tbuckley/cabot-search huggingface dataset:
Obtaining informed consent for clinical tumor and germline exome sequencing of newly diagnosed childhood cancer patients
Authors: Sarah Scollon, Katie Bergstrom, Robin A Kerstein, Tao Wang, Susan G Hilsenbeck, Uma Ramamurthy, Richard A Gibbs, Christine M Eng, Murali M Chintagumpala, Stacey L Berg, Laurence B McCullough, Amy L McGuire, Sharon E Plon, D Williams Parsons
Journal: Genome Medicine (2014)

Abstract Background Effectively educating families about the risks and benefits of genomic tests such as whole exome sequencing (WES) offers numerous challenges, including the complexity of test results and potential loss of privacy. Research on best practices for obtaining informed consent (IC) in a variety of clinical settings is needed. The BASIC3 study of clinical tumor and germline WES in an ethnically diverse cohort of newly diagnosed pediatric cancer patients offers the opportunity to study the IC process in the setting of critical illness. We report on our experience for the first 100 families enrolled, including study participation rates, reasons for declining enrollment, assessment of clinical and demographic factors that might impact study enrollment, and preferences of parents for participation in optional genomics study procedures. Methods A specifically trained IC team offered study enrollment to parents of eligible children for procedures including clinical tumor and germline WES with results deposited in the medical record and disclosure of both diagnostic and incidental results to the family. Optional study procedures were also offered, such as receiving recessive carrier status and deposition of data into research databases. Stated reasons for declining participation were recorded. Clinical and demographic data were collected and comparisons made between enrolled and non-enrolled patients. Results Over 15 months, 100 of 121 (83%) eligible families elected to enroll in the study. No significant differences in enrollment were detected based on factors such as race, ethnicity, use of Spanish interpreters and Spanish consent forms, and tumor features (central nervous system versus non-central nervous system, availability of tumor for WES). The most common reason provided for declining enrollment (10% of families) was being overwhelmed by the new cancer diagnosis. Risks specific to clinical genomics, such as privacy concerns, were less commonly reported (5.5%). More than 85% of parents consented to each of the optional study procedures. Conclusions An IC process was developed that utilizes a specialized IC team, active communication with the oncology team, and an emphasis on scheduling flexibility. Most parents were willing to participate in a clinical germline and tumor WES study as well as optional procedures such as genomic data sharing independent of race, ethnicity or language spoken.
The rise and fall of malaria in a west African rural community, Dielmo, Senegal, from 1990 to 2012: a 22 year longitudinal study
Authors: Jean-François Trape, Adama Tall, Cheikh Sokhna, Alioune Badara Ly, Nafissatou Diagne, Ousmane Ndiath, Catherine Mazenot, Vincent Richard, Abdoulaye Badiane, Fambaye Dieye-Ba, Joseph Faye, Gora Ndiaye, Fatoumata Diene Sarr, Clémentine Roucher, Charles Bouganali, Hubert Bassène, Aissatou Touré-Baldé, Christian Roussilhon, Ronald Perraut, André Spiegel, Jean-Louis Sarthou, Luiz Pereira da Silva, Odile Mercereau-Puijalon, Pierre Druilhe, Christophe Rogier
Journal: The Lancet Infectious Diseases (2014)
Genome-wide detection and analysis of homologous recombination among sequenced strains of Escherichia coli.
Authors: Bob Mau, Jeremy D Glasner, Aaron E Darling, Nicole T Perna
Journal: Genome biology (2006)

Abstract Background Comparisons of complete bacterial genomes reveal evidence of lateral transfer of DNA across otherwise clonally diverging lineages. Some lateral transfer events result in acquisition of novel genomic segments and are easily detected through genome comparison. Other more subtle lateral transfers involve homologous recombination events that result in substitution of alleles within conserved genomic regions. This type of event is observed infrequently among distantly related organisms. It is reported to be more common within species, but the frequency has been difficult to quantify since the sequences under comparison tend to have relatively few polymorphic sites. Results Here we report a genome-wide assessment of homologous recombination among a collection of six complete Escherichia coli and Shigella flexneri genome sequences. We construct a whole-genome multiple alignment and identify clusters of polymorphic sites that exhibit atypical patterns of nucleotide substitution using a random walk-based method. The analysis reveals one large segment (approximately 100 kb) and 186 smaller clusters of single base pair differences that suggest lateral exchange between lineages. These clusters include portions of 10% of the 3,100 genes conserved in six genomes. Statistical analysis of the functional roles of these genes reveals that several classes of genes are over-represented, including those involved in recombination, transport and motility. Conclusion We demonstrate that intraspecific recombination in E. coli is much more common than previously appreciated and may show a bias for certain types of genes. The described method provides high-specificity, conservative inference of past recombination events.
An Oral Preparation of Mesalamine as Long-Term Maintenance Therapy for Ulcerative Colitis
Authors: Stephen B. Hanauer
Journal: Annals of Internal Medicine (1996)

