tbuckley/cabot-search huggingface dataset:
Exome sequencing resolves apparent incidental findings and reveals further complexity of SH3TC2 variant alleles causing Charcot-Marie-Tooth neuropathy
Authors: James R Lupski, Claudia Gonzaga-Jauregui, Yaping Yang, Matthew N Bainbridge, Shalini Jhangiani, Christian J Buhay, Christie L Kovar, Min Wang, Alicia C Hawes, Jeffrey G Reid, Christine Eng, Donna M Muzny, Richard A Gibbs
Journal: Genome Medicine (2013)

The debate regarding the relative merits of whole genome sequencing (WGS) versus exome sequencing (ES) centers around comparative cost, average depth of coverage for each interrogated base, and their relative efficiency in the identification of medically actionable variants from the myriad of variants identified by each approach. Nevertheless, few genomes have been subjected to both WGS and ES, using multiple next generation sequencing platforms. In addition, no personal genome has been so extensively analyzed using DNA derived from peripheral blood as opposed to DNA from transformed cell lines that may either accumulate mutations during propagation or clonally expand mosaic variants during cell transformation and propagation.We investigated a genome that was studied previously by SOLiD chemistry using both ES and WGS, and now perform six independent ES assays (Illumina GAII (x2), Illumina HiSeq (x2), Life Technologies' Personal Genome Machine (PGM) and Proton), and one additional WGS (Illumina HiSeq).We compared the variants identified by the different methods and provide insights into the differences among variants identified between ES runs in the same technology platform and among different sequencing technologies. We resolved the true genotypes of medically actionable variants identified in the proband through orthogonal experimental approaches. Furthermore, ES identified an additional SH3TC2 variant (p.M1?) that likely contributes to the phenotype in the proband.ES identified additional medically actionable variant calls and helped resolve ambiguous single nucleotide variants (SNV) documenting the power of increased depth of coverage of the captured targeted regions. Comparative analyses of WGS and ES reveal that pseudogenes and segmental duplications may explain some instances of apparent disease mutations in unaffected individuals.
Distribution and metabolism of intravenously administered trefoil factor 2/porcine spasmolytic polypeptide in the rat
Authors: S S Poulsen, J Thulesen, E Nexø, L Thim
Journal: Gut (1998)

Trefoil peptides are secreted by mucus producing cells in the gastrointestinal tract and are supposed to be involved in oligomerisation processes of the mucin glycoproteins in the lumen. Endocrine functions have also been suggested.To target possible binding sites for iodine-125 labelled porcine spasmolytic polypeptide (pSP) in an in vivo rat model.125I-pSP was given by intravenous injection to female Sprague-Dawley rats. The distribution of 125I-pSP was assessed by gamma counting of samples of organs and by autoradiography of paraffin wax embedded sections. The degradation of 125I-pSP was studied by trichloroacetic acid precipitation, and the saturability of binding by administration of excess unlabelled peptide.125I-pSP was taken up in the kidneys and the gastrointestinal tract and was excreted almost unmetabolised in the urine. In the stomach, it could be displaced by unlabelled pSP in a dose dependent manner. Autoradiography showed grains in mucous neck cells, parietal cells, the mucus layer, and the pyloric glands of the stomach; in Brunner's glands and the Paneth cells in the small intestine; and in cells in the lower part of the crypts in the colon.125I-pSP from the circulatory system is taken up by mucus producing cells in the gastrointestinal tract. The binding can be displaced by non-radioactive pSP, suggesting the presence of a receptor.
Results from the International Conference of Experts on Intra-abdominal Hypertension and Abdominal Compartment Syndrome. I. Definitions
Authors: Manu L. N. G. Malbrain, Michael L. Cheatham, Andrew Kirkpatrick, Michael Sugrue, Michael Parr, Jan De Waele, Zsolt Balogh, Ari Leppäniemi, Claudia Olvera, Rao Ivatury, Scott D’Amours, Julia Wendon, Ken Hillman, Kenth Johansson, Karel Kolkman, Alexander Wilmer
Journal: Intensive Care Medicine (2006)
RRHP: a tag-based approach for 5-hydroxymethylcytosine mapping at single-site resolution
Authors: Adam Petterson, Tzu Hung Chung, Darany Tan, Xueguang Sun, Xi-Yu Jia
Journal: Genome biology (2014)

