Miracle-dz/UniFAR-FTUs huggingface dataset:
Clinical and hematological relevance of JAK2 V617F and CALR mutations in BCR-ABL-negative ET patients

ABSTRACT Background: Classical BCR-ABL1-negative myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia (ET), and primary myelofibrosis frequently harbor JAK2, MPL, and CALR somatic mutations. Methods: AS-PCR for JAK2 V617F, pyrosequencing for MPL W515L/K, and PCR-fragment analysis for CALR exon 9 mutations were established to analyze genomic DNA isolated from peripheral blood samples of 58 newly diagnosed ET patients in Thailand. Results: JAK2 V617F was detected in 41 patients (71%) and CALR exon 9 mutation was positive in eight patients (14%), whereas no mutation of MPL W515L/K was observed in this study. Patients with CALR mutation were older (p = 0.023) and exhibited lower number of platelet count (p = 0.041) than patients without CALR mutation. Two previously known CALR mutation types were identified in this study (six patients with CALR-type 1 and two patients with CALR-type 2). Additionally, no co-existence of JAK2 V617F and CALR mutations was identified in this work. Conclusion: We reported the frequency of JAK2 V617F, MPL W515L/K, and CALR mutations in Thai patients with ET. Clinical and hematological phenotypes of patients were associated with JAK2 and CALR mutation statuses. The combination of laboratory testing for the detection of JAK2, CALR, and MPL mutations is necessary to improve the diagnosis and classification of BCR-ABL1-negative MPN.
Aging is associated with greater nuclear NFκB, reduced IκBα, and increased expression of proinflammatory cytokines in vascular endothelial cells of healthy humans

The vascular endothelium may develop a proinflammatory profile with aging, but evidence is limited in humans. Expression of inflammatory proteins was determined in vascular endothelial cells (EC) obtained from peripheral veins of 24 young (23 ± 1 years, mean ± SE) and 36 older (63 ± 1) healthy men and women using quantitative immunofluorescence. The older subjects had lower vascular endothelium‐dependent dilation (forearm blood flow responses to acetylcholine, p < 0.05), and higher plasma concentrations of C‐reactive protein, interleukin‐6 (IL‐6), and oxidized low‐density lipoprotein (all p < 0.05), but not tumor necrosis factor‐α (TNF‐α). Total (O: 0.52 ± 0.04 vs. Y: 0.33 ± 0.05 NFκB/HUVEC intensity, p < 0.05) and nuclear (O: 0.59 ± 0.04 vs. Y: 0.41 ± 0.04) expression of nuclear factor κ B p65 (NFκB), a proinflammatory gene transcription factor, was greater in EC from the older subjects (p < 0.05). EC expression of the inhibitor (of nuclear translocation) of NFκB (IκBα) was lower in the older subjects (O: 0.16 ± 0.02 vs. Y: 0.24 ± 0.03, p < 0.05), whereas IκB kinase (IκK) was not different. EC expression of the proinflammatory proteins IL‐6 (O: 0.42 ± 0.06 vs. Y: 0.29 ± 0.03, p < 0.05), TNF‐α (O: 0.52 ± 0.06 vs. Y: 0.33 ± 0.05, p < 0.05) and monocyte chemoattractant protein 1 (MCP‐1) (O: 0.59 ± 0.06 vs. Y: 0.38 ± 0.02, p < 0.05) was greater in the older subjects, whereas cyclooxygenase 2 and the receptor for advanced glycation end‐products did not differ. These findings indicate that impaired function with aging in healthy adults is associated with the development of a proinflammatory phenotype in the vascular endothelium that could be caused in part by reduced IκB‐mediated inhibition of NFκB.
A study of the “slack-string” knife-edge diffraction model

When determining diffraction loss over irregular terrain, there is always an engineering tradeoff between the accuracy of the diffraction models' predictions and the computational complexity of the models. This paper presents the results of an investigation of a multiple knife-edge diffraction model, the “slack-string” model. The model is tested here using a subset of a database of knife-edge profiles designed for comparative analysis of different diffraction models' predictive accuracies. The results of the “slack-string” model are shown against the results of the other knifeedge diffraction models.
Maternal characteristics and treatment needs as predictors of dental health services utilisation among Mexican school children.