Objective: To compare the safety and efficacy of a pH-sensitive, polymer-coated oral formulation of mesalamine (Asacol, Procter & Gamble Pharmaceuticals, Cincinnati, Ohio) with those of placebo in maintaining remission in patients with ulcerative colitis. Design: Multicenter, double-blind, placebo-controlled, randomized clinical trial. Setting: Eight private practices, five university-based medical centers, and four hospitals or clinics. Patients: 264 patients with ulcerative colitis that had been maintained in remission for at least 1 month while the patients were receiving stable doses of sulfasalazine or any oral mesalamine product. Intervention: Coated mesalamine at oral dosages of 0.8 g/d or 1.6 g/d or matching placebo for 6 months. Measurements: Treatment success, defined as maintenance of remission after 6 months, and treatment failure, defined as relapse during the study (as indicated by proctosigmoidoscopy at 1, 3, or 6 months of treatment) or withdrawal due to adverse events. Safety was assessed on the basis of laboratory analyses and patient- and investigator-noted adverse events. Results: 189 patients were compliant with the protocol for 6 months or stopped receiving therapy because of relapse or adverse events. Of these 189 patients, 25 of the 63 patients (39.7%) in the placebo group had treatment success compared with 40 of the 68 patients (58.8% [95% CI, 46.4% to 71.3%]) in the group receiving mesalamine, 0.8 g/d (P = 0.036) and 38 of the 58 patients (65.5% [CI, 52.4% to 78.6%]) in the group receiving mesalamine, 1.6 g/d (P = 0.006). In the intention-to-treat analysis of all patients, 42 of the 87 patients (48.3%) in the placebo group had treatment success compared with 57 of the 90 patients (63.3% [CI, 52.8% to 73.8%]) in the group receiving mesalamine, 0.8 g/d (P = 0.050) and 61 of the 87 patients (70.1% [CI, 59.9% to 80.3%]) in the group receiving mesalamine, 1.6 g/d (P = 0.005). Age, sex, and race were not found to predict treatment success or failure. The mesalamine tablet was well tolerated, and no clinically significant changes were seen in hematologic, hepatic, or renal laboratory profiles. Conclusion: Coated mesalamine at oral dosages of 0.8 g/d and 1.6 g/d is safe and effective in maintaining remission in patients with quiescent ulcerative colitis. *For a listing of members of The Mesalamine Study Group, see the Appendix.
THE MODE OF ACTION OF SULFANILAMIDE ON STREPTOCOCCUS. II
Authors: Frederick P. Gay, Ada R. Clark, Julia A. Street, Dorothy W. Miles
Journal: The Journal of Experimental Medicine (1939)

