tbuckley/cabot-search huggingface dataset:
Peripheral Flow Response to Transient Arterial Forearm Occlusion Does Not Reflect Myocardial Perfusion Reserve
Authors: Morten Bøttcher, Mette M. Madsen, Jens Refsgaard, Niels Henrik Buus, Inge Dørup, Torsten Toftegaard Nielsen, Keld Sørensen
Journal: Circulation (2001)

Ultrasonographic evaluation of systemic arterial function is widely available, and a close relation of endothelial function in the coronary and brachial arteries has been documented. It is unknown, however, whether a similar correlation exists for their 2 microcirculatory territories and thus whether assessment of the systemic microcirculation can be used similarly as a surrogate marker of myocardial perfusion.Twenty-three patients with documented coronary artery disease (CAD; 66+/-9 years old, 18 men), 16 patients with syndrome X (SX; 56+/-5 years old, 13 women), and 45 healthy control subjects (C; 34+/-9 years old, 22 men) were studied. Myocardial perfusion was measured at rest and after dipyridamole (0.56 mg. kg(-1). min(-1) over 4 minutes) by PET, and brachial artery blood flow was measured at rest and after transient forearm ischemia by standard Doppler ultrasound techniques. Dipyridamole increased myocardial perfusion in all groups (mL. g(-1). min(-1): CAD, 0.89+/-0.27 versus 1.62+/-0.67, P:<0.001; SX, 0.82+/-0.16 versus 1.67+/-0.49, P:<0.001; and C, 0.82+/-0.15 versus 2.32+/-0.64, P:<0.001). Postocclusion forearm flow increased similarly in all groups (CAD, 52+/-18 versus 174+/-77 mL/min, P:<0.001; SX, 49+/-29 versus 202+/-82 mL/min, P:<0.001; and C, 61+/-34 versus 229+/-108 mL/min, P:<0.001). No significant correlations were found between peripheral and myocardial microcirculatory beds for either resting flow, hyperemic flow, or flow reserve in any of the groups (r(2)<0.1, P:=NS).The peripheral perfusion responses to transient forearm ischemia do not correlate with dipyridamole-induced myocardial hyperemia. The lack of correlation indicates different mechanisms of microvascular activation or regulation and confirms that extrapolations between findings in the 2 vascular beds are not suitable.
Drugs for pre-osteoporosis: prevention or disease mongering?
Authors: Pablo Alonso-Coello, Alberto López García-Franco, Gordon Guyatt, Ray Moynihan
Journal: BMJ (2008)

After looking at data used to support treatment of women with slightly lowered bone mineral density, <b>Pablo Alonso-Coello</b><b>and colleagues </b>argue thatproponents have overstated the benefits and underplayed the harms
Effects of Intraocular Ranibizumab and Bevacizumab in Transgenic Mice Expressing Human Vascular Endothelial Growth Factor
Authors: Katsuaki Miki, Akiko Miki, Masato Matsuoka, Daisuke Muramatsu, Sean F. Hackett, Peter A. Campochiaro
Journal: Ophthalmology (2009)
Ritual circumcision and risk of autism spectrum disorder in 0- to 9-year-old boys: national cohort study in Denmark
Authors: Morten Frisch, Jacob Simonsen
Journal: Journal of the Royal Society of Medicine (2015)

