tbuckley/cabot-search huggingface dataset:
Impact of smoking and smoking cessation on cardiovascular events and mortality among older adults: meta-analysis of individual participant data from prospective cohort studies of the CHANCES consortium
Authors: U. Mons, A. Muezzinler, C. Gellert, B. Schottker, C. C. Abnet, M. Bobak, L. de Groot, N. D. Freedman, E. Jansen, F. Kee, D. Kromhout, K. Kuulasmaa, T. Laatikainen, M. G. O'Doherty, B. Bueno-de-Mesquita, P. Orfanos, A. Peters, Y. T. van der Schouw, T. Wilsgaard, A. Wolk, A. Trichopoulou, P. Boffetta, H. Brenner
Journal: BMJ (2015)

To investigate the impact of smoking and smoking cessation on cardiovascular mortality, acute coronary events, and stroke events in people aged 60 and older, and to calculate and report risk advancement periods for cardiovascular mortality in addition to traditional epidemiological relative risk measures.Individual participant meta-analysis using data from 25 cohorts participating in the CHANCES consortium. Data were harmonised, analysed separately employing Cox proportional hazard regression models, and combined by meta-analysis.Overall, 503,905 participants aged 60 and older were included in this study, of whom 37,952 died from cardiovascular disease. Random effects meta-analysis of the association of smoking status with cardiovascular mortality yielded a summary hazard ratio of 2.07 (95% CI 1.82 to 2.36) for current smokers and 1.37 (1.25 to 1.49) for former smokers compared with never smokers. Corresponding summary estimates for risk advancement periods were 5.50 years (4.25 to 6.75) for current smokers and 2.16 years (1.38 to 2.39) for former smokers. The excess risk in smokers increased with cigarette consumption in a dose-response manner, and decreased continuously with time since smoking cessation in former smokers. Relative risk estimates for acute coronary events and for stroke events were somewhat lower than for cardiovascular mortality, but patterns were similar.Our study corroborates and expands evidence from previous studies in showing that smoking is a strong independent risk factor of cardiovascular events and mortality even at older age, advancing cardiovascular mortality by more than five years, and demonstrating that smoking cessation in these age groups is still beneficial in reducing the excess risk.
Proapoptotic Activity of Bortezomib in Gastrointestinal Stromal Tumor Cells
Authors: Sebastian Bauer, Joshua A. Parry, Thomas Mühlenberg, Matthew F. Brown, Danushka Seneviratne, Payel Chatterjee, Anna Chin, Brian P. Rubin, Shih-Fan Kuan, Jonathan A. Fletcher, Stefan Duensing, Anette Duensing
Journal: Cancer Research (2009)

Gastrointestinal stromal tumors (GIST) are caused by activating mutations in the KIT or PDGFRA receptor tyrosine kinase genes. Although >85% of GIST patients treated with the small-molecule inhibitor imatinib mesylate (Gleevec) achieve disease stabilization, complete remissions are rare and a substantial proportion of patients develop resistance to imatinib over time. Upregulation of soluble, non-chromatin-bound histone H2AX has an important role in imatinib-induced apoptosis of GIST cells. Additionally, H2AX levels in untreated GIST are maintained at low levels by a pathway that involves KIT, phosphoinositide 3-kinase, and the ubiquitin-proteasome system. In this study, we asked whether bortezomib-mediated inhibition of the ubiquitin-proteasome machinery could lead to upregulation of histone H2AX and GIST cell death. We show that bortezomib rapidly triggers apoptosis in GIST cells through a combination of mechanisms involving H2AX upregulation and loss of KIT protein expression. Downregulation of KIT transcription was an underlying mechanism for bortezomib-mediated inhibition of KIT expression. In contrast, the nuclear factor-kappaB signaling pathway did not seem to play a major role in bortezomib-induced GIST cell death. Significantly, we found that bortezomib would induce apoptosis in two imatinib-resistant GIST cell lines as well as a short-term culture established from a primary imatinib-resistant GIST. Collectively, our results provide a rationale to test the efficacy of bortezomib in GIST patients with imatinib-sensitive or -resistant tumors.
Clinical implications of hepatitis C virus infection in MALT-type lymphoma of the ocular adnexa
Authors: A.J.M. Ferreri, E. Viale, M. Guidoboni, A. Giordano Resti, C. De Conciliis, L. Politi, A.A. Lettini, F. Sacchetti, R. Dolcetti, C. Doglioni, M. Ponzoni
Journal: Annals of Oncology (2006)
Two Drug Interaction Studies of Sirolimus in Combination with Sorafenib or Sunitinib in Patients with Advanced Malignancies
Authors: Tara C. Gangadhar, Ezra E.W. Cohen, Kehua Wu, Linda Janisch, David Geary, Masha Kocherginsky, Larry K. House, Jackie Ramirez, Samir D. Undevia, Michael L. Maitland, Gini F. Fleming, Mark J. Ratain
Journal: Clinical Cancer Research (2011)