The precise mode of therapeutic action of sulfanilamide on streptococcus can be arrived at only by considering the sum total of factors that inhibit or favor the natural growth of the microorganism under the experimental conditions that obtain, whether in vivo or in vitro. Too sweeping conclusions have hitherto been drawn from the study of a single variable factor, such as an unfavorable temperature or the absence or presence of peptone. We have attempted here to analyze the factors that have hitherto been recognized and some new ones, but particularly the relationship of these factors to one another. The result obtained on adding sulfanilamide to the streptococcus in the test tube is usually bacteriostasis and not complete destruction of even small numbers of bacteria. This is on the condition that the suspending medium is a favorable one for the growth of the microorganism; the more growth-promoting the medium is the less the bacteriostasis. If, on the other hand, the medium is too poor, or one that in itself inhibits growth, the addition of sulfanilamide may lead to sterilization of the culture. The conditions for growth of the streptococcus in the body of the rabbit or mouse, depend on the strain of bacteria used, but are on the whole favorable. Defence, however, in the form of phagocytosis by both polymorphonuclear and by mononuclear cells is attempted even in the susceptible animal. When sulfanilamide is used to treat such an animal, or when sulfanilamide-grown (inhibited) streptococci are employed, phagocytosis is pronounced, whether studied in the test tube or in the animal body. In the rabbit the delay by sulfanilamide and resultant increased phagocytosis by polymorphonuclears allows mononuclear cells to accumulate and recovery may result. Sulfanilamide not only does not completely destroy the streptococcus but does not even impair its innate virulence. It acts upon the streptococcus not only by inhibiting growth but by a temporary inhibition of hemotoxin formation, but only under certain conditions. The drug does not neutralize hemotoxin already formed. No significant effect of sulfanilamide on the formation of leucocidin or fibrinolysin by streptococcus has been evident in our experiments. Sulfanilamide differs in one important respect from other drugs that are destructive either in the test tube or actually in the body, for protozoa and bacteria. Protozoa fix or adsorb arsenicals and acriflavine that kill them variably in vitro and in vivo. Streptococci fix both gentian violet and acriflavine, which dyes have marked destructive action in the test tube but are less effective in vivo. Sulfanilamide is not diminished at all by contact in vitro with large masses of streptococci, nor does the action of this drug render the microorganism more capable than untreated cocci to adsorb gentian violet or acriflavine, or to be destroyed by these highly bactericidal substances.
Comparative trial of two non-sedative H1 antihistamines, terfenadine and astemizole, for hay fever.
Authors: P H Howarth, S T Holgate
Journal: Thorax (1984)

Ninety patients participated in a randomised, double blind, placebo controlled comparison of terfenadine with astemizole in the treatment of hay fever. They entered the trial as a cohort before the grass pollen season and recorded daily their symptoms of itching eyes, sneezing, running nose, and blocked nose on visual analogue scales in diary cards. Over the eight weeks of the trial astemizole was significantly better than either terfenadine or placebo in alleviating itching eyes, sneezing, and running nose (p less than 0.0001) but no better than placebo for the treatment of blocked nose. The placebo was significantly better than terfenadine for the treatment of running nose and blocked nose (p less than 0.002). Neither of these H1 antihistamine drugs was associated with sedative adverse effects despite significantly inhibiting histamine induced skin weal responses. These results suggest that astemizole is a satisfactory non-sedative H1 antihistamine for maintenance treatment of hay fever. Terfenadine is ineffective by comparison.
COPD phenotypes in biomass smoke- versus tobacco smoke-exposed Mexican women
Authors: P. G. Camp, A. Ramirez-Venegas, R. H. Sansores, L. F. Alva, J. E. McDougall, D. D. Sin, P. D. Pare, N. L. Muller, C. I. S. Silva, C. E. Rojas, H. O. Coxson
Journal: European Respiratory Journal (2013)

