tbuckley/cabot-search huggingface dataset:
Common Infections in Patients Prescribed Systemic Glucocorticoids in Primary Care: A Population-Based Cohort Study
Authors: Laurence Fardet, Irene Petersen, Irwin Nazareth
Journal: PLoS Medicine (2016)

Little is known about the relative risk of common bacterial, viral, fungal, and parasitic infections in the general population of individuals exposed to systemic glucocorticoids, or about the impact of glucocorticoid exposure duration and predisposing factors on this risk.The hazard ratios of various common infections were assessed in 275,072 adults prescribed glucocorticoids orally for ≥15 d (women: 57.8%, median age: 63 [interquartile range 48-73] y) in comparison to those not prescribed glucocorticoids. For each infection, incidence rate ratios were calculated for five durations of exposure (ranging from 15-30 d to >12 mo), and risk factors were assessed. Data were extracted from The Health Improvement Network (THIN) primary care database. When compared to those with the same underlying disease but not exposed to glucocorticoids, the adjusted hazard ratios for infections with significantly higher risk in the glucocorticoid-exposed population ranged from 2.01 (95% CI 1.83-2.19; p < 0.001) for cutaneous cellulitis to 5.84 (95% CI 5.61-6.08; p < 0.001) for lower respiratory tract infection (LRTI). There was no difference in the risk of scabies, dermatophytosis and varicella. The relative increase in risk was stable over the durations of exposure, except for LRTI and local candidiasis, for which it was much higher during the first weeks of exposure. The risks of infection increased with age and were higher in those with diabetes, in those prescribed higher glucocorticoid doses, and in those with lower plasma albumin level. Most associations were also dependent on the underlying disease. A sensitivity analysis conducted on all individuals except those with asthma or chronic obstructive pulmonary disease produced similar results. Another sensitivity analysis assessing the impact of potential unmeasured confounders such as disease severity or concomitant prescription of chemotherapy suggested that it was unlikely that adjusting for these potential confounders would have radically changed the findings. Limitations of our study include the use of electronic medical records, which could have resulted in some degree of misclassification of the infectious outcomes; a possible reporting bias, as general practitioners could be more prone to record an infection in those exposed to glucocorticoids; and a low number of events for some outcomes such as scabies or varicella, which may have led to limited statistical power.The relative risk of LRTI and local candidiasis is very high during the first weeks of glucocorticoid exposure. Further studies are needed to assess whether low albumin level is a risk factor for infection by itself (e.g., by being associated with a higher free glucocorticoid fraction) or whether it reflects other underlying causes of general debilitation.
Soundings: Weapons of mass destruction
Authors: Imre Loefler
Journal: BMJ (2004)

The agricultural revolution was the first quantum leap in manipulating the environment and the industrial revolution was the second. The medical revolution is the third. Domestication, the harnessing of stored energy, and the eradication of hostile species were necessary before man could invade all niches on earth and multiply. The securement of man's biosphere began with the battle against lion and bear and wolf. Now the biological enemies are microscopic and submicroscopic—and our heroes are Jenner and Pasteur and Fleming rather than Theseus, who slayed the Minotaur, Perseus, the killer of Medusa, or Hercules, the accomplished exterminator of dangerous megafauna.

Our biological, chemical, and physical warfare against multitudes of living things is not only directed against those species that invade humans, but also against their vectors, pathogens to our domestic animals and plants, the vectors of these pathogens, and all living things which compete with us and our stock or cultivars.

A completely germ free world is unattainable, but is it a desirable objective? It entails environmental changes that represent new dangers to man and his chattels. Take antibiotic warfare, for example. Microbes are more resilient than we thought; 50 years of broadcasting poisonous substances has had little impact on the pyramid of life.

A justification for a campaign against infection may sound unnecessary. Of course, we do not want tuberculosis, not even in our cows, and we do not want rabies—even if this means doing away with the bat. The combined use of insecticides, pesticides, and herbicides can make economic sense, but only if economy is interpreted as maximising returns over a given period.

If species diversity is desirable, does the concept afford protection to the mosquito and even pathogens or only to the African violet, the Californian condor, and the panda?