Sirolimus is the prototypical mTOR inhibitor. Sorafenib and sunitinib are small molecule inhibitors of multiple kinases including VEGF receptor (VEGFR) kinases. These agents have different mechanisms of action, providing a strong rationale for combination.Patients with advanced cancer were assigned to receive either sirolimus or the VEGFR inhibitor alone for a 2-week lead-in period, followed by combination therapy. The primary end point of each trial was to determine whether a drug interaction exists between sirolimus and either sorafenib or sunitinib, as defined by a difference in C(max) for each drug alone compared with its C(max) during combination therapy.The sorafenib and sunitinib trials enrolled 34 and 23 patients, respectively. There were no clinically significant differences in C(max) for any of the drugs alone compared with the C(max) during combination therapy. Toxicity profiles were similar to those expected for each drug alone. One patient with adrenal cortical cancer had a partial response to sirolimus and sunitnib.Sirolimus can be safely combined with sorafenib or sunitinib. Our trial design is feasible and informative in screening for potential drug-drug interactions, using a relatively small number of patients and limited pharmacokinetic sampling.
HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4
Authors: Milena Schiraldi, Angela Raucci, Laura Martínez Muñoz, Elsa Livoti, Barbara Celona, Emilie Venereau, Tiziana Apuzzo, Francesco De Marchis, Mattia Pedotti, Angela Bachi, Marcus Thelen, Luca Varani, Mario Mellado, Amanda Proudfoot, Marco Emilio Bianchi, Mariagrazia Uguccioni
Journal: The Journal of Experimental Medicine (2012)

After tissue damage, inflammatory cells infiltrate the tissue and release proinflammatory cytokines. HMGB1 (high mobility group box 1), a nuclear protein released by necrotic and severely stressed cells, promotes cytokine release via its interaction with the TLR4 (Toll-like receptor 4) receptor and cell migration via an unknown mechanism. We show that HMGB1-induced recruitment of inflammatory cells depends on CXCL12. HMGB1 and CXCL12 form a heterocomplex, which we characterized by nuclear magnetic resonance and surface plasmon resonance, that acts exclusively through CXCR4 and not through other HMGB1 receptors. Fluorescence resonance energy transfer data show that the HMGB1–CXCL12 heterocomplex promotes different conformational rearrangements of CXCR4 from that of CXCL12 alone. Mononuclear cell recruitment in vivo into air pouches and injured muscles depends on the heterocomplex and is inhibited by AMD3100 and glycyrrhizin. Thus, inflammatory cell recruitment and activation both depend on HMGB1 via different mechanisms.
Congenital Dermatoglyphic Malformations and Psychosis: A Twin Study
Authors: Araceli Rosa, Lourdes Fañanas, H. Stefan Bracha, E. Fuller Torrey, Jim van Os
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: In a previous twin study, congenital dermatoglyphic abnormalities, such as ridge dissociations and abnormalities of palmar flexion creases, were more prevalent in twins with psychotic and related disorders than in comparison twins. This study was an attempt to replicate that finding in an independent study group. METHOD: Ridge dissociations and abnormal palmar flexion creases were assessed in monozygotic pairs concordant (19 pairs) and discordant (31 pairs) for psychosis and related disorders. RESULTS: The presence of either ridge dissociations or abnormal palmar flexion creases was higher in the combined group of affected concordant and discordant twins (37.7%), than in the nonaffected discordant twins (20.0%; odds ratio=2.4). In the discordant pairs, the presence of either abnormality was strongly associated with psychotic disorder (odds ratio=3.0). CONCLUSIONS: Factors affecting early fetal development may increase the risk for psychotic disorder. Differential exposure to such early risk factors may contribute to twin discordance for psychotic disorder.
Association Between Two Unlinked Loci at 8q24 and Prostate Cancer Risk Among European Americans
Authors: S. Lilly Zheng, Jielin Sun, Yu Cheng, Ge Li, Fang-Chi Hsu, Yi Zhu, Bao-Li Chang, Wennuan Liu, Jin Woo Kim, Aubrey R. Turner, Marta Gielzak, Guifang Yan, Sarah D. Isaacs, Kathleen E. Wiley, Jurga Sauvageot, Huann-Sheng Chen, Robin Gurganus, Leslie A. Mangold, Bruce J. Trock, Henrik Gronberg, David Duggan, John D. Carpten, Alan W. Partin, Patrick C. Walsh, Jianfeng Xu, William B. Isaacs
Journal: JNCI Journal of the National Cancer Institute (2007)

