tbuckley/cabot-search huggingface dataset:
Intragenic ATM Methylation in Peripheral Blood DNA as a Biomarker of Breast Cancer Risk
Authors: Kevin Brennan, Montserrat Garcia-Closas, Nick Orr, Olivia Fletcher, Michael Jones, Alan Ashworth, Anthony Swerdlow, Heather Thorne, Elio Riboli, Paolo Vineis, Miren Dorronsoro, Francoise Clavel-Chapelon, Salvatore Panico, N. Charlotte Onland-Moret, Dimitrios Trichopoulos, Rudolf Kaaks, Kay-Tee Khaw, Robert Brown, James M. Flanagan
Journal: Cancer Research (2012)

Abstract Few studies have evaluated the association between DNA methylation in white blood cells (WBC) and the risk of breast cancer. The evaluation of WBC DNA methylation as a biomarker of cancer risk is of particular importance as peripheral blood is often available in prospective cohorts and easier to obtain than tumor or normal tissues. Here, we used prediagnostic blood samples from three studies to analyze WBC DNA methylation of two ATM intragenic loci (ATMmvp2a and ATMmvp2b) and genome-wide DNA methylation in long interspersed nuclear element-1 (LINE1) repetitive elements. Samples were from a case–control study derived from a cohort of high-risk breast cancer families (KConFab) and nested case–control studies in two prospective cohorts: Breakthrough Generations Study (BGS) and European Prospective Investigation into Cancer and Nutrition (EPIC). Bisulfite pyrosequencing was used to quantify methylation from 640 incident cases of invasive breast cancer and 741 controls. Quintile analyses for ATMmvp2a showed an increased risk of breast cancer limited to women in the highest quintile [OR, 1.89; 95% confidence interval (CI), 1.36–2.64; P = 1.64 × 10−4]. We found no significant differences in estimates across studies or in analyses stratified by family history or menopausal status. However, a more consistent association was observed in younger than in older women and individually significant in KConFab and BGS, but not EPIC. We observed no differences in LINE1 or ATMmvp2b methylation between cases and controls. Together, our findings indicate that WBC DNA methylation levels at ATM could be a marker of breast cancer risk and further support the pursuit of epigenome-wide association studies of peripheral blood DNA methylation. Cancer Res; 72(9); 2304–13. ©2012 AACR.
A Role for the Tec Family Tyrosine Kinase Txk in T Cell Activation and Thymocyte Selection
Authors: Connie L. Sommers, Ronald L. Rabin, Alexander Grinberg, Henry C. Tsay, Joshua Farber, Paul E. Love
Journal: The Journal of Experimental Medicine (1999)

Summary Recent data indicate that several members of the Tec family of protein tyrosine kinases function in antigen receptor signal transduction. Txk, a Tec family protein tyrosine kinase, is expressed in both immature and mature T cells and in mast cells. By overexpressing Txk in T cells throughout development, we found that Txk specifically augments the phospholipase C (PLC)-γ1–mediated calcium signal transduction pathway upon T cell antigen receptor (TCR) engagement. Although Txk is structurally different from inducible T cell kinase (Itk), another Tec family member expressed in T cells, expression of the Txk transgene could partially rescue defects in positive selection and signaling in itk−/− mice. Conversely, in the itk+/+ (wild-type) background, overexpression of Txk inhibited positive selection of TCR transgenic thymocytes, presumably due to induction of cell death. These results identify a role for Txk in TCR signal transduction, T cell development, and selection and suggest that the Tec family kinases Itk and Txk perform analogous functions.
Effect of monthly vitamin D3 supplementation in healthy adults on adverse effects of earthquakes: randomised controlled trial
Authors: S. Slow, C. M. Florkowski, S. T. Chambers, P. C. Priest, A. W. Stewart, L. C. Jennings, J. H. Livesey, C. A. Camargo, R. Scragg, D. R. Murdoch
Journal: BMJ (2014)

