tbuckley/cabot-search huggingface dataset:
Avoiding Missing Data Biases in Phylogenomic Inference: An Empirical Study in the Landfowl (Aves: Galliformes)
Authors: Peter A Hosner, Brant C Faircloth, Travis C Glenn, Edward L Braun, Rebecca T Kimball
Journal: Molecular Biology and Evolution (2015)

Production of massive DNA sequence data sets is transforming phylogenetic inference, but best practices for analyzing such data sets are not well established. One uncertainty is robustness to missing data, particularly in coalescent frameworks. To understand the effects of increasing matrix size and loci at the cost of increasing missing data, we produced a 90 taxon, 2.2 megabase, 4,800 locus sequence matrix of landfowl using target capture of ultraconserved elements. We then compared phylogenies estimated with concatenated maximum likelihood, quartet-based methods executed on concatenated matrices and gene tree reconciliation methods, across five thresholds of missing data. Results of maximum likelihood and quartet analyses were similar, well resolved, and demonstrated increasing support with increasing matrix size and sparseness. Conversely, gene tree reconciliation produced unexpected relationships when we included all informative loci, with certain taxa placed toward the root compared with other approaches. Inspection of these taxa identified a prevalence of short average contigs, which potentially biased gene tree inference and caused erroneous results in gene tree reconciliation. This suggests that the more problematic missing data in gene tree-based analyses are partial sequences rather than entire missing sequences from locus alignments. Limiting gene tree reconciliation to the most informative loci solved this problem, producing well-supported topologies congruent with concatenation and quartet methods. Collectively, our analyses provide a well-resolved phylogeny of landfowl, including strong support for previously problematic relationships such as those among junglefowl (Gallus), and clarify the position of two enigmatic galliform genera (Lerwa, Melanoperdix) not sampled in previous molecular phylogenetic studies.
Assessment of response using FDG-PET and CT in a phase I study of AMN107 alone or in combination with imatinib (IM) in patients with imatinib-resistant (IM-R) gastrointestinal stromal tumors (GIST)
Authors: A. D. Van Den Abbeele, A. S. Barnes, D. J. De Vries, J. T. Yap, P. Reichardt, P. G. Casalli, M. Von Mehren, J. O’Neel, W. Hayes, G. D. Demetri
Journal: Journal of Clinical Oncology (2006)

3087 Background: Although IM induces durable clinical benefit in pts with metastatic GIST, resistance to this single agent may emerge over time and new approaches are needed. AMN107 is a new agent rationally designed to inhibit in a structurally different manner the tyrosine kinase activities of KIT, PDGFR, and Bcr-Abl. Since AMN107 has demonstrated the ability to inhibit the proliferation of both IM-sensitive and IM-R GIST cells in vitro, a clinical trial was begun to test this agent with rapid assessment of impact using FDG-PET. Methods: Pts with IM-R GIST were treated with AMN107 alone (400 mg p.o. bid), or a combination of IM (400 mg p.o. bid) and inter-cohort dose escalations of AMN107 (200 mg qd, 400 mg qd, and 400 mg p.o. bid). FDG-PET and CT were performed at baseline and after 1 and 4 wks on therapy. Maximum standardized uptake values (SUVmax) were measured in 11 pts in up to 5 lesions with the greatest FDG uptake/pt (n=46 lesions). For each patient, the summation SUVmax (sSUVmax) of all lesions was calculated at each time point. Percentage change in SUVmax and sSUVmax was calculated at wks 1 and 4 compared to baseline. Metabolic response was assessed using EORTC thresholds for % SUVmax change (PR≤ -25% &lt;SD&lt; +25%≤ PD). The longest diameters of all lesions analyzed by PET were measured on corresponding CT images, summed at each time point, and the % change was calculated at wks 1 and 4 compared to baseline. CT response was assessed using conventional RECIST thresholds. Results: At 1 wk, PET imaging of 11 evaluable pts documented metabolic PR in 3/11, SD in 7/11, and PD in 1/11. After 4 wks on therapy, 2 pts whose PET was stable after 1 wk had converted to metabolic PR, and all other imaging results were unchanged. The CT response for all 11 pts was SD after 1 and 4 wks on therapy. Conclusions: These findings suggest that a metabolic response to AMN107, or the combination of AMN107 plus IM, is seen with FDG-PET while CT anatomic response remains SD at 1 and 4 wks. [Table: see text] [Table: see text]
Pim1 kinase affects allergic asthma in a HDM-driven mice model
Authors: Maaike de Vries, Irene H. Heijink, Laura Hesse, Antoon J.M. van Oosterhout, Martijn C. Nawijn
Journal: European Respiratory Journal (2014)

Allergic asthma is characterized by airway inflammation, remodelling and hyperreactivity (AHR) and it has been hypothesized that disruption of the epithelial barrier plays a key role in its pathogenesis. Since it is known that Pim1 kinase is important for eosinophil survival and we previously observed a decrease in epithelial barrier function of airway epithelial cells upon inhibition of Pim1 kinase activity, we aimed to further explore the role of Pim1 kinase in the development of allergic asthma.

