tbuckley/cabot-search huggingface dataset:
Stem Cell Tourism and Doctors' Duties to Minors—A View From Canada
Authors: Amy Zarzeczny, Timothy Caulfield
Journal: The American Journal of Bioethics (2010)

While the clinical promise of much stem cell research remains largely theoretical, patients are nonetheless pursuing unproven stem cell therapies in jurisdictions around the world—a phenomenon referred to as "stem cell tourism." These treatments are generally advertised on a direct-to-consumer basis via the Internet. Research shows portrayals of stem cell medicine on such websites are overly optimistic and the claims made are unsubstantiated by published evidence. However, anecdotal evidence suggests that parents are pursing these "treatments" for their children, despite potential physical and financial risk. Physicians are in a unique position as they can be expected to be involved in, or privy to, such decisions. In this paper, we consider what duties physicians may have toward minor patients whose parents/guardians wish to engage in stem cell tourism on their behalf. We use the Canadian perspective to address the broadly relevant issues raised by this trend.
Preservation of Pregnancy in a Patient With Acute Abdominal Pain Secondary to Advanced and Hemorrhagic Yolk Sac Tumor of the Right Ovary
Authors: Luciano Souza Viana, Audrey Tieko Tsunoda, João Soares Nunes, Jose Humberto Tavares Guerreiro Fregnani, Marcelo Andrade Vieira, Ana Karina Nascimento Borges, Carlos Eduardo Mattos da Cunha Andrade, Sérgio Vicente Serrano
Journal: Journal of Clinical Oncology (2011)
Effects of different antibiotic classes on airway bacteria in stable COPD using culture and molecular techniques: a randomised controlled trial
Authors: Simon E Brill, Martin Law, Ethaar El-Emir, James P Allinson, Phillip James, Victoria Maddox, Gavin C Donaldson, Timothy D McHugh, William O Cookson, Miriam F Moffatt, Irwin Nazareth, John R Hurst, Peter M A Calverley, Michael J Sweeting, Jadwiga A Wedzicha
Journal: Thorax (2015)

Long-term antibiotic therapy is used to prevent exacerbations of COPD but there is uncertainty over whether this reduces airway bacteria. The optimum antibiotic choice remains unknown. We conducted an exploratory trial in stable patients with COPD comparing three antibiotic regimens against placebo.This was a single-centre, single-blind, randomised placebo-controlled trial. Patients aged ≥45 years with COPD, FEV1<80% predicted and chronic productive cough were randomised to receive either moxifloxacin 400 mg daily for 5 days every 4 weeks, doxycycline 100 mg/day, azithromycin 250 mg 3 times a week or one placebo tablet daily for 13 weeks. The primary outcome was the change in total cultured bacterial load in sputum from baseline; secondary outcomes included bacterial load by 16S quantitative PCR (qPCR), sputum inflammation and antibiotic resistance.99 patients were randomised; 86 completed follow-up, were able to expectorate sputum and were analysed. After adjustment, there was a non-significant reduction in bacterial load of 0.42 log10 cfu/mL (95% CI -0.08 to 0.91, p=0.10) with moxifloxacin, 0.11 (-0.33 to 0.55, p=0.62) with doxycycline and 0.08 (-0.38 to 0.54, p=0.73) with azithromycin from placebo, respectively. There were also no significant changes in bacterial load measured by 16S qPCR or in airway inflammation. More treatment-related adverse events occurred with moxifloxacin. Of note, mean inhibitory concentrations of cultured isolates increased by at least three times over placebo in all treatment arms.Total airway bacterial load did not decrease significantly after 3 months of antibiotic therapy. Large increases in antibiotic resistance were seen in all treatment groups and this has important implications for future studies.clinicaltrials.gov (NCT01398072).
Naphthoquinone enhances antigen-related airway inflammation in mice
Authors: K. Inoue, H. Takano, K. Hiyoshi, T. Ichinose, K. Sadakane, R. Yanagisawa, S. Tomura, Y. Kumagai
Journal: European Respiratory Journal (2006)

