tbuckley/cabot-search huggingface dataset:
Progesterone Receptor Signaling in the Microenvironment of Endometrial Cancer Influences Its Response to Hormonal Therapy
Authors: Deanna M. Janzen, Miguel A. Rosales, Daniel Y. Paik, Daniel S. Lee, Daniel A. Smith, Owen N. Witte, M. Luisa Iruela-Arispe, Sanaz Memarzadeh
Journal: Cancer Research (2013)

Progesterone, an agonist for the progesterone receptor (PR), can be an efficacious and well-tolerated treatment in endometrial cancer. The clinical use of progesterone is limited because of the lack of biomarkers that predict hormone sensitivity. Despite its efficacy in cancer therapy, mechanisms and site of action for progesterone remain unknown. Using an in vivo endometrial cancer mouse model driven by clinically relevant genetic changes but dichotomous responses to hormonal therapy, we show that signaling through stromal PR is necessary and sufficient for progesterone antitumor effects. Endometrial cancers resulting from epithelial loss of PTEN (PTENKO) were hormone sensitive and had abundant expression of stromal PR. Stromal deletion of PR as a single genetic change in these tumors induced progesterone resistance indicating that paracrine signaling through the stroma is essential for the progesterone therapeutic effects. A hormone-refractory endometrial tumor with low levels of stromal PR developed when activation of KRAS was coupled with PTEN-loss (PTENKO/Kras). The innate progesterone resistance in PTENKO/Kras tumors stemmed from methylation of PR in the tumor microenvironment. Add-back of stromal PR expressed from a constitutively active promoter sensitized these tumors to progesterone therapy. Results show that signaling through stromal PR is sufficient for inducing hormone responsiveness. Our findings suggest that epigenetic derepression of stromal PR could be a potential therapeutic target for sensitizing hormone-refractory endometrial tumors to progesterone therapy. On the basis of these results, stromal expression of PR may emerge as a reliable biomarker in predicting response to hormonal therapy.
INFLUENCE OF DELTA INFECTION ON SEVERITY OF HEPATITIS B
Authors: Antonina Smedile, Giorgio Verme, Antonietta Cargnel, Pietro Dentico, Pierre Opolon, Diego Vergani, Patrizia Farci, Francesco Caredda, Nicola Caporaso, Christian Trepo, Alex Gimson, Roger Williams, Mario Rizzetto
Journal: The Lancet (1982)
Comparative sequence of myosin light chains from normal and hypertrophied human hearts.
Authors: C Klotz, J J Leger, M Elzinga
Journal: Circulation Research (1982)

Myosin light chains from normal and hypertrophied human hearts were partially sequenced in order to see whether structural modifications of these light subunits could provide a molecular basis for the changes observed in heart properties and in myosin enzymatic activity. Normal light chains were prepared form hearts taken at autopsy, weighing 350 g or less and apparently devoid of myocardial disease. "Hypertrophied cardiac myosin light chains" were prepared from two greatly hypertrophied hearts, weighing 600 and750 g. No amino acid substitutions, deletions, or additions were observed in the light chains from hypertrophied hearts. The third light chain previously reported in human cardiac myosin and related to hypertrophy was found to be a proteolytic product of LC2. The comparison between human and beef cardiac myosin light chains indicated that the sequences of these subunits of the myosin molecule are highly conserved.
Deficiency of the Stress Kinase P38α Results in Embryonic Lethality
Authors: Melanie Allen, Linne Svensson, Marsha Roach, John Hambor, John McNeish, Christopher A. Gabel
Journal: The Journal of Experimental Medicine (2000)

The mitogen-activated protein (MAP) kinase p38 is a key component of stress response pathways and the target of cytokine-suppressing antiinflammatory drugs (CSAIDs). A genetic approach was employed to inactivate the gene encoding one p38 isoform, p38α. Mice null for the p38α allele die during embryonic development. p38α1/− embryonic stem (ES) cells grown in the presence of high neomycin concentrations demonstrated conversion of the wild-type allele to a targeted allele. p38α−/− ES cells lacked p38α protein and failed to activate MAP kinase–activated protein (MAPKAP) kinase 2 in response to chemical stress inducers. In contrast, p38α1/+ ES cells and primary embryonic fibroblasts responded to stress stimuli and phosphorylated p38α, and activated MAPKAP kinase 2. After in vitro differentiation, both wild-type and p38α−/− ES cells yielded cells that expressed the interleukin 1 receptor (IL-1R). p38α1/+ but not p38α−/− IL-1R–positive cells responded to IL-1 activation to produce IL-6. Comparison of chemical-induced apoptosis processes revealed no significant difference between the p38α1/+ and p38α−/− ES cells. Therefore, these studies demonstrate that p38α is a major upstream activator of MAPKAP kinase 2 and a key component of the IL-1 signaling pathway. However, p38α does not serve an indispensable role in apoptosis.
CD44 is a macrophage binding site for Mycobacterium tuberculosis that mediates macrophage recruitment and protective immunity against tuberculosis
Authors: Jaklien C. Leemans, Sandrine Florquin, Mirjam Heikens, Steven T. Pals, Ronald van der Neut, Tom van der Poll
Journal: Journal of Clinical Investigation (2003)