We hypothesised that biomass smoke exposure is associated with an airway-predominant chronic obstructive pulmonary disease (COPD) phenotype, while tobacco-related COPD is associated with an emphysema-predominant phenotype. In this cross-sectional study, female never-smokers with COPD and biomass exposure (n=21) and female ex-cigarette smokers with COPD without biomass exposure (n=22) completed computed tomography (CT) at inspiration and expiration, pulmonary function, blood gas, exercise tolerance, and quality of life measures. Two radiologists scored the extent of emphysema and air trapping on CT. Quantitative emphysema severity and distribution and airway wall thickness were calculated using specialised software. Women in the tobacco group had significantly more emphysema than the biomass group (radiologist score 2.3 versus 0.7, p=0.001; emphysema on CT 27% versus 19%, p=0.046; and a larger size of emphysematous spaces, p=0.006). Women in the biomass group had significantly more air trapping than the tobacco group (radiologist score 2.6 and 1.5, respectively; p=0.02) and also scored lower on the symptom, activities and confidence domains of the quality of life assessment and had lower oxygen saturation at rest and during exercise (p<0.05). Biomass smoke exposure is associated with less emphysema but more air trapping than tobacco smoke exposure, suggesting an airway-predominant phenotype.
Differential Effects of Respiratory Syncytial Virus and Adenovirus on Mononuclear Cell Cytokine Responses
Authors: PATRICIA V. DÍAZ, WILLIAM J. CALHOUN, KIM L. HINTON, LUIS F. AVENDAÑO, ALDO GAGGERO, VALESKA SIMON, SONIA M. ARREDONDO, RICARDO PINTO, ARMANDO DÍAZ
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Respiratory syncytial virus (RSV) and adenovirus (Advs) serotype 3 (Adv3) and 7h (Adv7h) are associated with mild to severe respiratory infection and are indistinguishable during the acute phases of the illnesses. However, outcome and long-term prognosis are different with both infections. RSV infection is associated with later development of asthma, and Adv, mainly Adv7h, with severe lung damage, bronchiectasis, and hyperlucent lung. We hypothesized that this difference could be partly due to different immune responses induced by these viruses. To test this hypothesis we quantified TCD4 + , TCD8 + , and BCD19 + expressing the interleukin-2 receptor-alpha chain (CD25) and interferon- γ (IFN- γ ), interleukin (IL)-10, and IL-4 in the supernatant of peripheral blood mononuclear cells (PBMC) from school children infected in vitro with and without RSV, Adv7h, and Adv3 and after phytohemagglutinin (PHA) stimulation in the presence or absence of these viruses at a multiplicity of infection (MOI) of 1. PBMC from every child produced more IL-10 (p ⩽ 0.05) when infected with RSV than with Advs and noninfected control, and Adv induced more (p ⩽ 0.05) IFN- γ than did RSV and control. The IL-10/IFN- γ ratio was significantly higher (p ⩽ 0.05) in RSV-infected and significantly lower (p ⩽ 0.05) in Adv-infected PBMC, than in noninfected cells. PHA-stimulated BCD19 + RSV- infected cells expressed more (p ⩽ 0.05) IL-2R than did Adv-infected cells. These results suggest that Advs induce a Th-1-type immune response that is not seen with RSV. These patterns persist despite intersubject variation in the absolute quantity of cytokine produced.
High Seroprevalence of Antibodies to Human Herpesvirus-8 in Egyptian Children: Evidence of Nonsexual Transmission
Authors: M. Andreoni, G. El-Sawaf, G. Rezza, B. Ensoli, E. Nicastri, L. Ventura, L. Ercoli, L. Sarmati, G. Rocchi
Journal: JNCI Journal of the National Cancer Institute (1999)

BACKGROUND: In western countries, human herpesvirus-8 (HHV-8) appears to be transmitted mainly by sexual contact. To evaluate the role of other transmission routes, especially in developing countries, we estimated the seroprevalence of HHV-8 in Egyptian children, who, if seropositive, would have acquired the virus through a nonsexual route. METHODS: Sera from 196 children (<1-12 years of age), 20 adolescents (13-20 years of age), and 30 young adults (21-25 years of age) attending a vaccination program in Alexandria, Egypt, were studied. Immunofluorescence assays were used to detect antibodies against HHV-8 lytic-phase antigens (anti-lytic) and latent-phase antigens (anti-latent). Antibodies against Epstein-Barr virus viral cap antigen, cytomegalovirus, and HHV-6 were detected by enzyme-linked immunosorbent assays. Seroprevalence of these herpesviruses was calculated after stratifying the subjects by age. RESULTS: Anti-lytic and anti-latent HHV-8 antibodies were detected in 44.7% and 8.5% of the study participants, respectively. The prevalence of anti-lytic antibodies tended to increase with age, exceeding 50% in children older than 6 years; once children reached the age of 10 years, the prevalence tended to stabilize. The seroprevalence of other herpesviruses tended to be higher than that of HHV-8, ranging from approximately 83% to more than 97% in the 9- to 12-year age group. One- to 3-year-old children had higher titers of anti-lytic HHV-8 antibodies than children in the other age groups. Anti-latent antibodies were more frequently detected in individuals with high anti-lytic antibody titers. CONCLUSIONS: HHV-8 antibodies are highly prevalent in Egyptian children, suggesting that, in developing countries, HHV-8 infection may be acquired early in life through routes other than sexual transmission. The lower seroprevalence of HHV-8 relative to that of the other herpesviruses suggests that HHV-8 is less transmissible than other common herpesviruses.
Unexpected Role of the Copper Transporter ATP7A in PDGF-Induced Vascular Smooth Muscle Cell Migration
Authors: Takashi Ashino, Varadarajan Sudhahar, Norifumi Urao, Jin Oshikawa, Gin-Fu Chen, Huan Wang, Yuqing Huo, Lydia Finney, Stefan Vogt, Ronald D. McKinney, Edward B. Maryon, Jack H. Kaplan, Masuko Ushio-Fukai, Tohru Fukai
Journal: Circulation Research (2010)

