Molecular and clinical pharmacology of psoriasis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/136054/1/cpt1974165part2919.pd

Lung Cancer in a U.S. Population with Low to Moderate Arsenic Exposure

BackgroundLittle is known about the carcinogenic potential of arsenic in areas with low to moderate concentrations of arsenic (< 100 microg/L) in drinking water.ObjectivesWe examined associations between arsenic and lung cancer.MethodsA population-based case-control study of primary incident lung cancer was conducted in 10 counties in two U.S. states, New Hampshire and Vermont. The study included 223 lung cancer cases and 238 controls, each of whom provided toenail clippings for arsenic exposure measurement by inductively coupled-plasma mass spectrometry. We estimated odds ratios (ORs) of the association between arsenic exposure and lung cancer using unconditional logistic regression with adjustment for potential confounders (age, sex, race/ethnicity, smoking pack-years, education, body mass index, fish servings per week, and toenail selenium level).ResultsArsenic exposure was associated with small-cell and squamous-cell carcinoma of the lung [OR = 2.75; 95% confidence interval (CI), 1.00-7.57] for toenail arsenic concentration > or = 0.114 microg/g, versus < 0.05 microg/g. A history of lung disease (bronchitis, chronic obstructive pulmonary disease, or fibrosis) was positively associated with lung cancer (OR = 2.86; 95% CI, 1.39-5.91). We also observed an elevated risk of lung cancer among participants with a history of lung disease and toenail arsenic > or = 0.05 microg/g (OR = 4.78; 95% CI, 1.87-12.2) than among individuals with low toenail arsenic and no history of lung disease.ConclusionAlthough this study supports the possibility of an increased risk of specific lung cancer histologic types at lower levels of arsenic exposure, we recommend large-scale population-based studies

The Contribution of Benzene to Smoking-Induced Leukemia

Cigarette smoking is associated with an increased risk of leukemia; benzene, an established leukemogen, is present in cigarette smoke. By combining epidemiologic data on the health effects of smoking with risk assessment techniques for low-dose extrapolation, we assessed the proportion of smoking-induced total leukemia and acute myeloid leukemia (AML) attributable to the benzene in cigarette smoke. We fit both linear and quadratic models to data from two benzene-exposed occupational cohorts to estimate the leukemogenic potency of benzene. Using multiple-decrement life tables, we calculated lifetime risks of total leukemia and AML deaths for never, light, and heavy smokers. We repeated these calculations, removing the effect of benzene in cigarettes based on the estimated potencies. From these life tables we determined smoking-attributable risks and benzene-attributable risks. The ratio of the latter to the former constitutes the proportion of smoking-induced cases attributable to benzene. Based on linear potency models, the benzene in cigarette smoke contributed from 8 to 48% of smoking-induced total leukemia deaths [95% upper confidence limit (UCL), 20-66%], and from 12 to 58% of smoking-induced AML deaths (95% UCL, 19-121%). The inclusion of a quadratic term yielded results that were comparable; however, potency models with only quadratic terms resulted in much lower attributable fractions--all < 1%. Thus, benzene is estimated to be responsible for approximately one-tenth to one-half of smoking-induced total leukemia mortality and up to three-fifths of smoking-related AML mortality. In contrast to theoretical arguments that linear models substantially overestimate low-dose risk, linear extrapolations from empirical data over a dose range of 10- to 100-fold resulted in plausible predictions

Associations involving delays (particularly long delays) between certain weather parameters and geomagnetic activity

Four sunspot-minimum periods (1963-1966, 1971-1977, 1983-1987 and 1992-1997) have been examined for the results which are presented. Using several different weather parameters, tropospheric gravity waves, enhanced cold fronts and two rainfall data sets in Eastern Australia, associations at reasonably high levels of significance have been found with enhanced geomagnetic activity (EGA). Statistically this EGA involved either short delays of several days or long delays of about 20 days. The geomagnetic parameters used were (a) the AE index (b) the hourly H component for a number of stations and (c) the daily K-P-sum value. The K-P-sum analyses have shown that the EGA associated with the delays form part of four or five cycles of recurrent geomagnetic activity for 27-day periodicities. Furthermore statistically two recurrent cycles are found to exist concurrently, one apparently related to the short delays and the other to the long delays. Periodicities of 13.5 days are created because the two sets are displaced from each other by approximately this interval. A brief reference is made to the 13.5 periodicity known to exist for geomagnetic activity and the evidence in the literature for active regions on the sun to be displaced by 180 degrees of solar longitude