Cell migration and phagocytosis are both important for controlling Mycobacterium tuberculosis infection and are critically dependent on the reorganization of the cytoskeleton. Since CD44 is an adhesion molecule involved in inflammatory responses and is connected to the actin cytoskeleton, we investigated the role of CD44 in both these processes. Macrophage (Mφ) recruitment into M. tuberculosis–infected lungs and delayed-type hypersensitivity sites was impaired in CD44-deficient (CD44–/–) mice. In addition, the number of T lymphocytes and the concentration of the protective key cytokine IFN-γ were reduced in the lungs of infected CD44–/– mice. The production of IFN-γ by splenocytes of CD44–/– mice was profoundly increased upon antigen-specific stimulation. Flow cytometry analysis revealed that soluble CD44 can directly bind to virulent M. tuberculosis. Mycobacteria also interacted with Mφ-associated CD44, as reflected by reduced binding and internalization of bacilli by CD44–/– Mφs. This suggests that CD44 is a receptor on Mφs for binding of M. tuberculosis. CD44–/– mice displayed a decreased survival and an enhanced mycobacterial outgrowth in lungs and liver during pulmonary tuberculosis. In summary, we have identified CD44 as a new Mφ binding site for M. tuberculosis that mediates mycobacterial phagocytosis, Mφ recruitment, and protective immunity against pulmonary tuberculosis.
Metabolic Rates of ATP Transfer Through Creatine Kinase (CK Flux) Predict Clinical Heart Failure Events and Death
Authors: Paul A. Bottomley, Gurusher S. Panjrath, Shenghan Lai, Glenn A. Hirsch, Katherine Wu, Samer S. Najjar, Angela Steinberg, Gary Gerstenblith, Robert G. Weiss
Journal: Science Translational Medicine (2013)

Reduced rates of adenosine triphosphate synthesis through myocardial creatine kinase (CK flux) predict adverse clinical events in patients with heart failure.
A cluster of pediatric metallic mercury exposure cases treated with meso-2,3-dimercaptosuccinic acid (DMSA)
Authors: J Forman, J Moline, E Cernichiari, S Sayegh, J C Torres, M M Landrigan, J Hudson, H N Adel, P J Landrigan
Journal: Environmental Health Perspectives (2000)

Nine children and their mother were exposed to vapors of metallic mercury. The source of the exposure appears to have been a 6-oz vial of mercury taken from a neighbor's home. The neighbor reportedly operated a business preparing mercury-filled amulets for practitioners of the Afro-Caribbean religion Santeria. At diagnosis, urinary mercury levels in the children ranged from 61 to 1,213 microg/g creatinine, with a geometric mean of 214.3 microg/m creatinine. All of the children were asymptomatic. To prevent development of neurotoxicity, we treated the children with oral meso-2,3-dimercaptosuccinic acid (DMSA). During chelation, the geometric mean urine level rose initially by 268% to 573.2 microg mercury/g creatinine (p<0.0005). At the 6-week follow-up examination after treatment, the geometric mean urine mercury level had fallen to 102.1 microg/g creatinine, which was 17.8% of the geometric mean level observed during treatment (p<0.0005) and 47.6% of the original baseline level (p<0.001). Thus, oral chelation with DMSA produced a significant mercury diuresis in these children. We observed no adverse side effects of treatment. DMSA appears to be an effective and safe chelating agent for treatment of pediatric overexposure to metallic mercury.
Personal Health Record Design: Qualitative Exploration of Issues Inhibiting Optimal Use
Authors: Kevin T. Fuji, Amy A. Abbott, Kimberly A. Galt
Journal: Diabetes Care (2013)

Personal health records (PHRs) have been purported to enhance patients’ self-management of diabetes (1). However, few studies have examined the barriers to PHR use resulting from design issues identified by actual users (2). To address this gap, interviews were conducted with 59 patients 3 to 6 months after receiving hands-on training in the use of the Microsoft Health Vault for PHRs to manage their diabetes-related health information. Health Vault was selected because of its universal accessibility and functionalities meeting the greatest number of patient desires (3). The central question guiding the interviews was “How have you used the PHR to manage your diabetes-related health information?” Data were analyzed through a process of coding, category development of similar codes, and overarching theme development.