The discovery that fanatical hygiene, antibiotic use in infants, and perhaps even vaccinations are detrimental to the maturing immune system and are associated with allergies, asthma, and autoimmune disease should be a warning: our aggression against the rest of the universe is demonstrably detrimental to our wellbeing.
Brief Report: JNK‐2 Controls Aggrecan Degradation in Murine Articular Cartilage and the Development of Experimental Osteoarthritis
Authors: Heba M. Ismail, Jadwiga Miotla‐Zarebska, Linda Troeberg, Xiaodi Tang, Bryony Stott, Kazuhiro Yamamoto, Hideaki Nagase, Amanda J. Fosang, Tonia L. Vincent, Jeremy Saklatvala
Journal: Arthritis & Rheumatology (2015)

Objective The pathogenesis of osteoarthritis (OA) is poorly understood. Loss of the proteoglycan aggrecan from cartilage is an early event. Recently, we identified a role for the JNK pathway, particularly JNK‐2, in human articular chondrocytes in vitro in regulating aggrecan degradation. The present study was undertaken to investigate whether JNK‐2 has a similar function in vivo and to examine its role in gene expression. Methods Aggrecan fragments were analyzed by Western blotting. OA was induced by destabilization of the medial meniscus (DMM) and assessed at 4, 8, and 12 weeks after surgery. Knee sections were stained with Safranin O. Medial compartments were scored by histologic grading for aggrecan loss and cartilage damage. RNA was extracted from JNK‐2 −/− and wild‐type mouse knees 6 hours after DMM or after interleukin‐1 stimulation of the proximal epiphysis, and expression of 33 DMM‐regulated genes was analyzed with quantitative polymerase chain reaction–customized array cards. Results In vitro, basal and interleukin‐1– or tumor necrosis factor–stimulated release of aggrecanase‐generated aggrecan fragments was greatly reduced in cartilage from JNK‐2 −/− mice. In the OA model, JNK‐2 −/− mice exhibited significant reduction of aggrecanase‐generated fragments and cartilage damage. Of 33 genes investigated, 13 were significantly down‐regulated in JNK‐2 −/− mice compared with wild‐type mice, following DMM. These included Has1 , Adamts4 , Tnf , Il6 , Il18 , Il18rap , Il1a , Inhba , Cd68 , Ngf , Ccr2 , Wnt16 , and Tnfaip6 , but not Adamts5 . Conclusion Our results demonstrate that JNK‐2 regulates aggrecan degradation in cultured murine cartilage and surgically induced OA in vivo following mechanical destabilization of the knee joint. This implicates the JNK signaling pathway in OA and suggests potential novel approaches to therapy.
Diagnostic, prognostic and predictive value of cell-free miRNAs in prostate cancer: a systematic review
Authors: Edgars Endzeliņš, Vita Melne, Zane Kalniņa, Vilnis Lietuvietis, Una Riekstiņa, Alicia Llorente, Aija Linē
Journal: Molecular Cancer (2016)

Prostate cancer, the second most frequently diagnosed cancer in males worldwide, is estimated to be diagnosed in 1.1 million men per year. Introduction of PSA testing substantially improved early detection of prostate cancer, however it also led to overdiagnosis and subsequent overtreatment of patients with an indolent disease. Treatment outcome and management of prostate cancer could be improved by the development of non-invasive biomarker assays that aid in increasing the sensitivity and specificity of prostate cancer screening, help to distinguish aggressive from indolent disease and guide therapeutic decisions. Prostate cancer cells release miRNAs into the bloodstream, where they exist incorporated into ribonucleoprotein complexes or extracellular vesicles. Later, cell-free miRNAs have been found in various other biofluids. The initial RNA sequencing studies suggested that most of the circulating cell-free miRNAs in healthy individuals are derived from blood cells, while specific disease-associated miRNA signatures may appear in the circulation of patients affected with various diseases, including cancer. This raised a hope that cell-free miRNAs may serve as non-invasive biomarkers for prostate cancer. Indeed, a number of cell-free miRNAs that potentially may serve as diagnostic, prognostic or predictive biomarkers have been discovered in blood or other biofluids of prostate cancer patients and need to be validated in appropriately designed longitudinal studies and clinical trials. In this review, we systematically summarise studies investigating cell-free miRNAs in biofluids of prostate cancer patients and discuss the utility of the identified biomarkers in various clinical scenarios. Furthermore, we discuss the possible mechanisms of miRNA release into biofluids and outline the biological questions and technical challenges that have arisen from these studies.
Abstract B09: Differential effect of microenvironment on tumor phenotype using an immature T cell lymphoma mouse model
Authors: Philip J. Lucas, Ronald E. Gress
Journal: Cancer Research (2016)