AIM To determine whether maternal characteristics and treatment needs are associated with dental health services utilization (DHSU) in school children. MATERIALS AND METHODS A cross-sectional study in 1373 school children aged 6- 12 years in elementary schools in Campeche, Mexico collected family and sociodemographic characteristics; an oral examination was conducted. The dependent variable was DHSU in the year preceding the study. RESULTS DHSU prevalence was 65.5%. The variables associated (p<0.05) with DHSU in the final multivariate model were age (OR=1.27), maternal schooling (OR=1.07), mother's attitude toward oral health (OR=1.39), frequency of tooth brushing (OR=1.83), enamel defects (OR=1.55), and unmet oral health needs (moderate: OR=1.42 and high: OR=2.30). CONCLUSION Specific sociodemographic and maternal variables were associated with DHSU. Strategies are needed to increase appropriate and timely use of services to improve health status.
Role for Human Immunodeficiency Virus Type 1 Tat Protein in Suppression of Viral Reverse Transcriptase Activity during Late Stages of Viral Replication

ABSTRACT We have examined the role of the human immunodeficiency virus type 1 (HIV-1) Tat protein in the regulation of reverse transcription. We show that a two-exon but not a one-exon form of Tat markedly suppressed cell-free reverse transcriptase (RT) activity. Conversely, viruses expressing two-exon Tat (pNL43 and pNL101) showed rapid replication kinetics and more efficient endogenous RT activity compared with viruses expressing one-exon Tat (pM1ex). The pM1ex virions, as well as pM1ex-infected cells, also contained higher levels of viral DNA than did either the pNL43 or pNL101 viruses, indicating that reverse transcription might have continued during later stages of viral replication in the absence of the second Tat exon. Moreover, degradation of viral genomic RNA was more apparent in the pM1ex virions. Accordingly, we propose that the two-exon Tat may help augment viral infectivity by suppressing the reverse transcription reaction during late stages of viral synthesis and by preventing the synthesis of potentially deleterious viral DNA products.
Quantitative Characterization of Tob Interactions Provides the Thermodynamic Basis for Translation Termination-coupled Deadenylase Regulation*

Translation termination-coupled deadenylation is the first and often the rate-limiting step of eukaryotic mRNA decay in which two deadenylases, Ccr4-Caf1 and Pan2, play key roles. One of the deadenylases, Caf1, associates with Tob, which recruits Caf1 to the poly(A) tail through interactions with a cytoplasmic poly(A)-binding protein 1 (PABPC1). We previously proposed that the competition between Tob and eRF3 (a translation termination factor that interacts with PABPC1) is responsible for the regulation of deadenylase activity. However, the molecular mechanism of the regulation should be addressed by investigating the binding affinity and the cellular levels of these proteins. In this work, we characterized the human Tob interactions with Caf1 and a C-terminal domain of PABPC1 (PABC). Nuclear magnetic resonance (NMR) and Western blot analyses revealed that Tob consists of a structured N-terminal BTG-Tob domain and an unstructured C-terminal region with two conserved PAM2 (PABPC1-interacting motif 2) motifs. The BTG-TOB domain associates with Caf1, whereas the C-terminal PAM2 motif binds to PABC, with a Kd value of 20 μm. Furthermore, we demonstrated that the levels of eRF3 and Tob in HeLa cells are 4–5 μm and less than 0.2 μm, respectively. On the basis of these results, we propose a thermodynamic mechanism for the translation termination-coupled deadenylation mediated by the Tob-Caf1 complex.
Reconciling divergent results of the latest parenteral nutrition studies in the ICU