To determine whether supplementation with vitamin D improves resilience to the adverse effects of earthquakes.Opportunistic addition to an established randomised double blind placebo controlled trial.Christchurch, New Zealand, where a prolonged series of catastrophic earthquakes beginning on 4 September 2010 occurred, which caused widespread destruction, fatalities, and extensive psychological damage.322 healthy adults (241 women; 81 men) aged 18-67 who were already participating in the vitamin D and acute respiratory infections study (VIDARIS) between February 2010 and November 2011.Participants were randomised to receive an oral dose of either 200,000 IU vitamin D3 monthly for two months then 100,000 IU monthly (n=161) or placebo (n=161) for a total of 18 months.This is a post hoc analysis from the previously published VIDARIS trial. The primary endpoint in the current analysis was the self reported effects and overall adverse impact of the Christchurch earthquakes as assessed by questionnaire four months after the most destructive earthquake on 22 February 2011, which was used as the index event. The secondary end point was the number of "psychological" adverse events that participants reported at their usual monthly appointments as part of the original VIDARIS trial.308 participants completed the earthquake impact questionnaire (n=152 in the vitamin D group and 156 in the placebo group). There was no significant difference in the number of self reported adverse effects between those receiving vitamin D supplementation and those receiving placebo. There was also no difference in the overall adverse impact score between treatment groups (χ(2) P=0.44). The exception was that those in the vitamin D group experienced more adverse effects on family relationships (22% v 13%; χ(2) P=0.03). The number of psychological adverse events-such as fatigue, stress, anxiety, and insomnia-that participants reported at their usual monthly appointments was significantly higher after the earthquake (χ(2) P=0.007) but did not differ between treatment groups.In this trial, vitamin D supplementation did not reduce the adverse impact of earthquakes in healthy adults. Trial registration Australian New Zealand Clinical Trials Registry (anzctr.org.au) ACTRN12609000486224.
Effect of Spontaneous Breathing Trial Duration on Outcome of Attempts to Discontinue Mechanical Ventilation
Authors: ANDRÉS ESTEBAN, INMACULADA ALÍA, MARTIN J. TOBIN, ANSELMO GIL, FEDERICO GORDO, INMACULADA VALLVERDÚ, LLUIS BLANCH, ALFONSO BONET, ANTONIA VÁZQUEZ, RAUL de PABLO, ANTONIO TORRES, MIGUEL A. de la CAL, SANTIAGO MACÍAS
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

The duration of spontaneous breathing trials before extubation has been set at 2 h in research studies, but the optimal duration is not known. We conducted a prospective, multicenter study involving 526 ventilator-supported patients considered ready for weaning, to compare clinical outcomes for trials of spontaneous breathing with target durations of 30 and 120 min. Of the 270 and 256 patients in the 30- and 120-min trial groups, respectively, 237 (87.8%) and 216 (84.8%), respectively, completed the trial without distress and were extubated (p = 0.32); 32 (13.5%) and 29 (13.4%), respectively, of these patients required reintubation within 48 h. The percentage of patients who remained extubated for 48 h after a spontaneous breathing trial did not differ in the 30- and 120-min trial groups (75.9% versus 73.0%, respectively, p = 0.43). The 30- and 120-min trial groups had similar within-unit mortality rates (13 and 9%, respectively) and in-hospital mortality rates (19 and 18%, respectively). Reintubation was required in 61 (13.5%) patients, and these patients had a higher mortality (20 of 61, 32.8%) than did patients who tolerated extubation (18 of 392, 4.6%) (p < 0.001). Neither measurements of respiratory frequency, heart rate, systolic blood pressure, and oxygen saturation during the trial, nor other functional measurements before the trial discriminated between patients who required reintubation from those who tolerated extubation. In conclusion, after a first trial of spontaneous breathing, successful extubation was achieved equally effectively with trials targeted to last 30 and 120 min.
Developing role of HPV in cervical cancer prevention
Authors: H. C. Kitchener, K. Denton, K. Soldan, E. J. Crosbie
Journal: BMJ (2013)

#### Summary points

Since the Cervical Screening Programme was introduced in England, the incidence of cervical cancer has fallen by 44% and number of deaths from the disease by 70% (fig 1⇓). This effect has also been seen in other countries.1 2 The discovery of human papillomavirus (HPV) DNA in cervical cancer and in subsequent molecular biology and epidemiological studies shows that persistent cervical infection with “high risk” HPV types is a necessary cause of cervical cancer. This finding has led to two major developments in cervical cancer control: immunisation as a means of primary prevention and HPV testing in cervical screening, which is poised to replace cytology as the primary screening modality. This article reviews the evidence base for evolving from exfoliative cytology alone to a dual approach of HPV vaccination and HPV based cervical screening. …
Human Atrial Ion Channel and Transporter Subunit Gene-Expression Remodeling Associated With Valvular Heart Disease and Atrial Fibrillation
Authors: Nathalie Gaborit, Marja Steenman, Guillaume Lamirault, Nolwenn Le Meur, Sabrina Le Bouter, Gilles Lande, Jean Léger, Flavien Charpentier, Torsten Christ, Dobromir Dobrev, Denis Escande, Stanley Nattel, Sophie Demolombe
Journal: Circulation (2005)

