tbuckley/cabot-search huggingface dataset:
RE: A Model Too Far
Authors: R. Etzioni, R. Gulati
Journal: JNCI Journal of the National Cancer Institute (2014)

Freidlin and Korn’s editorial (1) concerning our article on prostate cancer overdiagnosis questioned the utility of our personalized overdiagnosis estimates for informing treatment decision making. Their comments suggest that knowing the risk of overdiagnosis does not help to inform about the outcomes of various treatment options after diagnosis. However, overdiagnosis informs about the outcome of a key treatment option—that of no treatment. Consider the dilemma faced by a patient who has just been diagnosed with prostate cancer after a screening test. Knowing that treatment can reduce the risk of dying from cancer but the treatment could leave him impotent or incontinent, should he be treated or not? The value of our results is that they inform the patient about what might happen if his cancer were to be left untreated. Thus, for a 50-year-old man with a biopsy Gleason score of 7 and a prostate-specific antigen of 4.5ng/mL, there is a high risk (risk of 9 of 10) that he will have to deal with a symptomatic tumor at some point in his life if he does not treat his cancer, whereas for an 80-year-old man with a Gleason score 6 and a prostate-specific antigen of 5ng/mL, this risk is much lower, approximately one in five. For this older patient, if he does absolutely nothing at this point, there is an 80% chance that his cancer will never cause symptoms or problems. This kind of information could be very helpful in persuading many older, low-risk patients to consider active surveillance, which is likely to be the single most important change in clinical practice to reduce the problem of overtreatment.

Freidlin and Korn also critique our modeling approach, stating that “the most reliable and transparent approach to estimating overdiagnosis … is with an appropriate analysis of data from a randomized screening trial” (1). However they do not tell us what an “appropriate analysis” might be. Conventional statistical analysis runs into problems when attempting to infer overdiagnosis frequencies from trials because whether a case has been overdiagnosed is not observable. There have been attempts to use observed excess incidence in the screened arm as a proxy for overdiagnosis, but this approach, because it typically produces inflated estimates (2), particularly under insufficient follow-up, which is a limitation of all published prostate screening trials. A modeling approach goes beneath the surface of empirical data and can be applied to trials as well as to population incidence data. This approach has a long history in the biostatistics literature [eg, (3,4)]. In general, we support a healthy and constructive skepticism of models. Yet, in this this situation, only a model can provide personalized estimates of the chance that a screen-detected prostate cancer has been overdiagnosed, and the resulting nomogram adds materially to the information currently available for patients considering the option of no treatment.
Human eosinophil major basic protein is an endogenous allosteric antagonist at the inhibitory muscarinic M2 receptor.
Authors: D B Jacoby, G J Gleich, A D Fryer
Journal: Journal of Clinical Investigation (1993)

The effect of human eosinophil major basic protein (MBP) as well as other eosinophil proteins, on binding of [3H]N-methyl-scopolamine ([3H]NMS: 1 x 10(-10) M) to muscarinic M2 receptors in heart membranes and M3 receptors in submandibular gland membranes was studied. MBP inhibited specific binding of [3H]NMS to M2 receptors but not to M3 receptors. MBP also inhibited atropine-induced dissociation of [3H]NMS-receptor complexes in a dose-dependent fashion, demonstrating that the interaction of MBP with the M2 muscarinic receptor is allosteric. This effect of MBP suggests that it may function as an endogenous allosteric inhibitor of agonist binding to the M2 muscarinic receptor. Inhibition of [3H]NMS binding by MBP was reversible by treatment with heparin, which binds and neutralizes MBP. Eosinophil peroxidase (EPO) also inhibited specific binding of [3H]NMS to M2 receptors but not to M3 receptors and inhibited atropine-induced dissociation of [3H]NMS-receptor complexes. On a molar basis, EPO is less potent than MBP. Neither eosinophil cationic protein nor eosinophil-derived neurotoxin affected binding of [3H]NMS to M2 receptors. Thus both MBP and EPO are selective allosteric antagonists at M2 receptors. The effects of these proteins may be important causes of M2 receptor dysfunction and enhanced vagally mediated bronchoconstriction in asthma.
Response to Letter Regarding Article, “Risk of Thromboembolism in Heart Failure: An Analysis from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)”
Authors: Ronald S. Freudenberger, Anne S. Hellkamp, Daniel B. Mark, Kerry L. Lee, Jonathan L. Halperin, Jeanne Poole, Jill Anderson, George Johnson, Gust H. Bardy
Journal: Circulation (2008)
Scotland's Health and Health Services
Authors: B. Christie
Journal: BMJ (2003)

There is something going on in Scotland that is almost unique in the developed world. It has nothing to do with misty glens, fiery alcoholic drinks, or skirling pipe music. It has to do with population decline. In 2001 there were 5000 more deaths in Scotland than there were births. The population peaked in the mid-1970s and has been declining slowly ever since.