Purpose of reviewRecent studies on the optimal modalities to feed patients during the ICU stay show divergent results. The level and the timing of energy provision is a critical issue, associated with the clinical outcome. These results questioned the clinical relevance of the recent guidelines issued by American, Canadian and European academic societies. Recent findingsFour recent prospective randomized studies enrolled critically ill patients who received various nutritional regimens and tested the effect of nutritional support on outcome. The Tight Calorie balance Control Study (TICACOS) targeted on calorie administration according to measured energy expenditure and found increased ICU morbidity but improved hospital mortality. The large EpaNIC study compared ‘early’ with ‘late’ (parenteral nutrition) nutrition, mostly in patients after cardiac surgery, and found an increased morbidity associated with early parenteral nutrition. The supplemental parenteral nutrition (SPN) study randomized the patients after 3 days and targeted the calories administered by parenteral nutrition as a complement to unsuccessful enteral nutrition using indirect calorimetry. The SPN resulted in less nosocomial infections and shorter duration of mechanical ventilation. Finally, a recent Australian study enrolled patients unable to be early fed enterally to receive, or not, parenteral nutrition targeted at 1500 kcal. No complications were noted in the parenteral nutrition group. Lessons from all these studies are summarized and should help in designing better studies and guidelines. SummaryThe critical analysis of recent prospective studies comparing various levels of calorie administration, enteral versus parenteral nutrition and enteral versus SPN confirms the recommendations to avoid underfeeding and overfeeding. Parenteral nutrition, required if enteral feeding is failing, and if adjusted up to a measured optimal level, may improve outcome. More studies on the optimal level of energy and protein administration to optimize the clinical outcome are required to fine tune current guidelines.
Automated drug dispensing system reduces medication errors in an intensive care setting

Objectives:We aimed to assess the impact of an automated dispensing system on the incidence of medication errors related to picking, preparation, and administration of drugs in a medical intensive care unit. We also evaluated the clinical significance of such errors and user satisfaction. Design:Preintervention and postintervention study involving a control and an intervention medical intensive care unit. Setting:Two medical intensive care units in the same department of a 2,000-bed university hospital. Patients:Adult medical intensive care patients. Interventions:After a 2-month observation period, we implemented an automated dispensing system in one of the units (study unit) chosen randomly, with the other unit being the control. Measurements and Main Results:The overall error rate was expressed as a percentage of total opportunities for error. The severity of errors was classified according to National Coordinating Council for Medication Error Reporting and Prevention categories by an expert committee. User satisfaction was assessed through self-administered questionnaires completed by nurses. A total of 1,476 medications for 115 patients were observed. After automated dispensing system implementation, we observed a reduced percentage of total opportunities for error in the study compared to the control unit (13.5% and 18.6%, respectively; p < .05); however, no significant difference was observed before automated dispensing system implementation (20.4% and 19.3%, respectively; not significant). Before-and-after comparisons in the study unit also showed a significantly reduced percentage of total opportunities for error (20.4% and 13.5%; p < .01). An analysis of detailed opportunities for error showed a significant impact of the automated dispensing system in reducing preparation errors (p < .05). Most errors caused no harm (National Coordinating Council for Medication Error Reporting and Prevention category C). The automated dispensing system did not reduce errors causing harm. Finally, the mean for working conditions improved from 1.0 ± 0.8 to 2.5 ± 0.8 on the four-point Likert scale. Conclusions:The implementation of an automated dispensing system reduced overall medication errors related to picking, preparation, and administration of drugs in the intensive care unit. Furthermore, most nurses favored the new drug dispensation organization.
In vivo DTI parameter choice using Monte-Carlo diffusion simulations in a model of brain white matter

Introduction Diffusion Tensor Imaging (DTI) has been proposed to visualize the fibres of brain white matter (WM) based on the selectivity of the maximal apparent diffusion coefficient (ADC) which correspond to the water diffusion along the axons. DTI potentially provides more detailed information about tissue organization but significant questions remain concerning different relations between tissue microstructure, brain water compartments, the connectivity of cerebral areas with ADC values and experimental DTI parameters. In this study, simulated diffusion-weighted signal in a model of WM was developed [1-3] in order to study the relationship between diffusion time (tdif) and ADC values. In vivo water diffusion experiments on rat brain were performed and compared to the simulated data.
Antibody to a human DNA repair protein allows for cloning of a Drosophila cDNA that encodes an apurinic endonuclease

The cDNA of a Drosophila DNA repair gene, AP3, was cloned by screening an embryonic lambda gt11 expression library with an antibody that was originally prepared against a purified human apurinic-apyrimidinic (AP) endonuclease. The 1.2-kilobase (kb) AP3 cDNA mapped to a region on the third chromosome where a number of mutagen-sensitive alleles were located. The cDNA clone yielded an in vitro translation product of 35,000 daltons, in agreement with the predicted size of the translation product of the only open reading frame of AP3, and identical to the molecular size of an AP endonuclease activity recovered following sodium dodecyl sulfate-polyacrylamide gel electrophoresis of Drosophila extracts. The C-terminal portion of the predicted protein contained regions of presumptive DNA-binding domains, while the DNA sequence at the amino end of AP3 showed similarity to the Escherichia coli recA gene. AP3 is expressed as an abundant 1.3-kb mRNA that is detected throughout the life cycle of Drosophila melanogaster. Another 3.5-kb mRNA also hybridized to the AP3 cDNA, but this species was restricted to the early stages of development.
A phase II trial of ZD6474 in patients with hereditary metastatic medullary thyroid cancer.