Pim1 -deficient and wild-type control mice were intranasally sensitized with house dust mite (HDM) or PBS for 5 weeks, where after the AHR upon metacholine challenge was measured with flexivent. BAL fluid and blood was collected and cellular composition in the BAL fluid was determined. Furthermore, the levels of IL-5, IL-10, KC and IgE were measured by ELISA.

Both groups of mice sensitized with HDM developed significant AHR compared to PBS-treated mice, which was independent of genotype. Analysis of the inflammatory cells in BAL fluid showed an increase in inflammatory mononuclear cells and eosinophils in the HDM sensitized mice, though the number of eosinophils showed a trend towards decreased numbers in the Pim1 -deficient mice. Interestingly, a significant increase in IL-5, IL-10, KC and IgE was observed in the HDM sensitized Pim1 -deficient mice compared to their wild-type counterparts.

In conclusion, although we could not determine differences in AHR in the absence of Pim1 kinase activity, the observed increase in the cytokine levels indicates a divergent role for Pim1 kinase in regulating the inflammatory cytokine response versus eosinophilic inflammation in allergic asthma that should be further investigated.
Characterization of molecular features of pediatric urothelial bladder carcinomas.
Authors: Ana Collazo Lorduy, Mireia Castillo-Martin, Grace Hyun, Nataliya Gladoun, Carlos Cordon-Cardo
Journal: Journal of Clinical Oncology (2015)

345 Background: Bladder cancer is a rare entity in the pediatric population making it difficult to define surveillance protocols and long term outcomes. Notably, most pediatric tumors are low grade and non-muscle invasive and do not recur. In order to determine the source of the different natural history between pediatric population and adults, we hypothesized that pediatric bladder cancer may potentially stem from different molecular pathways than its adult form. Our main objective was to study the molecular pathogenesis in this rare disease using immunohistochemical (IHC) and mutational analysis of the main known genes involved in bladder cancer. Methods: Paraffin-embedded tissue slides of bladder tumors from three pediatric patients were retrospectively identified from our institution's pathology archives (1990-present) and re-evaluated. Clinical data was reviewed. FGFR3, H-RAS, and PI3K mutational analysis of the most well-known mutated spots was conducted by PCR amplification and Sanger sequencing. IHC analysis was conducted using antibodies against p53, Pten, Rb, EGFR, Her2Neu and ki-67. Results: Two patients had low-grade Ta disease, whereas the other tumor was classified as a Papillary Urothelial Neoplasm of Low Malignant Potential (PUNLMP). None of the lesions recurred. Two patients were female and one was male. The ages at diagnosis were 13, 11, and 17, with a mean follow-up of 5.2 years (Range: 1.5-8.0 years). All specimens showed H-RAS G12V mutation, whereas they were characterized by wild-type FGFR3 and PI3K. Nuclear p53 was not detected, whereas PTEN and Rb expression were maintained. EGFR was homogenously expressed in the three cases, and Her2Neu was negative. The proliferation rate analyzed by Ki-67 expression was very low in all cases (&lt;5%). Conclusions: Pediatric tumors may arise from a pathway that is not initiated by FGFR3 or p53 mutations, but by H-RAS mutations. This distinction may explain the relatively few recurrences seen in the pediatric population. Molecular investigation of larger series of pediatric tumors is warranted, and will aid in determining the surveillance and the clinical follow up, if any, needed in this rare entity.
Abstract 322: Report of Adverse Effects From a U.S. Registry of Patients Undergoing Targeted Temperature Management Following Cardiac Arrest
Authors: Gail Delfin, Anne V Grossestreuer, David F Gaieski, Susan E Archer, Andi Bilson, Benjamin S Abella, Marion Leary
Journal: Circulation (2013)