Based on converging observations in animal, clinical and ecological studies, we hypothesised a possible impact of ritual circumcision on the subsequent risk of autism spectrum disorder (ASD) in young boys.
Noninvasive Detection of Response and Resistance in <i>EGFR</i>-Mutant Lung Cancer Using Quantitative Next-Generation Genotyping of Cell-Free Plasma DNA
Authors: Geoffrey R. Oxnard, Cloud P. Paweletz, Yanan Kuang, Stacy L. Mach, Allison O'Connell, Melissa M. Messineo, Jason J. Luke, Mohit Butaney, Paul Kirschmeier, David M. Jackman, Pasi A. Jänne
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Tumor genotyping using cell-free plasma DNA (cfDNA) has the potential to allow noninvasive assessment of tumor biology, yet many existing assays are cumbersome and vulnerable to false-positive results. We sought to determine whether droplet digital PCR (ddPCR) of cfDNA would allow highly specific and quantitative assessment of tumor genotype. Experimental Design: ddPCR assays for EGFR, KRAS, and BRAF mutations were developed using plasma collected from patients with advanced lung cancer or melanoma of a known tumor genotype. Sensitivity and specificity were determined using cancers with nonoverlapping genotypes as positive and negative controls. Serial assessment of response and resistance was studied in patients with EGFR-mutant lung cancer on a prospective trial of erlotinib. Results: We identified a reference range for EGFR L858R and exon 19 deletions in specimens from KRAS-mutant lung cancer, allowing identification of candidate thresholds with high sensitivity and 100% specificity. Received operative characteristic curve analysis of four assays demonstrated an area under the curve in the range of 0.80 to 0.94. Sensitivity improved in specimens with optimal cfDNA concentrations. Serial plasma genotyping of EGFR-mutant lung cancer on erlotinib demonstrated pretreatment detection of EGFR mutations, complete plasma response in most cases, and increasing levels of EGFR T790M emerging before objective progression. Conclusions: Noninvasive genotyping of cfDNA using ddPCR demonstrates assay qualities that could allow effective translation into a clinical diagnostic. Serial quantification of plasma genotype allows noninvasive assessment of response and resistance, including detection of resistance mutations up to 16 weeks before radiographic progression. Clin Cancer Res; 20(6); 1698–705. ©2014 AACR.
Mining Tissue Microarray Data to Uncover Combinations of Biomarker Expression Patterns that Improve Intermediate Staging and Grading of Clear Cell Renal Cell Cancer
Authors: Corinne Dahinden, Barbara Ingold, Peter Wild, Gunther Boysen, Van-Duc Luu, Matteo Montani, Glen Kristiansen, Tullio Sulser, Peter Bühlmann, Holger Moch, Peter Schraml
Journal: Clinical Cancer Research (2009)

Tumor stage and nuclear grade are the most important prognostic parameters of clear cell renal cell carcinoma (ccRCC). The progression risk of ccRCC remains difficult to predict particularly for tumors with organ-confined stage and intermediate differentiation grade. Elucidating molecular pathways deregulated in ccRCC may point to novel prognostic parameters that facilitate planning of therapeutic approaches.Using tissue microarrays, expression patterns of 15 different proteins were evaluated in over 800 ccRCC patients to analyze pathways reported to be physiologically controlled by the tumor suppressors von Hippel-Lindau protein and phosphatase and tensin homologue (PTEN). Tumor staging and grading were improved by performing variable selection using Cox regression and a recursive bootstrap elimination scheme.Patients with pT2 and pT3 tumors that were p27 and CAIX positive had a better outcome than those with all remaining marker combinations. A prolonged survival among patients with intermediate grade (grade 2) correlated with both nuclear p27 and cytoplasmic PTEN expression, as well as with inactive, nonphosphorylated ribosomal protein S6. By applying graphical log-linear modeling for over 700 ccRCC for which the molecular parameters were available, only a weak conditional dependence existed between the expression of p27, PTEN, CAIX, and p-S6, suggesting that the dysregulation of several independent pathways are crucial for tumor progression.The use of recursive bootstrap elimination, as well as graphical log-linear modeling for comprehensive tissue microarray (TMA) data analysis allows the unraveling of complex molecular contexts and may improve predictive evaluations for patients with advanced renal cancer.
Prognostic and Predictive Importance of p53 and RAS for Adjuvant Chemotherapy in Non–Small-Cell Lung Cancer
Authors: Ming-Sound Tsao, Sarit Aviel-Ronen, Keyue Ding, Davina Lau, Ni Liu, Akira Sakurada, Marlo Whitehead, Chang-Qi Zhu, Robert Livingston, David H. Johnson, James Rigas, Lesley Seymour, Timothy Winton, Frances A. Shepherd
Journal: Journal of Clinical Oncology (2007)

