tbuckley/cabot-search huggingface dataset:
Statistical analysis of disease onset and lifetime data from tumorigenicity experiments.
Authors: S W Lagakos, L M Ryan
Journal: Environmental Health Perspectives (1985)

We present and discuss several methods for analyzing rodent tumorigenicity experiments. Two approaches are based on the age and tumor status (present/absent) of each animal at the time of death, and assume either that the tumor type is nonlethal or instantly lethal. Two other approaches avoid such restrictive assumptions about tumor lethality by requiring additional types of data. One method assumes that animals are randomly sacrificed at various ages throughout the study. The second approach requires that each animal which develops the tumor be classified as dying either from the tumor or from other causes.
Exogenous administration of heme oxygenase-1 by gene transfer provides protection against hyperoxia-induced lung injury
Authors: Leo E. Otterbein, Jay K. Kolls, Lin L. Mantell, Julia L. Cook, Jawed Alam, Augustine M.K. Choi
Journal: Journal of Clinical Investigation (1999)

Heme oxygenase-1 (HO-1) confers protection against a variety of oxidant-induced cell and tissue injury. In this study, we examined whether exogenous administration of HO-1 by gene transfer could also confer protection. We first demonstrated the feasibility of overexpressing HO-1 in the lung by gene transfer. A fragment of the rat HO-1 cDNA clone containing the entire coding region was cloned into plasmid pAC-CMVpLpA, and recombinant adenoviruses containing the rat HO-1 cDNA fragment Ad5-HO-1 were generated by homologous recombination. Intratracheal administration of Ad5-HO-1 resulted in a time-dependent increase in expression of HO-1 mRNA and protein in the rat lungs. Increased HO-1 protein expression was detected diffusely in the bronchiolar epithelium of rats receiving Ad5-HO-1, as assessed by immunohistochemical studies. We then examined whether ectopic expression of HO-1 could confer protection against hyperoxia-induced lung injury. Rats receiving Ad5-HO-1, but not AdV-βGal, a recombinant adenovirus expressing Escherichia coli β-galactosidase, before exposure to hyperoxia (>99% O2) exhibited marked reduction in lung injury, as assessed by volume of pleural effusion and histological analyses (significant reduction of edema, hemorrhage, and inflammation). In addition, rats receiving Ad5-HO-1 also exhibited increased survivability against hyperoxic stress when compared with rats receiving AdV-βGal. Expression of the antioxidant enzymes manganese superoxide dismutase (Mn-SOD) and copper-zinc superoxide dismutase (CuZn-SOD) and of L-ferritin and H-ferritin was not affected by Ad5-HO-1 administration. Furthermore, rats treated with Ad5-HO-1 exhibited attenuation of hyperoxia-induced neutrophil inflammation and apoptosis. Taken together, these data suggest the feasibility of high-level HO-1 expression in the rat lung by gene delivery. To our knowledge, we have demonstrated for the first time that HO-1 can provide protection against hyperoxia-induced lung injury in vivo by modulation of neutrophil inflammation and lung apoptosis.
Non-Specialist Psychosocial Interventions for Children and Adolescents with Intellectual Disability or Lower-Functioning Autism Spectrum Disorders: A Systematic Review
Authors: Brian Reichow, Chiara Servili, M. Taghi Yasamy, Corrado Barbui, Shekhar Saxena
Journal: PLoS Medicine (2013)

In a systematic review, Brian Reichow and colleagues assess the evidence that non-specialist care providers in community settings can provide effective interventions for children and adolescents with intellectual disabilities or lower-functioning autism spectrum disorders. Please see later in the article for the Editors' Summary
Loss, mutation and deregulation of L3MBTL4 in breast cancers
Authors: Lynda Addou-Klouche, José Adélaïde, Pascal Finetti, Nathalie Cervera, Anthony Ferrari, Ismahane Bekhouche, Fabrice Sircoulomb, Christos Sotiriou, Patrice Viens, Soraya Moulessehoul, François Bertucci, Daniel Birnbaum, Max Chaffanet
Journal: Molecular Cancer (2010)

