p53BP1, and CHK1 but not g-H2AX to the sites of DNAdamage. Following exposure to IR, AUY922 treatment abrogated IR-induced phospho (p)-ATR and p-CHK1 levels, but significantly enhanced g-H2AX levels. AUY922 treatment also increased IR-induced accumulation of the cells in G2–M phase of the cell cycle, inhibited the repair of IR-induced DNA damage, and augmented IR-mediated loss of clonogenic survival. Short hairpin RNA–mediated depletion of ATR also inhibited IR-induced p-ATR and p-CHK1, but increased g-H2AX levels, sensitizing cancer cells to IR-induced apoptosis and loss of clonogenic survival. These findings indicate that ATR is a bona fide hsp90 client protein and post-IR administration of AUY922, by inhibiting ATR-CHK1–mediated DDR, sensitizes cancer cells to IR.Mol Cancer Ther; 10(7); 1194–206. 2011 AACR.
Hydrogen Peroxide Removes TRPM4 Current Desensitization Conferring Increased Vulnerability to Necrotic Cell Death*

Necrosis is associated with an increase in plasma membrane permeability, cell swelling, and loss of membrane integrity with subsequent release of cytoplasmic constituents. Severe redox imbalance by overproduction of reactive oxygen species is one of the main causes of necrosis. Here we demonstrate that H2O2 induces a sustained activity of TRPM4, a Ca2+-activated, Ca2+-impermeant nonselective cation channel resulting in an increased vulnerability to cell death. In HEK 293 cells overexpressing TRPM4, H2O2 was found to eliminate in a dose-dependent manner TRPM4 desensitization. Site-directed mutagenesis experiments revealed that the Cys1093 residue is crucial for the H2O2-mediated loss of desensitization. In HeLa cells, which endogenously express TRPM4, H2O2 elicited necrosis as well as apoptosis. H2O2-mediated necrosis but not apoptosis was abolished by replacement of external Na+ ions with sucrose or the non-permeant cation N-methyl-d-glucamine and by knocking down TRPM4 with a shRNA directed against TRPM4. Conversely, transient overexpression of TRPM4 in HeLa cells in which TRPM4 was previously silenced re-established vulnerability to H2O2-induced necrotic cell death. In addition, HeLa cells exposed to H2O2 displayed an irreversible loss of membrane potential, which was prevented by TRPM4 knockdown.
Examining the neural mechanisms involved in the affective and pragmatic coding of prosody

The vocal expression of humans includes expressions of emotions, such as anger or happiness, and pragmatic intonations, such as interrogative or affirmative, embedded within the language. These two types of prosody are differently affected by the so-called push and pull effects. Push effects, influenced by psychophysiological activities, strongly affect emotional prosody, whereas pull effects, influenced by cultural rules of expression, predominantly affect intonation or pragmatic prosody, even though both processes influence all prosodic production. Two empirical studies are described that exemplify the possibilities of dissociating emotional and linguistic prosody decoding at the neurological level. The first study was conducted to investigate the impairments in prosody recognition related to left or right temporo-parietal brain-damaged patients. The second study used electroencephalography in healthy participants to investigate the timing of information processing during emotional and linguistic prosody recognition tasks. The results highlight the importance of considering not only the distinction of different types of prosody, but also the relevance of the task realized by the participants to better understand information processes related to human vocal expression at the suprasegmental level.
AMD Radeon™ HD 7970 with graphics core next (GCN) architecture

This article consists of a collection of slides from the author's conference presentation on AMD's Radeon HD 7970. Some of the specific topics discussed include: AMD products' core architecture; multimedia and display system specifications; GCN architectures that support multiple product configurations; VLIW SIMD versus GCN quad SIMD processing comparisons; and GCN architecture design.
External quality assessment of methylmalonic acid and total homocysteine.