5533 Background: Medullary thyroid carcinoma (MTC) is the most common cause of death in patients with hereditary syndromes caused by specific mutations in the RET protooncogene. RET activation is the oncogenic event, which results in intrinsic RET receptor tyrosine kinase activity, but other pathways, such as VEGFR- and EGFR-dependent signaling, also participate in tumor growth and development. ZD6474 is a once-daily oral agent that selectively targets RET, VEGFR and EGFR tyrosine kinases. The clinical activity of ZD6474 was evaluated in patients with hereditary MTC. METHODS In this open-label Phase II study, patients with unresectable, measurable, locally advanced or metastatic hereditary MTC and a RET germline mutation received once-daily oral doses of ZD6474 300 mg. The primary objective was to assess the objective tumor response (RECIST). Secondary objectives included assessments of biochemical response (determined by changes in plasma levels of calcitonin [CTN]) and safety/tolerability of ZD6474. An exploratory objective was to measure plasma levels of carcinoembryonic antigen (CEA). RESULTS As of 30 November 2005, 16 patients (6 male/10 female; median age 50 years, range 22-77) had entered the study and received initial treatment with ZD6474 300mg. The median duration of treatment was 136 days (range 16-353). Fifteen patients were evaluable for tumor response, CTN, and CEA. Objective tumor assessments have demonstrated partial responses in 3 patients (n = 2 confirmed; n = 1 unconfirmed), stable disease in 10 patients (n = 8, ≥8 and <24 weeks; n = 2, ≥24 weeks) and progressive disease in 2 patients. A >50% decrease from baseline in plasma CTN levels has been maintained for at least 4 weeks in 12/15 patients; a decrease in plasma CEA levels of the same magnitude and duration has been observed in 6/15 patients. Common adverse events (AEs) were diarrhea (n = 12) and nausea, rash and fatigue (each n = 11). CTC grade 3 AEs attributable to ZD6474 were QTc interval prolongation (n = 3), and diarrhea, skin rash and hypertension (each n = 2). CONCLUSIONS ZD6474 shows promising evidence of clinical activity in patients with hereditary MTC. These are preliminary data and patients are still being recruited to this ongoing study. [Table: see text].
Replication timing aberrations and aneuploidy in peripheral blood lymphocytes of breast cancer patients.

BACKGROUND Peripheral blood lymphocytes of patients with hematological malignancies or solid tumors, such as renal cell carcinoma or prostate cancer, display epigenetic aberrations (loss of synchronous replication of allelic counterparts) and genetic changes (aneuploidy) characteristic of the cancerous phenotype. This study sought to determine whether such alterations could differentiate breast cancer patients from cancer-free subjects. METHODS The HER2 locus-an oncogene assigned to chromosome 17 whose amplification is associated with breast cancer (BCA)-and the pericentromeric satellite sequence of chromosome 17 (CEN17) were used for replication timing assessments. Aneuploidy was monitored by enumerating the copy numbers of chromosome 17. Replication timing and aneuploidy were detected cytogenetically using fluorescence in situ hybridization technology applied to phytohemagglutinin-stimulated lymphocytes of 20 women with BCA and 10 control subjects. RESULTS We showed that both the HER2 and CEN17 loci in the stimulated BCA lymphocytes altered their characteristic pattern of synchronous replication and exhibited asynchronicity. In addition, there was an increase in chromosome 17 aneuploidy. The frequency of cells displaying asynchronous replication in the patients' samples was significantly higher (P < 10(-12) for HER2 and P < 10(-6) for CEN17) than the corresponding values in the control samples. Similarly, aneuploidy in patients' cells was significantly higher (P < 10(-9)) than that in the controls. CONCLUSIONS The HER2 and CEN17 aberrant replication differentiated clearly between BCA patients and control subjects. Thus, monitoring the replication of these genes offers potential blood markers for the detection and monitoring of breast cancer.
An adaptive network-based fuzzy inference system for estimating the duration of medical services: A case study