Rationale: Copper, an essential nutrient, has been implicated in vascular remodeling and atherosclerosis with unknown mechanism. Bioavailability of intracellular copper is regulated not only by the copper importer CTR1 (copper transporter 1) but also by the copper exporter ATP7A (Menkes ATPase), whose function is achieved through copper-dependent translocation from trans -Golgi network (TGN). Platelet-derived growth factor (PDGF) promotes vascular smooth muscle cell (VSMC) migration, a key component of neointimal formation. Objective: To determine the role of copper transporter ATP7A in PDGF-induced VSMC migration. Methods and Results: Depletion of ATP7A inhibited VSMC migration in response to PDGF or wound scratch in a CTR1/copper-dependent manner. PDGF stimulation promoted ATP7A translocation from the TGN to lipid rafts, which localized at the leading edge, where it colocalized with PDGF receptor and Rac1, in migrating VSMCs. Mechanistically, ATP7A small interfering RNA or CTR small interfering RNA prevented PDGF-induced Rac1 translocation to the leading edge, thereby inhibiting lamellipodia formation. In addition, ATP7A depletion prevented a PDGF-induced decrease in copper level and secretory copper enzyme precursor prolysyl oxidase (Pro-LOX) in lipid raft fraction, as well as PDGF-induced increase in LOX activity. In vivo, ATP7A expression was markedly increased and copper accumulation was observed by synchrotron-based x-ray fluorescence microscopy at neointimal VSMCs in wire injury model. Conclusions: These findings suggest that ATP7A plays an important role in copper-dependent PDGF-stimulated VSMC migration via recruiting Rac1 to lipid rafts at the leading edge, as well as regulating LOX activity. This may contribute to neointimal formation after vascular injury. Our findings provide insight into ATP7A as a novel therapeutic target for vascular remodeling and atherosclerosis.
We must give children a voice in advance care planning
Authors: B. Taylor
Journal: BMJ (2012)

Advance care planning (ACP) has become a key component of end of life care, but it involves far more than just conversations about whether or not to resuscitate. The wishes and preferences of the person concerned must be identified before they are too unwell to be involved in decision making. However, insufficient research and guidance exist on involving children and adolescents in advance care planning.

Retrospective interviews with the parents of children who had an advance care plan found the process helpful in assuring that the best care was obtained for their child, and in avoiding unnecessary suffering and preserving quality of life.1 Perhaps unsurprisingly, these plans focused exclusively on medical interventions, covering decisions around resuscitation, artificial feeding, intubation and ventilation, antibiotic use, and admission to hospital. Parents reported “having peace of mind” and retaining a sense of control once they had signed the plan, but it is unclear whether their children experienced …
Epstein-Barr Virus (EBV)-Encoded RNA Promotes Growth of EBV-Infected T Cells through Interleukin-9 Induction
Authors: Lixin Yang, Katsuyuki Aozasa, Kazuo Oshimi, Kenzo Takada
Journal: Cancer Research (2004)

Abstract EBV associates with various T-cell-proliferating diseases such as chronic active EBV infection and nasal lymphoma. In contrast to B cells, which are highly susceptible to EBV infection in vitro, T cells are refractory to EBV infection in vitro, and it has been difficult to examine the effects of EBV infection on T cells. We recently generated EBV recombinants with a selectable marker, which made it possible to select EBV-infected cells even when the efficiency of infection was low. Using the recombinant virus, we found that a human T-cell line, MT-2, was susceptible to EBV infection, and we succeeded in isolating EBV-infected cell clones with type II EBV latency, which was identical with those seen in EBV-infected T cells in vivo. EBV-infected MT-2 cell clones had shorter cell doubling times and higher saturation density than non-EBV-infected counterparts. We found that EBV-positive MT-2 cells expressed higher levels of interleukin (IL)-9 than EBV-negative MT-2 cells at the transcriptional level. It was also demonstrated that EBV-encoded small RNA was responsible for IL-9 expression. Addition of recombinant IL-9 accelerated the growth of MT-2 cells, whereas growth of the EBV-converted MT-2 cells was blocked by treatment with an anti-IL-9 antibody. These results suggest that IL-9 induced by EBV-encoded small RNA acts as an autocrine growth factor for EBV-infected T cells. Analysis of nasal lymphoma biopsies indicated that three of four specimens expressed IL-9. The present findings suggest that EBV directly affects the pathogenesis of EBV-associated T-cell diseases.