BACKGROUND The use of analyses for methylmalonic acid (MMA) and total homocysteine (HCY) in plasma has become widespread. Realizing the need for external quality assessment for these measurements, we started a program in 1997. The results for 1998 are reviewed in this report. METHODS Fourteen laboratories participated with 15 sets of results for MMA, and 28 laboratories participated with 34 sets of results for HCY. Results for four identical samples, made up from the same unmodified serum (MMA) or EDTA-plasma (HCY) pool, sent out under different identifications, were used for assessing the imprecision. Samples made up from the same pools supplemented with MMA or L-HCY to three concentrations were used for assessing the recovery. By using literature data for the biological variation, quality goals for both analytes were calculated. RESULTS The overall within-laboratory CV was 12% for MMA and 7.5% for HCY. Gas chromatography-mass spectrometric HCY results had lower imprecision than the HPLC or immunoassay results. For MMA, no significant between-laboratory component of variance was found. Only results for HCY obtained with HPLC methods showed significant between-laboratory variance. CONCLUSIONS Eight of the 15 participants achieved the minimum imprecision goal for MMA vs 9 of the 34 participants for HCY. The minimum quality goals for bias as approximated by the recovery were achieved by 13 participants for MMA and 26 for HCY.
Paclitaxel-eluting or sirolimus-eluting stents to prevent restenosis in diabetic patients.

BACKGROUND Drug-eluting stents are highly effective in reducing the rate of in-stent restenosis. It is not known whether there are differences in the effectiveness of currently approved drug-eluting stents in the high-risk subgroup of patients with diabetes mellitus. METHODS We enrolled 250 patients with diabetes and coronary artery disease: 125 were randomly assigned to receive paclitaxel-eluting stents, and 125 to receive sirolimus-eluting stents. The primary end point was in-segment late luminal loss. Secondary end points were angiographic restenosis (defined as in-segment stenosis of at least 50 percent at follow-up angiography) and the need for revascularization of the target lesion during a nine-month follow-up period. The study was designed to show noninferiority of the paclitaxel stent as compared with the sirolimus stent, defined as a difference in the extent of in-segment late luminal loss of no more than 0.16 mm. RESULTS The extent of in-segment late luminal loss was 0.24 mm (95 percent confidence interval, 0.09 to 0.39) greater in the paclitaxel-stent group than in the sirolimus-stent group (P=0.002). In-segment restenosis was identified on follow-up angiography in 16.5 percent of the patients in the paclitaxel-stent group and 6.9 percent of the patients in the sirolimus-stent group (P=0.03). Target-lesion revascularization was performed in 12.0 percent of the patients in the paclitaxel-stent group and 6.4 percent of the patients in the sirolimus-stent group (P=0.13). CONCLUSIONS In patients with diabetes mellitus and coronary artery disease, use of the sirolimus-eluting stent is associated with a decrease in the extent of late luminal loss, as compared with use of the paclitaxel-eluting stent, suggesting a reduced risk of restenosis.
MobiTest: a cross-platform tool for testing mobile applications

Testing is an essential part of the software development lifecycle. However, it can cost a lot of time and money to perform. For mobile applications, this problem is further exacerbated by the need to develop apps in a short time-span and for multiple platforms. This paper proposes MobiTest, a cross-platform automated testing tool for mobile applications, which uses a domain-specific language for mobile interfaces. With it, developers can define a single suite of tests that can then be run for the same application on multiple platforms simultaneously, with considerable savings in time and money.
Surrogate-Based Multi-Objective Optimization of Electrical Machine Designs Facilitating Tolerance Analysis

Multi-objective optimization algorithms are becoming ever more popular in the field of electrical machine design as they provide engineers with an automated way of efficiently exploring huge design spaces when searching for machines that are simultaneously highly competitive regarding several objectives, such as efficiency, material costs, torque ripple, and others. Apart from exhibiting these good target characteristics, a good design should also be robust, i.e., it should not be very sensitive to slight changes in its design parameters as this would either seriously impact production costs or make the physical machine behave differently than its (optimized) computer simulation model. This paper is focused on describing how global surrogate models (i.e., nonlinear regression models), that are created in order to reduce the dependence on finite-element (FE) simulations during the multi-objective optimization run, can be easily reused to perform very fast local and global tolerance/sensitivity analyses of generated designs. While obtained in a fraction of the time required by the complementary FE-based approach, the surrogate-based sensitivity estimates are able to provide accurate and valuable information regarding the robustness of electrical machine designs. Ultimately, by integrating robustness-related information with Pareto front projections, we aim to provide engineers with much clearer pictures of the specific problem-related tradeoffs discovered by the automated design optimization procedure.
Abstract and discrete models for uncertain spatiotemporal data