The current authors have previously demonstrated that diesel exhaust particles (DEP) enhance antigen-related airway inflammation in mice. Furthermore, a recent study has shown that organic chemicals in DEP, rather than their carbonaceous nuclei, are important contributors to the aggravating effects of airway inflammation. However, the components in DEP responsible for the enhancing effects on the model remain to be identified. The current authors investigated the effects of naphthoquinone (NQ), one of the extractable chemical compounds of DEP, on antigen-related airway inflammation, local expression of cytokine proteins, and antigen-specific immunoglobulin (Ig) production in mice. Pulmonary exposure to NQ dose-dependently aggravated antigen-related airway inflammation, as characterised by infiltration of eosinophils and lymphocytes around the airways and an increase in goblet cells in the bronchial epithelium. Combined exposure to NQ and antigen enhanced the local expression of interleukin (IL)-4, IL-5, eotaxin, macrophage chemoattractant protein-1 and keratinocyte chemoattractant, compared with exposure to antigen or NQ alone. Also, NQ exhibited adjuvant activity for the antigen-specific production of IgG 1 and IgG 2a . These results provide the first experimental evidence that naphthoquinone can enhance antigen-related airway inflammation in vivo , and that naphthoquinone can, to some extent, partly play a role in the pathogenesis of diesel exhaust particle toxicity on the condition.
Renal protection from ischemia mediated by A2A adenosine receptors on bone marrow–derived cells
Authors: Yuan-Ji Day, Liping Huang, Marcia J. McDuffie, Diane L. Rosin, Hong Ye, Jiang-Fan Chen, Michael A. Schwarzschild, J. Stephen Fink, Joel Linden, Mark D. Okusa
Journal: Journal of Clinical Investigation (2003)

Activation of A2A adenosine receptors (A2ARs) protects kidneys from ischemia-reperfusion injury (IRI). A2ARs are expressed on bone marrow–derived (BM-derived) cells and renal smooth muscle, epithelial, and endothelial cells. To measure the contribution of A2ARs on BM-derived cells in suppressing renal IRI, we examined the effects of a selective agonist of A2ARs, ATL146e, in chimeric mice in which BM was ablated by lethal radiation and reconstituted with donor BM cells derived from GFP, A2AR-KO, or WT mice to produce GFP→WT, A2A-KO→WT, or WT→WT mouse chimera. We found little or no repopulation of renal vascular endothelial cells by donor BM with or without renal IRI. ATL146e had no effect on IRI in A2A-KO mice or A2A-KO→WT chimera, but reduced the rise in plasma creatinine from IRI by 75% in WT mice and by 60% in WT→WT chimera. ATL146e reduced the induction of IL-6, IL-1β, IL-1ra, and TGF-α mRNA in WT→WT mice but not in A2A-KO→WT mice. Plasma creatinine was significantly greater in A2A-KO than in WT mice after IRI, suggesting some renal protection by endogenous adenosine. We conclude that protection from renal IRI by A2AR agonists or endogenous adenosine requires activation of receptors expressed on BM-derived cells.
Pseudohypertension and the Osier Maneuver-Reply
Authors: Bruce M. Psaty
Journal: JAMA (1993)

<h3>In Reply.</h3> —The letter by Dr Golden raises the question of pseudohypertension. Intra-arterial readings are not practicable in large epidemiologic studies. In the design of the Cardiovascular Health Study, we considered but chose not to include Osler's maneuver, in part because the reproducibility or reliability of the measure is so poor.<sup>1</sup>Tsapatsaris and colleagues<sup>1</sup>call it "an inadequate test." In our analysis, we excluded subjects with clinical cardiovascular disease, and fewer than 30 were 85 years of age or older. The prevalence of pseudohypertension was therefore likely to be small. The Cardiovascular Health Study methods for measuring blood pressure were the same as those used in many of the major epidemiologic studies and the randomized clinical trials, including the Systolic Hypertension in the Elderly Project.<sup>2</sup>In the Systolic Hypertension in the Elderly Project, the use of diuretics to treat isolated systolic hypertension reduced the incidence of fatal
Adjunctive Treatment With a Dopamine Partial Agonist, Aripiprazole, for Antipsychotic-Induced Hyperprolactinemia: A Placebo-Controlled Trial
Authors: Joo-Cheol Shim, Jae-Goo K Shin, Deanna L Kelly, Do-Un Jung, Young-Soo Seo, Kwang-Hyeon Liu, Ji-Hong Shon, Robert R Conley
Journal: American Journal of Psychiatry (2007)