Recent studies have provided evidence of associations between genetic markers at human chromosome 8q24 and an increased risk of prostate cancer. We examined whether multiple independent risk variants exist in this region and whether the strength of observed associations differs as a function of disease aggressiveness.We evaluated associations between 18 single-nucleotide polymorphisms (SNPs) in a 1-Mb interval at 8q24 and the risk of prostate cancer among 1563 case patients (1017 of whom had high-grade [Gleason score > or = 7] and/or non-organ-confined disease) and 576 control subjects of European American ancestry. Differences in genotype frequencies between case and control subjects were compared using logistic regression analysis, with adjustment for age, and the Wald chi-square test. All statistical tests were two-sided.We identified multiple SNPs in a 50-kb region (referred to as locus 1) that are in linkage disequilibrium with a previously reported risk-associated SNP at 8q24, rs1447295, but were more strongly associated with prostate cancer risk in our study population. We also identified a novel susceptibility SNP, rs6983267, at a second locus (locus 2) that is approximately 70 kb centromeric of rs1447295 and in linkage equilibrium with, and independent of, locus 1. Risk alleles at locus 2 were common in our study population (minor allele frequency approximately 50%, 25% homozygous for risk-associated allele). Analysis of the National Cancer Institute's Cancer Genetic Markers of Susceptibility (CGEMS) prostate cancer association study database alone and in combination with our data provided further evidence for this second prostate cancer risk locus; in the combined analysis, the allele frequencies for rs6983267 differed statistically significantly between case patients and control subjects (P = 1.61 x 10(-9)). We also identified a third locus at 8q24, approximately 400 kb centromeric to locus 2, that was statistically significantly associated with prostate cancer risk in a combined analysis of our data and CGEMS study data (P = 6.8 x 10(-4)). A joint analysis of loci 1 and 2 indicated that 35% of the control subjects carried risk genotypes at one or both these loci; compared with men with the non-risk genotype at both loci, men with risk genotypes at both loci had an odds ratio of prostate cancer of 2.68 (95% confidence interval [CI] = 1.62 to 4.43) and men with risk genotypes at either locus had an odds ratio of prostate cancer of 1.70 (95% CI = 1.39 to 2.07).Three loci at 8q24 are independent genetic risk factors for prostate cancer.
Atmospheric Pressure Effects on Tumor Growth: Hypobaric Anoxia and Growth of a Murine Transplantable Tumor<xref ref-type="fn" rid="fn2">2</xref><xref ref-type="fn" rid="fn3">3</xref>
Authors: B L Herndon, J J Lally, M Hacker
Journal: JNCI Journal of the National Cancer Institute (1983)

Inasmuch as solid tumor growth and some intervention methods for tumor control have often been related to the low oxygen levels in tumor tissue, and a special role for hypoxia, perhaps even in oncogenesis, has been suggested by observations of unexpectedly low tumor incidence in mice caged a lifetime in the environment of a simulated altitude, inbred C3H/HeN mammary tumor virus-positive mice bearing transplanted tumors (16/C murine mammary adenocarcinoma) were exposed to atmospheric pressure variants ranging from 0.33 to 2.0 in different sequences 24 hours/day. Breathing gases included air, 100% oxygen, and other nitrogen-oxygen combinations. Exposure to the pressure sequences was continuous, beginning on the third day after tlJllilOr inoculation and continUing until planned necropsy at 1, 2, or 3 weeks. Actual tumor weight was used as a measure of effect. Mice caged at simulated altitude had tumors that averaged 45% of the weight of control tumors. The maximum effect occurred with continuous 2-week exposure to 0.43 atm, beginning on day 3 of tumor growth. At necropsy, these experimental tumors weighed an average of 15% of the control tumor weight. Life-span studies showed a maximum of 36% increase in longevity in the hypobaric pressure-exposed mice when compared to that of unexposed controls.
Dendritic Cell Responses to Early Murine Cytomegalovirus Infection
Authors: Marc Dalod, Tanya Hamilton, Rachelle Salomon, Thais P. Salazar-Mather, Stanley C. Henry, John D. Hamilton, Christine A. Biron
Journal: The Journal of Experimental Medicine (2003)

