Population Cancer Risks Associated with Coal Mining: A Systematic Review

BACKGROUND: Coal is produced across 25 states and provides 42% of US energy. With production expected to increase 7.6% by 2035, proximate populations remain at risk of exposure to carcinogenic coal products such as silica dust and organic compounds. It is unclear if population exposure is associated with increased risk, or even which cancers have been studied in this regard. METHODS: We performed a systematic review of English-language manuscripts published since 1980 to determine if coal mining exposure was associated with increased cancer risk (incidence and mortality). RESULTS: Of 34 studies identified, 27 studied coal mining as an occupational exposure (coal miner cohort or as a retrospective risk factor) but only seven explored health effects in surrounding populations. Overall, risk assessments were reported for 20 cancer site categories, but their results and frequency varied considerably. Incidence and mortality risk assessments were: negative (no increase) for 12 sites; positive for 1 site; and discordant for 7 sites (e.g. lung, gastric). However, 10 sites had only a single study reporting incidence risk (4 sites had none), and 11 sites had only a single study reporting mortality risk (2 sites had none). The ecological study data were particularly meager, reporting assessments for only 9 sites. While mortality assessments were reported for each, 6 had only a single report and only 2 sites had reported incidence assessments. CONCLUSIONS: The reported assessments are too meager, and at times contradictory, to make definitive conclusions about population cancer risk due to coal mining. However, the preponderance of this and other data support many of Hill\u27s criteria for causation. The paucity of data regarding population exposure and risk, the widespread geographical extent of coal mining activity, and the continuing importance of coal for US energy, warrant further studies of population exposure and risk

Mechanical Behavior of Melt‐Mixed 3D Hierarchical Graphene/Polypropylene Nanocomposites

The mechanical properties of novel low percolation melt-mixed 3D hierarchical graphene/polypropylene nanocomposites are analyzed in this study. The analysis spans a broad range of techniques and time scales, from impact to tensile, dynamic mechanical behavior, and creep. The applicability of the time–temperature superposition principle and its limitations in the construction of the master curve for the isotactic polypropylene (iPP)-based graphene nanocomposites has been verified and presented. The Williams–Landel–Ferry method has been used to evaluate the dynamics and also Cole–Cole curves were presented to verify the thermorheological character of the nanocomposites. Short term (quasi-static) tensile tests, creep, and impact strength measurements were used to evaluate the load transfer efficiency. A significant increase of Young’s modulus with increasing filler content indicates reasonably good dispersion and adhesion between the iPP and the filler. The Young’s modulus results were compared with predicted modulus values using Halpin–Tsai model. An increase in brittleness resulting in lower impact strength values has also been recorded

Increased C-reactive protein is associated with the severity of thoracic radiotherapy-induced cardiomyopathy

Background: Irradiation of the heart during cancer radiotherapy is associated with a dose-dependent risk of heart failure. Animal studies have demonstrated that irradiation leads to an inflammatory response within the heart as well as a reduction in cardiac reserve. In the current study we aimed to evaluate whether inflammatory biomarkers correlated with changes in cardiac function and reserve after radiotherapy for breast or lung cancer. Methods and results: We studied 25 subjects with a history of breast or lung cancer without a prior diagnosis of cardiovascular disease or heart failure, 1.8 years [0.4–3.6] post-radiotherapy involving at least 5 Gray (Gy) to at least 10% of the heart. High-sensitivity C-reactive protein (CRP) was abnormal (≥2 mg/L) in 16 (64%) subjects. Cardiac function and reserve was measured with Doppler echocardiography before and after exercise and defined as left-ventricular ejection fraction (LVEF), early diastolic mitral annulus velocity (e’), and increase in LV outflow tract velocity time integral cardiac output (cardiac reserve) with exercise. Subjects with abnormal CRP had significantly lower LVEF (51 [44–59] % vs 61 [52–64] %, P = 0.039), lower e’ (7.4 [6.6–7.9] cm/sec vs 9.9 [8.3–12.0] cm/sec, P = 0.010), and smaller cardiac reserve (+ 1.5 [1.2–1.7] L/min vs + 1.9 [1.7–2.2] L/min, P = 0.024). Conclusion: Elevated systemic inflammation is associated with impaired left-ventricular systolic and diastolic function both at rest and during exercise in subjects who have received radiotherapy with significant incidental heart dose for the treatment of cancer

Egr-1 induces DARPP-32 expression in striatal medium spiny neurons via a conserved intragenic element.