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Eds Kevin Woods, David Carter 

The Nuffield Trust, £28.50, pp 328

ISBN 0117032417

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By 2021 there will be 20% fewer teenagers and 25% more people aged over 60. This is …

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CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies
Authors: Holbrook E. Kohrt, Roch Houot, Matthew J. Goldstein, Kipp Weiskopf, Ash A. Alizadeh, Josh Brody, Antonia Müller, Russell Pachynski, Debra Czerwinski, Steven Coutre, Mark P. Chao, Lieping Chen, Thomas F. Tedder, Ronald Levy
Journal: Blood (2010)
Efficacy of Intravitreal Bevacizumab for Stage 3+ Retinopathy of Prematurity
Authors: Helen A. Mintz-Hittner, Kathleen A. Kennedy, Alice Z. Chuang
Journal: New England Journal of Medicine (2011)

Retinopathy of prematurity is a leading cause of childhood blindness worldwide. Peripheral retinal ablation with conventional (confluent) laser therapy is destructive, causes complications, and does not prevent all vision loss, especially in cases of retinopathy of prematurity affecting zone I of the eye. Case series in which patients were treated with vascular endothelial growth factor inhibitors suggest that these agents may be useful in treating retinopathy of prematurity.We conducted a prospective, controlled, randomized, stratified, multicenter trial to assess intravitreal bevacizumab monotherapy for zone I or zone II posterior stage 3+ (i.e., stage 3 with plus disease) retinopathy of prematurity. Infants were randomly assigned to receive intravitreal bevacizumab (0.625 mg in 0.025 ml of solution) or conventional laser therapy, bilaterally. The primary ocular outcome was recurrence of retinopathy of prematurity in one or both eyes requiring retreatment before 54 weeks' postmenstrual age.We enrolled 150 infants (total sample of 300 eyes); 143 infants survived to 54 weeks' postmenstrual age, and the 7 infants who died were not included in the primary-outcome analyses. Retinopathy of prematurity recurred in 4 infants in the bevacizumab group (6 of 140 eyes [4%]) and 19 infants in the laser-therapy group (32 of 146 eyes [22%], P=0.002). A significant treatment effect was found for zone I retinopathy of prematurity (P=0.003) but not for zone II disease (P=0.27).Intravitreal bevacizumab monotherapy, as compared with conventional laser therapy, in infants with stage 3+ retinopathy of prematurity showed a significant benefit for zone I but not zone II disease. Development of peripheral retinal vessels continued after treatment with intravitreal bevacizumab, but conventional laser therapy led to permanent destruction of the peripheral retina. This trial was too small to assess safety. (Funded by Research to Prevent Blindness and others; ClinicalTrials.gov number, NCT00622726.).
Mechanochemistry of Cardiac Muscle
Authors: PETER E. POOL, BRIAN M. CHANDLER, JAMES F. SPANN, EDMUND H. SONNENBLICK, EUGENE BRAUNWALD
Journal: Circulation Research (1969)

This investigation was designed to determine whether a defect in energy utilization exists in heart failure. Accordingly, the direct conversion of chemical energy to mechanical work was studied in right ventricular papillary muscles from normal cats and cats with experimental right ventricular failure secondary to pulmonary artery constriction. Energy production was inhibited by iodoacetic acid and N 2 . After resting or performing variable amounts of internal contractile element work under isometric conditions, muscles were instantly frozen, and the total amount of chemical energy (∼ P = creatine phosphate + ATP) used was correlated with work performed and the number of contractions. The contractile properties of papillary muscles from cats with heart failure were severely depressed. There was a significant depression in initial ∼P stores in muscles from cats with heart failure, but there was no significant change in the resting rate of ∼P utilization. Although the muscles from cats with heart failure performed, on the average, 13% as much work and were activated 64% as many times, the average amount of energy used was only 7% of that used by normal muscles. It is concluded that in this form of experimentally produced heart failure the utilization of ∼P is reduced but only in relation to the reduction in contractile element work and that the direct conversion of chemical energy to mechanical work is not an inefficient process in this state.
Allium Vegetables and Reduced Risk of Stomach Cancer
Authors: W.-C. You, W. J. Blot, Y.-S. Chang, A. Ershow, Z. T. Yang, Q. An, B. E. Henderson, J. F. Fraumeni, T.-G. Wang
Journal: JNCI Journal of the National Cancer Institute (1989)