Background: Targeted temperature management (TTM) has been shown to improve outcomes following resuscitation from cardiac arrest. Registry studies from Europe have illustrated an array of potential adverse effects (AEs) from post-arrest cooling, however the broad experience of US hospitals with regard to TTM-associated AEs has not been described. Objective: To identify incidence of AEs reported in a multicenter US registry of post-arrest patients treated with TTM. Methods: Retrospective chart review of post-arrest patients from 14 US hospitals who were treated with TTM and enrolled into the Penn Alliance for Therapeutic Hypothermia data registry (PATH). Results: A total of 675 patients received TTM after cardiac arrest between 1/2005 - 3/2013. Mean age was 59.3±15 yrs, 279/675 (41%) were female and 229/675 (34%) had shockable rhythms. Mean TTM duration was 24.7±9.8 hrs and rewarming duration of 14.3±7.9 hrs. Survival to hospital discharge occurred in 265/666 (40% - data missing in 9 patients); in survivors, 214/265 (81%) manifested Cerebral Performance Category scores of 1 or 2. Data on seizure activity were available for 359/675 patients (53%); 60/359 (17%) manifested seizure/myoclonus clinically or on EEG. AE data associated with the TTM process were available for 316/675 (47%) patients and not documented for 359 (53%). Hyperglycemia (&gt; 144 mg/dL glucose at ≥1 time points during TTM maintenance) was prevalent and reported in 251/316 (79%) patients. Of 316 patients, 157 (50%) described other specific AEs. Shivering was noted in 78/316 (25%) patients, treated most often by meperidine 38/78 (49%) or neuromuscular blockade 34/78 (44%). Fever occurred in 40/316 (13%) patients and dysrhythmias in 19/316 (6%). Three of 19 patients suffered re-arrest during TTM; one re-arrest patient was below target temperature (32-34 o C). Hypokalemia was reported in 15/316 (5%) and hyperkalemia in 4/316 (1%) patients. Skin breakdown was specified in 15/316 (5%), bleeding in 8/316 (3%) patients- 3 requiring transfusion - and pneumonia in 7/316 (2%). Conclusions: In this patient cohort enrolled in a US post-arrest care registry, incidence of AEs is comparable to previous reports. Specifically, bleeding complications were infrequent and comparable to non-US studies.
Delamanid and Bedaquiline Resistance in <i>Mycobacterium tuberculosis</i> Ancestral Beijing Genotype Causing Extensively Drug-Resistant Tuberculosis in a Tibetan Refugee
Authors: Harald Hoffmann, Thomas A. Kohl, Sabine Hofmann-Thiel, Matthias Merker, Patrick Beckert, Katia Jaton, Lubov Nedialkova, Evgeni Sahalchyk, Thomas Rothe, Peter M. Keller, Stefan Niemann
Journal: American Journal of Respiratory and Critical Care Medicine (2016)
Utility of tumor markers for the early detection of metastatic breast cancer
Authors: I. Ertl, V. Heinemann, I. Bauerfeind, M. Untch, D. Laessig, D. Nagel, D. Seidel, P. Stieber
Journal: Journal of Clinical Oncology (2008)

1072 Background: With the aim of early detection of metastatic disease (=asymptomatic patients) breast cancer patients are monitored in a prospective trial every 6 weeks by using kinetics of CEA and CA15–3. Methods: Among the 494 patients participating in our trial we analysed the clinical data of those who developed distant metastases (n=61). A reproducible increase of CEA (Abbott, AxSYM) or CA15–3 (Roche, Elecsys) ≥100%, corresponding to a predefined specificity of 98%, was the indicator for metastases. Results: 61 patients developed metastases. 35 patients (57%, of these 80% ER+ and/or PR+, 38% HER2 positive primary tumors) showed the previously defined increase of CEA or CA15–3 at the time of first metastases (true-positive, TP). In 24 patients (39%) CA15–3 alone, in 8 patients (13%) CEA alone and in 3 patients (5%) both markers increased. 26 patients (43%, of these 69% ER+ and/or PR+, 12.5% HER2 positive primary tumors) did not have increased tumor markers at the time of first metastases (false-negative, FN). 92% of the FN patients had a delayed increase of markers at further progression. The median disease-free interval until detection of metastases did not differ between TP (44.1 months) and FN patients (42.3 months) (p=0.8). All TP patients were asymptomatic at the time of recurrence. ER/PR and HER2 expression did not differ significantly between TP and FN patients (p=0.4 and p=0.1, respectively), but triple negativity (ER-, PR- and HER2-) was more frequent in FN patients (p=0.03). All patients with liver-only metastases were TP (n=11, p=0.0002), 8 (73%) of them suffered from oligometastases. All patients with brain-only metastases were FN (n=3, p=0.1). Conclusions: 57% of the patients with distant metastases were TP, including all patients with liver-only metastases. Of these, 8 (73%) suffered from oligometastases. If early detection of asymptomatic and oligometastatic disease will allow early interventions and thereby improves treatment outcome needs to be shown in the future. No significant financial relationships to disclose.
Traumatic rupture of the diaphragm: Experience with 112 patients
Authors: Petros Michos, Athanassios Stamatelopoulos, Ioannis Gakidis, Christos Chatziantoniou
Journal: European Respiratory Journal (2012)

