Miracle-dz/UniFAR-FTUs huggingface dataset:
Effects of cell cycle phase on low-dose hyper-radiosensitivity.

PURPOSE To examine the low-dose radiation response of human glioma cell lines separated into different cell-cycle phases and to determine if low-dose hyper-radiosensitivity (HRS) differs in populations defined by cell-cycle position. To assess whether predictions of the outcome of multiple low-dose regimens should take account of cell-cycle effects. MATERIALS AND METHODS The clonogenic survival of G1, G2 and S phase cells was measured after exposure to single doses of X-rays in two human glioma cell lines. One cell line (T98G) showed marked HRS when asynchronous cells were irradiated, while the other (U373) did not. Separation of populations and high-resolution cell counting was achieved using a fluorescence activated cell sorter. Sorted cell populations were irradiated with 240 kVp X-rays to doses between 0.05 and 5Gy. The resulting cell-survival versus dose data were comparatively fitted using the linear-quadratic and induced-repair models in order to assess the degree of HRS. RESULTS In both cell lines the low-dose response was altered when different populations were irradiated. In T98G cells, all populations showed HRS, but this was most marked in G2 phase cells. In U373 cells, no HRS was found in G1 or S phase cells, but HRS was demonstrable in G2 phase cells. CONCLUSIONS HRS was expressed by the whole cell population of T98G cells but the size of the effect varied with cell-cycle phase and was most marked in the G2 population. In U373 cells, the effect could only be demonstrated in G2 cells. This implies that HRS is primarily a response of G2 phase cells and that this response dominates that seen in asynchronous populations. Actively proliferating cell populations may therefore demonstrate a greater increase in radiosensitivity to very low radiation doses compared with quiescent populations.
Efficacy and tolerability of the perindopril/indapamide combination therapy for hypertension: the PRIMUS study*

ABSTRACT Background: Tight blood pressure (BP) control is required to reduce cardiovascular morbidity and mortality. Objective: To evaluate the efficacy and tolerability of the first line combination perindopril/indapamide in hypertension in daily practice. Design and methods: In this prospective, open-label, observational trial, 1892 general practitioners in Germany recruited patients with hypertension ( n = 8023; mean age 59.6 years, 48.1% males, body mass index 27.6 kg/m2, systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg) between October 2002 and December 2004. Patients received perindopril 2 mg/indapamide 0.625 mg for 12 weeks. BP measured in the general practice setting, safety, and tolerability were evaluated after 4 and 12 weeks. Results: At baseline, most patients had moderate to severe hypertension (78%); initial BP was 164.6/95.8 mmHg. At inclusion, 38% of the patients were newly diagnosed hypertensives (mean BP 166.1/97.2 mmHg) and 58% of patients had uncontrolled BP despite preexisting antihypertensive treatment (163.5/94.9 mmHg). Previous treatment consisted of β‐blockers (49.5%), ACE inhibitors (36.4%), calcium-antagonists (29.3%), diuretics (28.8%), AT‐I receptor antagonists (7.1%), and other treatments (8.1%). In the entire study cohort, treatment with perindopril/indapamide significantly decreased systolic BP (27.9 mmHg), diastolic BP (13.7 mmHg), and pulse pressure (14.2 mmHg), compared with baseline ( p < 0.0001); 96% of patients responded to treatment and in 50% of patients BP was normalized (< 140/90 mmHg). Treatment dose was doubled in 9.5% of patients. Similar results were found in various subgroup analyses (newly diagnosed patients, the elderly, and patients with isolated systolic hypertension, additional cardiovascular risk factors, associated diseases, or target organ damage). The most frequent adverse events (< 1% of patients) were dry cough and nausea. Conclusions: The open-label, observational study PRIMUS, extends the existing evidence that the first line combination treatment of hypertension with perindopril/indapamide is effective, safe, and well tolerated in a representative cross-section of patients with newly diagnosed or pretreated but uncontrolled hypertension in daily practice.
The helminth parasites of two sympatric species of the genus Apodemus (Rodentia, Muridae) from south-eastern Slovakia