The aim of this study is twofold. First one is to derive a feasible numerical prediction model for the duration of medical services in a medical institution that could be used by the hospital management within their quality assurance and improvement processes. The second aim is to develop a freeware software tool, which implements an adaptive artificial neural network-based fuzzy inference system with a user-friendly interface that can be effectively used by both technical and non-technical people. Some promising results have been obtained which show that both of these objectives have been successfully achieved to some extent.
Detection of Chicken Anemia Virus DNA in Embryonal Tissues and Eggshell Membranes

Abstract Chicken infectious anemia virus (CIAV) is a ubiquitous and highly resistant virus of chickens that causes anemia and death in chicks less than 3 wk of age and immunosuppression in chickens older than 3 wk of age. The production of specific-pathogen-free eggs free of CIAV is essential for research and vaccine production. Currently, flocks are screened for CIAV by antibody tests to ensure freedom from CIAV infection. Recent evidence, however, indicates that chickens may carry and vertically transmit CIAV DNA independently of their antibody status. In this study, we tested embryos and eggshell membrane residues by nested polymerase chain reaction (PCR) as a sensitive method of detecting CIAV DNA. CIAV DNA could be detected in the blastodisks and semen obtained from antibody-positive and -negative chickens. Examination of different tissues between 18 and 20 days of incubation indicated that many but not all organs of individual embryos were positive. The lymphoid organs and gonads had the highest incidence of CIAV DNA, which was significantly different (P < 0.05) from the incidence in the liver. Eggshell membrane samples from embryos or newly hatched chicks were an excellent noninvasive source for the detection of CIAV DNA, identifying significantly more positive embryos than did pooled lymphoid organs. The use of dexamethasone injections as a method to improve the detection of carrier birds did not result in an increase of vertical transmission or cause seroconversion in the treated hens. A combination of testing eggshell membrane residues at hatch and periodic testing of blood DNA by nested PCR can be used to identify chickens carrying CIAV DNA and may be used to eradicate carrier birds.
Expression of functional c‐kit receptors rescues the genetic defect of W mutant mast cells.

Loss‐of‐function mutations in the gene for the c‐kit tyrosine kinase receptor are strongly implicated in the developmental abnormalities of W mutant mice. To dissect further the relationship between kit and the W phenotype, retroviruses carrying the normal murine c‐kit gene were constructed. In infected cells, the level of c‐kit expression from these vectors varied markedly with different promoter elements, the 5′ viral LTR proving to be the most effective. When introduced into cells which normally do not express c‐kit, ectopic kit receptors transduced a ligand (Steel factor)‐dependent proliferative signal in IL‐3‐dependent DA‐1 myeloid cells and induced transformation in fibroblasts. Primary mutant mast cells were used to examine the effects of reconstituting functional kit expression in cells affected by W mutations. Exogenous c‐kit expression rescued the defective proliferative response to Steel factor of cells from both W/Wv and W/W mutant mice. Moreover, functional kit expression also restored the capacity of W/Wv mast cells to survive and differentiate in vivo. These results imply that defective c‐kit receptor function is sufficient to generate the W mutant phenotype.
Geochronology of Wadi Tushka: Lost Tributary of the Nile

The Sadat Canal, now under construction, is designed to drain excess water from Lake Nasser to the Western Desert by way of Wadi Tushka, a sand-filled, dry-wash tributary of the Nile 34 kilometers north of Abu Simbel. Core-drilling logs made by the Aswan High Dam Authority prior to excavation of the Sadat Canal and along 48 kilometers of its axis reveal as much as 33 meters of unconsolidated sand and gravel over Mesozoic bedrock and under surficial dune sand and playa muds of Holocene age. Excavation of the canal revealed Acheulean artifacts 6.7 meters below the surface in fluvial sediments capped by a buried, red calcic paleosol. These data are interpreted as evidence for the existence of a major tributary of the Nile during the late middle Pleistocene. The tributary drained the Kiseiba-Dungul Depression and possibly the Kharga Depression as well. Chalcedony-armored mudstones in the depressions are believed to be saline lake deposits possibly related to a lake that drained to the Nile by way of Wadi Tushka, thus entrenching the divide between the depression and the valley. Gross correlations with Pleistocene deposits of the Nile Valley and the Kharga Depression are based upon archeological evidence only until more precise geochronology can be applied to the problem.