Twenty-three of the 59 participants (39%) sustained PHR use. Table 1 displays the demographic, clinical, and thematic comparisons between PHR users and nonusers. Three themes describing barriers to use from patients’ perspectives could be traced back to PHR design considerations.

View this table:

Table 1 
Demographic characteristics …
Resequencing Data Provide No Evidence for a Human Bottleneck in Africa during the Penultimate Glacial Period
Authors: Per Sjödin, Agnès E. Sjöstrand, Mattias Jakobsson, Michael G.B. Blum
Journal: Molecular Biology and Evolution (2012)

Based on the accumulation of genetic, climatic, and fossil evidence, a central theory in paleoanthropology stipulates that a demographic bottleneck coincided with the origin of our species Homo Sapiens. This theory proposes that anatomically modern humans--which were only present in Africa at the time--experienced a drastic bottleneck during the penultimate glacial age (130-190 kya) when a cold and dry climate prevailed. Two scenarios have been proposed to describe the bottleneck, which involve either a fragmentation of the range occupied by humans or the survival of one small group of humans. Here, we analyze DNA sequence data from 61 nuclear loci sequenced in three African populations using Approximate Bayesian Computation and numerical simulations. In contrast to the bottleneck theory, we show that a simple model without any bottleneck during the penultimate ice age has the greatest statistical support compared with bottleneck models. Although the proposed bottleneck is ancient, occurring at least 130 kya, we can discard the possibility that it did not leave detectable footprints in the DNA sequence data except if the bottleneck involves a less than a 3-fold reduction in population size. Finally, we confirm that a simple model without a bottleneck is able to reproduce the main features of the observed patterns of genetic variation. We conclude that models of Pleistocene refugium for modern human origins now require substantial revision.
Eight Hours of Nightly Continuous Positive Airway Pressure Treatment of Obstructive Sleep Apnea Improves Glucose Metabolism in Patients with Prediabetes. A Randomized Controlled Trial
Authors: Sushmita Pamidi, Kristen Wroblewski, Magdalena Stepien, Khalid Sharif-Sidi, Jennifer Kilkus, Harry Whitmore, Esra Tasali
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Rationale: Although obstructive sleep apnea (OSA) is associated with impaired glucose tolerance and diabetes, it remains unclear whether OSA treatment with continuous positive airway pressure (CPAP) has metabolic benefits.Objectives: To determine the effect of 8-hour nightly CPAP treatment on glucose metabolism in individuals with prediabetes and OSA.Methods: In a randomized controlled parallel group study, 39 participants were randomly assigned to receive either 8-hour nightly CPAP (n = 26) or oral placebo (n = 13). Sleep was polysomnographically recorded in the laboratory on each night. CPAP adherence was ensured by continuous supervision. Participants continued their daily routine activities outside the laboratory. Glucose metabolism was assessed at baseline and after 2 weeks of assigned treatment using both the oral and intravenous glucose tolerance tests. The primary outcome was the overall glucose response as quantified by the area under the curve for glucose during 2-hour oral glucose tolerance testing. Secondary outcomes included fasting and 2-hour glucose and insulin, the area under the curves for insulin and insulin secretion, norepinephrine, insulin sensitivity, acute insulin response to glucose, and 24-hour blood pressure.Measurements and Main Results: The overall glucose response was reduced (treatment difference: −1,276.9 [mg/dl] · min [95% confidence interval, −2,392.4 to −161.5]; P = 0.03) and insulin sensitivity was improved (treatment difference: 0.77 [mU/L]−1 · min−1 [95% confidence interval, 0.03–1.52]; P = 0.04) with CPAP as compared with placebo. Additionally, norepinephrine levels and 24-hour blood pressure were reduced with CPAP as compared with placebo.Conclusions: In patients with prediabetes, 8-hour nightly CPAP treatment for 2 weeks improves glucose metabolism compared with placebo. Thus, CPAP treatment may be beneficial for metabolic risk reduction.Clinical trial registered with www.clinicaltrials.gov (NCT 01156116)
A randomized phase III trial comparing standard and high-dose pemetrexed as second-line treatment in patients with locally advanced or metastatic non-small-cell lung cancer
Authors: M.H. Cullen, P. Zatloukal, S. Sörenson, S. Novello, J.R. Fischer, A.A. Joy, M. Zereu, P. Peterson, C.M. Visseren-Grul, N. Iscoe
Journal: Annals of Oncology (2008)
IgG subclasses in smokers with chronic bronchitis and recurrent exacerbations
Authors: I Qvarfordt, G C Riise, B A Andersson, S Larsson
Journal: Thorax (2001)