Objective: Hyperprolactinemia and associated side effects often occur with antipsychotics. The authors investigated the effect of adjunctive treatment with aripiprazole on hyperprolactinemia and psychopathology in patients with schizophrenia maintained with haloperidol. Method: Fifty-six patients with hyperprolactinemia taking haloperidol were enrolled. Haloperidol dose was fixed; aripiprazole was dosed at 15 mg/day for the first 4 weeks, then 30 mg/day for the following 4 weeks. Serum prolactin, haloperidol, and aripiprazole levels were measured. Symptoms and side effects were assessed with the Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Negative Symptoms, Clinical Global Impression symptom scale, Simpson-Angus Rating Scale, and Barnes Akathisia Rating Scale at weeks 1, 2, 4, 6, and 8. Results: Prolactin levels of patients receiving aripiprazole significantly decreased over time, demonstrating a significant time effect and a time-by-group interaction. In the aripiprazole group, 88.5% of patients at week 8 had prolactin levels normalize compared to 3.6% of patients receiving placebo. Among 11 female patients with menstrual disturbances randomly assigned to aripiprazole, seven patients regained menstruation during the study, whereas none receiving placebo did. Plasma levels of haloperidol were not significantly altered. No significant time effect and time-by-group interactions on BPRS, Scale for the Assessment of Negative Symptoms, and Simpson-Angus Rating Scale scores were noted. Conclusions: Adjunctive aripiprazole treatment reversed hyperprolactinemia in both sexes, resulting in reinstatement of menstruation in female patients, with no significant effects on psychopathology and extrapyramidal symptoms. Aripiprazole has higher affinity to dopamine D 2 receptors than haloperidol, which is the likely cause of this observation.
Evolution of Ribonuclease Inhibitor by Exon Duplication
Authors: Marcia C. Haigis, Eric S. Haag, Ronald T. Raines
Journal: Molecular Biology and Evolution (2002)

The leucine-rich repeat (LRR) is a prevalent structural motif that mediates specific protein-protein interactions (Kobe and Deisenhofer 1995b). The LRR is defined by a region of 20–29 residues that contains the consensus sequence: XLXXLXLXXN, where L, N, and X are leucine, asparagine, and any residue, respectively. Typically, LRRs are displayed in 1–30 tandem copies within a protein. The first crystalline structure of an LRR-containing protein revealed a new protein fold (Kobe and Deisenhofer 1993) (fig. 1A and B). In porcine ribonuclease inhibitor (RI [Hofsteenge 1997]), the LRRs are arranged tandemly in a horseshoe shape with 16 a-helices encasing a parallel b-sheet of 17 strands. Hydrophobic forces between the consensus leucine residues appear to stabilize the b-sheet. RI is able to bind tightly to members of the ribonuclease (RNase) A superfamily, which not only catalyze RNA degradation but also mediate angiogenesis, cytotoxicity, and the host-defense response (D’Alessio and Riordan 1997; Raines 1998; Leland and Raines 2001). The RI fold is conserved in other proteins containing LRRs. Human U2A9 is a small nuclear protein that contains five LRRs and binds to U2B0 to form an active spliceosomal complex. Another protein, Skp2, contains both 10 LRRs that function as a protein-binding domain and an F-box motif that binds to the catalytic core of ubiquitin-protein ligases. The LRRs in U2A9 and Skp2 adopt an RI-like fold (Price, Evans, and Nagai 1998; Schulman et al. 2000). The crystalline structures of U2A9 bound to U2B0 and those of RI bound to RNase A and angiogenin reveal that the parallel b-sheet formed by the LRRs furnishes the surface for interacting with other proteins (Kobe and Deisenhofer 1995a; Papageorgiou, Shapiro, and Acharya 1997; Price, Evans, and Nagai 1998). The modularity of the LRR is consistent with the evolution of RI by gene duplication. To test this hypothesis, we investigated the genomic structure of human RI. Our findings provide a new insight into the evolution of RI as well as the many proteins containing LRRs or other modules. Human RI consists of alternating 28or 29-residue LRR units (Kobe and Deisenhofer 1993; Papageorgiou,
A phase II study of gefitinib and irradiation in children with newly diagnosed brainstem gliomas: A report from the Pediatric Brain Tumor Consortium
Authors: I. F. Pollack, C. F. Stewart, M. Kocak, T. Y. Poussaint, A. Broniscer, A. Banerjee, J. G. Douglas, L. E. Kun, J. M. Boyett, J. R. Geyer
Journal: Neuro-Oncology (2011)