Summary form only given. We deal with the uncertainty in spatial and spatiotemporal databases. Due to lack of accurate measurements, or rapid changes in time, spatial and spatiotemporal data are often uncertain. Our work presents new abstract and discrete models for uncertain spatial and spatiotemporal information. The models are based on the principle that one knows that the uncertain object, regardless of type, must be within a certain area.
Leukocytosis at Diagnosis in Patients with Essential Thrombocythemia Is a Risk Factor for Transformation into Myelofibrosis

Myelofibrosis (MF) represents the major long-term complication of essential thrombocythemia (ET). There is evidence that leukocytosis at diagnosis is associated with poorer survival in patients with ET. In this study, we retrospectively evaluated 143 patients with ET, diagnosed in agreement with WHO criteria, followed in a single centre over >10 years. Nine of them transformed into MF (post-essential thrombocythemia-myelofibrosis PET-MF). We compared PET-MF data at diagnosis with that of the remaining 134 patients (ET-1) and with a selected sub-group of ET-1 (ET-2, 19 pats) sex, age and follow-up duration matched to PET-MF. The PET-MF evolution rate was 4.6 per 1000 person-years; white blood cells count (WBC) count, haemoglobin levels and hematocrit were higher in PET-MF than in ET-1 (P = 0.01) while only WBC was higher than in ET-2 (P = 0.01). With multivariate analysis, only WBC count retained its signifi-cance. Our study highlights the prognostic relevance of leukocytosis on myelofibrotic transformation of ET.
Hospital readmission after a pancreaticoduodenectomy: an emerging quality metric?

BACKGROUND Hospital readmission has attracted attention from policymakers as a measure of quality and a target for cost reduction. The aim of the study was to evaluate the frequency and patterns of rehospitalization after a pancreaticoduodenectomy (PD). METHODS The records of all patients undergoing a PD at an academic medical centre for malignant or benign diagnoses between January 2006 and September 2011 were retrospectively reviewed. The incidence, aetiology and predictors of subsequent readmission(s) were analysed. RESULTS Of 257 consecutive patients who underwent a PD, 50 (19.7%) were readmitted within 30 days from discharge. Both the presence of any post-operative complication (P = 0.049) and discharge to a nursing/rehabilitation facility or to home with health care services (P = 0.018) were associated with readmission. The most common reasons for readmission were diet intolerance (36.0%), pancreatic fistula/abscess (26.0%) and superficial wound infection (8.0%). Nine (18.0%) readmissions had lengths of stay of 2 days or less and in four of those (8.0%) diagnostic evaluation was eventually negative. CONCLUSION Approximately one-fifth of patients require hospital readmission within 30 days of discharge after a PD. A small fraction of these readmissions are short (2 days or less) and may be preventable or manageable in the outpatient setting.
Effects of cococonut water and simvastatin in the treatment of sepsis and hemorrhagic shock in rats.

PURPOSE: To evaluate the effects of modified coconut water as fluid of resuscitation combined with simvastatin in hemorrhagic shock and sepsis model in rats. METHODS: Four groups of Wistar rats with hemorrhagic shock and abdominal sepsis were studied (n=8/group). Rats were bled and maintained at a mean blood pressure 35mmHg for 60min. They were then resuscitated with: 1) saline 0.9%; 2) coconut water+3% NaCl; 3) coconut water+NaCl 3%+simvastatin microemulsion (10 mg/kg i.v.; 4) normal coconut water. At 8h post-resuscitation, blood and lungs were collected for exams. RESULTS: Clinical scores, TNF-α, IL-1β, liver/kidney proof levels, and lung injury were significantly reduced in coconut water+NaCl 3%+simvastatin group treated rats, comparing with the other resuscitation treatments. CONCLUSIONS: Resuscitation with coconut water with Nacl 3%+simvastatin had a significant beneficial effect on downregulating cytokines and decreasing lung injury in a rat model of abdominal sepsis and hemorrhagic shock. We also demonstrated that coconut water with Nacl 3%+simvastatin administration clearly made liver and kidney function better and improved clinical score.
Structural Characterization of Kadcoccinin A: A Sesquiterpenoid with a Tricyclo[4.4.0.0(3,10)]decane Scaffold from Kadsura coccinea.