Background-Tobacco smokers have lower serum levels of IgG than nonsmokers.IgG subclass deficiency is common in patients with recurrent respiratory infections.Recurrent bronchial infections are common in smokers with chronic bronchitis (CB).We have investigated whether susceptibility to recurrent exacerbations in smokers with CB is associated with altered IgG subclass levels or IgG subclass deficiency.Methods-Serum levels of IgG, IgA, IgM, and IgG subclasses 1-4 were determined by radial immunodiVusion in 100 subjects: 33 smokers with stable CB and recurrent exacerbations, 24 asymptomatic smokers, and 43 healthy never smokers.Systemic tobacco exposure was verified and excluded using a serum cotinine ELISA.Immunoglobulin data were log transformed to enable use of parametric statistical methods.Results-Compared with never smokers, both patients with CB and asymptomatic smokers had significantly lower levels of IgG (median 9.7 g/l (range 5.6-15.2) and 9.9 (6.1-12.1)g/l v 12.0 (6.9-18.5)g/l) and IgG2 (2.8 (0.9-5.9) g/l and 2.5 (1.0-6.3)g/l v 4.0 (1.7-10.2) g/l).The estimated ratio of median values between the patients with CB and never smokers was 0.78 (95% confidence interval (CI) 0.69 to 0.89) for IgG and 0.65 (95% CI 0.50 to 0.83) for IgG2.The corresponding ratios between asymptomatic smokers and never smokers were 0.79 (95% CI 0.69 to 0.91) and 0.60 (95% CI 0.50 to 0.83), respectively.There were no significant diVerences between the smoking groups.Conclusions-Susceptibility to recurrent exacerbations in smokers with CB is not associated with lower levels of IgG subclasses than can be accounted for by smoking per se.
Cost-Effectiveness of Androgen Suppression Therapies in Advanced Prostate Cancer
Authors: A. M. Bayoumi
Journal: JNCI Journal of the National Cancer Institute (2000)

Background: The costs and side effects of several antiandrogen therapies for advanced prostate cancer differ substantially. We estimated the cost-effectiveness of antiandrogen therapies for advanced prostate cancer. Methods: We performed a cost-effectiveness analysis using a Markov model based on a formal meta-analysis and literature review. The base case was assumed to be a 65-year-old man with a clinically evident, local recurrence of prostate cancer. The model used a societal perspective and a time horizon of 20 years. Six androgen suppression strategies were evaluated: diethylstilbestrol (DES), orchiectomy, a nonsteroidal antiandrogen (NSAA), a luteinizing hormone-releasing hormone (LHRH) agonist, and combinations of an NSAA with an LHRH agonist or orchiectomy. Outcome measures were survival, quality-adjusted life years (QALYs), lifetime costs, and incremental cost-effectiveness ratios. Results: DES, the least expensive therapy, had a discounted lifetime cost of $3600 and the lowest quality-adjusted survival, 4.6 QALYs. At a cost of $7000, orchiectomy was associated with 5.1 QALYs, resulting in an incremental cost-effectiveness ratio of $7500/QALY relative to DES. All other strategies—LHRH agonists, NSAA, and both combined androgen blockade strategies—had higher costs and lower quality-adjusted survival than orchiectomy. These results were sensitive to the quality of life associated with orchiectomy and the efficacy of combined androgen blockade, and they changed little when prostate-specific antigen results were used to guide therapy. Under a wide range of other assumptions, the cost-effectiveness of orchiectomy relative to DES was consistently less than $20 000/QALY. Androgen suppression therapies were most cost-effective if initiated after patients became symptomatic from prostate metastases. Conclusions: For men who accept it, orchiectomy is likely to be the most cost-effective androgen suppression strategy. Combined androgen blockade is the least economically attractive option, yielding small health benefits at high relative costs.
Impaired Bone Marrow Microenvironment and Immune Function in T Cell Protein Tyrosine Phosphatase–deficient Mice
Authors: Kong E. You-Ten, Eric S. Muise, Annick Itié, Eva Michaliszyn, John Wagner, Serge Jothy, Wayne S. Lapp, Michel L. Tremblay
Journal: The Journal of Experimental Medicine (1997)

