The Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) program is an NCI-funded initiative with an objective to develop tools to optimize low-dose CT (LDCT) lung cancer screening. Here, ...we describe the rationale and design for the Risk Biomarker and Nodule Malignancy projects within INTEGRAL.
The overarching goal of these projects is to systematically investigate circulating protein markers to include on a panel for use (i) pre-LDCT, to identify people likely to benefit from screening, and (ii) post-LDCT, to differentiate benign versus malignant nodules. To identify informative proteins, the Risk Biomarker project measured 1161 proteins in a nested-case control study within 2 prospective cohorts (n = 252 lung cancer cases and 252 controls) and replicated associations for a subset of proteins in 4 cohorts (n = 479 cases and 479 controls). Eligible participants had a current or former history of smoking and cases were diagnosed up to 3 years following blood draw. The Nodule Malignancy project measured 1078 proteins among participants with a heavy smoking history within four LDCT screening studies (n = 425 cases diagnosed up to 5 years following blood draw, 430 benign-nodule controls, and 398 nodule-free controls).
The INTEGRAL panel will enable absolute quantification of 21 proteins. We will evaluate its performance in the Risk Biomarker project using a case-cohort study including 14 cohorts (n = 1696 cases and 2926 subcohort representatives), and in the Nodule Malignancy project within five LDCT screening studies (n = 675 cases, 680 benign-nodule controls, and 648 nodule-free controls). Future progress to advance lung cancer early detection biomarkers will require carefully designed validation, translational, and comparative studies.
The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to ...risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10(-11); African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.
The Working Party recommends (section 9.5) that clear information on the standards of infection prevention and control should be available to promote confidence in the quality of care provided.1 To ...assist, the following four information leaflets have been created. The purpose of these leaflets is to explain the meaning of multidrug-resistant Gram-negative organisms and, more specifically, carbapenem-resistant organisms; to assist healthcare workers, patients, relatives, and visitors in understanding why these bacteria are a problem; and to explain what precautions can be taken to help prevent the spread of these bacteria. 1 reference
The recent demonstration that adenosine 3′,5′-cyclic monophosphate (cAMP)-dependent protein kinase A (PKA) plays an oncogenic role in a number of important cancers has led to a renaissance in drug ...development interest targeting this kinase. We therefore have established a suite of biochemical, cell-based, and structural biology assays for identifying and evaluating new pharmacophores for PKA inhibition. This discovery process started with a 384-well high-throughput screen of more than 200,000 substances, including fractionated natural product extracts. Identified active compounds were further prioritized in biochemical, biophysical, and cell-based assays. Priority lead compounds were assessed in detail to fully characterize several previously unrecognized PKA pharmacophores including the generation of new X-ray crystallography structures demonstrating unique interactions between PKA and bound inhibitor molecules.
The cognitive abilities of older persons vary greatly, even among those with similar amounts of Alzheimer disease (AD) pathology, suggesting differences in neural reserve. Although its neurobiologic ...basis is not well understood, reserve may reflect differences in the ability to compensate for the deleterious effects of pathology by recruiting alternative or additional brain networks to perform a specific task. If this is an effective compensatory strategy, then involvement of additional cognitive systems may help maintain function in other cognitive systems despite the accumulation of pathology.
We tested the hypothesis that processing resources, specifically perceptual speed and working memory, modify the associations of AD pathology with other cognitive systems.
A total of 103 older participants of the Rush Memory and Aging Project underwent detailed annual clinical evaluations and brain autopsy. Five cognitive systems including perceptual speed, working memory, semantic memory, visuospatial abilities, and episodic memory were assessed proximate to death, and AD pathology including tau tangles and amyloid load were quantified postmortem.
In multiple regression models adjusted for age, sex, and education, processing resources reduced the associations of tangles with other cognitive systems, such that persons with higher levels of perceptual speed and working memory performed better on semantic memory and visuospatial abilities despite the burden of tangles. Perceptual speed also reduced the associations of amyloid with semantic memory, visuospatial abilities, and episodic memory.
These findings suggest that processing resources may help compensate for the deleterious effects of Alzheimer disease pathology on other cognitive systems in older persons.
Summary We describe a software tool specifically developed to support the monitoring and reporting of the occurrence of surgical site infections (SSI) in hospitals. The tool uses data collected ...routinely by a London teaching hospital as part of its infection surveillance system, which includes post-discharge follow-up. Based on these data, the tool is used to generate graphs showing cumulative infections over time and variable life-adjusted display (VLAD) charts that account for the expected specialty average infection risk. The user can select, along with other options, the definition of infection used in the preparation of the graphs. Using an illustrative example of SSI monitoring in orthopaedic surgery, we demonstrate the tool and its intended use to trigger further scrutiny rather than draw firm conclusions. We show that the tool has the ability to generate departmental debate, which should ultimately lead to the increased safety of surgical patients. We recommend adopting the tool and VLAD charts wherever surgical site surveillance is continuous.
Systemic glucocorticoids are first-line treatment options for autoimmune blistering diseases; however, their long-term use is associated with significant toxicities.
To evaluate the side effects of ...steroid-sparing agents and compare them with those of steroids.
We searched Cochrane Reviews, Embase, MEDLINE, and Scopus between October 1978 and May 2020 using the keywords “bullous pemphigoid,” “pemphigus,” “autoimmune blistering diseases,” and “side effects.” A total of 31 randomized controlled trials and retrospective case series were critically appraised.
This review includes a total of 1685 patients with autoimmune blistering diseases, of whom 781 had bullous pemphigoid and 904 had either pemphigus vulgaris or pemphigus foliaceous.
A major limitation is that because adjuvants are generally used in combination with steroids, only 12 of the studies reviewed included a “steroid-only” arm to allow for a direct comparison of side effects. Additionally, there is inadequate literature and lack of standardized grade reporting of specific side effects of each steroid-sparing agent.
In the future, researchers should consider implementing the Common Terminology Criteria for Adverse Events, version 5.0, for reporting of all side effects to allow for consistency and standardization. It would be useful to have an index similar to the Glucocorticoid Toxicity Index to quantify these side effects.
Suppressor of cytokine signaling-3 (SOCS3) is the main intracellular regulator of signaling by granulocyte colony-stimulating factor, an immune-modulatory cytokine used to mobilize stem cells for ...transplantation. We have therefore studied the contribution of SOCS3 to the spectrum of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT). Grafts from SOCS3−/Δvav donor mice in which SOCS3 deficiency is restricted to the hematopoietic compartment had an augmented capacity to induce acute GVHD. With the use of SOCS3−/ΔLysM and SOCS3−/Δlck donors in which SOCS3 deficiency was restricted to the myeloid or T-cell lineage, respectively, we confirmed SOCS3 deficiency promoted acute GVHD mortality and histopathology within the gastrointestinal tract by effects solely within the donor T cell. SOCS3−/Δlck donor T cells underwent enhanced alloantigen-dependent proliferation and generation of interleukin-10 (IL-10), IL-17, and interferon-γ (IFNγ) after SCT. The enhanced capacity of the SOCS3−/Δlck donor T cell to induce acute GVHD was dependent on IFNγ but independent of IL-10 or IL-17. Surprisingly, SOCS3−/Δlck donor T cells also induced severe, transforming growth factor β– and IFNγ-dependent, sclerodermatous GVHD. Thus, the delivery of small molecule SOCS3 mimetics may prove to be useful for the inhibition of both acute and chronic GVHD.
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