Current methods for genomic mapping of 5-hydroxymethylcytosine (5hmC) have been limited by either costly sequencing depth, high DNA input, or lack of single-base resolution. We present an approach called Reduced Representation 5-Hydroxymethylcytosine Profiling (RRHP) to map 5hmC sites at single-base resolution by exploiting the use of beta-glucosyltransferase to inhibit enzymatic digestion at the junction where adapters are ligated to a genomic library. Therefore, only library fragments presenting glucosylated 5hmC residues at the junction are sequenced. RRHP can detect sites with low 5hmC abundance, and when combined with RRBS data, 5-methylcytosine and 5-hydroxymethylcytosine can be compared at a specific site.
Plasma Leptin Levels and Incidence of Heart Failure, Cardiovascular Disease, and Total Mortality in Elderly Individuals
Authors: Wolfgang Lieb, Lisa M. Sullivan, Tamara B. Harris, Ronenn Roubenoff, Emelia J. Benjamin, Daniel Levy, Caroline S. Fox, Thomas J. Wang, Peter W. Wilson, William B. Kannel, Ramachandran S. Vasan
Journal: Diabetes Care (2008)

OBJECTIVE Obesity predisposes individuals to congestive heart failure (CHF) and cardiovascular disease (CVD). Leptin regulates energy homeostasis, is elevated in obesity, and influences ventricular and vascular remodeling. We tested the hypothesis that leptin levels are associated with greater risk of CHF, CVD, and mortality in elderly individuals. RESEARCH DESIGN AND METHODS We evaluated 818 elderly (mean age 79 years, 62% women) Framingham Study participants attending a routine examination at which plasma leptin was assayed. RESULTS Leptin levels were higher in women and strongly correlated with BMI (P &amp;lt; 0.0001). On follow-up (mean 8.0 years), 129 (of 775 free of CHF) participants developed CHF, 187 (of 532 free of CVD) experienced a first CVD event, and 391 individuals died. In multivariable Cox regression models adjusting for established risk factors, log-leptin was positively associated with incidence of CHF and CVD (hazard ratio [HR] per SD increment 1.26 [95% CI 1.03–1.55] and 1.28 [1.09–1.50], respectively). Additional adjustment for BMI nullified the association with CHF (0.97 [0.75–1.24]) but only modestly attenuated the relation to CVD incidence (1.23 [1.00–1.51], P = 0.052). We observed a nonlinear, U-shaped relation between log-leptin and mortality (P = 0.005 for quadratic term) with greater risk of death evident at both low and high leptin levels. CONCLUSIONS In our moderate-sized community-based elderly sample, higher circulating leptin levels were associated with a greater risk of CHF and CVD, but leptin did not provide incremental prognostic information beyond BMI. Additional investigations are warranted to elucidate the U-shaped relation of leptin to mortality.
Association of androgenetic alopecia with metabolic syndrome in men: a community-based survey
Authors: L-H. Su, T.H-H. Chen
Journal: British Journal of Dermatology (2010)

Several previous studies have investigated the association between factors related to metabolic syndrome, which is known to increase the risk of type 2 diabetes mellitus and cardiovascular disease, and androgenetic alopecia (AGA). However, the results of these studies have been inconsistent.To determine if there is an association between metabolic syndrome and AGA after adjustment for potential confounders.A population-based cross-sectional survey was conducted in Tainan, Taiwan. A total of 740 subjects aged 40-91 years participated in the survey between April and June 2005. The Norwood classification was used to assess the degree of hair loss. Information on components of metabolic syndrome together with other possible risk factors was collected.A statistically significant association was found between AGA and the presence of metabolic syndrome [odds ratio (OR) 1.67, 95% confidence interval (CI) 1.01-2.74] as well as between AGA and the number of fulfilled metabolic syndrome components (OR 1.21, 95% CI 1.03-1.42) after controlling for age, family history of AGA and smoking status. Among metabolic syndrome components, high-density lipoprotein cholesterol (HDL-C) (OR 2.36, 95% CI 1.41-3.95; P = 0.001) was revealed as the most important factor associated with AGA.Our population-based study found a significant association between AGA and metabolic syndrome; among the components of metabolic syndrome, HDL-C was found to be of particular importance. This finding may have significant implications for the identification of metabolic syndrome in patients with moderate or severe AGA. Early intervention for metabolic syndrome is critical to reduce the risk and complications of cardiovascular disease and type 2 diabetes mellitus later in life.
Consortium Sandbox: Building and Sharing Resources
Authors: Mark D. Lim
Journal: Science Translational Medicine (2014)