Abstract Human T cell lymphomas of an immature phenotype with mediastinal origin are classified as T cell lymphoblastic lymphomas (T-LBL) and comprise 85-90% of all lymphoblastic lymphomas. Treatment of T-LBL can be challenging because of the metastasizing nature of the disease, which commonly localizes to the bone marrow and can be found in other organs such as liver and spleen. We have developed a mouse T-LBL model by establishing a cell line from a spontaneous mediastinal tumor found in a T cell receptor (TCR) transgenic mouse strain. The resulting T-LBL like cell line, JMR4, has a known TCR (2C), known alloreactivity (H-2Ld), and known stimulating self-peptide (SIYR). JMR4 has an immature T cell phenotype, which includes a mixture of CD4+/CD8+, CD4lo/CD8+, CD4+/CD8lo and CD4+ cells. Other T cell markers, such as CD5, CD24 and CD69 are expressed at various levels depending on the phenotypic subset. The 2C TCR, which can be detected using the 1B2 idiotypic mAb, has been shown to be functional using flow cytometric analysis following TCR stimulation using peptide loaded thymic stromal feeder cells. In addition, JMR4 can be phenotypically altered (CD4/CD8/CD5/CD69 expression levels) differentially in vitro using the bone marrow stromal cell line OP9 and OP9DL, suggesting that it has pluripotency. Finally, when JMR4 is injected into sub-lethally irradiated mice, it develops into a multi-organ lymphoma. Interestingly, the phenotype of the JMR4 cells, based on CD4 and CD8 expression levels, is differentially regulated depending on organ type and MHC of the host, making JMR4 an ideal model to study the complex interactions of a tumor with its microenvironment. Understanding the mechanisms involved in tumor microenvironment (TME) induced changes to tumor cells should be important in understanding metastatic tumor progression and in designing new treatment regimens. Citation Format: Philip J. Lucas, Ronald E. Gress. Differential effect of microenvironment on tumor phenotype using an immature T cell lymphoma mouse model. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B09.
Radiation in pediatric Hodgkin's disease.
Authors: S S Donaldson, K R Lamborn
Journal: Journal of Clinical Oncology (1998)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1998.16.1.391 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 9440772 Radiation in pediatric Hodgkin's disease. S S DonaldsonxS S DonaldsonSearch for articles by this author , K R LambornxK R LambornSearch for articles by this author https://doi.org/10.1200/JCO.1998.16.1.391 First Page PDF © 1998 by American Society of Clinical Oncology
The South Oaks Gambling Screen (SOGS): a new instrument for the identification of pathological gamblers
Authors: H R Lesieur, S B Blume
Journal: American Journal of Psychiatry (1987)

The South Oaks Gambling Screen is a 20-item questionnaire based on DSM-III criteria for pathological gambling. It may be self-administered or administered by nonprofessional or professional interviewers. A total of 1,616 subjects were involved in its development: 867 patients with diagnoses of substance abuse and pathological gambling, 213 members of Gamblers Anonymous, 384 university students, and 152 hospital employees. Independent validation by family members and counselors was obtained for the calibration sample, and internal consistency and test-retest reliability were established. The instrument correlates well with the criteria of the revised version of DSM-III (DSM-III-R). It offers a convenient means to screen clinical populations of alcoholics and drug abusers, as well as general populations, for pathological gambling.
Aortic Aneurysms
Authors: John L. Zeller, Alison E. Burke, Richard M. Glass
Journal: JAMA (2007)

Aortic AneurysmsT he aorta is the body' s largest artery and carries oxygen-rich blood from the heart to the rest of the body.The wall of the aorta is very elastic and can normally stretch and then shrink back as needed to adapt to blood flow.However, some medical conditions can weaken the arterial wall.These factors, along with the wear and tear that naturally occurs with aging, can result in a weak aortic wall that may stretch and bulge outwards.An aortic aneurysm is a stretched and bulging section in the wall of the aorta.A bulging or enlarged vessel is weakened and can burst or rupture, resulting in life-threatening bleeding.This condition is the 10th leading cause of death in men 65 to 74 years of age in the United States.The January 24/31, 2007, issue of JAMA includes an article about aortic aneurysms caused by underlying inflammation (response to cellular injury).
Isolation and analysis of the mechanism of action of an inactivator of C4b in normal human serum.
Authors: N R Cooper
Journal: The Journal of Experimental Medicine (1975)