DARPP-32 (dopamine and adenosine 3\u27, 5\u27-cyclic monophosphate cAMP-regulated phosphoprotein, 32 kDa) is a striatal-enriched protein that mediates signaling by dopamine and other first messengers in the medium spiny neurons. The transcriptional mechanisms that regulate striatal DARPP-32 expression remain enigmatic and are a subject of much interest in the efforts to induce a striatal phenotype in stem cells. We report the identification and characterization of a conserved region, also known as H10, in intron IV of the gene that codes for DARPP-32 (Ppp1r1b). This DNA sequence forms multiunit complexes with nuclear proteins from adult and embryonic striata of mice and rats. Purification of proteins from these complexes identified early growth response-1 (Egr-1). The interaction between Egr-1 and H10 was confirmed in vitro and in vivo by super-shift and chromatin immunoprecipitation assays, respectively. Importantly, brain-derived neurotrophic factor (BDNF), a known inducer of DARPP-32 and Egr-1 expression, enhanced Egr-1 binding to H10 in vitro. Moreover, overexpression of Egr-1 in primary striatal neurons induced the expression of DARPP-32, whereas a dominant-negative Egr-1 blocked DARPP-32 induction by BDNF. Together, this study identifies Egr-1 as a transcriptional activator of the Ppp1r1b gene and provides insight into the molecular mechanisms that regulate medium spiny neuron maturation

The circadian clock regulates rhythmic erythropoietin expression in the murine kidney

Generation of circadian rhythms is cell-autonomous and relies on a transcription/translation feedback loop controlled by a family of circadian clock transcription factor activators including CLOCK, BMAL1 and repressors such as CRY1 and CRY2. The aim of the present study was to examine both the molecular mechanism and the hemopoietic implication of circadian erythropoietin expression. Mutant mice with homozygous deletion of the core circadian clock genes cryptochromes 1 and 2 (Cry-null) were used to elucidate circadian erythropoietin regulation. Wild-type control mice exhibited a significant difference in kidney erythropoietin mRNA expression between circadian times 06 and 18. In parallel, a significantly higher number of erythropoietin-producing cells in the kidney (by RNAscope®) and significantly higher levels of circulating erythropoietin protein (by ELISA) were detected at circadian time 18. Such changes were abolished in Cry-null mice and were independent from oxygen tension, oxygen saturation, or expression of hypoxia-inducible factor 2 alpha, indicating that circadian erythropoietin expression is transcriptionally regulated by CRY1 and CRY2. Reporter gene assays showed that the CLOCK/BMAL1 heterodimer activated an E-box element in the 5' erythropoietin promoter. RNAscope® in situ hybridization confirmed the presence of Bmal1 in erythropoietin-producing cells of the kidney. In Cry-null mice, a significantly reduced number of reticulocytes was found while erythrocyte numbers and hematocrit were unchanged. Thus, circadian erythropoietin regulation in the normoxic adult murine kidney is transcriptionally controlled by master circadian activators CLOCK/BMAL1, and repressors CRY1/CRY2. These findings may have implications for kidney physiology and disease, laboratory diagnostics, and anemia therapy

Association of a Frailty Screening Initiative With Postoperative Survival at 30, 180, and 365 Days

IMPORTANCE As the US population ages, the number of operations performed on elderly patients will likely increase. Frailty predicts postoperative mortality and morbidity more than age alone, thus presenting opportunities to identify the highest-risk surgical patients and improve their outcomes. OBJECTIVE To examine the effect of the Frailty Screening Initiative (FSI) on mortality and complications by comparing the surgical outcomes of a cohort of surgical patients treated before and after implementation of the FSI. DESIGN, SETTING, AND PARTICIPANTS This single-site, facility-wide, prospective cohort quality improvement project studied all 9153 patients from a level 1b Veterans Affairs medical center who presented for major, elective, noncardiac surgery from October 1, 2007, to July 1, 2014. INTERVENTIONS Assessment of preoperative frailty in all patients scheduled for elective surgery began in July 2011. Frailty was assessed with the Risk Analysis Index (RAI), and the records of all frail patients (RAI score,≥ 21) were flagged for administrative review by the chief of surgery (or designee) before the scheduled operation. On the basis of this review, clinicians from surgery, anesthesia, critical care, and palliative care were notified of the patient’s frailty and associated surgical risks; if indicated, perioperative plans were modified based on team input. MAIN OUTCOMES AND MEASURES Postoperative mortality at 30, 180, and 365 days. RESULTS From October 1, 2007, to July 1, 2014, a total of 9153 patients underwent surgery (mean [SD] age, 60.3 [13.5] years; female, 653 [7.1%]; and white, 7096 [79.8%]). Overall 30-day mortality decreased from 1.6%(84 of 5275 patients) to 0.7%(26 of 3878 patients, P \u3c .001) after FSI implementation. Improvement was greatest among frail patients (12.2% [24 of 197 patients] to 3.8% [16 of 424 patients], P \u3c .001), although mortality rates also decreased among the robust patients (1.2% [60 of 5078 patients] to 0.3% [10 of 3454 patients], P \u3c .001). The magnitude of improvement among frail patients increased at 180 (23.9% [47 of 197 patients] to 7.7% [30 of 389 patients], P \u3c .001) and 365 days (34.5% [68 of 197 patients] to 11.7% [36 of 309 patients], P \u3c .001). Multivariable models revealed improved survival after FSI implementation, controlling for age, frailty, and predicted mortality (adjusted odds ratio for 180-day survival, 2.87; 95% CI, 1.98-4.16). CONCLUSIONS AND RELEVANCE Implementation of the FSI was associated with reduced mortality, suggesting the feasibility of widespread screening of patients preoperatively to identify frailty and the efficacy of system-level initiatives aimed at improving their surgical outcomes. Additional investigation is required to establish a causal connection