Some common challenges of biomedical product translation-scientific, regulatory, adoption, and reimbursement-can best be addressed by the broad sharing of resources or tools. But, such aids remain undeveloped because the undertaking requires expertise from multiple research sectors as well as validation across organizations. Biomedical resource development can benefit from directed consortia-a partnership framework that provides neutral and temporary collaborative environments for several, oftentimes competing, organizations and leverages the aggregated intellect and resources of stakeholders so as to create versatile solutions. By analyzing 369 biomedical research consortia, we tracked consortia growth around the world and gained insight into how this partnership model advances biomedical research. Our analyses suggest that research-by-consortium provides benefit to biomedical science, but the model needs further optimization before it can be fully integrated into the biomedical research pipeline.
Body Composition as an Independent Determinant of 5-Fluorouracil–Based Chemotherapy Toxicity
Authors: Carla M.M. Prado, Vickie E. Baracos, Linda J. McCargar, Marina Mourtzakis, Karen E. Mulder, Tony Reiman, Charles A. Butts, Andrew G. Scarfe, Michael B. Sawyer
Journal: Clinical Cancer Research (2007)

Evidence suggests that lean body mass (LBM) may be useful to normalize doses of chemotherapy. Data from a prospective study were used to determine if the highest doses of 5-fluorouracil (5-FU) per kilogram LBM would be associated with dose-limiting toxicity in stage II/III colon cancer patients treated with 5-FU and leucovorin.Toxicity after cycle 1 was graded according to National Cancer Institute Common Toxicity Criteria, version 2.0. Muscle tissue was measured by computerized tomography. An extrapolation to the LBM compartment of the whole body was employed.Mean values of 5-FU/LBM of the entire population were different in terms of presence or absence of toxicity (P = 0.036). A cut point of 20 mg 5-FU/kg LBM seemed to be a threshold for developing toxicity (P = 0.005). This observation was pertinent to women (odds ratio, 16.73; P = 0.021). Women in this study had a relatively low proportion of LBM relative to their body surface area.Our study shows that low LBM is a significant predictor of toxicity in female patients administered 5-FU using the convention of dosing per unit of body surface area. We conclude that variation in toxicity between females and males may be partially explained by this feature of body composition.
FOXP3 Expression and Prognosis: Role of Both the Tumor and T Cells
Authors: Hailing Lu
Journal: Journal of Clinical Oncology (2009)

FOXP3 is a transcription factor that is well known to be the hallmark of immune suppressive T regulatory cells (Tregs), especially thymically derived natural Tregs. 1 Lack of FOXP3-expressing T cells can lead to autoimmune disease, whereas an abundance of FOXP3expressing T cells can result in immune deficiency. Increased levels of FOXP3-positive Tregs in peripheral blood and tumor have been reported in patients with various types of cancer, including ovarian, 2,3 breast, 4 and other tumors. 5 Abundance of FOXP3-positive Tregs in tumors has been associated with worse prognosis. 2-4 For example, Batesetal 4 reportedthathighnumbersofFOXP3-positiveTregswere identifiedinpatientswithductalcarcinomainsituatincreasedriskof relapse, and in patients with invasive breast tumors with both shorter relapse-freeandoverallsurvival.Inadditiontotheirpotentialvaluein predicting disease progression and relapse, FOXP3-positive Tregs haverecentlybeenreportedtobeamarkerformonitoringtherapeutic response. A recent study has suggested that pathologic complete response of breast carcinoma to neoadjuvant chemotherapy is associated with the disappearance of tumor-infiltrating FOXP3-positive Tregs. 6 Furthermore,FOXP3hasbeenstudiedasatherapeutictarget, andithasbeenshownthatvaccinationtoeradicateFOXP3-expressing cellsenhancestumorimmunity. 7 IthadbeenassumedthatTregswere the major cell type mediating immune suppression regulated by FOXP3 expression. Only recently has it been demonstrated that the tumor cell itself can express FOXP3.
Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy
Authors: Maurizio Zangari, Elias Anaissie, Bart Barlogie, Ashraf Badros, Raman Desikan, A. Viju Gopal, Christopher Morris, Amir Toor, Eric Siegel, Louis Fink, Guido Tricot
Journal: Blood (2001)
MicroRNA-21 Knockdown Disrupts Glioma Growth <i>In vivo</i> and Displays Synergistic Cytotoxicity with Neural Precursor Cell–Delivered S-TRAIL in Human Gliomas
Authors: Maarten F. Corsten, Rafael Miranda, Randa Kasmieh, Anna M. Krichevsky, Ralph Weissleder, Khalid Shah
Journal: Cancer Research (2007)