Interviews with 564 patients with stomach cancer and 1,131 controls in an area of China where gastric cancer rates are high revealed a significant reduction in gastric cancer risk with increasing consumption of allium vegetables. Pearsons in the highest quartile of intake experienced only 40% of the risk of those in the lowest. Protective effects were seen for garlic, onions, and other allim foods. Although additional research is needed before etiologic inferences can be made, the findings are consistent with recent reports of tumor inhibition following administration of allium compounds in experimental animals.
Evolution of RPS4Y
Authors: A. W. Bergen, M. Pratt, P. T. Mehlman, D. Goldman
Journal: Molecular Biology and Evolution (1998)

Sequence variation within RPS4Y, a ribosomal protein gene located in the nonpseudoautosomal region of the Y chromosome, was used to elucidate the origin of this gene in primates. Complete coding and additional flanking sequences (949 bp) of the RPS4Y locus were determined in four nonhuman primate species. Phylogenetic reconstruction of RPS4 sequence evolution supports the monophyly of mammalian RPS4 and RPS4Y. Molecular evolutionary rate estimation reveals significantly elevated rates of DNA and protein evolution in RPS4Y compared with its X-chromosome homologs. These rates enable us to estimate the timing of the transposition of RPS4X to the Y chromosome (95% confidence interval, 32 MYA-74 MYA), and this estimate was verified by Southern hybridization analysis of prosimian and simian genomic DNA. These data support a transposition event of ancestral primate RPS4X to the Y chromosome prior to the divergence of Prosimii.
Toll-Like Receptors Are Part of the Innate Immune Defense System of Sponges (Demospongiae: Porifera)
Authors: M. Wiens, M. Korzhev, S. Perovic-Ottstadt, B. Luthringer, D. Brandt, S. Klein, W. E. G. Muller
Journal: Molecular Biology and Evolution (2006)

During evolution and with the emergence of multicellular animals, the need arose to ward off foreign organisms that threaten the integrity of the animal body. Among many different receptors that participate in the recognition of microbial invaders, toll-like receptors (TLRs) play an essential role in mediating the innate immune response. After binding distinct microbial components, TLRs activate intracellular signaling cascades that result in an induced expression of diverse antimicrobial molecules. Because sponges (phylum Porifera) are filter feeders, they are abundantly exposed to microorganisms that represent a potential threat. Here, we describe the identification, cloning, and deduced protein sequence from 3 major elements of the poriferan innate response (to bacterial lipopeptides): the TLR, the IL-1 receptor–associated kinase-4–like protein (IRAK-4l), and a novel effector caspase from the demosponge Suberites domuncula. Each molecule shares significant sequence similarity with its homologues in higher Metazoa. Sequence homologies were found in particular within the family-specific domains toll/interleukin-1 receptor/resistance (TLR family), Ser/Thr/Tyr kinase domain (IRAK family), and CASc (caspase family). In addition, in situ hybridization and immunohistological analyses revealed an abundance of SDTLR (TLR) transcripts in epithelial layers of the sponge surface (exopinacoderm and endopinacoderm). Furthermore, it is shown that both SDTLR and SDIRAK-4 like (IRAK) are expressed constitutively, regardless of treatment with synthetic triacyl lipopeptide Pam3Cys-Ser-(Lys)4. In contrast, SDCASL (caspase) expression is highly Pam3Cys-Ser-(Lys)4 inducible. However, blocking of the lipopeptide with recombinant TLR prior to its application completely prevented the induced expression of this poriferan caspase. These results underscore that the phylogenetically oldest extant metazoan phylum is provided already with the signaling pathways of the antimicrobial host-defense system of Metazoa.
Epidemiology of sleep apnoea/hypopnoea syndrome and sleep-disordered breathing
Authors: P. Jennum, R. L. Riha
Journal: European Respiratory Journal (2009)