Kadcoccinin A (1), a cage-like sesquiterpenoid possessing a tricyclo[4.4. 0.0(3,10)]decane scaffold, and the biosynthetically related kadcoccinin B (2) were isolated from the stems of Kadsura coccinea. Their structures and absolute configurations were determined from extensive spectroscopic analysis and quantum chemical calculations. Additionally, their cytotoxic and antifungal effects were initially evaluated, and a plausible biosynthetic pathway was proposed.
Cytotoxic and hormonal treatment for metastatic breast cancer: a systematic review of published randomized trials involving 31,510 women.

PURPOSE A systematic review of randomized clinical trials (RCTs) was undertaken to assess the effectiveness of medical treatment for metastatic breast cancer. METHODS RCTs published between 1975 and 1997 have been classified according to 12 therapeutic comparisons: (1) polychemotherapy (PCHT) agents versus single agent; (2) PCHT regimens with anthracycline versus PCHT without anthracycline; (3) other PCHT versus cyclophosphamide, methotrexate, and fluorouracil (CMF); (4) chemotherapy (CHT) with epirubicin versus CHT with doxorubicin; (5) CHT versus same CHT delivered with less intensive schedules; (6) other endocrine therapy (OET) versus tamoxifen; (7) OET plus tamoxifen versus tamoxifen alone; (8) OET versus medroxyprogesterone; (9) OET versus aromatase inhibitors; (10) OET versus megestrol; (11) endocrine therapy (ET) versus same ET at lower doses; and (12) CHT plus ET versus CHT. Tumor response rates, mortality hazards ratio (HR) and frequency of severe side effects were the outcome measures. RESULTS A total of 189 eligible trials (31,510 patients) were identified. All provided response rates and 133 (70%) data or survival curves needed for calculation of the HR. In eight of 12 comparisons, statistically significant differences for response emerged (1, 2, 3, 5, 7, 8, 11, 12); all but no. 8 favored the first term of the comparison. Overall survival analysis showed better results of (a) PCHT versus single-agent CHT (HR=0.82; 95% confidence interval [CI], 0.75 to 0.90); (b) CHT with doxorubicin versus CHT with epirubicin (HR=1.13; 95% CI, 1.00 to 1.27); (c) CHT versus the same CHT delivered with less intensive schedules (HR=0.90; 95% CI, 0.83 to 0.97); (d) ET versus the same ET at lower doses (HR=0.86; 95% CI, 0.77 to 0.97). Quality of life was measured in only 2,995 of 31,510 patients (9.5%). CONCLUSION Despite some evidence of effectiveness of specific regimens, the relevance of these findings is limited by the modest survival benefit and the lack of evaluation of the quality-of-life impact of these treatments.
Demand-side management alternatives

This paper provides an overview of demand-side management (DSM) alternatives. It covers the general state of the art, projected developments, and the application of DSM alternatives. It starts with a background discussion of DSM which provides the reader with a historical reference and an understanding of the types of needs DSM alternatives can address and the benefits they can provide. Categories of DSM alternatives are then described. General design, application, and issues involved are discussed. Although it is not possible to discuss DSM alternatives in complete detail, specific information based on actual installations is presented. Also, typical values, costs, and load impacts are given in most cases.
Influence of intranasal immunization with synthetic peptides corresponding to conserved epitopes of M protein on mucosal colonization by group A streptococci