Traumatic diaphragmatic rupture is reported with increasing frequency and is associated with high morbidity and mortality. The purpose of this study was to present our experience with the management of this injury,112 patients with TDR were treated in our hospital between January 1989 and Dicember 2011. They were 89men (79,46%) and 23 women (20,5%). Mean age was 36.57 years (range 15-76 years).

Rupture of the diaphragm was left-sided in 74 patients (67%), right-sided in 35 (31,25%), and bilateral in 3 (2,6%). Blunt trauma accounted for the injuries of 89 patients (79,46%). Early diagnosis was obtained in 98 patients (87,5%).

The diagnosis was established preoperatively in 29 patients (25,83%), and intra-operatively in 83 (74,1%). Multiple associated injuries were observed in 106 patients (94,64%). Postoperative complications were observed in 12 (10,71%), and the overall mortality was 14%. Injury severity score (ISS) and haemorrhagic shock upon admission strongly influence the outcome. A high index of suspicion and a thorough examination of both hemi diaphragms during laparotomy is recommended in order to avoid early or late complications.
Ex vivo isolation of RCC-reactive CD8<sup>+</sup> CTL clones from HLA-identical allogeneic donor T cell lines stimulated by CD80-transfected tumor cells
Authors: S. S. Tykodi, J. A. Thompson, B. M. Sandmaier, M. B. Maris, R. Storb, T. J. Manley, S. R. Riddell, E. H. Warren
Journal: Journal of Clinical Oncology (2007)

15625 Background: Regression of metastatic renal cell carcinoma (mRCC) is observed in a minority of patients treated by immunotherapies such as interleukin-2 (IL-2), interferon-a (IFN-a), or reduced-intensity allogeneic hematopoietic cell transplantation. However, the development of specific cellular immunotherapies for mRCC has been hindered by the lack of molecularly characterized T cell antigens with preferential expression on RCC cells. We have developed an ex vivo strategy for the isolation of RCC-reactive CD8 + CTL clones that may facilitate the identification of novel RCC-associated T cell antigens. Methods: RCC tumor lines were established from two patients with mRCC presenting to our institution for allogeneic HCT received from either an HLA-matched sibling or volunteer unrelated donor. Irradiated RCC tumor lines that were unmodified or transfected with a cDNA for human CD80 were used to stimulate responder CD8 + T cells isolated from pretransplant patient (autologous) or donor-derived (allogeneic) blood samples in mixed lymphocyte/tumor cell (MLTC) cultures supplemented with recombinant human IL-7 and IL-12 (stimulation #1) or IL-2 (2nd and subsequent stimulations). T cell lines with anti-tumor activity measured by IFN-γ ELISA were then cloned by limiting dilution. Results: After two or more in vitro stimulations, allogeneic CD8 + T cell lines stimulated by CD80- transfected RCC tumor cells, but not the other MLTC culture combinations tested demonstrated tumor-specific IFN-γ release. CD3 + /CD8 + /TCRaβ + CTL clones with potent in vitro anti-tumor activity for unmodified RCC tumor were isolated from both sibling- and unrelated- donor derived T cell lines. Three such clones with unique specificities for allogeneic targets recognized the unmodified RCC tumor but not LCL or fibroblast target cells isolated from the same patient suggesting tumor-restricted expression of the target antigens. Conclusions: Ex vivo MLTC culture utilizing CD80-transfected RCC tumor and HLA- matched allogeneic responder CD8 + T cells warrants further study as a strategy to isolate CTL clones that may be used to identify novel RCC-associated T cell antigens. No significant financial relationships to disclose.
Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial
Authors: Arlene Chan, Suzette Delaloge, Frankie A Holmes, Beverly Moy, Hiroji Iwata, Vernon J Harvey, Nicholas J Robert, Tajana Silovski, Erhan Gokmen, Gunter von Minckwitz, Bent Ejlertsen, Stephen K L Chia, Janine Mansi, Carlos H Barrios, Michael Gnant, Marc Buyse, Ira Gore, John Smith, Graydon Harker, Norikazu Masuda, Katarina Petrakova, Angel Guerrero Zotano, Nicholas Iannotti, Gladys Rodriguez, Pierfrancesco Tassone, Alvin Wong, Richard Bryce, Yining Ye, Bin Yao, Miguel Martin
Journal: The Lancet Oncology (2016)
Renal Clearance of Mineral Metabolism Biomarkers
Authors: Adriana J van Ballegooijen, Eugene P Rhee, Sammy Elmariah, Ian H de Boer, Bryan Kestenbaum
Journal: Journal of the American Society of Nephrology (2015)