Abstract Background Many alterations are involved in mammary oncogenesis, including amplifications of oncogenes and losses of tumor suppressor genes (TSG). Losses may affect almost all chromosome arms and many TSGs remain to be identified. Results We studied 307 primary breast tumors and 47 breast cancer cell lines by high resolution array comparative genomic hybridization (aCGH). We identified a region on 18p11.31 lost in about 20% of the tumors and 40% of the cell lines. The minimal common region of loss (Chr18:6,366,938-6,375,929 bp) targeted the L3MBTL4 gene. This gene was also targeted by breakage in one tumor and in two cell lines. We studied the exon sequence of L3MBTL4 in 180 primary tumor samples and 47 cell lines and found six missense and one nonsense heterozygous mutations. Compared with normal breast tissue, L3MBTL4 mRNA expression was downregulated in 73% of the tumors notably in luminal, ERBB2 and normal-like subtypes. Losses of the 18p11 region were associated with low L3MBTL4 expression level. Integrated analysis combining genome and gene expression profiles of the same tumors pointed to 14 other potential 18p TSG candidates. Downregulated expression of ZFP161, PPP4R1 and YES1 was correlated with luminal B molecular subtype. Low ZFP161 gene expression was associated with adverse clinical outcome. Conclusion We have identified L3MBTL4 as a potential TSG of chromosome arm 18p. The gene is targeted by deletion, breakage and mutations and its mRNA is downregulated in breast tumors. Additional 18p TSG candidates might explain the aggressive phenotype associated with the loss of 18p in breast tumors.
Cardiac Transplantation for Giant Sarcoma of the Left Ventricle
Authors: A. Hoffmeier, C. Etz, C. Schmid, V. Debus, H.G. Kehl, M. Ozgun, D. Maintz, T. Spieker, C. Franzius, G. Drees, M. Rothenburger, T.D.T. Tjan, A. Löher, H.H. Scheld
Journal: Circulation (2005)
Medication adherence in COPD: what have we learned?
Authors: M. K Han
Journal: Thorax (2009)

As physicians, we take great interest in the adherence of our patients to prescribed medications. This is based on our belief that the benefits of treatment will be greater in patients who take their medication regularly and less among those who do not. C Everett Koop is quoted as having said: “Drugs don’t work in patients who don’t take them”. The practice of faithfully complying with a medication regimen, however, may be just as important as the efficacy of the medication itself. In this month’s issue of Thorax , Vestbo et al 1 report that, among patients with chronic obstructive pulmonary disease (COPD) participating in the TORCH trial,2 adherers experienced significantly better survival and a lower risk of hospital admission due to exacerbations than non-adherers ( see page 939 ). These effects, however, were independent of treatment group.

In fact, a growing body of literature suggests that adherence to drug therapy in clinical trials—both medication and placebo regimens—predicts better outcomes. Many of these data have been generated from cardiovascular trials.3 In 1980 a report from the Coronary Drug Project significantly challenged traditional scientific thought regarding the relationship between adherence and disease outcomes.4 This randomised double-blind placebo controlled trial examined the effects of clofibrate on the survival of men who had experienced a myocardial infarction.5 Five-year mortality was similar for those …
Induction of gamma/delta T cells in murine salmonellosis by an avirulent but not by a virulent strain of Salmonella choleraesuis.
Authors: M Emoto, H Danbara, Y Yoshikai
Journal: The Journal of Experimental Medicine (1992)

To elucidate the relationship between the virulence of intracellular bacterium and its ability to induce gamma/delta T cells in the host during infection, we examined the differences in appearance of gamma/delta T cells in mice infected with Salmonella choleraesuis virulent strain RF-1 carrying a virulence plasmid of 50 kb, and with avirulent strain 31N-1 cured of the 50-kb plasmid. The number of gamma/delta T cells in the peritoneal cavity was increased to a significant level on day 3 after an intraperitoneal infection with a sublethal dose (5 x 10(4) colony-forming units) of avirulent strain 31N-1. On the other hand, no increase in the number of gamma/delta T cells was evident in the peritoneal cavity at any stage after infections with various doses of virulent strain RF-1, although the numbers of the bacteria were drastically increased. Similar to that seen in the peritoneal cavity, the number of gamma/delta T cells in the liver was significantly increased after an intraperitoneal infection with avirulent strain 31N-1 but not with virulent strain RF-1. The early appearing gamma/delta T cells during salmonellosis with avirulent stain 31N-1, which preferentially used V gamma 1/V delta 6, showed blastogenesis in response to purified protein derivative (PPD) derived from Mycobacterium tuberculosis. The gamma/delta T cells also responded to the peritoneal adherent cells in mice infected with avirulent strain 31N-1 6 d previously, which expressed a high level of endogenous heat-shock protein (hsp) homologous to the mycobacterial 65-kD hsp. The expression of the hsp, however, was not prominent in the adherent cells in mice infected with virulent strain RF-1. These results suggest that the gamma/delta T cells specific for PPD may play important roles in host defense against murine salmonellosis, and that the virulence of Salmonella may be inversely correlated with its ability to induce endogenous hsp in the infected macrophages, which in turn stimulate the gamma/delta T cells in the host during salmonellosis.
Personally measured weekly exposure to NO2 and respiratory health among preschool children
Authors: K. Mukala, J. Pekkanen, P. Tiittanen, S Alm, R.O. Salonen, J. Tuomisto
Journal: European Respiratory Journal (1999)