Differentiation of dendritic cells (DCs) into particular subsets may act to shape innate and adaptive immune responses, but little is known about how this occurs during infections. Plasmacytoid dendritic cells (PDCs) are major producers of interferon (IFN)-α/β in response to many viruses. Here, the functions of these and other splenic DC subsets are further analyzed after in vivo infection with murine cytomegalovirus (MCMV). Viral challenge induced PDC maturation, their production of high levels of innate cytokines, and their ability to activate natural killer (NK) cells. The conditions also licensed PDCs to efficiently activate CD8 T cells in vitro. Non-plasmacytoid DCs induced T lymphocyte activation in vitro. As MCMV preferentially infected CD8α+ DCs, however, restricted access to antigens may limit plasmacytoid and CD11b+ DC contribution to CD8 T cell activation. IFN-α/β regulated multiple DC responses, limiting viral replication in all DC and IL-12 production especially in the CD11b+ subset but promoting PDC accumulation and CD8α+ DC maturation. Thus, during defense against a viral infection, PDCs appear specialized for initiation of innate, and as a result of their production of IFN-α/β, regulate other DCs for induction of adaptive immunity. Therefore, they may orchestrate the DC subsets to shape endogenous immune responses to viruses.
HEPARINEMIA (?)
Authors: J. Garrott Allen, Margaret Sanderson, Mary Milham, Alice Kirschon, L. O. Jacobson
Journal: The Journal of Experimental Medicine (1948)

When the entire body of dogs was exposed to 450 units of Roentgen irradiation a hemorrhagic syndrome developed which was characterized by thrombo-cytopenia, prolonged clotting and bleeding times, and neutropenia. The prothrombin time remained normal until about 24 hours before death. The calcium, phosphorus, and magnesium levels were not altered. Fibrinogen was present but syneresis was poor. Toluidine blue and protamine sulfate, substances which can inhibit the biologic action of heparin, restored the clotting time to normal. The hemorrhagic state was not materially altered by transfusions, vitamin K, or vitamin C. Toluidine blue and protamine sulfate were ineffective in the control of hemorrhage produced by dicumarol. The defect responsible for bleeding after irradiation appeared to be the presence in the circulation of an anticoagulant whose properties, so far as tested, were indistinguishable from those of heparin.
Phase I dose escalation study of topotecan combined with alternating schedules of paclitaxel and carboplatin in advanced solid tumors
Authors: F.R. Dunphy, T.L. Dunleavy, B.R. Harrison, C.L. Cantrell, J.L. Visconti, S.M. Pincus, J.M. Richart, P.J. Petruska
Journal: Annals of Oncology (2001)
Fighting colorectal cancer: molecular epidemiology differences among Ashkenazi and Sephardic Jews and Palestinians
Authors: H. Darwish, I.E. Trejo, I. Shapira, S. Oweineh, M. Sughayer, L. Baron, E. Aljadeff, M. Silbermann, W. Sweidan, D. Zilberg, Z. Halpern, H. Hibshoosh, N. Arber
Journal: Annals of Oncology (2002)
Intrasubject variability in airway inflammation sampled by bronchoalveolar lavage in stable asthmatics
Authors: C Ward, PV Gardiner, H Booth, EH Walters
Journal: European Respiratory Journal (1995)

Despite the increasing complexity of bronchoalveolar lavage (BAL) studies in asthmatics there are few published data concerning the variability of inflammatory parameters measured using this technique. We studied the intrasubject variability of cellular and solute parameters in 20 clinically stable, symptomatic, mild-to-moderate asthmatics, in repeat 180 mL BAL procedures performed 1 month apart. During the study, there was no change in disease activity or medication. Mean (SD) forced expiratory volume in one second (FEV1) was 3.2 (1.09) L at the first BAL and 3.05 (0.98) L at the second. The geometric mean dose of methacholine provoking a 20% decrease in FEV1 (PD20) was 23 micrograms (range 2-1,170 micrograms) at the first BAL and 28 micrograms (range 2-400 micrograms) at the second. There was considerable variability in the BAL cellular and solute parameters measured over the two procedures. Estimates of power calculated for subsequent studies involving this type of subject group were made from the observed variability. Sample sizes of less than 15 mean that differences have to be large in order to be detected in repeat BAL samples. However, there is little improvement in the power of BAL studies for sample sizes greater than 20, indicating that there is little gain in recruiting more than this number of subjects. Thus, our study indicates that although studies of the pathophysiology underlying asthma using BAL require considerable commitment, they are practicable.
Identification and analysis of unitary pseudogenes: historic and contemporary gene losses in humans and other primates
Authors: Zhengdong D Zhang, Adam Frankish, Toby Hunt, Jennifer Harrow, Mark Gerstein
Journal: Genome biology (2010)