Application of area scaling analysis to identify natural killer cell and monocyte involvement in the GranToxiLux antibody dependent cell-mediated cytotoxicity assay

Several different assay methodologies have been described for the evaluation of HIV or SIV-specific antibody-dependent cell-mediated cytotoxicity (ADCC). Commonly used assays measure ADCC by evaluating effector cell functions, or by detecting elimination of target cells. Signaling through Fc receptors, cellular activation, cytotoxic granule exocytosis, or accumulation of cytolytic and immune signaling factors have been used to evaluate ADCC at the level of the effector cells. Alternatively, assays that measure killing or loss of target cells provide a direct assessment of the specific killing activity of antibodies capable of ADCC. Thus, each of these two distinct types of assays provides information on only one of the critical components of an ADCC event; either the effector cells involved, or the resulting effect on the target cell. We have developed a simple modification of our previously described high-throughput ADCC GranToxiLux (GTL) assay that uses area scaling analysis (ASA) to facilitate simultaneous quantification of ADCC activity at the target cell level, and assessment of the contribution of natural killer cells and monocytes to the total observed ADCC activity when whole human peripheral blood mononuclear cells are used as a source of effector cells. The modified analysis method requires no additional reagents and can, therefore, be easily included in prospective studies. Moreover, ASA can also often be applied to pre-existing ADCC-GTL datasets. Thus, incorporation of ASA to the ADCC-GTL assay provides an ancillary assessment of the ability of natural and vaccine-induced antibodies to recruit natural killer cells as well as monocytes against HIV or SIV; or to any other field of research for which this assay is applied

Estimation of GRB detection by FiberGLAST

FiberGLAST is one of several instrument concepts being developed for possible inclusion as the primary Gamma-ray Large Area Space Telescope (GLAST) instrument. The predicted FiberGLAST effective area is more than 12,000 cm2 for energies between 30 MeV and 300 GeV, with a field of view that is essentially flat from 0°–80°. The detector will achieve a sensitivity more than 10 times that of EGRET. We present results of simulations that illustrate the sensitivity of FiberGLAST for the detection of gamma-ray bursts

Health system barriers to strengthening vaccine-preventable disease surveillance and response in the context of decentralization: evidence from Georgia

BACKGROUND: A critical challenge in the health sector in developing countries is to ensure the quality and effectiveness of surveillance and public health response in an environment of decentralization. In Georgia, a country where there has been extensive decentralization of public health responsibilities over the last decade, an intervention was recently piloted to strengthen district-level local vaccine-preventable disease surveillance and response activities through improved capacity to analyze and use routinely collected data. The purpose of the study is 1) to assess the effectiveness of the intervention on motivation and perceived capacity to analyze and use information at the district-level, and 2) to assess the role that individual- and system-level factors play in influencing the effectiveness of the intervention. METHODS: A pre-post quasi-experimental research design is used for the quantitative evaluation. Data come from a baseline and two follow-up surveys of district-level health staff in 12 intervention and 3 control Center of Public Health (CPH) offices. These data were supplemented by record reviews in CPH offices as well as focus group discussions among CPH and health facility staff. RESULTS: The results of the study suggest that a number of expected improvements in perceived data availability and analysis occurred following the implementation of the intervention package, and that these improvements in analysis could be attributable to the intervention package. However, the study results also suggest that there exist several health systems barriers that constrained the effectiveness of the intervention in influencing the availability of data, analysis and response. CONCLUSION: To strengthen surveillance and response systems in Georgia, as well as in other countries, donor, governments, and other stakeholders should consider how health systems factors influence investments to improve the availability of data, analysis, and response. Linking the intervention to broader health sector reforms in management processes and organizational culture will be critical to ensure that efforts designed to promote evidence-based decision-making are successful, especially as they are scaled up to the national level