Abstract Despite the development of new glioma therapies that allow for tumor-targeted in situ delivery of cytotoxic drugs, tumor resistance to apoptosis remains a key impediment to effective treatment. Mounting evidence indicates that microRNAs (miRNA) might play a fundamental role in tumorigenesis, controlling cell proliferation and apoptosis. In gliomas, microRNA-21 (miR-21) levels have been reported to be elevated and their knockdown is associated with increased apoptotic activity. We hypothesized that suppression of miR-21 might sensitize gliomas for cytotoxic tumor therapy. With the use of locked nucleic acid (LNA)-antimiR-21 oligonucleotides, bimodal imaging vectors, and neural precursor cells (NPC) expressing a secretable variant of the cytotoxic agent tumor necrosis factor–related apoptosis inducing ligand (S-TRAIL), we show that the combined suppression of miR-21 and NPC-S-TRAIL leads to a synergistic increase in caspase activity and significantly decreased cell viability in human glioma cells in vitro. This phenomenon persists in vivo, as we observed complete eradication of LNA-antimiR-21–treated gliomas subjected to the presence of NPC-S-TRAIL in the murine brain. Our results reveal the efficacy of miR-21 antagonism in murine glioma models and implicate miR-21 as a target for therapeutic intervention. Furthermore, our findings provide the basis for developing combination therapies using miRNA modulation and cytotoxic tumor therapies. [Cancer Res 2007;67(19):8994–9000]
The effect of uremia on tumor necrosis factor-alpha release after an in vitro whole-blood endotoxin challenge.
Authors: C W Oettinger, L A Bland, J C Oliver, M J Arduino, S K McAllister, M S Favero
Journal: Journal of the American Society of Nephrology (1994)

Uremia has been associated with immunologic aberrations, including anergy, increased susceptibility to infections, and reduced phagocytic activity of polymorphonuclear leukocytes. In this study, cytokine release in uremic and nonuremic blood after in vitro endotoxin stimulation was studied. Blood from nonuremic controls, chronic renal failure patients not on dialysis, and chronic hemodialysis patients predialysis and postdialysis was spiked with 10 ng/mL of Escherichia coli endotoxin and incubated for 2 and 26 h. Plasma tumor necrosis factor-alpha (TNF alpha) concentrations were determined by ELISA after each incubation period. To further study which uremic blood component may be responsible for enhanced release of TNF alpha, plasma and cellular components of chronic renal failure patients and controls were switched and then given an in vitro endotoxin stimulation (1 ng/mL). It was found that (1) TNF alpha release is enhanced by uremia and is exacerbated with progressive declines in renal function, (2) enhanced TNF alpha release is related to a blood cellular phenomenon induced by uremia, and (3) enhanced TNF alpha release in hemodialysis patients is associated with a prolonged stimulation and/or reduced plasma elimination of TNF alpha.
1342 STUDY OF GENETIC VARIATION IN IL28B AND VERTICAL TRANSMISSION OF HEPATITIS C VIRUS AND SPONTANEOUS CLEARANCE OF CHILDHOOD HCV INFECTION
Authors: A. Ruiz Estremera, J.A. Munoz-Gamez, R. Cmiles-Perez, M.A. Salmerón Ruiz, P. Munoz de Rueda, J. Casado, A. Carazo, A. Gila, A. Martin, E.J. Pavon, J. Leon, L. Sanjuan-Nuñez, A. Palacios, J. Salmerón
Journal: Journal of Hepatology (2011)
mRNA Expression of Transforming Growth Factor Alpha in Human Breast Carcinomas and Its Activity in Effusions of Breast Cancer Patients
Authors: F. Ciardiello, N. Kim, D. S. Liscia, C. Bianco, R. Lidereau, G. Merlo, R. Callahan, J. Greiner, C. Szpak, W. Kidwell, J. Schlom, D. S. Salomon
Journal: JNCI Journal of the National Cancer Institute (1989)

Transforming growth factor alpha (TGF alpha) mRNA expression was measured by Northern blot analysis in 18 human, primary, infiltrating, ductal breast carcinomas. Expression of a 4.8-kilobase TGF alpha mRNA transcript was detected in nine of 18 tumors. No evidence was observed of any gross amplifications or major rearrangements of the TGF alpha gene in the breast carcinoma specimens. Biologically active and immunoreactive TGF alpha was measured in the pleural effusions or in the ascitic fluids from 37 noncancer and 63 cancer patients. The TGF alpha activity detected ranged from 0.2 to 26 ng/mL in most effusions from both groups. However, 29 of 63 (46%) of the effusions from cancer patients exhibited TGF alpha levels that were 6 ng/mL or higher, whereas only seven of 37 (19%) of those from noncancer patients exceeded this level (P less than .03). In particular, effusions obtained from breast cancer patients showed a significantly higher level of TGF alpha, compared with those from noncancer patients (P less than .001). Effusions from 14 cancer patients also contained elevated levels of two tumor-associated antigens, CEA and/or TAG-72, and within this group, nine also had elevated levels of TGF alpha.
Peptide-containing nerve fibres in the gut wall in Crohn's disease.
Authors: K Sjolund, O B Schaffalitzky, D E Muckadell, J Fahrenkrug, R Hakanson, B G Peterson, F Sundler
Journal: Gut (1983)