Epidemiological studies have revealed a high prevalence of sleep-disordered breathing in the community (up to 20%). A subset of these patients has concurrent symptoms of excessive daytime sleepiness attributable to their nocturnal breathing disorder and is classified as having obstructive sleep apnoea/hypopnoea syndrome (4–5% of the middle-aged population). There is strong evidence for an association of sleep apnoea with cardiovascular and cerebrovascular morbidity, as well as adverse public health consequences. Treatment and diagnosis have remained largely unchanged over the past 25 yrs. In moderate-to-severe obstructive sleep apnoea/hypopnoea syndrome, treatment with continuous positive airway pressure has been shown to be effective. Questions remain as to how to screen patients with sleep-disordered breathing. Should time-consuming diagnostic procedures with high sensitivity and specificity be employed, or should simpler methods be applied for screening populations at risk, e.g. in the primary care sector?
Fibroblast Growth Factor 2 and Estrogen Control the Balance of Histone 3 Modifications Targeting MAGE-A3 in Pituitary Neoplasia
Authors: Xuegong Zhu, Sylvia L. Asa, Shereen Ezzat
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Four members of the fibroblast growth factor receptor (FGFR) family transduce signals of a diverse group of FGF ligands. The FGFR2-IIIb isoform is abundantly present in the normal pituitary gland with contrasting down-regulation in neoplastic pituitary cells. cDNA profiling identified the cancer-testis antigen melanoma-associated antigen A3 (MAGE-A3) as a putative target negatively regulated by FGFR2. Experimental Design: Comparisons were made between normal and neoplastic human and mouse pituitary cells. Gene expression was examined by reverse transcription-PCR, DNA methylation was determined by methylation-specific PCR and combined bisulfite restriction analysis, and histone modification marks were identified by chromatin immunoprecipitation. Results: Normal human pituitary tissue that expresses FGFR2-IIIb does not express MAGE-A3; in contrast, pituitary tumors that are FGFR2 negative show abundant MAGE-A3 mRNA expression. MAGE-A3 expression correlates with the presence and extent of DNA promoter methylation; more frequent and higher-degree methylation is present in the normal gland compared with pituitary tumors. Conversely, pituitary tumors are hypomethylated, particularly in females where MAGE-A3 expression is nearly thrice higher than in males. Estradiol treatment induces MAGE-A3 through enhanced histone 3 acetylation and diminished methylation. The effects of estradiol are directly opposed by FGF7/FGFR2-IIIb. Down-regulation of MAGE-A3 results in p53 transcriptional induction, also through reciprocal histone acetylation and methylation modifications. Conclusions: These findings highlight MAGE-A3 as a target of FGFR2-IIIb and estrogen action and provide evidence for a common histone-modifying network in the control of the balance between opposing signals.
Rapid diagnosis of FHL3 by flow cytometric detection of intraplatelet Munc13-4 protein
Authors: Yuuki Murata, Takahiro Yasumi, Ryutaro Shirakawa, Kazushi Izawa, Hidemasa Sakai, Junya Abe, Naoko Tanaka, Tomoki Kawai, Koichi Oshima, Megumu Saito, Ryuta Nishikomori, Osamu Ohara, Eiichi Ishii, Tatsutoshi Nakahata, Hisanori Horiuchi, Toshio Heike
Journal: Blood (2011)
WEE1 Inhibition Alleviates Resistance to Immune Attack of Tumor Cells Undergoing Epithelial–Mesenchymal Transition
Authors: Duane H. Hamilton, Bruce Huang, Romaine I. Fernando, Kwong-Yok Tsang, Claudia Palena
Journal: Cancer Research (2014)

Aberrant expression of the T-box transcription factor brachyury in human carcinomas drives the phenomenon of epithelial-mesenchymal transition (EMT), a phenotypic modulation that facilitates tumor dissemination and resistance to conventional therapies, including chemotherapy and radiotherapy. By generating isogenic cancer cell lines with various levels of brachyury expression, we demonstrate that high levels of brachyury also significantly reduce the susceptibility of cancer cells to lysis by both antigen-specific T cells and natural killer cells. Our results indicated that resistance of brachyury-high tumor cells to immune-mediated attack was due to inefficient caspase-dependent apoptosis, manifested as inefficient nuclear lamin degradation in the presence of activated effector caspases. We correlated this phenomenon with loss of cell-cycle-dependent kinase 1 (CDK1), which mediates lamin phosphorylation. In support of a causal connection, pretreatment of tumor cells with a specific inhibitor of WEE1, a negative regulator kinase of CDK1, could counter the defective apoptosis of tumor cells expressing high levels of brachyury. Thus, our findings suggested that reconstituting CDK1 activity to threshold levels may be sufficient to restore immunosurveillance of mesenchymal-like cancer cells that have escaped previous immune detection or eradication.
Association Between Maternal Use of Folic Acid Supplements and Risk of Autism Spectrum Disorders in Children
Authors: Pål Surén, Christine Roth, Michaeline Bresnahan, Margaretha Haugen, Mady Hornig, Deborah Hirtz, Kari Kveim Lie, W. Ian Lipkin, Per Magnus, Ted Reichborn-Kjennerud, Synnve Schjølberg, George Davey Smith, Anne-Siri Øyen, Ezra Susser, Camilla Stoltenberg
Journal: JAMA (2013)