Valvular heart disease (VHD), which often leads to atrial fibrillation (AF), and AF both cause ion-channel remodeling. We evaluated the ion-channel gene expression profile of VHD patients, in permanent AF (AF-VHD) or in sinus rhythm (SR-VHD), in comparison with patients without AF or VHD, respectively.We used microarrays containing probes for human ion-channel and Ca2+-regulator genes to quantify mRNA expression in atrial tissues from 7 SR-VHD patients and 11 AF-VHD patients relative to 11 control patients in SR without structural heart disease (SR-CAD). From the data set, we selected for detailed analysis 59 transcripts expressed in the human heart. SR-VHD patients differentially expressed 24/59 ion-channel and Ca2+-regulator transcripts. There was significant overlap between VHD groups, with 66% of genes altered in SR-VHD patients being similarly modified in AF-VHD. Statistical differences between the AF- and SR-VHD groups identified the specific molecular portrait of AF, which involved 12 genes that were further confirmed by real-time reverse transcription-polymerase chain reaction. For example, phospholamban, the beta-subunit MinK (KCNE1) and MIRP2 (KCNE3), and the 2-pore potassium channel TWIK-1 were upregulated in AF-VHD compared with SR-VHD, whereas the T-type calcium-channel Cav3.1 and the transient-outward potassium channel Kv4.3 were downregulated. Two-way hierarchical clustering separated SR-VHD from AF-VHD patients. AF-related changes in L-type Ca2+-current and inward-rectifier current were confirmed at protein and functional levels. Finally, for 13 selected genes, SR restoration reversed ion-channel remodeling.VHD extensively remodels cardiac ion-channel and transporter expression, and AF alters ion-channel expression in VHD patients.
Alignment Errors Strongly Impact Likelihood-Based Tests for Comparing Topologies
Authors: Eli Levy Karin, Edward Susko, Tal Pupko
Journal: Molecular Biology and Evolution (2014)

Estimating phylogenetic trees from sequence data is an extremely challenging and important statistical task. Within the maximum-likelihood paradigm, the best tree is a point estimate. To determine how strongly the data support such an evolutionary scenario, a hypothesis testing methodology is required. To this end, the Kishino–Hasegawa (KH) test was developed to determine whether one topology is significantly more supported by the sequence data than another one. This test and its derivatives are widely used in phylogenetics and phylogenomics. Here, we show that the KH test is biased in the presence of alignment error and can lead to erroneous conclusions. Using simulations we demonstrated that due to alignment errors the KH test often rejects one of the competing topologies, even though both topologies are equally supported by the data. Specifically, we show that the KH test favors the guide tree used to align the analyzed sequences. Further, branch length optimization renders the test too conservative. We propose two possible corrections for these biases. First, we evaluated the impact of removing unreliable alignment columns and found out that it decreases the bias at the cost of substantially reducing the test's power. Second, we developed a parametric test that entirely abolishes the biases without data filtering. This test incorporates the alignment construction step into the test's hypothesis, thus removing the above guide tree effect. We extend this methodology for the case of multiple-topology comparisons and demonstrate the applicability of the new methodology on an exemplary data set.
Evaluation of Cognitive Function Associated With Chemotherapy: A Review of Published Studies and Recommendations for Future Research
Authors: Janette Vardy, Sean Rourke, Ian F. Tannock
Journal: Journal of Clinical Oncology (2007)