The T cell protein tyrosine phosphatase (TC-PTP) is one of the most abundant mammalian tyrosine phosphatases in hematopoietic cells; however, its role in hematopoietic cell function remains unknown. In this report, we investigated the physiological function(s) of TC-PTP by generating TC-PTP–deficient mutant mice. The three genotypes (+/+, +/−, −/−) showed mendelian segregation at birth (1:2:1) demonstrating that the absence of TC-PTP was not lethal in utero, but all homozygous mutant mice died by 3–5 wk of age, displaying runting, splenomegaly, and lymphadenopathy. Homozygous mice exhibited specific defects in bone marrow (BM), B cell lymphopoiesis, and erythropoiesis, as well as impaired T and B cell functions. However, myeloid and macrophage development in the BM and T cell development in the thymus were not significantly affected. BM transplantation experiments showed that hematopoietic failure in TC-PTP −/− animals was not due to a stem cell defect, but rather to a stromal cell deficiency. This study demonstrates that TC-PTP plays a significant role in both hematopoiesis and immune function.
Fall in the prevalence of chronic gastritis over 15 years: analysis of outpatient series in Finland from 1977, 1985, and 1992.
Authors: P Sipponen, T Helske, P Jarvinen, H Hyvarinen, K Seppala, M Siurala
Journal: Gut (1994)

To investigate whether the occurrence of chronic gastritis (and Helicobacter pylori acquisition) has changed in Finland in the past 15 years, the prevalence rates of chronic gastritis in biopsy specimens in consecutive series of outpatients (aged 20 or more) who had undergone diagnostic upper gastrointestinal endoscopy in 1977 (702 patients), 1985 (1309 patients), or 1992 (1447 patients) were compared. The prevalences of gastritis in these series were also compared with that in a random sample (438 subjects) of people who underwent endoscopy in 1974-76. It seemed that the prevalence of gastritis was significantly lower in the outpatients in 1992 than in the random endoscopy sample in 1974-76. The reduction was most noticeable in young age groups (20-49 years) in which the decline was 38% (drop from 66% to 41%). In addition, it seemed that the prevalence of gastritis was very dissimilar in different birth cohorts. The prevalence was high (70-80%) in 1977, 1985, and 1992 in the cohorts born at the beginning of the century and lower (40-50%) in those born during later decades. The prevalence rates had remained unchanged in the same cohorts over the 15 years (from 1977 to 1992) suggesting that the people had mainly been infected with H pylori and contracted gastritis before the age of 20. In conclusion, gastritis is a cohort phenomenon and its prevalence has fallen in Finland in the last 15 years. This decrease is caused by a decline of the rate of H pylori acquisition in birth cohorts, particularly in childhood and adolescence (below age of 20).
The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice.
Authors: R A Seder, W E Paul, M M Davis, B Fazekas de St Groth
Journal: The Journal of Experimental Medicine (1992)

To study the factors that determine whether CD4+ T cells produce interleukin 4 (IL-4) or interferon gamma (IFN-gamma) upon stimulation we used a system allowing naive T cells to be primed in vitro by specific antigen. Dense CD4+ T cells were purified from mice that expressed transgenes encoding a T cell receptor specific for pigeon cytochrome C peptide 88-104 in association with I-Ek. These T cells produced very limited amounts of IL-4 and IFN-gamma upon immediate challenge with 88-104 and antigen-presenting cells (APC). However, after an initial "priming" culture in which they were incubated for 4 d in the presence of 88-104, APC, and 1,000 U/ml IL-4, the T cells acquired the capacity to produce substantial amounts of IL-4 upon rechallenge but made very little IFN-gamma. Cells primed in the absence of IL-4 produced IFN-gamma upon rechallenge but virtually no IL-4. The inhibitory effect of IL-4 on IFN-gamma production did not appear to be mediated by the induction of IL-10 production since IL-10 addition to initial cultures did not suppress priming for IFN-gamma production, nor did anti-IL-10 block the inhibitory effect of IL-4. IFN-gamma itself did not increase priming for IFN-gamma production, nor did anti-IFN-gamma reduce such priming. IFN-gamma did, however, diminish priming for IL-4 production when limiting amounts of IL-4 (100 U/ml) were used in the initial culture. The dominant effect of IL-4 in determining the lymphokine-producing phenotype of primed cells was observed with dendritic cells (DC), activated B cells, and I-Ek-transfected fibroblasts as APC. However, the different APC did vary in their potency, with DC being superior to activated B cells, which were superior to transfected fibroblasts.