This phase II study was designed to assess the safety and efficacy of gefitinib given with and following radiation therapy in children newly diagnosed with a poor prognosis brainstem glioma. Eligible patients were those with a previously untreated nondisseminated diffuse intrinsic brainstem glioma. Histological confirmation was not required, provided patients had a characteristic clinical history and MRI findings. Treatment consisted of gefitinib, administered orally, 250 mg/m2/day, during standard external beam radiotherapy, continuing for up to 13 monthly courses in the absence of disease progression or unacceptable toxicity. Toxicities, particularly intratumoral hemorrhage, were monitored. Pharmacokinetics and investigational imaging studies were performed in consenting patients. Forty-three eligible patients were included in the study. Therapy was well tolerated; only 4 patients were withdrawn from the study for dose-limiting toxicity after receiving therapy for 6, 9, 17, and 24 weeks. The 12- and 24-month progression-free survival rates were 20.9 ±5.6 % and 9.3 ±4%, respectively. Overall survival rates were 56.4 ±7.6% and 19.6 ±5.9%, respectively, which appear nominally superior to other contemporaneous Pediatric Brain Tumor Consortium trials. Three patients remain progression-free survivors with ≥36 months follow-up. The observation that a subset of children with this generally fatal tumor experienced long-term progression-free survival, coupled with recent observations regarding the molecular features of brainstem gliomas, raises the possibility that prospective molecular characterization may allow enrichment of treatment responders and improvement in outcome results in future studies of biologically targeted agents.
Interpretation of genetic variants
Authors: Patrick R Sosnay, Garry R Cutting
Journal: Thorax (2013)

Sequencing of the human genome and introduction of clinical next-generation sequencing enable discovery of all DNA variants carried by an individual. Variants may be solely responsible for disease, may contribute to disease, or may have no influence on the development of disease. Interpreting the effect of these variants upon disease is a major challenge for medicine. Although the process is still evolving, certain methods are useful in discriminating the effect of variants upon phenotype. These methods have been employed to the greatest extent in Mendelian disorders where deleterious changes in one gene can cause disease. Here, we briefly review the relative merits of these methods, with emphasis on using a comprehensive approach modelled after the analysis of variants that causes cystic fibrosis.
Pandemic influenza A(H1N1) virus infection in solid organ transplant recipients: impact of viral and non-viral co-infection
Authors: E. Cordero, P. Pérez-Romero, A. Moreno, O. Len, M. Montejo, E. Vidal, P. Martín-Dávila, M.C. Fariñas, N. Fernández-Sabé, M. Giannella, J. Pachón
Journal: Clinical Microbiology and Infection (2011)
The frequency of tuberculosis chemoprophylaxis prior to TNF-α inhibitor treatment, and the incidence tuberculosis infection using a two-step screening algorithm for latent tuberculosis infection: data from the BioRx.si registry
Authors: Matija Tomšič, Žiga Rotar
Journal: Annals of the Rheumatic Diseases (2012)

Glucuronidation is a major detoxification pathway of drugs and xenobiotics that are catalyzed by the UDP-glucuronosyltransferase (UGT) superfamily. Determination of the protein levels of the individual UGT isoforms in human tissues is required for the successful extrapolation of in vitro metabolic data to in vivo clearance. Most previous studies evaluating UGT isoform expression were limited to the mRNA level because of the high degree of amino acid sequence homology between UGT isoforms that has hampered the availability of isoform-specific antibodies. In this study, we generated a peptide-specific monoclonal antibody against human UGT1A9. We demonstrated that this antibody does not cross-react with the other UGT1A isoforms including UGT1A7, UGT1A8, and UGT1A10 and shows a high degree of amino acid sequence similarity with UGT1A9. Using this antibody, we found that UGT1A9 protein is expressed in the kidney and the liver but not in the jejunum or the ileum, consistent with previous reports of mRNA expression. In a panel of 20 individual human livers, the UGT1A9 protein levels exhibited 9-fold variability. It is noteworthy that the relative UGT1A9 protein levels were not correlated with the UGT1A9 mRNA level (<i>r</i> = −0.13), like other UGT isoforms reported previously, suggesting the importance of evaluating UGT isoform expression at protein levels. In conclusion, we generated a specific monoclonal antibody against UGT1A9 and evaluated the distribution and relative expression levels of the UGT1A9 protein in human tissues. This antibody may serve as a useful tool for further studies of UGT1A9 to evaluate its physiological, pharmacological, and toxicological roles in human tissues.
Lifetime Risk of Melanoma in CDKN2A Mutation Carriers in a Population-Based Sample
Authors: Colin B. Begg, Irene Orlow, Amanda J. Hummer, Bruce K. Armstrong, Anne Kricker, Loraine D. Marrett, Robert C. Millikan, Stephen B. Gruber, Hoda Anton-Culver, Roberto Zanetti, Richard P. Gallagher, Terence Dwyer, Timothy R. Rebbeck, Nandita Mitra, Klaus Busam, Lynn From, Marianne Berwick
Journal: JNCI Journal of the National Cancer Institute (2005)