Thermochromic Metal Halide Perovskite Windows with Ideal Transition Temperatures

Urban centers across the globe are responsible for a significant fraction of energy consumption and CO2 emission. As urban centers continue to grow, the popularity of glass as cladding material in urban buildings is an alarming trend. Dynamic windows reduce heating and cooling loads in buildings by passive heating in cold seasons and mitigating solar heat gain in hot seasons. In this work, we develop a mesoscopic building energy model that demonstrates reduced building energy consumption when thermochromic windows are employed. Savings are realized across eight disparate climate zones of the United States. We use the model to determine the ideal critical transition temperature of 20 to 27.5 {\deg}C for thermochromic windows based on metal halide perovskite materials. Ideal transition temperatures are realized experimentally in composite metal halide perovskite film composed of perovskite crystals and an adjacent reservoir phase. The transition temperature is controlled by co-intercalating methanol, instead of water, with methylammonium iodide and tailoring the hydrogen-bonding chemistry of the reservoir phase. Thermochromic windows based on metal halide perovskites represent a clear opportunity to mitigate the effects of energy-hungry buildings

A prospective study of XRCC1 (X-ray cross-complementing group 1) polymorphisms and breast cancer risk

INTRODUCTION: The gene XRCC1 (X-ray repair cross-complementing group 1) encodes a protein involved in DNA base excision repair. Two non-synonymous polymorphisms in XRCC1 (Arg194Trp and Arg399Gln) have been shown to alter DNA repair capacity in some studies in vitro. However, results of previous association studies of these two XRCC1 variants and breast cancer have been inconsistent. We examined the association between polymorphisms in XRCC1 and breast cancer in the American Cancer Society Cancer Prevention Study II (CPS-II) Nutrition Cohort, a large prospective study of cancer incidence in the USA. METHODS: Among the 21,965 women who were cancer-free in 1992 and gave blood between 1998 and 2001, 502 postmenopausal breast cancer cases were diagnosed between 1992 and 2001; 502 controls were matched to cases on age, race/ethnicity, and date of blood collection. Genotyping on DNA extracted from buffy coat was performed with Taqman. Conditional logistic regression was used to examine the association between each polymorphism and breast cancer risk controlling for breast cancer risk factors. We also examined whether factors associated with DNA damage, such as smoking and antioxidant intake, modified the association between XRCC1 polymorphisms and breast cancer. RESULTS: We observed a significant inverse association between Trp194 carriers (Trp/Trp and Trp/Arg) compared with Trp194 non-carriers in relation to breast cancer (Arg/Arg) (odds ratio (OR) 0.62, 95% confidence interval (CI) 0.40 to 0.95). The inverse association between breast cancer and Trp194 carriers compared with non-carriers was slightly stronger among smokers (OR 0.47, 95% CI 0.24 to 0.94) than never smokers (OR 0.78, 95% CI 0.43 to 1.40). An increased risk associated with the Arg399Gln polymorphism (Gln/Gln versus Arg/Arg) was observed only among women who reported ever smoking cigarettes (OR 2.76, 95% CI 1.36 to 5.63), and not in women who were lifelong non-smokers (OR 0.64, 95% CI 0.33 to 1.26). No other factor examined modified the association between XRCC1 polymorphisms and breast cancer risk. CONCLUSION: Our results support the hypothesis that genetic variation in XRCC1, particularly in Arg194Trp, may influence postmenopausal breast cancer risk. In our study, genetic variation in XRCC1 Arg399Gln was associated with breast cancer risk only among women with a history of smoking cigarettes

Clonal karyotype evolution involving ring chromosome 1 with myelodysplastic syndrome subtype RAEB-t progressing into acute leukemia

s Karyotypic evolution is a well-known phenomenon in patients with malignant hernatological disorders during disease progression. We describe a 50-year-old male patient who had originally presented with pancytopenia in October 1992. The diagnosis of a myelodysplastic syndrome (MDS) FAB subtype RAEB-t was established in April 1993 by histological bone marrow (BM) examination, and therapy with low-dose cytosine arabinoside was initiated. In a phase of partial hernatological remission, cytogenetic assessment in August 1993 revealed a ring chromosome 1 in 13 of 21 metaphases beside BM cells with normal karyotypes {[}46,XY,r(1)(p35q31)/46,XY]. One month later, the patient progressed to an acute myeloid leukemia (AML), subtype M4 with 40% BM blasts and cytogenetic examination showed clonal evolution by the appearance of additional numerical aberrations in addition to the ring chromosome{[}46,XY,r(1),+8,-21/45,XY,r(1),+8,-21,-22/46, XY]. Intensive chemotherapy and radiotherapy was applied to induce remission in preparation for allogeneic bone marrow transplantation (BMT) from the patient's HLA-compatible son. After BMT, complete remission was clinically, hematologically and cytogenetically (normal male karyotype) confirmed. A complete hematopoietic chimerism was demonstrated. A relapse in January 1997 was successfully treated using donor lymphocyte infusion and donor peripheral blood stem cells (PB-SC) in combination with GM-CSF as immunostimulating agent in April 1997, and the patient's clinical condition remained stable as of January 2005. This is an interesting case of a patient with AML secondary to MDS. With the ring chromosome 1 we also describe a rare cytogenetic abnormality that predicted the poor prognosis of the patient, but the patient could be cured by adoptive immunotherapy and the application of donor's PB-SC. This case confirms the value of cytogenetic analysis in characterizing the malignant clone in hernatological neoplasias, the importance of controlling the quality of an induced remission and of the detection of a progress of the disease. Copyright (c) 2006 S. Karger AG, Basel