The helminths of two sympatric species of rodents, the striped field mouse Apodemus agrarius and the yellow-necked mouse, Apodemus flavicollis from Slovakia were studied to determine whether there are similarities in the composition of the helminth fauna of two closely related host species living in the same area. A total of twelve species of helminths were identified in these rodent populations, including Brachylaima sp. (Trematoda); Hymenolepis diminuta (Rudolphi, 1819), Mesocestoides sp. larvae, Rodentolepis fraterna (Stiles, 1906), Rodentolepis straminea (Goeze, 1782), Skrjabinotaenia lobata (Baer, 1925), Taenia taeniaeformis larvae (Batsch, 1786) (Cestoda); Aonchotheca annulosa (Dujardin, 1845), Heligmosomoides polygyrus (Dujardin, 1845), Heterakis spumosa Schneider, 1866, Mastophorus muris (Gmelin, 1790) and Syphacia stroma (Linstow, 1884) (Nematoda). In A. agrarius, H. polygyrus was the most prevalent, as well as the most abundant helminth, but R. fraterna was the species with the highest mean intensity. In contrast, S. stroma dominated the A. flavicollis helminth fauna with the highest prevalence, mean abundance and mean intensity. Both rodent populations harboured nine helminth species, although the mean individual species richness was significantly higher in A. agrarius than in A. flavicollis. The analysis of helminth diversity at both component and infracommunity levels revealed differences between the two rodent populations, which are most likely attributable to the specific host ecology.
Original report. Testicular torsion in neonates and infants: sonographic features in 30 patients.

OBJECTIVE The purpose of this study was to illustrate the spectrum of sonographic findings in testicular torsion in a large series of neonates and infants. These patterns and their evolution have, to our knowledge, not been described previously. CONCLUSION The sonographic appearance of testicular torsion in neonates and infants can be divided into three types. We believe that the findings represent different stages in the evolution of testicular torsion.
Activation of the pp60c‐src kinase by middle T antigen binding or by dephosphorylation.

The transforming protein of polyoma virus, middle T antigen, associates with the protein tyrosine kinase pp60c‐src, and analysis of mutants of middle T suggests that this complex plays an important role in transformation by polyoma. It has recently been reported that pp60c‐src from polyoma virus‐transformed cells has enhanced tyrosine kinase activity in vitro. The data presented here confirm these findings and show that the enhanced kinase activity of pp60c‐src is due to an increase in the Vmax of the enzyme. Sucrose density gradient analysis demonstrates that only the form of pp60c‐src which is bound to middle T antigen is activated. The difference in enzyme activity between pp60c‐src from normal and middle T‐transformed cells is more marked when the enzyme is prepared from lysates containing the phosphotyrosine protein phosphatase inhibitor, sodium orthovanadate. pp60c‐src from middle T transformed cells is unaffected, but pp60c‐src from normal cells has reduced kinase activity if dephosphorylation is prevented. The kinase activity of pp60c‐src thus appears to be regulated by its degree of phosphorylation at tyrosine, and data are presented which support this hypothesis. pp60c‐src is the first example of a protein tyrosine kinase whose activity is inhibited by phosphorylation at tyrosine. Middle T antigen may increase the kinase activity of pp60c‐src by preventing phosphorylation at this regulatory site.
Psychosocial Consequences for Children of a Parent With Cancer: A Pilot Study

When cancer is diagnosed in a parent, this may also have consequences for the children. The purpose of this pilot study was to gain more insight into the psychosocial consequences for children of a parent with cancer, from the perspective of both the children and their parents. For this study, 14 families participated in semistructured interviews and completed standardized questionnaires. Interviews were tape-recorded, transcribed, and analyzed using content analysis techniques. No significant difference was found in behavioral and emotional problems between the children in these families and the normative sample. However, parents reported problems on a borderline and clinically elevated level in one third of the children, and three of seven children self-reported problems on these levels. The interview results showed that parents reported (temporary) behavioral problems in most children during the acute stage of their parents’ illness. Other problems, such as anxiety, sleeping disorders, and compulsive behavior, persisted for longer. Parents reported that their children had more problems than the children themselves reported. This finding was not supported by the quantitative analysis. The results from the Child Behavior Checklist and the Dutch version of the Family Adaptability and Cohesion Evaluation Scales showed that children of families with poor family functioning were more vulnerable. In particular, extremely high adaptation (chaotic) and extremely low family cohesion (disengaged) seemed related to the prevalence of emotional and behavioral problems in these children. Absence of home healthcare was an additional burden for adolescent children.
Duct ectasia in the male