Nitrogen dioxide is known as a deep lung irritant. The aim of this study was to find out whether the relatively low ambient air NO2 concentrations in the northern city of Helsinki had an impact on the respiratory health of children. The association between personal exposure to ambient air NO2 and respiratory health was investigated in a 13-week follow-up study among 163 preschool children aged 3-6 yrs. Personal weekly average exposure to NO2 was measured by passive diffusion samplers attached to the outer garments. Symptoms were recorded daily in a diary by the parents. Among 53 children, peak expiratory flow (PEF) was measured at home in the mornings and evenings. The association between NO2 exposure and respiratory symptoms was examined with Poisson regression. The median personal NO2 exposure was 21.1 microg x m(-3) (range 4-99 microg x m(-3)). An increased risk of cough was associated with increasing NO2 exposure (risk ratio = 1.52; 95% confidence interval 1.00-2.31). There was no such association between personal weekly NO2 exposure and nasal symptoms, but a nonsignificant negative association was found between the exposure and the weekly average deviation in PEF. In conclusion, even low ambient air NO2 concentrations can increase the risk of respiratory symptoms among preschool children.
Epigenetic Roles of MLL Oncoproteins Are Dependent on NF-κB
Authors: Hsu-Ping Kuo, Zhong Wang, Dung-Fang Lee, Masayuki Iwasaki, Jesus Duque-Afonso, Stephen H.K. Wong, Chiou-Hong Lin, Maria E. Figueroa, Jie Su, Ihor R. Lemischka, Michael L. Cleary
Journal: Cancer Cell (2013)
Trials in Neuropathic Diabetic Foot Ulceration
Authors: Andrew J. M. Boulton, David G. Armstrong
Journal: Diabetes Care (2003)

Diabetic foot ulceration is a serious and expensive complication with considerable morbidity that affects up to 15% of diabetic patients during their lifetime; moreover, ∼80% of amputations are preceded by foot ulcers (1). Despite these facts, Mason et al. (2) concluded in their systematic review of treatments for foot lesions that the evidence base for treatments is poor. Furthermore, they criticized the majority of published trials of potentially promising treatments for neuropathic ulcers as being small, inadequately powered, and failing to use standardized methods and outcomes.

It is therefore refreshing to read the work of Kalani et al. (3) in this issue of Diabetes Care . In a well-designed controlled trial, patients with neuroischemic ulcers were randomized to receive daily subcutaneous low-molecular weight heparin (LMWH) or placebo. Those randomized to LMWH had significantly better outcomes with respect to healing rates and amputation. There are also potentially exciting new treatments for ischemic limbs in diabetes (4,5). Therapeutic …
Highly Dynamic Exon Shuffling in Candidate Pathogen Receptors ... What if Brown Algae Were Capable of Adaptive Immunity?
Authors: A. Zambounis, M. Elias, L. Sterck, F. Maumus, C. M. M. Gachon
Journal: Molecular Biology and Evolution (2011)