A major virulence factor of group A streptococci is M protein, a surface-exposed fibrillar molecule of which there exist more than 80 distinct serological types. Antigenic variability resides largely in the amino-terminal region of M protein, whereas the carboxy-terminal half of the molecule is highly conserved among different M serotypes. We sought to determine whether mucosal immunization with conserved epitopes of M protein influences the course of mucosal colonization by group A streptococci in a mouse model. Synthetic peptides corresponding to sequences in the conserved region of M protein were covalently linked to the mucosal adjuvant cholera toxin B subunit. Mice were immunized intranasally with the peptide-cholera toxin B subunit conjugate or with cholera toxin B subunit alone and then challenged intranasally with live streptococci. Pharyngeal colonization by streptococci was measured for up to 15 days postchallenge. Mice immunized with synthetic peptides showed a significant reduction in colonization compared with the control group. The data demonstrate that immunity evoked by conserved portions of M protein influences the outcome of group A streptococcal infection at the nasopharyngeal mucosa in a mouse model.
Assessment of cooling effect on neonatal pain during heel prick blood sampling: A randomized clinical trial

Background: Heel prick blood sampling is a painful and stressful procedure performed in NICUs (Neonatal Intensive Care Unit) to collect blood samples for some diagnostic laboratory tests. The local cold is a simple, effective and safe analgesia in newborns. Due to the side effects of pharmacological methods of analgesia and also the relative impact of non-drug methods available, it can be a good alternative for them. Methods: The current study was a double-blind clinical trial, the infants were born in Imam Khomeini Ahvaz in 2016 and randomly assigned to the case and control groups. In the case group, 20 s after exposure to cold compress on the heels, samples were taken and the control group without exposure to cold compress samples were taken. Pain assessment was performed by CRIES (Pain Scales and Pain Assessment) scale. Data collected by SPSS software version 22 and T-test were analyzed statistically. Results: The current study was conducted on 68 infants assigned to the case and control groups. Study participants included more boys (60.95%) than girls. All infants enrolled in the current study were 1 d old with Apgar scores of 9-10. In the case group, 90.62% of the subjects had scores 4. In the control group, 40.62% of the subjects had scores 4. There was a statistically significant difference in CRIES score between the groups (P-value 4 indicates severe pain). There was no significant difference between the case and control groups in the level of arterial oxygen saturation. Conclusions: This study showed that local cold can reduce the level of pain caused by heel prick blood sampling and can decrease early and late complications of pain in infants.
A predictive model for optimizing acceptance and use of mHealth interventions in low-resource settings: A case of Mamacare prototype

The health status of women and children is considered as a reflection of the present society and a predictor of the future generations. Unfortunately, numerous challenges emanating from poverty, inadequate resources, illiteracy and cultural barriers contribute to poor health and high mortality rate in low-resource settings. To address these challenges, there are numerous mHealth interventions seeking to exploit opportunities provided by over 90% mobile penetration in developing countries. However, research shows that most of the interventions have failed to justify their value proposition to motivate integration into the conventional healthcare systems. This poor up-take requires a holistic approach in order to align mHealth solutions to consumer needs in the intended context of use. In this paper, we present a conceptual model named TIPFit that forms the basis for predicting acceptance and use of mHealth intervention at the design stage. To measure the predictive power of the model, we conducted repeated measures experiment using a cohort of 79 randomly selected subjects. During design of mHealth intervention named Mamacare, we operationalized TIPFit model into blueprints used for prototyping Mamacare; and indicators for data collection during the experiment. To analyze the pre-intervention dataset, we used Partial Least Squares Structural Equation Modelling (PLS-SEM) that predicted 66.9% acceptance and 60.7% intended use. To evaluate the predictive power of the model, the cohort was recruited into Mamacare intervention that involved sending targeted SMS alerts as well as receiving real-time data on vital signs such as blood pressure. Results from datasets obtained after exposing the subjects to the intervention demonstrated 60.2% acceptance and 47.6% actual use. Although there was significant difference between our prediction and actual outcome, the study demonstrates that use of TIPFit model at the design stage is crucial to predicting fit and utilization of mHealth solutions in low-resource settings. Furthermore, the study shows that the proposed model can be tailored into a tool for evaluating intervention's progress towards attainment of desired health outcome.