Three cases of inflammatory duct ectasia occurring in the male breast are described. The clinical presentation of the disease in the male closely resembles that in the female. Nipple retraction, nipple discharge, periareolar inflammation and bilateral involvement are all seen. Conservative measures produced unsatisfactory results similar to those in women. A similar operative approach to that used in women is advocated.
Noninvasive molecular imaging of c-Myc activation in living mice

The cytoplasmic Myc protein (c-Myc) regulates various human genes and is dysregulated in many human cancers. Phosphorylation mediates the protein activation of c-Myc and is essential for the function of this transcription factor in normal cell behavior and tumor growth. To date, however, the targeting of Myc as a therapeutic approach for cancer treatment has been achieved primarily at the nonprotein level. We have developed a molecular imaging sensor for noninvasive imaging of c-Myc activity in living subjects using a split Firefly luciferase (FL) complementation strategy to detect and quantify the phosphorylation-mediated interaction between glycogen synthase kinase 3β (GSK3β) and c-Myc. This sensor system consists of two fusion proteins, GSK 35–433-CFL and NFL-c-Myc, in which specific fragments of GSK3β and c-Myc are fused with C-terminal and N-terminal fragments of the split FL, respectively. The sensor detects phosphorylation-specific GSK3β–c-Myc interaction, the imaging signal of which correlates with the steady-state and temporal regulation of c-Myc phosphorylation in cell culture. The sensor also detects inhibition of c-Myc activity via differential pathways, allowing noninvasive monitoring of c-Myc–targeted drug efficacy in intact cells and living mice. Notably, this drug inhibition is detected before changes in tumor size are apparent in mouse xenograft and liver tumor models. This reporter system not only provides an innovative way to investigate the role of functional c-Myc in normal and cancer-related biological processes, but also facilitates c-Myc–targeted drug development by providing a rapid quantitative approach to assessing cancer response to therapy in living subjects.
Determinants of Reactivity and Selectivity in Soluble Epoxide Hydrolase from Quantum Mechanics/Molecular Mechanics Modeling

Soluble epoxide hydrolase (sEH) is an enzyme involved in drug metabolism that catalyzes the hydrolysis of epoxides to form their corresponding diols. sEH has a broad substrate range and shows high regio- and enantioselectivity for nucleophilic ring opening by Asp333. Epoxide hydrolases therefore have potential synthetic applications. We have used combined quantum mechanics/molecular mechanics (QM/MM) umbrella sampling molecular dynamics (MD) simulations (at the AM1/CHARMM22 level) and high-level ab initio (SCS-MP2) QM/MM calculations to analyze the reactions, and determinants of selectivity, for two substrates: trans-stilbene oxide (t-SO) and trans-diphenylpropene oxide (t-DPPO). The calculated free energy barriers from the QM/MM (AM1/CHARMM22) umbrella sampling MD simulations show a lower barrier for phenyl attack in t-DPPO, compared with that for benzylic attack, in agreement with experiment. Activation barriers in agreement with experimental rate constants are obtained only with the highest level of QM theory (SCS-MP2) used. Our results show that the selectivity of the ring-opening reaction is influenced by several factors, including proximity to the nucleophile, electronic stabilization of the transition state, and hydrogen bonding to two active site tyrosine residues. The protonation state of His523 during nucleophilic attack has also been investigated, and our results show that the protonated form is most consistent with experimental findings. The work presented here illustrates how determinants of selectivity can be identified from QM/MM simulations. These insights may also provide useful information for the design of novel catalysts for use in the synthesis of enantiopure compounds.
Phototherapy in Vitiligo: Assessing the Compliance, Response and Patient's Perception about Disease and Treatment