Prenatal folic acid supplements reduce the risk of neural tube defects in children, but it has not been determined whether they protect against other neurodevelopmental disorders.To examine the association between maternal use of prenatal folic acid supplements and subsequent risk of autism spectrum disorders (ASDs) (autistic disorder, Asperger syndrome, pervasive developmental disorder-not otherwise specified [PDD-NOS]) in children.The study sample of 85,176 children was derived from the population-based, prospective Norwegian Mother and Child Cohort Study (MoBa). The children were born in 2002-2008; by the end of follow-up on March 31, 2012, the age range was 3.3 through 10.2 years (mean, 6.4 years). The exposure of primary interest was use of folic acid from 4 weeks before to 8 weeks after the start of pregnancy, defined as the first day of the last menstrual period before conception. Relative risks of ASDs were estimated by odds ratios (ORs) with 95% CIs in a logistic regression analysis. Analyses were adjusted for maternal education level, year of birth, and parity.Specialist-confirmed diagnosis of ASDs.At the end of follow-up, 270 children in the study sample had been diagnosed with ASDs: 114 with autistic disorder, 56 with Asperger syndrome, and 100 with PDD-NOS. In children whose mothers took folic acid, 0.10% (64/61,042) had autistic disorder, compared with 0.21% (50/24,134) in those unexposed to folic acid. The adjusted OR for autistic disorder in children of folic acid users was 0.61 (95% CI, 0.41-0.90). No association was found with Asperger syndrome or PDD-NOS, but power was limited. Similar analyses for prenatal fish oil supplements showed no such association with autistic disorder, even though fish oil use was associated with the same maternal characteristics as folic acid use.Use of prenatal folic acid supplements around the time of conception was associated with a lower risk of autistic disorder in the MoBa cohort. Although these findings cannot establish causality, they do support prenatal folic acid supplementation.
A mutation in the α tropomyosin gene TPM3 associated with autosomal dominant nemaline myopathy
Authors: Nigel G. Laing, Stephen D. Wilton, Patrick A. Akkari, Shellie Dorosz, Karyn Boundy, Chris Kneebone, Peter Blumbergs, Sue White, Hugh Watkins, Donald R. Love, Eric Haan
Journal: Nature Genetics (1995)
Follow-Up Study of Adolescents Exposed to Di(2-Ethylhexyl) Phthalate (DEHP) as Neonates on Extracorporeal Membrane Oxygenation (ECMO) Support
Authors: Khodayar Rais-Bahrami, Susan Nunez, Mary E. Revenis, Naomi L.C. Luban, Billie L. Short
Journal: Environmental Health Perspectives (2004)

Di(2-ethylhexyl) phthalate (DEHP) is used to make polyvinyl chloride (PVC) plastic tubing soft and flexible. Animal data show that adverse effects of DEHP exposure may include reduced fertility, reduced sperm production in males, and ovarian dysfunction in females. Known treatments that involve high DEHP exposures are blood exchange transfusions, extracorporeal membrane oxygenation (ECMO), and cardiovascular surgery. Although potential exposure to DEHP in ECMO patients is significant, the exposure has not been associated with short-term toxicity. To evaluate long-term toxicity, we undertook a study of neonatal ECMO survivors to assess their onset of puberty and sexual maturity. We evaluated 13 male and 6 female subjects at 14-16 years of age who had undergone ECMO as neonates. All subjects had a complete physical examination including measurements for height, weight, head circumference, and pubertal assessment by Tanner staging. The testicular volume and the phallic length were measured in male participants. Laboratory tests included thyroid, liver, and renal function as well as measurements of luteinizing hormone, follicle-stimulating hormone, testosterone for males, and estradiol for females. Except for one patient with Marfan syndrome, the rest had normal growth percentile for age and sex. All had normal values for thyroid, liver, and renal functions. Sexual hormones were appropriate for the stage of pubertal maturity. Our results indicate that adolescents exposed to significant quantities of DEHP as neonates showed no significant adverse effects on their physical growth and pubertal maturity. Thyroid, liver, renal, and male and female gonadal functions tested were within normal range for age and sex distribution. Key Words: DEHP, ECMO, toxicity.