CKD leads to disturbances in multiple interrelated hormones that regulate bone and mineral metabolism. The renal handling of mineral metabolism hormones in humans is incompletely understood. We determined the single-pass renal clearance of parathyroid hormone, fibroblast growth factor 23, vitamin D metabolites, and phosphate from paired blood samples collected from the abdominal aorta and renal vein in 17 participants undergoing simultaneous right and left heart catheterization and estimated associations of eGFR with the renal elimination of metabolites. The mean age ±SD of the study population was 71.4±10.0 years and 11 participants (65%) were male. We found a relatively large mean±SD single-pass renal extraction of parathyroid hormone (44.2%±10.3%) that exceeded the extraction of creatinine (22.1%±7.9%). The proportionate renal extraction of parathyroid hormone correlated with eGFR. The renal extraction of fibroblast growth factor 23 was, on average, lower than that of parathyroid hormone with greater variability across individuals (17.1%±19.5%). There were no differences in the mean concentrations of vitamin D metabolites across the renal vein and artery. In summary, we demonstrate substantial single-pass renal extraction of parathyroid hormone at a rate that exceeds glomerular filtration. Impaired renal clearance of parathyroid hormone may contribute to secondary hyperparathyroidism in CKD.
Forecasting Cancer Trends to Optimize Control Strategies
Authors: Dwight T. Janerich
Journal: JNCI Journal of the National Cancer Institute (1984)

Population projections and age-stratified cancer rates were used to forecast the trends for cancer occurrence for the United States during the coming decades: A progressive increase in the number of new cases is already predetermined by the high birth rate that occurred during the middle part of the century, and it will lead to nearly a doubling in the number of cases in about 4 decades. The demographic circumstances that determine the per capita costs of cancer are likely to worsen, because expected population trends will produce a deteriorating per capita economic base. Furthermore, the high costs of emerging treatment technologies are likely to magnify the deterioration ever further. Development of methods for cancer trend forecasting can provide a sound and accurate foundation for planning a comprehensive national strategy for optimal partitioning of research resources between the need for development of new treatments and the need for new research directed toward primary preventive measures.
CXCR4-CXCL12 axis: Pivotal role as a metastatic mediator in small cell sarcoma
Authors: S. N. Dumont, M. I. Aslam, J. C. McAuliffe, D. Yang, L. K. Nolden, C. O. Oyedeji, J. C. Trent
Journal: Journal of Clinical Oncology (2009)

10569 Background: The chemokine CXCL12, and its receptor CXCR4, are expressed in over 23 different types of cancers, and have been associated with the metastatic phenotype and inferior clinical outcomes. Given the poor prognosis after failure of front-line therapy for patients with metastatic Ewing's sarcoma (EWS) and rhabdomyosarcoma (RMS), we examined the functional role of CXCR4 in these small cell sarcoma in vitro. Methods: Human EWS and RMS cell lines and tissue were used to study CXCR4 expression and activation. Immunoblotting techniques were used to evaluate CXCR4 activation and inhibition. Cell viability, cell cycle, apoptosis, chemosensitivity, migration, and invasion assays were utilized to assess the effects of the small peptide CXCR4 antagonist, CTCE-9908 (Chemokine Therapeutics) on cultured cells. Results: CXCR4 was highly expressed on 46 % of human RMS tumor samples. CXCR4 underwent phosphorylation after stimulation with CXCL12 in EWS and RMS cell lines with downstream activation of Akt, p42/44 MAPK, JAK2 and PLCγ1 in select cell lines. CTCE-9908 was able to specifically inhibit downstream signaling of Akt, p42/44 MAPK and JAK2. Decrease in cell proliferation (20–30%, p &lt; .05), increase in cell apoptosis (20–40 %, p &lt; .05) and cell cycle arrest was also observed with CXCR4 blockade. CTCE-9908 significantly inhibited migration and invasion (68–93 %, p &lt; .05) in our cell lines. Conclusions: CXCR4-CXCL12 axis may be important in EWS and RMS metastasis. These results provide evidence that CTCE-9908 may be a novel therapy for these sarcomas. No significant financial relationships to disclose.