Purpose p53 and RAS are multifunctional proteins that are critical to cell cycle regulation, apoptosis, cell survival, gene transcription, response to stress, and DNA repair. We have evaluated the prognostic and predictive value of p53 gene/protein aberrations using tumor samples from JBR.10, a North American phase III intergroup trial that randomly assigned 482 patients with completely resected stage IB and II non–small-cell lung cancer (NSCLC) to receive four cycles of adjuvant cisplatin plus vinorelbine or observation alone. Methods p53 protein expression was evaluated by immunohistochemistry. Mutations in exons 5 to 9 of the p53 gene were determined by denaturing high-performance liquid chromatography and confirmed by sequencing. RAS mutations were identified by allelic specific oligonucleotide hybridization. Results Of 253 patients, 132 (52%) were positive for p53 protein overexpression. Untreated p53-positive patients had significantly shorter overall survival than did patients with p53-negative tumors (hazard ratio [HR] = 1.89; 95% CI, 1.07 to 3.34; P = .03). However, these p53-positive patients also had a significantly greater survival benefit from adjuvant chemotherapy (HR = 0.54; P = .02) compared with patients with p53-negative tumors (HR = 1.40; P = .26; interaction P = .02). Mutations of p53 and RAS genes were found in 124 (31%) of 397 and 117 (26%) of 450 patients, respectively. Mutations in these genes were neither prognostic for survival nor predictive of a differential benefit from adjuvant chemotherapy. Conclusion p53 protein overexpression is a significant prognostic marker of shortened survival, and also a significant predictive marker for a differentially greater benefit from adjuvant chemotherapy in completely resected NSCLC patients.
Phase I study of toremifene in patients with advanced cancer.
Authors: J T Hamm, D C Tormey, P C Kohler, D Haller, M Green, I Shemano
Journal: Journal of Clinical Oncology (1991)

A phase I multicenter evaluation of a novel antiestrogen, toremifene, was undertaken in postmenopausal women with various advanced difficult-to-treat malignancies. One hundred and seven women were treated at one of six dosage levels (10, 20, 40, 60, 200, or 400 mg/d orally) for at least 8 weeks. Weekly evaluations for toxicity were conducted. The most common side effects were nausea (31%), vomiting (12%), and hot flashes (29%). Five patients were removed from the study for possible adverse reactions: three patients experienced hypercalcemia; one experienced tremulousness, fatigue, and inability to think clearly; and one had vaginal bleeding. Twelve patients died while on study, 11 with disease progression and one with a pulmonary embolus. Sex hormone-binding globulin (SHBG) levels increased and there was a modest decline in serum antithrombin III levels. Four of 48 assessable patients had partial responses: three with breast cancer and one with endometrial cancer. Toremifene was generally well tolerated at the doses tested.
Eikenella corrodens Infections. Case report in two adolescent females with IDDM
Authors: Ron S Newfield, Ileana Vargas, Zilla Huma
Journal: Diabetes Care (1996)

OBJECTIVE To alert physicians caring for patients with diabetes to the microorganism Eikenella corrodens and to discuss the appropriate preventive and therapeutic measures to take against this potentially morbid opportunistic Gram-negative bacilli. CASES We present two cases of extra-oral E. corrodens infections in adolescent females with IDDM. The first patient had diabetes of 4 years' duration, which was moderately well controlled. Chronic finger biting resulted in a complex felon that evolved gradually and worsened while the patient received cephalexin orally. Delay in seeking further intervention resulted in necrosis of her distal fingertip and nail bed. The second patient had poorly controlled diabetes for 5 years. She developed an acute thigh abscess at an insulin injection site that resolved after drainage and intravenous antibiotics. CONCLUSIONS E. corrodens commonly inhabits the human oral cavity and becomes a pathogen mostly when host defenses are impaired, causing abscesses and infections that are at times fatal. Patients with IDDM are compromised hosts and with daily microtrauma to their skin via glucose monitoring and insulin injections, are prone to develop E. corrodens infections that can be introduced through oral secretions by licking or biting their skin. Educational efforts aimed at preventing exposure of traumatized skin to oral secretions can minimize the risk of E. corrodens infections in compromised hosts. Early intravenous administration of antibiotics, bearing in mind E. corrodens resistance to clindamycin, metronidazole, and other antibiotics, coupled with prompt surgical intervention, is essential in successfully managing E. corrodens infections.
The Active Site of ICP47, a Herpes Simplex Virus–encoded Inhibitor of the Major Histocompatibility Complex (MHC)-encoded Peptide Transporter Associated with Antigen Processing (TAP), Maps to the NH2-terminal 35 Residues
Authors: Begoña Galocha, Ann Hill, Barbara C. Barnett, Aidan Dolan, Alejandra Raimondi, Richard F. Cook, Joseph Brunner, Duncan J. McGeoch, Hidde L. Ploegh
Journal: The Journal of Experimental Medicine (1997)