Purpose There is evidence that some cancer survivors suffer cognitive impairment after chemotherapy. Determining if a patient has cognitive impairment is challenging, especially because impairment is usually subtle. Patients and Methods We assessed the design of studies evaluating cognitive function during or after chemotherapy in adult patients with solid tumors. We also reviewed methods used to evaluate cognitive function in subjects with other diseases and make recommendations for future studies. Results We identified 22 studies that met our criteria: 82% included women with breast cancer. Eight studies were longitudinal, 12 were cross-sectional, and two were follow-ups of cross-sectional studies. Sixteen studies used a battery of neuropsychological (NP) tests to assess subjects, and 13 included a control group. Ten studies (45%) had no explicit definition of cognitive impairment; most others used z scores or T scores and defined impairment based on standard deviations below the mean, but there was no consistency in for the cutoff point used or the number of tests required. Conclusion There is no consistency in defining cognitive impairment, in the NP batteries used, or in statistical methods in studies of cognitive function of cancer patients. We suggest guidelines to define criteria for cognitive impairment. Use of summary scores and control groups is recommended. Practice effect should be adjusted for in longitudinal studies. A balance is needed between comprehensive batteries and briefer tests, which still need to be sensitive to mild impairment.
Genetic Analysis of the <b> <i>RNASEL</i> </b> Gene in Hereditary, Familial, and Sporadic Prostate Cancer
Authors: Fredrik Wiklund, Björn-Anders Jonsson, Anthony J. Brookes, Linda Strömqvist, Jan Adolfsson, Monica Emanuelsson, Hans-Olov Adami, Katarina Augustsson-Bälter, Henrik Grönberg
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The RNASEL gene has been proposed as a candidate gene for the HPC1 locus through a positional cloning and candidate gene approach. Cosegregation between the truncating mutation E265X and disease in a hereditary prostate cancer (HPC) family and association between prostate cancer risk and the common missense variant R462Q has been reported. To additionally evaluate the possible role of RNASEL in susceptibility to prostate cancer risk, we performed a comprehensive genetic analysis of sequence variants in RNASEL in the Swedish population. Experimental Design: Using 1624 prostate cancer cases and 801 unaffected controls, the truncating mutation E265X and five common sequence variants, including the two missense mutations R462Q and D541E, were evaluated for association between genotypes/haplotypes and prostate cancer risk. Results: The prevalence of E265X carriers among unaffected controls and prostate cancer patients was almost identical (1.9 and 1.8% in controls and cases, respectively), and evidence for segregation of E265X with disease was not observed within any HPC family. Overall, the analyses of common sequence variants provided limited evidence for association with prostate cancer risk. We found a marginally significant inverse association between the missense mutation D541E and sporadic prostate cancer risk (odds ratio, 0.77; 95% confidence interval, 0.59–1.00) and reduced risk of prostate cancer in carriers of two different haplotypes being completely discordant. Conclusions: Considering the high quality in genotyping and the size of this study, these results provide solid evidence against a major role of RNASEL in prostate cancer etiology in Sweden.
A Novel Association Between Nondipping and Painful Diabetic Polyneuropathy
Authors: Cinzia D’Amato, Roberto Morganti, Federica Di Gennaro, Carla Greco, Girolama A. Marfia, Vincenza Spallone
Journal: Diabetes Care (2014)

We hypothesized the meaningful coexistence of neuropathic pain and nondipping in painful diabetic polyneuropathy (PDPN).In 113 patients with PDPN, with painless diabetic polyneuropathy (DPN(+)) and without DPN (DPN(-)), neuropathic pain, sleep, risk for obstructive sleep apnea (OSA), autonomic function, and blood pressure (BP) circadian pattern were assessed using the Douleur Neuropathique en 4 Questions (DN4), the Medical Outcomes Study Sleep Scale, the Berlin Questionnaire, cardiovascular reflex tests, and ambulatory BP monitoring.Patients with PDPN showed higher nighttime systolic BP (130.4 ± 15.6 mmHg) than both DPN(-) (119.9 ± 10.6 mmHg; P < 0.0001) and DPN(+) patients (124.2 ± 12.3 mmHg; P < 0.05), and lower day-night difference (∆) in systolic BP (5.5 ± 6.5 vs. 8.6 ± 7.7%; P < 0.05) and diastolic BP than DPN(-) patients. In a stepwise regression analysis, orthostatic hypotension, high risk for OSA, and PDPN (DN4 interview) were independent determinants of ∆ in systolic BP (r = 0.46; P = 0.0001), ∆ in diastolic BP, and nighttime systolic BP.PDPN is associated with higher nocturnal systolic BP and impaired BP circadian pattern independent of pain-related comorbidities, suggesting a condition of high cardiovascular risk.
Double blind comparison of omeprazole (40 mg od) versus cimetidine (400 mg qd) in the treatment of symptomatic erosive reflux oesophagitis, assessed endoscopically, histologically and by 24 h pH monitoring.
Authors: T C Dehn, H A Shepherd, D Colin-Jones, M G Kettlewell, N J Carroll
Journal: Gut (1990)