Aspirin and NSAID use and lung cancer risk: a pooled analysis in the International Lung Cancer Consortium (ILCCO)

Purpose: To investigate the hypothesis that non-steroidal anti-inflammatory drugs (NSAIDs) lower lung cancer risk. Methods: We analysed pooled individual-level data from seven case-control and one cohort study in the International Lung Cancer Consortium (ILCCO). Relative risks for lung cancer associated with self-reported history of aspirin and other NSAID use were estimated within individual studies using logistic regression or proportional hazards models, adjusted for packyears of smoking, age, calendar period, ethnicity and education and were combined using random effects meta-analysis. Results: A total of 4,309 lung cancer cases (mean age at diagnosis 65 years, 45% adenocarcinoma and 22% squamous-cell carcinoma) and 58,301 non-cases/controls were included. Amongst controls, 34% had used NSAIDs in the past (81% of them used aspirin). After adjustment for negative confounding by smoking, ever-NSAID use (affirmative answer to the study-specific question on NSAID use) was associated with a 26% reduction (95% confidence interval 8 to 41%) in lung cancer risk in men, but not in women (3% increase (-11% to 30%)). In men, the association was stronger in current and former smokers, and for squamous-cell carcinoma than for adenocarcinomas, but there was no trend with duration of use. No differences were found in the effects on lung cancer risk of aspirin and non-aspirin NSAIDs. Conclusions Evidence from ILCCO suggests that NSAID use in men confers a modest protection for lung cancer, especially amongst ever-smokers. Additional investigation is needed regarding the possible effects of age, duration, dose and type of NSAID and whether effect modification by smoking status or sex exists

Bempedoic acid safety analysis: Pooled data from four phase 3 clinical trials

Background An ongoing need exists for safe and effective lipid-lowering therapies (LLTs) for patients unable to achieve desired lipid levels with current treatment options. Objective The objective of this study was to describe the safety profile of bempedoic acid, an oral, first-in-class, adenosine triphosphate (ATP)–citrate lyase inhibitor that significantly reduces low-density lipoprotein cholesterol (LDL-C) levels by 17.4%–28.5% vs placebo. Methods This was a pooled analysis of four phase 3, randomized (2:1), double-blind, placebo-controlled studies in patients with hypercholesterolemia who required additional LDL-C lowering, despite stable maximally-tolerated LLT. Patients received 180 mg of bempedoic acid (n = 2424) or placebo (n = 1197) once daily for 12 to 52 weeks. Assessments included treatment-emergent adverse events (TEAEs) and clinical laboratory tests. Results Of 3621 patients (the median drug exposure: 363 days), exposure-adjusted TEAE rates were 87.1/100 and 82.9/100 person-years (PY) for bempedoic acid and placebo, respectively. No single TEAE influenced the difference in rates. TEAEs leading to discontinuation occurred at rates of 13.4/100 and 8.9/100 PY for bempedoic acid vs placebo, with the most common cause being myalgia, which occurred less frequently with bempedoic acid vs placebo (1.5/100 vs 2.0/100 PY). Rates of myalgia and muscle weakness were comparable vs placebo. Bempedoic acid was associated with mild increases in blood urea nitrogen, creatinine, and uric acid and decreases in hemoglobin. These laboratory abnormalities were apparent by week 4, stable over time, and reversible after treatment cessation. Gout incidence was 1.6/100 vs 0.5/100 PY in the bempedoic acid vs placebo groups. New-onset diabetes/hyperglycemia occurred less frequently with bempedoic acid vs placebo (4.7/100 vs 6.4/100 PY). The safety profile was consistent across subgroups. Conclusions Bempedoic acid is generally safe and well tolerated among patients with hypercholesterolemia who require additional LLT

Comparing complex impedance and bias step measurements of Simons Observatory transition edge sensors

The Simons Observatory (SO) will perform ground-based observations of the cosmic microwave background (CMB) with several small and large aperture telescopes, each outfitted with thousands to tens of thousands of superconducting aluminum manganese (AlMn) transition-edge sensor bolometers (TESs). In-situ characterization of TES responsivities and effective time constants will be required multiple times each observing-day for calibrating time-streams during CMB map-making. Effective time constants are typically estimated in the field by briefly applying small amplitude square-waves on top of the TES DC biases, and fitting exponential decays in the bolometer response. These so-called "bias step" measurements can be rapidly implemented across entire arrays and therefore are attractive because they take up little observing time. However, individual detector complex impedance measurements, while too slow to implement during observations, can provide a fuller picture of the TES model and a better understanding of its temporal response. Here, we present the results of dark TES characterization of many prototype SO bolometers and compare the effective thermal time constants measured via bias steps to those derived from complex impedance data.Comment: 10 pages, 6 figures, SPIE Astronomical Telescopes + Instrumentation 2020, Paper Number: 11453-18