The herpes simplex virus (HSV) immediate early protein ICP47 inhibits the transporter associated with antigen processing (TAP)-dependent peptide translocation. As a consequence, empty major histocompatibility complex (MHC) class I molecules are retained in the endoplasmic reticulum and recognition of HSV-infected cells by cytotoxic T lymphocytes is abolished. We chemically synthesized full-length ICP47 (sICP47) and show that sICP47 inhibits TAP-dependent peptide translocation in human cells. Its biological activity is indistinguishable from that of recombinant ICP47 (rICP47). By using synthetic peptides, we mapped the core sequence of ICP47 minimally required for TAP inhibition to residues 2–35. This segment is located within the region of the molecule conserved between ICP47 from HSV-1 and HSV-2. Through alanine scanning substitution we identified three segments within this region that are critical for the ability to inhibit TAP function. The interaction of ICP47 with TAP is unlikely to mimic precisely that of the transported peptides, as deduced from differential labeling of the TAP1 and TAP2 subunits using sICP47 fragments with chemical cross-linkers.
A phase III randomised trial of LV5FU2 + irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802)
Authors: M. Ychou, J.-L. Raoul, J.-Y. Douillard, S. Gourgou-Bourgade, R. Bugat, L. Mineur, F. Viret, Y. Becouarn, O. Bouché, E. Gamelin, M. Ducreux, T. Conroy, J.-F. Seitz, L. Bedenne, A. Kramar
Journal: Annals of Oncology (2009)
Molecular Evolution of Protein Conformational Changes Revealed by a Network of Evolutionarily Coupled Residues
Authors: Jouhyun Jeon, Hyun-Jun Nam, Yoon Sup Choi, Jae-Seong Yang, Jihye Hwang, Sanguk Kim
Journal: Molecular Biology and Evolution (2011)

An improved understanding of protein conformational changes has broad implications for elucidating the mechanisms of various biological processes and for the design of protein engineering experiments. Understanding rearrangements of residue interactions is a key component in the challenge of describing structural transitions. Evolutionary properties of protein sequences and structures are extensively studied; however, evolution of protein motions, especially with respect to interaction rearrangements, has yet to be explored. Here, we investigated the relationship between sequence evolution and protein conformational changes and discovered that structural transitions are encoded in amino acid sequences as coevolving residue pairs. Furthermore, we found that highly coevolving residues are clustered in the flexible regions of proteins and facilitate structural transitions by forming and disrupting their interactions cooperatively. Our results provide insight into the evolution of protein conformational changes and help to identify residues important for structural transitions.
Metabolomic Biomarkers in a Model of Asthma Exacerbation
Authors: Erik J. Saude, Idongesit P. Obiefuna, Ray L. Somorjai, Farnam Ajamian, Christopher Skappak, Taisir Ahmad, Brion K. Dolenko, Brian D. Sykes, Redwan Moqbel, Darryl J. Adamko
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Airway obstruction in patients with asthma is associated with airway dysfunction and inflammation. Objective measurements including sputum analysis can guide therapy, but this is often not possible in typical clinical settings. Metabolomics is the study of molecules generated by metabolic pathways. We hypothesize that airway dysfunction and inflammation in an animal model of asthma would produce unique patterns of urine metabolites measured by multivariate statistical analysis of high-resolution proton nuclear magnetic resonance ((1)H NMR) spectroscopy data.To develop a noninvasive means of monitoring asthma status by metabolomics and urine sampling.Five groups of guinea pigs were studied: control, control treated with dexamethasone, sensitized (ovalbumin, administered intraperitoneally), sensitized and challenged (ovalbumin, administered intraperitoneally, plus ovalbumin aerosol), and sensitized-challenged with dexamethasone. Airway hyperreactivity (AHR) to histamine (administered intravenously) and inflammation were measured. Multivariate statistical analysis of NMR spectra based on a library of known urine metabolites was performed by partial least-squares discriminant analysis. In addition, the raw NMR spectra exported as xy-trace data underwent linear discriminant analysis.Challenged guinea pigs developed AHR and increased inflammation compared with sensitized or control animals. Dexamethasone significantly improved AHR. Using concentration differences in metabolites, partial least-squares discriminant analysis could discriminate challenged animals with 90% accuracy. Using only three or four regions of the NMR spectra, linear discriminant analysis-based classification demonstrated 80-90% separation of the animal groups.Urine metabolites correlate with airway dysfunction in an asthma model. Urine NMR analysis is a promising, noninvasive technique for monitoring asthma in humans.
Optical Redox Ratio Differentiates Breast Cancer Cell Lines Based on Estrogen Receptor Status
Authors: Julie Hanson Ostrander, Christine M. McMahon, Siya Lem, Stacy R. Millon, J. Quincy Brown, Victoria L. Seewaldt, Nimmi Ramanujam
Journal: Cancer Research (2010)