Context: Vitiligo is a chronic, benign, but emotionally frustrating autoimmune disorder of depigmentation, with an incidence of 0.25-2.5% in India, the treatment of which is equally frustrating to the patient, as well as the doctor. Phototherapy is the first line treatment in many cases, which needs to be given at frequent sittings for long periods of time. As there is no satisfactory, short term treatment, many vitiligo patients, though enthusiastic in the beginning, become defaulters after a few weeks or months. Aims: This study was conducted to assess the compliance to phototherapy (PUVA and NB-UVB), determine the reasons for non-compliance, to calculate the overall response to phototherapy and to know about the patients’ perception about improvement of lesions. Materials and Methods: All files of the patients who attended phototherapy for Vitiligo in the department for a period of 4 years from January 2007 were analyzed and the patients were contacted via mail or telephone and were made to answer questionnaire regarding their disease. Conclusions: At the end of this retrospective questionnaire based study we concluded that only a quarter of the patients underwent regular phototherapy, among which the younger patients and those with widespread disease and facial lesions were more compliant. Educational status and sex had no impact on default status.
Nebivolol: a third-generation beta-blocker that augments vascular nitric oxide release: endothelial beta(2)-adrenergic receptor-mediated nitric oxide production.

BACKGROUND Nebivolol is a beta(1)-selective adrenergic receptor antagonist with proposed nitric oxide (NO)-mediated vasodilating properties in humans. In this study, we explored whether nebivolol indeed induces NO production and, if so, by what mechanism. We hypothesized that not nebivolol itself but rather its metabolites augment NO production. METHODS AND RESULTS Mouse thoracic aorta segments were bathed in an organ chamber. Administration of nebivolol did not affect NO production. When nebivolol was allowed to metabolize in vivo in mice, addition of plasma of these mice caused a sustained 2-fold increase in NO release. Interestingly, coadministration of a selective beta(2)-adrenergic receptor antagonist (butoxamine) prevented the response. Immunohistochemistry and Western blot analysis demonstrated the presence of beta(2)- but not beta(1)-adrenergic receptors on endothelial cells. In the absence of calcium, metabolized nebivolol failed to increase NO production, suggesting a role for calcium-dependent NO synthase. With digital fluorescence imaging, a rapid and sustained rise in endothelial cytosolic free Ca(2+) concentration was observed after administration of metabolized nebivolol, which also was abrogated by butoxamine pretreatment. CONCLUSIONS In vivo metabolized nebivolol increases vascular NO production. This phenomenon involves endothelial beta(2)-adrenergic receptor ligation, with a subsequent rise in endothelial free [Ca(2+)](i) and endothelial NO synthase-dependent NO production. This may be an important mechanism underlying the nebivolol-induced, NO-mediated arterial dilation in humans.
Baseline Magnetic Resonance Imaging Parameters and Stroke Outcome in Patients Treated by Intravenous Tissue Plasminogen Activator

Background and Purpose— We designed a prospective sequential pretreatment and posttreatment MRI study to assess the relation between neuroimaging parameters and clinical outcome in patients treated with intravenous recombinant tissue-type plasminogen activator (rtPA). Methods— Patients with symptoms of acute hemispheric ischemic stroke were recruited. The National Institutes of Health Stroke Scale (NIHSS) score was assessed at baseline and at days 1, 7, and 60, and the modified Rankin scale (mRS) at day 60, by which outcome was classified in terms of independence (mRS score 0, 1, or 2) or severe disability or death (mRS score 3 through 6), was assigned. Multimodal stroke MRI was performed at presentation and repeated at day 1. MRI procedures included magnetic resonance angiography, T2* gradient-echo sequence, echoplanar imaging, and isotropic diffusion- (DWI) and perfusion-weighted (PWI) imaging. Patients were treated with intravenous rtPA after MRI completion. Results— Twenty-nine patients (16 men and 13 women; mean±SD age, 65±14 years) underwent MRI; the mean time from symptom onset to treatment was 255±62 minutes. Twenty-six patients had a vessel occlusion, and 15 patients experienced a partial (Thrombolysis in Myocardial Infarction [TIMI]-2) or total (TIMI-3) recanalization at day 1, whereas 11 patients had a persistent occlusion. Mean NIHSS scores at day 60 were 5.7±5.4 if recanalization had occurred and 14±2 in cases of persistent occlusion. According to the mRS, 13 patients were independent (mRS 0 through 2), whereas severe disability or death (mRS 3 through 6) was observed in 15 patients. A better outcome was observed when recanalization was achieved (r =−0.68, P =0.0002). PWI volume and time to peak (TTP) within the DWI lesion assessed before therapy were correlated with day-60 NIHSS score (PWI volume:r =0.51, P =0.006, TTP:r =0.35, P =0.07). The day-0 DWI abnormality volume was well correlated with day-60 NIHSS score (r =0.58, P =0.001). Multiple regression linear analysis showed that 2 factors mainly influenced clinical outcome: (1) recanalization, with a high correlation with NIHSS score at day 60 (P =0.0001) and (2) day-0 DWI lesion volume, which is closely associated with day-60 NIHSS score (P =0.03). Conclusions— Baseline DWI volume and recanalization are the main factors influencing clinical outcome after rtPA for ischemic stroke.
Low serum adiponectin predicts future risk for asthma in women.