Abstract Background Unitary pseudogenes are a class of unprocessed pseudogenes without functioning counterparts in the genome. They constitute only a small fraction of annotated pseudogenes in the human genome. However, as they represent distinct functional losses over time, they shed light on the unique features of humans in primate evolution. Results We have developed a pipeline to detect human unitary pseudogenes through analyzing the global inventory of orthologs between the human genome and its mammalian relatives. We focus on gene losses along the human lineage after the divergence from rodents about 75 million years ago. In total, we identify 76 unitary pseudogenes, including previously annotated ones, and many novel ones. By comparing each of these to its functioning ortholog in other mammals, we can approximately date the creation of each unitary pseudogene (that is, the gene 'death date') and show that for our group of 76, the functional genes appear to be disabled at a fairly uniform rate throughout primate evolution - not all at once, correlated, for instance, with the 'Alu burst'. Furthermore, we identify 11 unitary pseudogenes that are polymorphic - that is, they have both nonfunctional and functional alleles currently segregating in the human population. Comparing them with their orthologs in other primates, we find that two of them are in fact pseudogenes in non-human primates, suggesting that they represent cases of a gene being resurrected in the human lineage. Conclusions This analysis of unitary pseudogenes provides insights into the evolutionary constraints faced by different organisms and the timescales of functional gene loss in humans.
Desmoid Tumors in a Dutch Cohort of Patients With Familial Adenomatous Polyposis
Authors: Marry H. Nieuwenhuis, Wouter De Vos Tot Nederveen Cappel, Akke Botma, Fokko M. Nagengast, Jan H. Kleibeuker, Elisabeth M.H. Mathus–Vliegen, Evelien Dekker, Jan Dees, Juul Wijnen, Hans F.A. Vasen
Journal: Clinical Gastroenterology and Hepatology (2008)
The early origins of COPD in severe asthma: the one thing that leads to another or the two things that come together?
Authors: Joerg Mattes, Peter G Gibson
Journal: Thorax (2014)

Chronic obstructive pulmonary disease (COPD) is diagnosed during middle to late adult life, when significant airflow limitation has already developed by the time the disease is recognised. What if the origins of COPD occurred much earlier? If this were true, it would have major implications for detection (screening) and prevention of COPD. Convincing evidence is hard to obtain, because it requires exceptionally long follow-up, such as half a life span, a period that is often longer than the average career of a researcher! Williams and McNichol established such a longitudinal asthma study from a 1957 birth cohort, and now Tai et al 1 evaluate for an association between childhood asthma and adult COPD. They followed-up a cohort of 6–7-year-old children over more than four decades, of whom 197 survivors completed lung function testing and questionnaires at age 50 years. The most important result reported by the authors was that children with more severe asthma were at increased risk (OR 32; 95% CI, 3 to 269) of developing adult COPD. Specifically, of those who had more severe asthma in childhood, 44% (15/34) were diagnosed with adult COPD and 41% (14/34) with adult asthma, while 15% (5/34) showed asthma remission at age 50 years. By contrast, adult COPD affected only 8% (13/163) of those who had intermittent or no childhood asthma. Thus, adults who suffered from more severe asthma in childhood have more commonly COPD.

Several other results reported here are of interest. First, previous or current tobacco …
New Murine Model for Hepatocellular Carcinoma: Transgenic Mice Expressing Metallothionein--Ovine Growth Hormone Fusion Gene
Authors: J. M. Orian, K. Tamakoshi, I. R. Mackay, M. R. Brandon
Journal: JNCI Journal of the National Cancer Institute (1990)

Hepatocellular carcinomas developed at a high frequency in the livers of transgenic (C57BL/6 × SJL/J)F 1 mice under the influence of growth hormone. Three lines of giant transgenic mice expressing a mouse metallothionein-ovine growth hormone fusion gene were generated. The giant mice weighed twice as much as control littermates. The three lines of giant mice expressing very high levels of growth hormone were bred over several generations. Mice from all three lines developed hepatocellular tumors, including adenoma and carcinoma. The occurrence of tumors was age-dependent, and their incidence increased to 70% of the mice studied after 43 weeks of age. Pathologic changes in the livers resembled those observed in rats in which hepatocellular carcinomas are induced chemically. Transgenic mice carrying the metallothioneinovine growth hormone fusion gene represent a new model for hepatocellular carcinogenesis. This model exemplifies the oncogenic potential for a sustained proliferative growth stimulus within an organ. [J Natl Cancer Inst 82: 393–398, 1990]