Autofluorescence spectroscopy is a powerful imaging technique that exploits endogenous fluorophores. The endogenous fluorophores NADH and flavin adenine dinucleotide (FAD) are two of the principal electron donors and acceptors in cellular metabolism, respectively. The optical oxidation-reduction (redox) ratio is a measure of cellular metabolism and can be determined by the ratio of NADH/FAD. We hypothesized that there would be a significant difference in the optical redox ratio of normal mammary epithelial cells compared with breast tumor cell lines and that estrogen receptor (ER)-positive cells would have a higher redox ratio than ER-negative cells. To test our hypothesis, the optical redox ratio was determined by collecting the fluorescence emission for NADH and FAD via confocal microscopy. We observed a statistically significant increase in the optical redox ratio of cancer compared with normal cell lines (P < 0.05). Additionally, we observed a statistically significant increase in the optical redox ratio of ER(+) breast cancer cell lines. The level of ESR1 expression, determined by real-time PCR, directly correlated with the optical redox ratio (Pearson's correlation coefficient = 0.8122, P = 0.0024). Furthermore, treatment with tamoxifen and ICI 182,870 statistically decreased the optical redox ratio of only ER(+) breast cancer cell lines. The results of this study raise the important possibility that fluorescence spectroscopy can be used to identify subtypes of breast cancer based on receptor status, monitor response to therapy, or potentially predict response to therapy. This source of optical contrast could be a potentially useful tool for drug screening in preclinical models.
Circulating CD34 <sup>+</sup> Progenitor Cells and Risk of Mortality in a Population With Coronary Artery Disease
Authors: Riyaz S. Patel, Qunna Li, Nima Ghasemzadeh, Danny J. Eapen, Lauren D. Moss, A. Umair Janjua, Pankaj Manocha, Hatem Al Kassem, Emir Veledar, Habib Samady, W. Robert Taylor, A. Maziar Zafari, Laurence Sperling, Viola Vaccarino, Edmund K. Waller, Arshed A. Quyyumi
Journal: Circulation Research (2014)

Rationale: Low circulating progenitor cell numbers and activity may reflect impaired intrinsic regenerative/reparative potential, but it remains uncertain whether this translates into a worse prognosis. Objectives: To investigate whether low numbers of progenitor cells associate with a greater risk of mortality in a population at high cardiovascular risk. Methods and Results: Patients undergoing coronary angiography were recruited into 2 cohorts (1, n=502 and 2, n=403) over separate time periods. Progenitor cells were enumerated by flow cytometry as CD45 med+ blood mononuclear cells expressing CD34, with additional quantification of subsets coexpressing CD133, vascular endothelial growth factor receptor 2, and chemokine (C-X-C motif) receptor 4. Coefficient of variation for CD34 cells was 2.9% and 4.8%, 21.6% and 6.5% for the respective subsets. Each cohort was followed for a mean of 2.7 and 1.2 years, respectively, for the primary end point of all-cause death. There was an inverse association between CD34 + and CD34 + /CD133 + cell counts and risk of death in cohort 1 (β=−0.92, P =0.043 and β=−1.64, P =0.019, respectively) that was confirmed in cohort 2 (β=−1.25, P =0.020 and β=−1.81, P =0.015, respectively). Covariate-adjusted hazard ratios in the pooled cohort (n=905) were 3.54 (1.67–7.50) and 2.46 (1.18–5.13), respectively. CD34 + /CD133 + cell counts improved risk prediction metrics beyond standard risk factors. Conclusions: Reduced circulating progenitor cell counts, identified primarily as CD34 + mononuclear cells or its subset expressing CD133, are associated with risk of death in individuals with coronary artery disease, suggesting that impaired endogenous regenerative capacity is associated with increased mortality. These findings have implications for biological understanding, risk prediction, and cell selection for cell-based therapies.