RATIONALE Our previous cross-sectional study showed that serum adiponectin is inversely associated with asthma among women. However, it is not known if serum adiponectin predicts future development of asthma or if asthma affects subsequent serum adiponectin concentrations among women. OBJECTIVES To determine longitudinal association between serum adiponectin and incident asthma among women. METHODS We used data from examinations at Years 10, 15, and 20 of the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. In our primary analysis, the association of CARDIA Year 15 serum adiponectin concentration with Year 20 incident asthma was evaluated. In our secondary analysis, the converse direction, that is, the association of CARDIA Year 10 prevalent asthma with Year 15 serum adiponectin, was evaluated, using logistic regression techniques. MEASUREMENTS AND MAIN RESULTS Our primary analysis included 1,450 women, mostly premenopausal. Multivariable analyses demonstrated that the lowest tertile of Year 15 serum adiponectin concentration (<7 mg/L) predicted significantly higher risk for incident asthma at Year 20 among women (odds ratio, 2.07; 95% confidence interval, 1.05, 4.10), and particularly among current smokers (interaction P = 0.051). Further, low serum adiponectin was more important than body mass index in predicting the risk for incident asthma among women. We also showed that the converse relationship was not true; that is, Year 10 prevalent asthma did not predict Year 15 serum adiponectin concentrations in women. CONCLUSIONS Serum adiponectin affects future risk for asthma in women and not vice versa. Measures that raise systemic adiponectin concentrations may lead to newer ways to prevent asthma among women, particularly among those who smoke.
Immuno-PET Quantitation of de2-7 Epidermal Growth Factor Receptor Expression in Glioma Using 124I-IMP-R4–Labeled Antibody ch806

Overexpression, activation, and mutations of the epidermal growth factor receptor (EGFR) are commonly found in solid tumors. The aim of this study was to develop a PET-based method for detecting the constitutively active mutant de2-7 EGFR, which is associated with disease progression and resistance to chemotherapy and radiotherapy in glioma. Methods: The chimeric antibody ch806, which selectively binds an epitope of the EGFR that is exposed only on overexpressed, mutant, or ligand-activated forms of the receptor, was conjugated to the radiohalogen 124I via the residualizing ligand IMP-R4, and in vitro properties were characterized. In vivo biodistribution and small-animal PET studies were performed in BALB/c nude mice bearing U87MG.de2-7 glioma xenografts. Imaging results were correlated with measured tumor uptake of the radioconjugate. Results: 124I-IMP-R4-ch806 had an immunoreactivity of 78.3% and was stable for 7 d when incubated in serum in vitro. The biodistribution analysis of 124I-IMP-R4-ch806 demonstrated a maximal uptake of 30.95 ± 6.01 percentage injected dose per gram (%ID/g) in U87MG.de2-7 xenografts at 48 h after injection, with prolonged tumor retention (6.07 ± 0.80 %ID/g at 216 h after injection). The tumor-to-blood ratio increased from 0.44 at 4 h after injection to a maximum of 4.70 at 168 h after injection. PET of 124I-IMP-R4-ch806 biodistribution was able to clearly detect the U87MG.de2-7 tumors at 24 h after injection and for at least 168 h after injection. Correlation between tumor PET image quantitation of 124I-IMP-R4-ch806 and %ID/g determined from resected tissues (r = 0.9350) was excellent. Conclusion: These results show that immuno-PET with 124I-IMP-R4-ch806 is feasible and allows noninvasive quantitation of de2-7 EGFR expression in vivo.