<b>425</b> <h3><b>Objectives:</b></h3> Liver Imaging Reporting and Data System (LI-RADS), designed for all patients at risk for hepatocellular carcinoma was developed by the American College of Radiology and designed for utilization with CT and MRI studies of the liver. Application with FDG PET-MRI however is still under investigation. <h3><b>Methods:</b></h3> We performed a retrospective review of 10 patients undergoing enhanced FDG PET-MRI studies with known cirrhosis or metastatic cancer. There were 6 males with 4 females with average age 65.5 yrs. All subjects were imaged with hepatobiliary contrast agent-enhanced MRI and/or CT studies with follow up FDG PET-MRI utilizing a dedicated hybrid 3T MRI scanner. A board certified body radiologist and a board certified nuclear medicine physician interpreted each study separately, then with a consensus read. <h3><b>Results:</b></h3> Seven (70%) of the initial studies demonstrated vivid arterial enhancement, and three (30%) lesions demonstrated isointense signal or low signal intensity on arterial phase at time of initial exam. Tumor growth, washout and capsular enhancement were used as discriminator criteria to guide treatment. Six cases with greater than 20 mm lesions were considered LI-RADS 5 and had at least 2 additional discriminators. One case demonstrated tumor within the IVC and was considered LI-RADS 5V. The patients subsequently underwent either TACE procedure or radiation therapy. Three cases demonstrated FDG uptake with suggested microvascular invasion. <h3><b>Conclusion:</b></h3> Our experience clearly demonstrates the added value of LI-RADS in streamlining treatment and optimizing patient care, particularly in LI-RADS category 4 and 5 cases. However, FDG uptake is variable in these patients and may suggest more aggressive microvascular invasion in those patients with hepatic uptake of FDG. <b>Research Support:</b> None.
Effects of chelating agents on oral uptake and renal deposition and excretion of cadmium.
Authors: B Engström
Journal: Environmental Health Perspectives (1984)

The gastrointestinal absorption, transport, tissue deposition and excretion of cadmium was studied in adult male mice given a single oral LD50 dose of 109Cd-labeled CdCl2 alone or in combination with nitrilotriacetic acid (NTA), sodium tripolyphosphate (STPP) or ethylenediaminetetraacetic acid (EDTA). Blood, intestinal mucosa, liver and kidneys were analyzed for 109Cd at different times after exposure and the influence of the chelating agents on Cd binding to metallothionein and other tissue ligands was also studied. Acute toxicity was noted. Complex formation between Cd and EDTA was studied in solutions containing Cd:EDTA at 1:04 and 1:4 molar ratios. Adult male mice were exposed orally or by direct infusion into the stomach to either of the two solutions (containing an LD50 dose of Cd). Body retention and tissue deposition of Cd was recorded after 4 (direct infusion) or 21 days (oral exposure), and the mortality in different exposure groups observed. Adult male were also exposed to a low oral dose of 109Cd-labeled cadmium (0.5 mg/kg), followed by 18 months continuous administration of NTA, (500 ppm) STPP (500 ppm) or EDTA (50 ppm) in the drinking water or the chelating agent in combination with Cd (50 ppm), Cd alone (50 ppm) or deionized water. Whole-body retention of 109Cd, tissue deposition of 109Cd and total Cd and development of proteinuria were observed. When cadmium was given with an excess of EDTA, all Cd ions were bound in a 1:1 Cd-EDTA complex. Decreased acute toxicity was observed which was related to increased body elimination of cadmium. The Cd passes though the body still bound to EDTA and is excreted via the kidneys in this form. Similar results were found in mice exposed to Cd + NTA, while gavage of CD + STPP led to an initially decreased systemic uptake of Cd and thereafter to a prolongation of the biological half-time and thus a comparatively higher body retention of the metal. Cd may form a 2:1 complex with EDTA in the presence of excess cadmium. An increased retention and toxicity of cadmium was seen after direct infusion of this solution, while gavage resulted in a decreased toxicity. The effect of different chelating agents on acute cadmium toxicity and metabolism seemed to be due to changes in the stability of the administered chelate complexes, due to variation in pH and to the availability of metal binding ligands such as metallothionein in vivo. NTA, STPP and EDTA had no effect on the metabolism or toxicity of cadmium after long-term low dose oral exposure.