A complement regulatory principle, C4b inactivator, was isolated in a partially purified form from normal human serum. The C4b inactivator, a beta1-globulin with an approximate mol wt of 88,000 daltons, and which may be identical to C3b inactivator, cleaved C4b in free solution or on the surface of cells and rendered it unable to participate in hemolytic reactions or to interact with cells, having receptors for C4b. C/b inactivator functioned by cleaving the alpha-polypeptide chain of C4b at a single site which was sufficient to dissociate the molecule into two fragments, C4c and C4d, and to inactivate it biological function. Certain structural correlates of C4 functions deriving from these studies are discussed and a model for C4 structure based on these findings is presented.
Genomic Alteration–Driven Clinical Trial Designs in Oncology
Authors: Richard Simon
Journal: Annals of Internal Medicine (2016)

The established molecular heterogeneity of human cancers necessitates the development of new paradigms to serve as a reliable basis for precision medicine. The assumptions underlying some of the conventional approaches to clinical trial design and analysis are no longer appropriate because of the molecular heterogeneity of tumors of a given primary site. This article reviews some clinical trial designs that have been actively applied in the codevelopment of therapeutics and predictive biomarkers to inform their use in oncology. These include the enrichment design, the basket design, and the umbrella design. Oncology leads most other therapeutic areas in development of personalized or precision medicine. Personalized or precision medicine is practiced daily in oncology on the basis of tumor genomics and may evolve in other therapeutic areas as it has in oncology, rather than according to inherited polymorphisms as so often imagined. Consequently, some of the clinical trial designs described here may serve as a possible blueprint for therapeutic development in fields other than oncology.
Estimating Causal Effects of Local Air Pollution on Daily Deaths: Effect of Low Levels
Authors: Joel Schwartz, Marie-Abele Bind, Petros Koutrakis
Journal: Environmental Health Perspectives (2016)

Although many time-series studies have established associations of daily pollution variations with daily deaths, there are fewer at low concentrations, or focused on locally generated pollution, which is becoming more important as regulations reduce regional transport. Causal modeling approaches are also lacking.We used causal modeling to estimate the impact of local air pollution on mortality at low concentrations.Using an instrumental variable approach, we developed an instrument for variations in local pollution concentrations that is unlikely to be correlated with other causes of death, and examined its association with daily deaths in the Boston, Massachusetts, area. We combined height of the planetary boundary layer and wind speed, which affect concentrations of local emissions, to develop the instrument for particulate matter ≤ 2.5 μm (PM2.5), black carbon (BC), or nitrogen dioxide (NO2) variations that were independent of year, month, and temperature. We also used Granger causality to assess whether omitted variable confounding existed.We estimated that an interquartile range increase in the instrument for local PM2.5 was associated with a 0.90% increase in daily deaths (95% CI: 0.25, 1.56). A similar result was found for BC, and a weaker association with NO2. The Granger test found no evidence of omitted variable confounding for the instrument. A separate test confirmed the instrument was not associated with mortality independent of pollution. Furthermore, the association remained when all days with PM2.5 concentrations > 30 μg/m3 were excluded from the analysis (0.84% increase in daily deaths; 95% CI: 0.19, 1.50).We conclude that there is a causal association of local air pollution with daily deaths at concentrations below U.S. EPA standards. The estimated attributable risk in Boston exceeded 1,800 deaths during the study period, indicating that important public health benefits can follow from further control efforts. Citation: Schwartz J, Bind MA, Koutrakis P. 2017. Estimating causal effects of local air pollution on daily deaths: effect of low levels. Environ Health Perspect 125:23-29; http://dx.doi.org/10.1289/EHP232.
A Proposal for Combination of Lymph Node Ratio and Anatomic Location of Involved Lymph Nodes for Nodal Classification in Non–Small Cell Lung Cancer
Authors: Xiao Ding, Zhouguang Hui, Honghai Dai, Chengcheng Fan, Yu Men, Wei Ji, Jun Liang, Jima Lv, Zongmei Zhou, Qinfu Feng, Zefen Xiao, Dongfu Chen, Hongxing Zhang, Weibo Yin, Ning Lu, Jie He, Luhua Wang
Journal: Journal of Thoracic Oncology (2016)
Abstract P6-03-18: Outcome of FoundationOne testing in metastatic breast cancer therapy: A single center experience
Authors: Y Yuan, JE Mortimer
Journal: Cancer Research (2016)