Neurones containing VIP, substance P, or enkephalin were studied by immunocytochemistry in intestinal specimens from 27 patients with Crohn9s disease. Also several endocrine cell systems in the gut were examined. The results were compared with those from a control group of 26 patients. The relative frequency of various endocrine cells did not differ overtly from that in controls. Vasoactive intestinal polypeptide and substance P nerve fibres were distributed in all layers of the gut wall, including the submucosal and myenteric plexuses, whereas enkephalin fibres were restricted to the smooth muscle layer and the myenteric plexus. The distribution and frequency of the peptide-containing nerve fibres were the same in Crohn9s disease patients as in control patients. A proportion of these nerve fibres, however, were notably coarse in the Crohn9s disease patients. This was particularly apparent in the afflicted parts of the intestine although it was noted also in non-afflicted parts. The concentration of VIP and substance P (expressed as pmol/g wet weight) did not, however, exceed that of the control group.
Novel tests for diagnosing tuberculous pleural effusion: what works and what does not?
Authors: A. Trajman, M. Pai, K. Dheda, R. van Zyl Smit, A. A. Zwerling, R. Joshi, S. Kalantri, P. Daley, D. Menzies
Journal: European Respiratory Journal (2008)

Tuberculous pleuritis is a common manifestation of extrapulmonary tuberculosis and is the most common cause of pleural effusion in many countries. Conventional diagnostic tests, such as microscopic examination of the pleural fluid, biochemical tests, culture of pleural fluid, sputum or pleural tissue, and histopathological examination of pleural tissue, have known limitations. Due to these limitations, newer and more rapid diagnostic tests have been evaluated. In this review, the authors provide an overview of the performance of new diagnostic tests, including markers of specific and nonspecific immune response, nucleic acid amplification and detection, and predictive models based on combinations of markers. Directions for future development and evaluation of novel assays and biomarkers for pleural tuberculosis are also suggested.
Decreased incidence of knee posterior cruciate ligament injury in Australian Football League after ruck rule change
Authors: J W Orchard, H Seward
Journal: British Journal of Sports Medicine (2009)

Objective: To assess whether a rule change introduced in the Australian Football League (AFL) before the start of the 2005 season, to limit the run-up of ruckmen at the centre bounce, has been successful in reducing the incidence of knee posterior cruciate ligament (PCL) injuries Design: Cohort study with historical control. Setting: The AFL competition from 1992 to 2008 inclusive. Assessment of risk factors: The presence of a rule change (four seasons) compared with the previous 13 seasons (divided into two eras of seven and six seasons). Main outcome measure: Occurrence of knee PCL injury during a regular season or finals match, both from all causes and specifically from centre bounce ruck collision mechanisms. Results: From 1992 to 1998 there were 11.0 PCL injuries per 10 000 player-hours, with 0.8 ruck injuries per 10 000 centre bounces. From 1999 to 2004, the rates increased to 12.9 per 10 000 player-hours and 5.6 ruck injuries per 10 000 centre bounces (p&lt;0.01). The rates reduced to 5.9 PCL injuries per 10 000 player-hours and 0.9 ruck injuries per 10 000 centre bounces in the period 2005–2008 following the rule change (p&lt;0.01). There was a lower relative risk in 2005–2008 than in 1999–2004 of incurring a centre bounce ruck PCL injury (0.16 (95% CI 0.04 to 0.69)) or of sustaining any PCL injury (0.45 (95% CI 0.28 to 0.75)). Conclusion: A rule change in the AFL to limit the run-up of ruckmen at the centre bounce has successfully reduced the rate of PCL injuries with this mechanism, with the total incidence of PCL injuries also falling.
Contribution of bone marrow–derived endothelial cells to human tumor vasculature
Authors: Brock A Peters, Luis A Diaz, Kornelia Polyak, Leslie Meszler, Kathy Romans, Eva C Guinan, Joseph H Antin, David Myerson, Stanley R Hamilton, Bert Vogelstein, Kenneth W Kinzler, Christoph Lengauer
Journal: Nature Medicine (2005)