Pathogen recognition is the first step of immune reactions. In animals and plants, direct or indirect pathogen recognition is often mediated by a wealth of fast-evolving receptors, many of which contain ligand-binding and signal transduction domains, such as leucine-rich or tetratricopeptide repeat (LRR/TPR) and NB-ARC domains, respectively. In order to identify candidates potentially involved in algal defense, we mined the genome of the brown alga Ectocarpus siliculosus for homologues of these genes and assessed the evolutionary pressures acting upon them. We thus annotated all Ectocarpus LRR-containing genes, in particular an original group of LRR-containing GTPases of the ROCO family, and 24 NB-ARC–TPR proteins. They exhibit high birth and death rates, while a diversifying selection is acting on their LRR (respectively TPR) domain, probably affecting the ligand-binding specificities. Remarkably, each repeat is encoded by an exon, and the intense exon shuffling underpins the variability of LRR and TPR domains. We conclude that the Ectocarpus ROCO and NB-ARC–TPR families are excellent candidates for being involved in recognition/transduction events linked to immunity. We further hypothesize that brown algae may generate their immune repertoire via controlled somatic recombination, so far only known from the vertebrate adaptive immune systems.
CSPG4 as a Target of Antibody-Based Immunotherapy for Malignant Mesothelioma
Authors: Zeyana Rivera, Soldano Ferrone, Xinhui Wang, Sandro Jube, Haining Yang, Harvey I. Pass, Shreya Kanodia, Giovanni Gaudino, Michele Carbone
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Malignant mesothelioma (MM) is an aggressive cancer, resistant to current therapies. Membrane chondroitin sulphate proteoglycan 4 (CSPG4), which has been successfully targeted in melanoma and breast cancer, was found highly expressed in MM, but not in normal mesothelium. Therefore, we explored CSPG4 as a suitable target for monoclonal antibody (mAb)–based immunotherapy for MM. Experimental design: We assayed adhesion, motility, invasiveness, wound-healing, apoptosis, and anchorage-independent growth of MM cells on cell cultures. CSPG4 expression and signaling was studied by immunoblotting. The growth of MM severe combined immunodeficient (SCID) mice xenografts induced by PPM-Mill cells, engineered to express the luciferase reporter gene, was monitored by imaging, upon treatment with CSPG4 mAb TP41.2. Animal toxicity and survival were assayed in both tumor inhibition and therapeutic experiments. Results: CSPG4 was expressed on 6 out of 8 MM cell lines and in 25 out of 41 MM biopsies, with minimal expression in surrounding healthy cells. MM cell adhesion was mediated by CSPG4-dependent engagement of ECM. Cell adhesion was inhibited by mAb TP41.2 resulting in decreased phosphorylation of focal adhesion kinase (FAK) and AKT, reduced expression of cyclin D1 and apoptosis. Moreover, mAb TP41.2 significantly reduced MM cell motility, migration, and invasiveness, and inhibited MM growth in soft agar. In vivo, treatment with mAb TP41.2 prevented or inhibited the growth of MM xenografts in SCID mice, with a significant increase in animal survival. Conclusion: These results establish the safety of CSPG4 mAb-based immunotherapy and suggest that CSPG4 mAb-based immunotherapy may represent a novel approach for the treatment of MM. Clin Cancer Res; 18(19); 5352–63. ©2012 AACR.
Evidence for Diet Effects on the Composition of Silk Proteins Produced by Spiders
Authors: Catherine L. Craig, Christian Riekel, Marie E. Herberstein, Robert S. Weber, David Kaplan, Naomi E. Pierce
Journal: Molecular Biology and Evolution (2000)

Silks are highly expressed, secreted proteins that represent a substantial metabolic cost to the insects and spiders that produce them. Female spiders in the superfamily Araneoidea (the orb-spinning spiders and their close relatives) spin six different kinds of silk (three fibroins and three fibrous protein glues) that differ in amino acid content and protein structure. In addition to this diversity in silks produced by different glands, we found that individual spiders of the same species can spin dragline silks (drawn from the spider's ampullate gland) that vary in content as well. Freely foraging Argiope argentata (Araneae: Araneoidea), collected from 13 Caribbean islands, produced dragline silk that showed an inverse relationship between the amount of serine and glycine they contained. X-ray microdiffraction of the silks localized these differences to the amorphous regions of the protein that are thought to lend silks their elasticity. The crystalline regions of the proteins, which lend silks their strength, were unaffected. Laboratory experiments with Argiope keyserlingi suggested that variation in silk composition reflects the type of prey the spiders were fed but not the total amount of prey they received. Hence, it may be that the amino acid content (and perhaps the mechanical properties) of dragline silk spun by Argiope directly reflect the spiders' diet. The ability to vary silk composition and, possibly, function is particularly important for organisms that disperse broadly, such as Argiope, and that occupy diverse habitats with diverse populations of prey.
Association of Parental Heart Failure with Risk of Heart Failure in Offspring
Authors: Douglas S. Lee, Michael J. Pencina, Emelia J. Benjamin, Thomas J. Wang, Daniel Levy, Christopher J. O'Donnell, Byung-Ho Nam, Martin G. Larson, Ralph B. D'Agostino, Ramachandran S. Vasan
Journal: New England Journal of Medicine (2006)