Abstract Background: Next generation sequencing (NGS) has made genomic, mutation-driven, cancer medicine feasible. However, few studies have reported the importance of NGS in identifying mutation-driven treatment or whether such therapies are effective in women with metastatic breast cancer (MBC). We reviewed the impact of NGS in women with MBC at our institution. Methods: Among the medical oncologists who treat metastatic breast cancers at the City of Hope Comprehensive Cancer Center, we identified 21 patients with HER2 negative cancers, whose tumors were submitted for FoundationOne genomic profiling. We report the individual mutation profile, potential therapeutic options, and treatment outcome. Result: Of the 21 patients (pts), 13 had triple negative breast cancer (TNBC) and 12 of 13 (92%) had actionable mutation(s). Mutation profiles have been heterogeneous. Loss or mutations of TP53 were the most common genomic alteration in TNBC (12 of 13). Four pts received targeted therapies (everolimus in 3, pazopanib in 1) and all experienced at least partial clinical response. An additional 3 pts were treated with directed therapy but are too early to evaluate, 4 pts were not treated because of disease progression or clinical deterioration, and 1 pt was lost to follow-up. All 8 pts with ER+ disease had actionable mutations identified and 7 (88%) received targeted therapy (pazopanib in1, everolimus in 3, palbociclib in 3). All experienced at least partial clinical response; 1 was too ill for treatment. The most common genomic alterations are: PIK3CA mutation, PTEN loss, P53 mutation, FGFR mutation, and ZNF mutation. Conclusion: Targeted genomic sequencing through FoundationOne can identify mutations that are amenable to treatment with agents that are not generally approved for use in breast cancer. In order to test the benefit of target-directed therapy, tumor should be submitted for NGS while patients have a good performance status. Citation Format: Yuan Y, Mortimer JE. Outcome of FoundationOne testing in metastatic breast cancer therapy: A single center experience. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-03-18.
The caspase-8 inhibitor emricasan combines with the SMAC mimetic birinapant to induce necroptosis and treat acute myeloid leukemia
Authors: Gabriela Brumatti, Chunyan Ma, Najoua Lalaoui, Nhu-Y Nguyen, Mario Navarro, Maria C. Tanzer, Jennifer Richmond, Margherita Ghisi, Jessica M. Salmon, Natasha Silke, Giovanna Pomilio, Stefan P. Glaser, Elisha de Valle, Raffi Gugasyan, Mark A. Gurthridge, Stephen M. Condon, Ricky W. Johnstone, Richard Lock, Guy Salvesen, Andrew Wei, David L. Vaux, Paul G. Ekert, John Silke
Journal: Science Translational Medicine (2016)

Resistance to chemotherapy is a major problem in cancer treatment, and it is frequently associated with failure of tumor cells to undergo apoptosis. Birinapant, a clinical SMAC mimetic, had been designed to mimic the interaction between inhibitor of apoptosis proteins (IAPs) and SMAC/Diablo, thereby relieving IAP-mediated caspase inhibition and promoting apoptosis of cancer cells. We show that acute myeloid leukemia (AML) cells are sensitive to birinapant-induced death and that the clinical caspase inhibitor emricasan/IDN-6556 augments, rather than prevents, killing by birinapant. Deletion of caspase-8 sensitized AML to birinapant, whereas combined loss of caspase-8 and the necroptosis effector MLKL (mixed lineage kinase domain-like) prevented birinapant/IDN-6556-induced death, showing that inhibition of caspase-8 sensitizes AML cells to birinapant-induced necroptosis. However, loss of MLKL alone did not prevent a caspase-dependent birinapant/IDN-6556-induced death, implying that AML will be less likely to acquire resistance to this drug combination. A therapeutic breakthrough in AML has eluded researchers for decades. Demonstrated antileukemic efficacy and safety of the birinapant/emricasan combination in vivo suggest that induction of necroptosis warrants clinical investigation as a therapeutic opportunity in AML.