Germline mutations in the CDKN2A gene have been linked to melanoma incidence in many families with multiple cases of the disease. Previous studies of multiple-case families have indicated that the lifetime risk (i.e., penetrance) of melanoma in CDKN2A mutation carriers is very high, ranging from 58% in Europe to 91% in Australia by age 80 years. In this study, we examined lifetime melanoma risk among CDKN2A mutation carriers using carriers who were identified in a population-based study of melanoma.Probands for the study were incident case patients with either first or subsequent melanoma who were identified in nine geographic regions in Australia, Canada, the United States, and Italy. A total of 3626 probands (53% participation rate) with adequate DNA for analysis were recruited and genotyped for CDKN2A mutations. From the 3550 probands whose DNA could be amplified by polymerase chain reaction of CDKN2A exons 1alpha, 2, and 3 and surrounding regions, 65 mutation carriers were identified. Melanoma histories in first-degree relatives of these probands were used to calculate the lifetime risk in CDKN2A mutation carriers using the kin-cohort method.The risk of melanoma in CDKN2A mutation carriers was approximately 14% (95% CI = 8% to 22%) by age 50 years, 24% (95% CI = 15% to 34%) by age 70 years, and 28% (95% CI = 18% to 40%) by age 80 years. Eighteen probands had three or more first-degree relatives with melanoma, but only one was a carrier of a CDKN2A mutation.CDKN2A mutation carriers in the general population have a much lower risk of melanoma than that suggested by estimates obtained from multiple-case families. The preponderance of familial clustering of melanoma occurs in families without identifiable mutations in CDKN2A.
Macronutrients, fatty acids and cholesterol intake and endometrial cancer
Authors: E. Lucenteforte, R. Talamini, M. Montella, L. Dal Maso, A. Tavani, S. Deandrea, C. Pelucchi, S. Greggi, A. Zucchetto, F. Barbone, M. Parpinel, S. Franceschi, C. La Vecchia, E. Negri
Journal: Annals of Oncology (2007)
Dynamic Interplay of Oncogenes and T Cells Induces PD-L1 in the Tumor Microenvironment
Authors: Andrew J. Rech, Robert H. Vonderheide
Journal: Cancer Discovery (2013)

Abstract Summary: Tumor-infiltrating T cells have recently been found to upregulate immunosuppressive pathways, such as programmed cell death protein 1 ligand 1 (PD-L1), in a paracrine fashion on tumor cells, but tumor cell–intrinsic regulation of PD-L1 is another potential mechanism. In this issue of Cancer Discovery, Akbay and colleagues show that signaling via mutant EGF receptor (EGFR) in murine lung tumor cells directly upregulates tumor PD-L1 and that therapeutic blockade of this pathway improves survival in EGFR-driven preclinical models—highlighting the dynamic interplay and therapeutic opportunities of cancer cell biology and immune biology. Cancer Discov; 3(12); 1330–2. ©2013 AACR. See related article by Akbay et al., p. 1355
Multi-Institutional Validation of a New Renal Cancer–Specific Survival Nomogram
Authors: Pierre I. Karakiewicz, Alberto Briganti, Felix K.-H. Chun, Quoc-Dien Trinh, Paul Perrotte, Vincenzo Ficarra, Luca Cindolo, Alexandre De La Taille, Jacques Tostain, Peter F.A. Mulders, Laurent Salomon, Richard Zigeuner, Tommaso Prayer-Galetti, Denis Chautard, Antoine Valeri, Eric Lechevallier, Jean-Luc Descotes, Herve Lang, Arnaud Mejean, Jean-Jacques Patard
Journal: Journal of Clinical Oncology (2007)

We tested the hypothesis that the prediction of renal cancer-specific survival can be improved if traditional predictor variables are used within a prognostic nomogram.Two cohorts of patients treated with either radical or partial nephrectomy for renal cortical tumors were used: one (n = 2,530) for nomogram development and for internal validation (200 bootstrap resamples), and a second (n = 1,422) for external validation. Cox proportional hazards regression analyses modeled the 2002 TNM stages, tumor size, Fuhrman grade, histologic subtype, local symptoms, age, and sex. The accuracy of the nomogram was compared with an established staging scheme.Cancer-specific mortality was observed in 598 (23.6%) patients, whereas 200 (7.9%) died as a result of other causes. Follow-up ranged from 0.1 to 286 months (median, 38.8 months). External validation of the nomogram at 1, 2, 5, and 10 years after nephrectomy revealed predictive accuracy of 87.8%, 89.2%, 86.7%, and 88.8%, respectively. Conversely, the alternative staging scheme predicting at 2 and 5 years was less accurate, as evidenced by 86.1% (P = .006) and 83.9% (P = .02) estimates.The new nomogram is more contemporary, provides predictions that reach further in time and, compared with its alternative, which predicts at 2 and 5 years, generates 3.1% and 2.8% more accurate predictions, respectively.