The association between heart failure in parents and the prevalence of left ventricular systolic dysfunction and the risk of heart failure in their offspring has not been investigated in a community-based setting.We examined the cross-sectional association of heart failure in parents with the prevalence of left ventricular systolic dysfunction, as well as left ventricular mass, internal dimensions, and wall thickness, in 1497 participants of the Framingham Offspring Study (mean age, 57 years; 819 women) who underwent routine echocardiography. We also investigated prospectively whether heart failure in parents increased the risk of heart failure in 2214 offspring (mean age, 44 years; 1150 women).As compared with the 1039 participants whose parents did not have heart failure, the 458 participants in the cross-sectional cohort who had at least one parent with heart failure were more likely to have increased left ventricular mass (17.0 percent vs. 26.9 percent), left ventricular internal dimensions (18.6 percent vs. 23.4 percent), and left ventricular systolic dysfunction (3.1 percent vs. 5.7 percent); the multivariable-adjusted odds ratios were 1.35 (95 percent confidence interval, 0.99 to 1.84), 1.29 (95 percent confidence interval, 0.96 to 1.72), and 2.37 (95 percent confidence interval, 1.22 to 4.61), respectively. In the longitudinal cohort, heart failure developed in 90 offspring during follow-up (mean length of follow-up, 20 years). The age- and sex-adjusted 10-year incidence rates of heart failure were 2.72 percent among offspring with a parent with heart failure, as compared with 1.62 percent among those without a parent with heart failure. This increase in risk persisted after multivariable adjustment (hazard ratio, 1.70; 95 percent confidence interval, 1.11 to 2.60).Heart failure in parents is associated with an increased prevalence of left ventricular systolic dysfunction cross-sectionally and an elevated risk of heart failure longitudinally. Our data emphasize the contribution of familial factors to the heart-failure burden in the community.
The Asp <sub>9</sub> Asn Mutation in the Lipoprotein Lipase Gene Is Associated With Increased Progression of Coronary Atherosclerosis
Authors: J. Wouter Jukema, Ad J. van Boven, Bjo¨rn Groenemeijer, Aeilko H. Zwinderman, Johan H.C. Reiber, Albert V.G. Bruschke, J.A. Henneman, G.P. Molhoek, T. Bruin, H. Jansen, Eric Gagne´, Michael R. Hayden, John J.P. Kastelein
Journal: Circulation (1996)

Background Many patients suffering from premature coronary artery disease report a family history for such events. A mutation in a particular gene, which confers susceptibility for atherosclerosis, will be found more frequently in individuals suffering from coronary atherosclerosis than in the general population. We have recently reported the identification of an Asp 9 Asn substitution in the lipoprotein lipase (LPL) enzyme. We analyzed the impact of this mutation on the progression of coronary atherosclerosis and the effect of pravastatin in both carriers and noncarriers. Methods and Results All patients were enrolled in the quantitative coronary angiographic clinical trial REGRESS, which studied the impact of pravastatin therapy on coronary atherosclerosis. The Asp 9 Asn mutation was identified in 38 of 819 (4.8%) patients. Carriers of the mutation more often had a positive family history of cardiovascular disease and lower HDL cholesterol levels than noncarriers. In the placebo group, carriers showed more progression of coronary atherosclerosis than noncarriers: mean reduction of the minimum obstruction diameter of −0.25 mm versus −0.12 mm ( P =.029) and increase of percentage diameter stenosis of 6.4% versus 1.4% ( P =.004). Moreover, the adjusted relative risk for a clinical event for carriers was calculated at 2.16 (95% CI, 1.09 to 4.29; P =.027). Although the lipid-lowering effect of pravastatin was attenuated in carriers, it appeared that these patients showed a response similar to noncarriers in terms of less progression of atherosclerosis and event-free survival. Conclusions This study shows that heterozygosity for a mutation in the LPL gene, which causes only subtle changes in fasting plasma lipids, may promote the progression of coronary atherosclerosis and diminish clinical event–free survival.